Angiotensin ii type 2 receptor agonist and use thereof

Abstract

The present invention belongs to the pharmaceutical field, and relates to an angiotensin II type 2 receptor agonist and a use thereof, as well as a use of the compound in the treatment of diseases related to pulmonary fibrosis, specifically a compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug thereof, and a use thereof, the substituents in formula I having the same definitions as in the description.

Description

Angiotensin II type 2 receptor agonists and uses thereof

[0001] This application claims priority to the Chinese patent application No. 202410742505.9, filed on June 7, 2024, entitled "Angiotensin II type 2 receptor (AT2R) agonists and uses thereof", and to the Chinese patent application No. 202411381927.4, filed on September 30, 2024, entitled "Angiotensin II type 2 receptor (AT2R) agonists and uses thereof", the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and in particular relates to angiotensin II type 2 receptor agonists and uses thereof, and the use of such compounds for treating diseases related to the field of pulmonary fibrosis. BACKGROUND

[0003] Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosing interstitial pneumonia of unknown etiology, which is limited to the lung, more common in men than in women. The main manifestations are progressive dyspnea, accompanied by restrictive ventilatory dysfunction and gas exchange dysfunction, leading to hypoxemia, even respiratory failure, and poor prognosis. The pulmonary histology and high-resolution CT (HRCT) of the chest show usual interstitial pneumonia (UIP). The median survival of IPF patients from diagnosis is 2-5 years, and the 5-year survival rate is 20%-25%, which is called "cancer without cancer". (Pathogenesis and drug treatment progress of idiopathic pulmonary fibrosis [J]. China Medical Herald, 2021, 18(29): 45-48).

[0004] About 3 million people worldwide have IPF, with an incidence of about 3-13 / 100,000 and a prevalence of about 5-40 / 100,000 in the Asian population. In 2019, the prevalence of IPF in China was 2-29 / 100,000. The 2023 China Idiopathic Pulmonary Fibrosis Drug Industry Market Development Analysis pointed out that from 2015 to 2022, the number of people with IPF in China increased from 217,000 to 264,000. The conservative estimate of the number of people with IPF in our country is about 50-60 million. This disease mainly affects patients over the age of 50, and is more common in middle-aged and elderly male populations. With the progress of aging, improved diagnosis, and increased understanding of the disease, the number of confirmed cases of IPF is on the rise. It is estimated that in countries with inadequate diagnosis, such as China, Brazil, Russia, and India, there may be as many as a million patients who have not been diagnosed. (Data on file. Boehringer Ingelheim. DOF OFEV. RES. IPF / 08 / 11 January 2016. Worldwide Prevalence 2016; Podolanczuk AJ, et al. Eur Respir J. 2023 Apr 20; 61(4):2200957).

[0005] Recent studies have shown that angiotensin II (Ang II) acts on two GPCR (G protein-coupled receptor) subtypes, AT1R (Ang II type 1 receptor) and AT2R (Ang II type 2 receptor), and AT1R and AT2R have opposite physiological functions. AT2R is mainly expressed in type 2 alveolar epithelial cells and enteric glial cells. Under normal physiological conditions, type 2 alveolar epithelial cells are responsible for alveolar function repair.

[0006] Under the pathological state of pulmonary fibrosis, type 2 alveolar epithelial cells lose their ability to repair and maintain alveolar integrity, scar formation, release of pro-inflammatory and fibrotic mediators, and stimulation of fibroblasts to produce excessive collagen fibers, leading to fibrosis. Agonizing AT2R can counter-regulate the effects of AT1R, exerting vasodilation, anti-fibrosis, anti-proliferation, anti-inflammatory, and anti-hypertensive effects, and offsetting the harmful effects of AT1R. (Catch your breath: The protective role of the angiotensin AT2 receptor for the treatment of idiopathic pulmonary fibrosis. 2023).

[0007] Although international patent application WO 2002 / 096883 describes the preparation of compounds as Ang II receptor agonists. Compound C21 (N-tert-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide) described in this document as a selective AT2 receptor agonist has also been indicated to have potential use in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer treatment-related cardiotoxicity, peripheral neuropathy and systemic sclerosis, but there are still many problems to be solved in terms of drugability.

[0008] There are only two drugs for treating IPF-related diseases on the market in the world, namely pirfenidone and nintedanib. Due to the large side effects of the drugs, the drug withdrawal rate is very high. Within one year of use, the drug withdrawal rates of pirfenidone and nintedanib are 48.5% and 50.0%, respectively. In the future, with the progress of aging, the incidence and mortality rates are on the rise. Therefore, it is urgent to develop drugs with good efficacy and high safety to meet the huge clinical needs of IPF. SUMMARY

[0009] In one aspect, the present application provides a compound of Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug thereof:

[0010] R 1 selected from ethyl, n-propyl, isopropyl, n-butyl, isobutyl or cyclopropylmethyl;

[0011] X is selected from O or S;

[0012] Y is selected from CR 10 or N, R 10 selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-5 cycloalkyl, C 3-5 halocycloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

[0013] L is selected from O;

[0014] R 2 selected from C 1-6 alkyl or C 3-7 cycloalkyl, wherein the C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more hydrogen, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, halophenyl, 5- to 6-membered heteroaromatic ring group or OR 11 group, wherein the C 1-6 alkyl and C 3-7each cycloalkyl group is optionally substituted by one or more hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0015] R 11 selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 halocycloalkyl or C 3-7 cycloalkyl;

[0016] Ring A is selected from a phenyl ring;

[0017] R 3 selected from halogen, cyano or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by one or more halogen;

[0018] n = 0, 1 or 2;

[0019] R 4 and R 5 are selected from hydrogen, fluorine or methyl; R 6 and R 7 are selected from hydrogen, fluorine or methyl; R 8 and R 9 are selected from hydrogen, fluorine or methyl.

[0020] In some embodiments, the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or a prodrug thereof, X is selected from S;

[0021] Y is selected from CR 10 , R 10 is preferably selected from hydrogen, fluorine, methyl or trifluoromethyl.

[0022] In some embodiments, the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or a prodrug thereof, R 3 is preferably selected from fluorine, cyano or methyl.

[0023] In some embodiments, the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or a prodrug thereof, n is preferably selected from 0 or 1.

[0024] In some embodiments, the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or a prodrug thereof, the compound of Formula I is represented by Formula I-1:

[0025] wherein R 1 is selected from ethyl, n-propyl, i-propyl, n-butyl, i-butyl or cyclopropylmethyl;

[0026] L is selected from O;

[0027] R2 selected from C 1-6 alkyl or C 3-7 cycloalkyl, wherein said C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more hydrogen, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, halophenyl, 5- to 6-membered heteroaromatic ring group, or OR 11 group, wherein said C 1-6 alkyl and C 3-7 cycloalkyl are each optionally substituted with one or more hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0028] R 11 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 halocycloalkyl, or C 3-7 cycloalkyl;

[0029] Ring A is selected from a phenyl ring;

[0030] R 3 is selected from halogen, cyano, or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more halogen; n = 0, 1, or 2;

[0031] R 4 and R 5 are selected from hydrogen, fluorine, or methyl; R 6 and R 7 are selected from hydrogen, fluorine, or methyl; R 8 and R 9 are selected from hydrogen, fluorine, or methyl; R 10 is selected from hydrogen, fluorine, methyl, or trifluoromethyl.

[0032] In some embodiments, the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or a prodrug thereof, is represented by Formula I-2:

[0033] wherein R 1 is selected from ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or cyclopropylmethyl;

[0034] R 2 is selected from C 1-6 alkyl or C 3-7 cycloalkyl, wherein said C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more hydrogen, halogen, C 1-6 alkyl, C3-7 cycloalkyl, phenyl, halophenyl, 5- to 6-membered heteroaromatic ring group, or OR 11 group, wherein the C 1-6 alkyl and C 3-7 cycloalkyl are each optionally substituted with one or more hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0035] R 11 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 halocycloalkyl, or C 3-7 cycloalkyl;

[0036] R 3 is selected from halogen, cyano, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more halogen; n = 0, 1, or 2;

[0037] R 4 and R 5 are selected from hydrogen, fluorine, or methyl; R 6 and R 7 are selected from hydrogen, fluorine, or methyl; R 8 and R 9 are selected from hydrogen, fluorine, or methyl; R 10 is selected from hydrogen, fluorine, methyl, or trifluoromethyl.

[0038] In some embodiments, the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug thereof, is represented by Formula I-3:

[0039] wherein R 2 is selected from C 1-4 linear alkyl or cyclopropyl, wherein the C 1-4 linear alkyl can be substituted with one or more fluorine, methyl, ethyl, cyclopropyl, phenyl, pyridine, or OR 11 group, the cyclopropyl and phenyl can be substituted with one or more halogen or methyl; R 11 is hydrogen, C 1-3 alkyl or C 3-5 cycloalkyl; R 3 is fluorine, chlorine, bromine, cyano, C 1-3 alkyl or C 1-3 fluoroalkyl; n = 0, 1, or 2;

[0040] R 6 and R 7 are selected from hydrogen, fluorine, or methyl; R 10 is hydrogen, methyl, or trifluoromethyl.

[0041] In some embodiments, the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or a prodrug thereof, is represented by Formula I-4:

[0042] wherein R 2 is selected from C 1-4 linear alkyl or cyclopropyl, wherein the C 1-4 linear alkyl can be substituted with one or more fluoro, methyl, ethyl, cyclopropyl, phenyl, pyridine or OR 11 group, the cyclopropyl and phenyl can be substituted with one or more fluoro or methyl; the R 11 is methyl; R 3 is fluoro; n = 0 or 1; R 6 and R 7 are both hydrogen or methyl; and R 10 is hydrogen or methyl.

[0043] In some embodiments, the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or a prodrug thereof, is selected from any of the following compounds:

[0044] A pharmaceutical composition, wherein it comprises the compound, stereoisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0045] Use of the compound, solvate, metabolite, co-crystal or prodrug thereof, or the aforementioned composition in the manufacture of a medicament for treating / preventing AT2R-mediated diseases.

[0046] The diseases include at least one of esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia, gastroesophageal reflux, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, liver disease, gallbladder disease, multiple organ failure, sepsis, xerostomia, gastritis, gastric retention, gastric acid hypersecretion, biliary tract disease, abdominal disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, angina pectoris, dysphagia, nausea, vomiting, Sjogren's syndrome, inflammatory disease, asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, renal failure, nephritis, renal hypertension, diabetic retinopathy, retinopathy of prematurity, retinal microangiopathy, ovulation mechanism disorder, hypertension, cardiac hypertrophy, heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, post-balloon dilation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic damage, erectile dysfunction, neointimal hyperplasia, cognitive dysfunction, feeding dysfunction, thirst, stroke, cerebral hemorrhage, cerebral embolism, cerebral infarction, hypertrophic disorder, prostatic hyperplasia, autoimmune disease, psoriasis, obesity, nerve regeneration, ulcer, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, cancer, apoptosis, tumor, hyperplasia, diabetes, neural damage, or organ rejection.

[0047] The diseases include at least one of asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis.

[0048] Detailed description of the invention

[0049] Unless otherwise indicated, the following terms have the meanings indicated below when used in the specification and claims.

[0050] "Alkyl" means a saturated aliphatic hydrocarbon group. Included are straight chain or branched chain groups containing 1 to 20 carbon atoms. Medium size alkyl groups containing 1 to 6 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, pentyl, and the like. Alkyl groups can be substituted or unsubstituted.

[0051] "Cx-y" is intended to include groups that can contain x to y carbons in a chain. For example, the term "C1-6" as used herein, represents, but is not limited to, C1, C2, C3, C4, C5, C6, C7, or C8. 1-6 "Alkyl" means a saturated aliphatic hydrocarbon group. Included are straight chain or branched chain groups containing 1 to 20 carbon atoms. Medium size alkyl groups containing 1 to 6 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, pentyl, and the like. Alkyl groups can be substituted or unsubstituted.

[0052] "Cycloalkyl" means a saturated carbocyclic ring. Exemplary cycloalkyl rings include cyclopropyl, cyclohexyl, and norbornane. Cycloalkyl groups can be optionally substituted with one or more substituents such as those described herein.

[0053] "Heteroaryl" or "heteroaromatic" includes aromatic monocyclic ring structures, preferably 5- to 6-membered rings, whose ring structure contains at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" or "heteroaromatic" also includes polycyclic ring systems having two or more rings, wherein two or more atoms are shared by two adjacent rings, wherein at least one of the rings is heteroaromatic, for example, the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl groups can be optionally substituted with one or more substituents such as those described herein.

[0054] "Halo" means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

[0055] By "optionally" is meant that the subsequent described event or circumstance can or can not occur, and the description includes both instances where the thing or circumstance occurs and where it does not.

[0056] In some embodiments, "substituted with one or more groups" means that one, two, three, or four hydrogen atoms in the designated atom or group are replaced, respectively, by the same or different group selected from the indicated range of groups. Unless otherwise indicated, the structural formulae described herein include all tautomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): for example, R, S configurations for asymmetric centers, (Z), (E) isomers for double bonds, and (Z), (E) conformational isomers. Thus, individual stereochemical isomers or mixtures thereof (e.g., enantiomeric, diastereomeric, or geometric (or conformational) isomers) of the compounds of the present application are within the scope of the present application.

[0057] The use of the terms "stereochemical" and "stereoisomeric" are used in the present application generally refer to the following references: S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994. The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, atropisomeric, and their mixtures, such as racemic mixtures, form part of the present application. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D, L or R, S are used to denote the absolute configuration of the molecule. The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, with (+) or 1 meaning that the compound is dextrorotary. The (-) or d form is levorotary. The chemical structures of these stereoisomers are identical but their orientations in space are mirror images of each other. A specific stereoisomer can be referred to as an enantiomer if its mirror image is not superimposable. Mixtures of enantiomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can result from racemic synthesis or resolution of a single enantiomer. The term "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric forms in which the specific orientations of the atoms and molecules are not identical, and which have no optical activity.

[0058] "stereoisomers" refer to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans), atropisomers, and the like.

[0059] The term "tautomer" or "tautomeric forms" refers to isomers of a molecule that differ only in the arrangement of atoms, or groups, that can be interconverted by a low energy process, such as a proton shift. For example, proton tautomers (i.e., proton- shifted tautomers) include tautomeric isomerization by proton shift, such as keto-enol and imine-enamine isomerization. Atom valence (bond order) tautomers include isomerization by reorganization of bonding electrons.

[0060] "chiral" is a molecule that has the property of not being superimposable with its mirror image; whereas "achiral" refers to a molecule that is superimposable with its mirror image.

[0061] "Enantiomer" refers to two isomers of a compound which are nonsuperimposable mirror images of one another.

[0062] "Diastereomer" refers to a stereoisomer of a compound which has two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high resolution analytical techniques such as electrophoresis and chromatography, for example HPLC.

[0063] In certain embodiments, the compositions of the present disclosure can comprise two or more enantiomers or diastereomers of a compound, wherein a single enantiomer or diastereomer comprises at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those skilled in the art.

[0064] In addition, substitution with heavier isotopes, particularly deuterium, i.e., 2 H or D, can afford certain therapeutic advantages. These advantages can result from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium is regarded as a reasonable substituent in compounds of formula (I), formula (II), formula (III), and formula (IV).

[0065] Unless otherwise stated, the compounds described herein are intended to include both vaults and vaults differing only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present disclosure, except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a carbon enriched in 13 C or 14 C, are within the scope of the present disclosure. The compounds of the present disclosure optionally contain non-natural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be labeled with isotopes such as, for example, deuterium (2H), tritium (3H), iodine 3 ( 125 I), or carbon 125 ( 14 C). Compounds labeled with 14 H, 2 C, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F,16 F、 17 F、 18 F、 33 S、 34 S、 35 S、 36 S、 35 Cl、 37 Cl、 79 Br、 81 Br and 125 Isotopic substitutions of all the atoms of the compounds of the present application are contemplated. All isotopologues of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0066] "Pharmaceutically acceptable salt" means those salts of the compounds of the present application which retain the biological effectiveness and properties of the parent compound. Such salts include:

[0067] (1) salts with acids, obtained by reaction of the free base of the parent compound with inorganic or organic acids, the inorganic acids including hydrochloric, hydrobromic, nitric, phosphoric, metaphosphoric, sulfuric, sulfurous and perchloric acids and the like, and the organic acids including acetic, propionic, allylic, oxalic, (D) or (L) malic, fumaric, maleic, hydroxybenzoic, gamma-hydroxybutyric, methoxybenzoic, phthalic, methanesulfonic, ethanesulfonic, naphthalene- 1 -sulfonic, naphthalene-2-sulfonic, p-toluenesulfonic, salicylic, tartaric, citric, lactic, mandelic, succinic or malonic acids and the like.

[0068] (2) salts formed by replacement of the acidic proton in the parent compound by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or by a organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

[0069] "Pharmaceutical composition" means a mixture of one or more of the compounds of the present application or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof with another chemical component, such as a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an animal.

[0070] "Solvate" means an association or complex of one or more solvent molecules with one of the compounds of the present application. Solvents which form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" means a solvate formed by the association or complexing of one or more water molecules with one of the compounds of the present application.

[0071] "Pharmaceutically acceptable carrier" means a non-active ingredient in a pharmaceutical composition that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to: calcium carbonate, calcium phosphate, various sugars (such as lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic or methacrylic polymers, gelatin, water, polyethylene glycol, propylene glycol, ethylene glycol, castor or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, etc.

[0072] In the aforementioned pharmaceutical composition, in addition to the pharmaceutically acceptable carrier, a pharmaceutically common auxiliary agent can also be included, such as: antibacterial agents, antifungal agents, antimicrobial agents, preservatives, toning agents, solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, pigments, fragrances or combinations thereof, etc. DETAILED DESCRIPTION

[0073] The technical solutions in the embodiments of the present application will be described clearly and completely below in combination with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0074] The structure of the compound is determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR determination is performed by a (Bruker Avance III 400) nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The LC-MS determination uses a Shimadzu liquid chromatograph-mass spectrometer (Shimadzu LC-MS2020 (ESI)). The HPLC determination uses a Shimadzu high-pressure liquid chromatograph (Shimadzu LC-20A). The MPLC (medium pressure preparative chromatography) uses a Gilson GX-281 reverse-phase preparative chromatograph. The thin-layer chromatography silica gel plate uses a Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification used for the thin-layer chromatography separation and purification product is 0.4mm-0.5mm. The silica gel chromatographic column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier. The SFC chiral resolution uses a Shimadzu high-pressure liquid chromatograph (Shimadzu LC-30AD SFC).

[0075] Commonly used organic solvents in the examples are expressed using abbreviations well known in the art, such as: DCM for dichloromethane; THF for tetrahydrofuran; Dioxane for 1,4-dioxane; DMF for N,N-dimethylformamide; MeOH for methanol; EtOH for ethanol; HOAc for acetic acid, etc.

[0076] Example 1. Butyl ((3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (Compound 1)

[0077] Synthetic Route:

[0078] Step 1: Preparation of N-(tert-butyl)thiophene-2-sulfonamide (1b)

[0079] Tert-butylamine (41.75 g, 570.81 mmol) was slowly added to a stirred solution of 2- thiophenesulfonyl chloride (25.00 g, 136.88 mmol) in dry tetrahydrofuran (250 mL) at 0 °C. The reaction was allowed to warm to room temperature and was terminated after 16 hours under nitrogen protection. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried, concentrated, and the target compound N-(tert-butyl)thiophene-2-sulfonamide (1b) was obtained. The product was used in the next step without further purification. 1 HNMR (400 MHz, CDC13) δ 7.61 (dd, J = 3.6, 1.2 Hz, 1H), 7.54 (dd, J = 5.2, 1.2 Hz, 1H), 7.04 (dd, J = 5.0, 3.8 Hz, 1H), 4.66 (s, 1H), 1.29 (s, 9H).

[0080] Step 2: Preparation of N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide (1c)

[0081] To a stirred solution of N-(tert-butyl)thiophene-2-sulfonamide (1b) (10.00 g, 45.60 mmol) in dry tetrahydrofuran (50 mL) was added dropwise n-butyllithium (1.6 M in n-hexane) (75 mL, 120.00 mmol) at -78 °C. After the addition was complete, the reaction was allowed to warm to -40 °C and stirred for 2 h under nitrogen. Iodoisobutane (16.45 g, 89.37 mmol) was added, and the reaction was allowed to warm to room temperature and stirred for 16 h under nitrogen. The reaction was quenched by the slow addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried, concentrated, and the crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 10 / 1) to give the target compound N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide (1c). 1 H NMR (400 MHz, CDC13) δ 7.43 (d, J = 4.0 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 4.62 (s, 1H), 2.69 (dd, J = 7.0, 0.6 Hz, 2H), 1.94 - 1.86 (m, 1H), 1.28 (s, 9H), 0.95 (d, J = 6.8 Hz, 6H).

[0082] Step 3: Preparation of (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (1d)

[0083] To a stirred solution of N-(tert-butyl)-5-isobutylthiophene-2-sulfonamide (1c) (3.50 g, 12.71 mmol) in dry tetrahydrofuran (500 mL) was added dropwise n-butyllithium (1.6 M in n-hexane) (23.9 mL, 38.24 mmol) at -78 °C. After the addition was complete, the reaction was stirred for 4 h at -20 °C under nitrogen, and triisopropyl borate (4.78 g, 25.42 mmol) was added. The reaction was then allowed to warm to room temperature and stirred for 16 h under nitrogen. The reaction was quenched by the slow addition of saturated aqueous ammonium chloride solution. The reaction was extracted with ethyl acetate. The combined organic layers were dried, concentrated, and the crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the target compound (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (1d). 1 H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 1H), 6.98 (s, 2H), 6.38 (s, 1H), 2.68 (d, J = 7.0 Hz, 2H), 1.90 - 1.80 (m, 1H), 1.15 (s, 9H), 0.91 (d, J = 6.4 Hz, 6H).

[0084] Step 4: Preparation of 2-(4-bromophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (If)

[0085] To a stirred solution of 5-(4-bromophenyl)pyrrolidin-2-one (le) (2.13 g, 8.87 mmol) in dichloromethane (10 mL) was added trimethyl oxonium tetrafluoroborate (2.62 g, 17.71 mmol) slowly at 0 °C. The reaction was then stirred at room temperature for 16 h before it was quenched with water. The reaction was diluted with water and extracted with dichloromethane. The combined organic layers were dried and concentrated to give the crude product, 2-(4-bromophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (If). The crude product was used directly in the next step without further purification. LC-MS (ESI) calcd for C 11 H 12 BrNO[M+H] + m / z 254.0; found 254.9.

[0086] Step 5: Preparation of 2-(4-bromophenyl)-N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-pyrrol-5-amine (Ig)

[0087] To a stirred solution of crude 2-(4-bromophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (If) (2.14 g, 8.87 mmol) in ethanol (10 mL) was added aminoacetaldehyde dimethyl acetal (0.93 g, 8.83 mmol) at room temperature. The reaction was then heated to 85 °C for 16 h before it was quenched. The reaction was concentrated and the crude product was purified by reverse phase C18 column chromatography (eluent: 0.1% formic acid in water / acetonitrile) to give the target compound, 2-(4-bromophenyl)-N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-pyrrol-5-amine (Ig). LC-MS (ESI) calcd for C 14 H 19 BrN2O2[M+H] + m / z 327.1; 329.1, found 327.0. 1 H NMR (400 MHz, CDC13) δ 8.44 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.02 (t, J = 7.2 Hz, 1H), 4.47 (t, J = 5.3 Hz, 1H), 3.48-3.46 (m, 6H), 3.36 (d, J = 5.3 Hz, 2H), 3.02-2.80 (m, 2H), 2.70-2.57 (m, 1H), 2.06-1.93 (m, 1H).

[0088] Step 6: Preparation of 5-(4-bromophenyl)-6,7-dihydro-5H-pyrrolo[l,2- a]imidazole (1h)

[0089] 2-(4-bromophenyl)-N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-pyrrol-5-amine (1g) (1.90 g, 5.81 mmol) was dispersed in hydrochloric acid (6 M, 20 mL) at room temperature, heated to 100 °C under nitrogen and stirring was terminated after 16 h. Concentration and purification of the crude product by reverse phase C18 column chromatography (eluent: 0.1% formic acid in water / acetonitrile) gave the target compound 5-(4-bromophenyl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole (1h). LC-MS (ESI) calcd for C 12 H 11 BrN2[M+H] + m / z 263.0; 265.0, found 263.0. 1 H NMR (400 MHz, CDC13) δ 7.55 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 1.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 1.6 Hz, 1H), 5.46 (t, J = 7.4 Hz, 1H), 3.48 - 3.14 (m, 3H), 2.68 - 2.50 (m, 1H).

[0090] Step 7: Preparation of N-(tert-butyl)-3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophene-2-sulfonamide (1i)

[0091] 5-(4-bromophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (1h) (1.60 g, 6.08 mmol), (2-(N-(tert-butyl)aminosulfonyl)-5-isobutylthiophen-3-yl)boronic acid (1d) (2.20 g, 7.03 mmol), potassium phosphate (3.90 g, 18.24 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.45 g, 0.61 mmol) were dispersed in a mixture of 1,4-dioxane (20 mL) and water (2 mL) under nitrogen protection at room temperature. The reaction mixture was heated to 90 °C and stirred for 2 hours under nitrogen protection before the reaction was terminated. The reaction solution was cooled to room temperature and diluted with water, extracted with ethyl acetate, the solutions were combined, dried, and the organic phase was concentrated. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1 to 3 / 1) to give the target compound N-(tert-butyl)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (1i). LC-MS (ESI) calculation for C 24 H 31 N3O2S2[M+H] + m / z 458.2, found 458.2.

[0092] Step 8: Preparation of 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (1j)

[0093] Compound N-(tert-butyl)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (1i) (0.71 g, 1.55 mmol) was dissolved in trifluoroacetic acid (10 mL) at room temperature, and anisole (1 mL) was added dropwise with stirring. The reaction solution was then heated to 30 °C and the reaction was terminated after 16 hours. The reaction was concentrated, and the crude product was purified by reverse-phase C18 column chromatography (eluent: acetonitrile / 0.1% formic acid aqueous solution = 0~1 / 1) to give the target compound 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (1j). LC-MS (ESI) calcd for C 20 H 23 N3O2S2[M+H] + m / z 402.1, found 402.2.

[0094] Step 9: Preparation of ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (Compound 1)

[0095] To a solution of 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophene-2-sulfonamide (1j) (0.10 g, 0.25 mmol) and N,N- diisopropylethylamine (0.06 g, 0.50 mmol) in dichloromethane (2 mL) was added dropwise butyl chloroformate (0.05 g, 0.37 mmol) at room temperature with stirring. The reaction was terminated after 1 hour at room temperature. The resulting reaction solution was concentrated and the crude product was purified by reverse phase C18 column chromatography (eluent: acetonitrile / 0.1% formic acid in water = 6 / 4) to give the target product ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (Compound 1). LC-MS (ESI) calcd for C 25 H 31 N3O4S2[M+H] + m / z 502.2, found 502.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.17 (s, 1H), 6.89 (s, 1H), 5.56 (t, J = 6.6 Hz, 1H), 3.81 (t, J = 6.6 Hz, 2H), 3.08 - 2.94 (m, 3H), 2.67 (d, J = 6.8 Hz, 2H), 1.90 - 1.75 (m, 1H), 1.40 - 1.31 (m, 2H), 1.26 - 1.18 (m, 4H), 0.93 (d, J = 6.8 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H).

[0096] Example 2. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid methyl ester (2A) and (S)-((3-(4-(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid methyl ester (2B)

[0097] Synthetic Route:

[0098] Step 1: Preparation of (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (1j-A) and (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (1j-B)

[0099] The compound 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (1j) was subjected to SFC (column: (250mm*25mm, 10μm); Mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (+0.1% 7.0mol / L Ammonia in MeOH)) to separate enantiomers (peak 1 and peak 2).

[0100] Peak 1 is the R configuration, i.e., (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (1j-A), LC-MS (ESI) calcd for C 20 H 23 N3O2S2[M+H] + m / z 402.1, found402.2, SFC characterization, column: (100mm*3.0mm, 3.0μm); Mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (0.1% DEA), retention time 1.94min; ee: >98%.

[0101] Peak 2 is in the S configuration, i.e., (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (1j-B), LC-MS (ESI) calcd for C 20 H 23 N3O2S2[M+H] + m / z 402.1, found 402.2, SFC characterization, column: (100mm*3.0mm, 3.0μm); Mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (0.1% DEA), retention time 1.19min; ee: >98%.

[0102] Step 2: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)methylcarbamate (2A) and (S)-((3-(4-(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)methylcarbamate (2B)

[0103] (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2- sulfonamide (1j-A) (0.03 g, 0.08 mmol) was dissolved in dichloromethane (1 mL) under nitrogen at room temperature with an ice water bath and stirring, N,N-diisopropylethylamine (0.03 g, 0.22 mmol) and methyl chloroformate (0.007 g, 0.067 mmol) were added sequentially. The reaction was then stirred at room temperature for 1 hour before being quenched. Diluted with water and extracted with dichloromethane. The combined organic phases were dried, concentrated and the resulting crude was separated by preparative HPLC (mobile phase: 33% acetonitrile / 10 mM aqueous ammonium bicarbonate) to give the target product (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)methylcarbamate (2A). LC-MS (ESI) calcd for C 22 H 25 N3O4S2[M+H] + m / z 460.1, found 460.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 3H), 7.11 (s, 1H), 6.83 (s, 1H), 5.54 - 5.47 (m, 1H), 3.32 (s, 3H), 3.15 - 2.93 (m, 3H), 2.64 (d, J = 7.2 Hz, 2H), 2.50 - 2.43 (m, 1H), 1.90 - 1.80 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H).

[0104] The target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid methyl ester (2B) was obtained using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2- sulfonamide (1j-B) as the starting material referring to the synthesis scheme of (R)-((3-(4-(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid methyl ester (2A). LC-MS (ESI) calcd for C 22 H 25 N3O4S2[M+H] + m / z 460.1, found 460.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 8.0 Hz, 2H), 7.30 (s, 1H), 7.21 (d, J = 8.3 Hz, 3H), 6.86 (s, 1H), 5.56 (t, J = 6.5 Hz, 1H), 3.37 (s, 3H), 3.20-2.95 (m, 4H), 2.66 (d, J = 7.0 Hz, 2H), 1.91-1.83 (m, 1H), 0.94 (d, J = 6.4 Hz, 6H).

[0105] Example 3. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (3A) and (S)-((3-(4-(6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (3B)

[0106] Synthetic route:

[0107] (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamic acid ethyl ester (3A) and (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (3B) were prepared

[0108] The target product (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (3A) was obtained according to the synthetic scheme of Reference Example 2, Step 2. LC-MS (ESI) calcd for C 23 H 27 N3O4S2[M+H] + m / z 474.2, found 474.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.0 Hz, 2H), 7.24 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.16 (s, 1H), 6.87 (s, 1H), 5.55 (t, J = 7.2 Hz, 1H), 3.84 (q, J = 7.1 Hz, 2H), 3.16 - 2.94 (m, 4H), 2.67 (d, J = 7.0 Hz, 2H), 1.90 - 1.83 (m, 1H), 1.03 (t, J = 7.1 Hz, 3H), 0.94 (d, J = 6.6 Hz, 6H).

[0109] The target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (3B) was obtained according to the synthetic scheme of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (3A), using (S)-3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (1j-B) as the starting material. LC-MS (ESI) calcd for C 23 H 27 N3O4S2[M+H] + m / z 474.2, found 474.4. 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.0 Hz, 2H), 7.24 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.15 (s, 1H), 6.87 (s, 1H), 5.54 (t, J = 6.7 Hz, 1H), 3.83 (q, J = 7.1 Hz, 2H), 3.20 - 2.92 (m, 4H), 2.66 (d, J = 7.0 Hz, 2H), 1.90 - 1.83 (m, 1H), 1.03 (t, J = 7.0 Hz, 3H), 0.94 (d, J = 6.8 Hz, 6H).

[0110] Example 4. (R)-propyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (4A) and (S)-propyl ((3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (4B)

[0111] Synthetic Route:

[0112] Step 1: Preparation of (R)-propyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)- 5-isobutylthiophen-2-yl)sulfonyl)carbamate (4A) and (S)-propyl ((3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (4B)

[0113] The target product (R)-propyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)- 5-isobutylthiophen-2-yl)sulfonyl)carbamate (4A) was obtained according to the synthetic scheme of Reference Example 2, Step 2. LC-MS (ESI) calcd for C 24 H 29 N3O4S2[M+H] + m / z 488.2, found 487.8. 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.1 Hz, 2H), 7.28 - 7.17 (m, 3H), 7.15 (s, 1H), 6.87 (s, 1H), 5.56 - 5.52 (m, 1H), 3.75 (t, J = 6.5 Hz, 2H), 3.15 - 2.95 (m, 4H), 2.67 (d, J = 6.9 Hz, 2H), 1.93 - 1.79 (m, 1H), 1.47 - 1.38 (m, 2H), 0.94 (d, J = 6.6 Hz, 6H), 0.77 (t, J = 7.4 Hz, 3H).

[0114] The target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid propyl ester (4B) was obtained using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2- sulfonamide absolute configuration di (1j-B) as the starting material, referring to the synthesis scheme of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid propyl ester (4A). LC-MS (ESI) calcd for C 24 H 29 N3O4S2[M+H] + m / z 488.2, found 488.0.

[0115] Example 5. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (5A) and (S)-((3-(4-(6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (5B)

[0116] Synthetic route:

[0117] Step 1: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (5A) and (S)-((3-(4-(6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (5B)

[0118] The target product (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (5A) was obtained referring to the synthesis scheme of Example 2 Step 2. LC-MS (ESI) calcd for C 25 H 31 N3O4S2[M+H] + m / z 502.2, found 502.5. 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.1 Hz, 2H), 7.28 - 7.17 (m, 3H), 7.15 (s, 1H), 6.88 (s, 1H), 5.57 - 5.51 (m, 1H), 3.78 (t, J = 6.5 Hz, 2H), 3.19 - 2.91 (m, 3H), 2.67 (d, J = 6.9 Hz, 2H), 2.50 - 2.40 (m, 1H), 1.93 - 1.79 (m, 1H), 1.40 - 1.34 (m, 2H), 1.25 - 1.12 (m, 2H), 0.94 (d, J = 6.6 Hz, 6H), 0.83 (t, J = 7.3 Hz, 3H).

[0119] Using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophene-2-sulfonamide (1j-B) as the starting material, following the synthetic protocol of (R)-butyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (5A), the target product (S)-butyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (5B) was obtained. LC-MS (ESI) calcd for C 25 H 31 N3O4S2[M+H] + m / z 502.2, found 502.5. 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.1 Hz, 2H), 7.28 - 7.17 (m, 3H), 7.15 (s, 1H), 6.88 (s, 1H), 5.57 - 5.51 (m, 1H), 3.78 (t, J = 6.5 Hz, 2H), 3.19 - 2.91 (m, 3H), 2.67 (d, J = 6.9 Hz, 2H), 2.50 - 2.40 (m, 1H), 1.93 - 1.79 (m, 1H), 1.40 - 1.34 (m, 2H), 1.25 - 1.12 (m, 2H), 0.94 (d, J = 6.6 Hz, 6H), 0.83 (t, J = 7.3 Hz, 3H).

[0120] Example 6. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-pyridin-2-ylmethyl ester (6A) and (S)- ((3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamic acid-pyridin-2-ylmethyl ester (6B)

[0121] Synthetic Route:

[0122] Step 1: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-2,2,2-trichloroethyl ester (6a-A)

[0123] The target product, (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-2,2,2-trichloroethyl ester (6a-A), was obtained following the synthetic scheme of Reference Example 2, Step 2. LC-MS (ESI) calcd for C 23 H 24 Cl3N3O4S2[M+H] + m / z 576.0; 578.0, found 576.1.

[0124] Step 2: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-pyridin-2-ylmethyl ester (6A)

[0125] (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-pyridin-2-ylmethyl ester (6a-A) (0.11 g, 0.19 mmol) was dissolved in acetonitrile (1 mL) at room temperature, and N,N- diisopropylethylamine (0.12 g, 0.95 mmol) and pyridin-2-ylmethanol (0.10 g, 0.95 mmol) were added sequentially to the reaction. The microwave tube was sealed, and the reaction was heated to 150 °C for 1 h before being terminated. It was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried, concentrated, and the resulting crude product was purified by preparative HPLC (mobile phase: 0.1% formic acid in water / acetonitrile) to give (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-pyridin-2-ylmethyl ester (6A). LC-MS (ESI) calcd for C 27 H 28 N4O4S2[M+H] + m / z 537.2, found 537.3. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.74 (d, J = 11.4 Hz, 3H), 7.40 (s, 1H), 7.31 - 7.21 (m, 4H), 7.15 (d, J = 7.7 Hz, 1H), 6.84 (s, 1H), 5.62 - 5.58 (m, 1H), 4.88 (s, 2H), 3.30 - 3.10 (m, 2H), 2.70 - 2.55 (m, 4H), 1.89 - 1.80 (m, 1H), 0.92 (d, J = 6.4 Hz, 6H).

[0126] Using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophene-2-sulfonamide (1j-B) as the starting material, the synthetic procedure of Example 6, Steps 1-2 was followed to give (S)-((3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid- pyridin-2-ylmethyl ester (6B). LC-MS (ESI) calcd for C 27 H 28 N4O4S2[M+H] +m / z 537.2, found 537.4. 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 8.2 Hz, 2H), 7.68 (dd, J = 13.4, 7.4 Hz, 1H), 7.27 - 7.18 (m, 1H), 7.14 - 7.09 (m, 1H), 7.06 (d, J = 8.3 Hz, 2H), 6.96 - 6.84 (m, 3H), 6.79 (s, 1H), 5.44 - 5.33 (m, 1H), 4.80 (s, 2H), 3.07 - 2.73 (m, 4H), 2.59 (d, J = 7.1 Hz, 2H), 1.80 - 1.88 (m, 1H), 0.92 (d, J = 6.7 Hz, 6H).

[0127] Example 7. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-4-fluorobenzyl ester (7A) and (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamic acid-4-fluorobenzyl ester (7B)

[0128] Synthetic Route:

[0129] Step 1: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-4-fluorobenzyl ester (7A) and (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamic acid-4-fluorobenzyl ester (7B)

[0130] The target product (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-4-fluorobenzyl ester (7A) was obtained according to the synthetic scheme of Reference Example 6, Steps 1-2. LC-MS (ESI) calcd for C 28 H 28 FN3O4S2[M+H] + m / z 554.2, found 554.4. 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 7.9 Hz, 2H), 7.36 (s, 1H), 7.29 - 7.19 (m, 5H), 7.13 (t, J = 8.9 Hz, 2H), 6.85 (s, 1H), 5.58 (t, J = 7.8 Hz, 1H), 4.83 (s, 2H), 3.25 - 3.00 (m, 3H), 2.64 (d, J = 7.0 Hz, 2H), 2.04 - 1.94 (m, 1H), 1.92 - 1.76 (m, 1H), 0.93 (d, J = 6.6 Hz, 6H).

[0131] Using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophene-2-sulfonamide (1j-B) as the starting material, the target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-4-fluorobenzyl ester (7B) was obtained according to the synthetic scheme of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid-4- fluorobenzyl ester (7A). LC-MS (ESI) calcd for C 28 H 28 FN3O4S2[M+H] + m / z 554.2, found 554.1.

[0132] Example 8. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl ester (8A) and (S)- ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamic acid cyclopropyl ester (8B)

[0133] Synthetic Route:

[0134] Step 1. Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)- 5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl ester (8A)

[0135] To a solution of (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophene-2-sulfonamide (1j-A) (0.03 g, 0.07 mmol) in dichloromethane (1 mL) was added (4-nitrophenyl) cyclopropyl carbonate (0.03 g, 0.15 mmol) and triethylamine (0.02 g, 0.22 mmol) at room temperature. The reaction was terminated after 16 h at 40 °C. The reaction was concentrated and the residue was separated by preparative HPLC (mobile phase: acetonitrile / 0.03% ammonia water = 25 / 75 ~ 30 / 70) to give the target product (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl ester (8A). LC-MS (ESI) calcd for C 24 H 27 N3O4S2[M+H] + m / z 486.1, found 486.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 7.9 Hz, 2H), 7.28 (s, 1H), 7.20 (d, J = 7.2 Hz, 3H), 6.84 (s, 1H), 5.57-5.53 (m, 1H), 3.71 (s, 1H), 3.15-3.00 (m, 3H), 2.71-2.60 (m, 3H), 1.94-1.79 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H), 0.47 (d, J = 6.7 Hz, 2H), 0.35 (s, 2H).

[0136] Using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene- 2-sulfonamide (1j-B) as the starting material, the synthesis of (R)-((3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl ester (8A) as a reference, the target product (S)-((3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl ester (8B) was obtained. LC-MS (ESI) calcd for C 24 H 27 N3O4S2[M+H] + m / z 486.1, found 486.3. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 8.1 Hz, 2H), 7.36 (s, 1H), 7.30 - 7.16 (m, 3H), 6.86 (s, 1H), 5.59 (t, J = 6.9 Hz, 1H), 3.81 - 3.69 (m, 1H), 3.20 - 3.04 (m, 4H), 2.67 (t, J = 10.4 Hz, 2H), 1.88 - 1.85 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H), 0.56 - 0.44 (m, 2H), 0.42 - 0.31 (m, 2H).

[0137] Example 9. (R)-Cyclopropylmethyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (9A) and (S)-cyclopropylmethyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamate (9B)

[0138] Synthetic Route:

[0139] Step 1: Preparation of (R)-cyclopropylmethyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (9A) and (S)-cyclopropylmethyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamate (9B)

[0140] The target product (R)-cyclopropylmethyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (9A) was obtained according to the synthetic scheme of Reference Example 6, Steps 1-2. LC-MS (ESI) calcd for C 25 H 29 N3O4S2[M+H] + m / z 500.2, found 500.6. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.07 (s, 1H), 7.03 (s, 1H), 6.82 (s, 1H), 5.46 (dd, J = 7.6, 5.6 Hz, 1H), 3.56 (d, J = 7.2 Hz, 2H), 3.11 - 2.84 (m, 3H), 2.63 (d, J = 6.8 Hz, 2H), 2.50 - 2.41 (m, 1H), 1.91 - 1.80 (m, 1H), 0.93 (d, J = 6.8 Hz, 7H), 0.42 - 0.37 (m, 2H), 0.14 - 0.09 (m, 2H).

[0141] Using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophene-2-sulfonamide (1j-B) as the starting material, following the synthetic protocol of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropylmethyl ester (9A), the target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropylmethyl ester (9B) was obtained. LC-MS (ESI) calcd for C 25 H 29 N3O4S2[M+H] + m / z 500.2, found 500.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.1 Hz, 2H), 7.27 - 7.09 (m, 4H), 6.87 (s, 1H), 5.54 (t, J = 6.7 Hz, 1H), 3.64 (d, J = 7.0 Hz, 2H), 3.18 - 2.89 (m, 4H), 2.66 (d, J = 7.0 Hz, 2H), 1.94 - 1.77 (m, 1H), 0.99 - 0.86 (m, 7H), 0.47 - 0.36 (m, 2H), 0.18 - 0.10 (m, 2H).

[0142] Example 10. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (11A) and (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (11B)

[0143] Synthesis route:

[0144] Step 1: Preparation of methyl 4-(4-bromo-2-fluorophenyl)-4-oxobutanoate (lib)

[0145] To a stirred solution of 1-bromo-3-fluorobenzene (11a) (15.00 g, 85.71 mmol) in anhydrous 1,2-dichloroethane (150 mL) was added dry aluminium trichloride (45.71 g, 342.86 mmol) at room temperature. The reaction was stirred at room temperature for 1 h under nitrogen atmosphere. To the mixture was added monomethyl succinyl chloride (25.81 g, 171.43 mmol) dropwise. The reaction was then heated to 70 °C and stirred for 16 h under nitrogen atmosphere before it was cooled down. The reaction was quenched with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic layers were dried and concentrated. The resulting crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 10 / 1) to give the target compound methyl 4-(4-bromo-2-fluorophenyl)-4-oxobutanoate (lib). LC-MS (ESI) calcd for C 11 H 10 BrFO3[M+H] + m / z 289.0; 291.0, found 288.9.

[0146] Step 2: Preparation of methyl 4-(4-bromo-2-fluorophenyl)-4-(hydroxyimino)butanoate (lie)

[0147] To a stirred solution of methyl 4-(4-bromo-2-fluorophenyl)-4-oxobutanoate (lib) (9.00 g, 31.13 mmol), hydroxylamine hydrochloride (5.41 g, 77.83 mmol), sodium acetate (7.66 g, 93.39 mmol) in methanol / water (60 mL / 20 mL) was added at room temperature. The reaction was heated to 80 °C and stirred for 2 h under nitrogen atmosphere before it was cooled down. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. The resulting crude product was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 100 / 8) to give the target compound methyl 4-(4-bromo-2-fluorophenyl)-4-(hydroxyimino)butanoate (lie). LC-MS (ESI) calcd for C 11 H 11 BrFNO3[M+H] + m / z 304.0; 306.0, found 303.9.

[0148] Step 3: Preparation of 5-(4-bromo-2-fluorophenyl)pyrrolidin-2-one (lid)

[0149] Methyl 4-(4-bromo-2-fluorophenyl)-4-(hydroxyimino)butanoate (11c) (8.50 g, 27.95 mmol) was dissolved in acetic acid (80 mL) at room temperature, and zinc powder (9.14 g, 139.75 mmol) was added portionwise with stirring. The reaction was heated to 80 °C and terminated after 16 h under nitrogen protection. The reaction was cooled, concentrated, and the resulting crude was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 1) to give the target compound 5-(4-bromo-2-fluorophenyl)pyrrolidin-2-one (11d). LC-MS (ESI) calcd for C 10 H9BrFNO[M+MeCN+H] + m / z 299.0; 301.0, found 299.1.

[0150] Step 4: Preparation of 2-(4-bromo-2-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (11e)

[0151] To a stirred solution of 5-(4-bromo-2-fluorophenyl)pyrrolidin-2-one (11d) (3.60 g, 13.95 mmol) in dry dichloromethane (15 mL) was added trimethyl oxonium tetrafluoroborate (4.13 g, 27.90 mmol) slowly at 0 °C under nitrogen protection. The reaction was terminated after 16 h at room temperature under nitrogen protection. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic phase was dried and concentrated. The target compound 2-(4-bromo-2-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (11e) was obtained. The crude was used directly in the next step without further purification. LC-MS (ESI) calcd for C 11 H 11 BrFNO[M+H] + m / z 272.0; 274.0, found 271.9.

[0152] Step 5: Preparation of 2-(4-bromo-2-fluorophenyl)-N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-pyrrol-5-amine (11f)

[0153] Aminoacetaldehyde dimethyl acetal (2.14 g, 20.34 mmol) was added to a solution of 2-(4-bromo-2-fluorophenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (11e) (3.69 g crude) in ethanol (25 mL) at room temperature and the reaction was then heated to 85 °C for 16 h. The reaction was cooled and concentrated and the crude product was purified by reverse phase C18 column chromatography (mobile phase: 0.1% formic acid in water / acetonitrile) to give the target compound 2-(4-bromo-2-fluorophenyl)-N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-pyrrol-5-amine (11f). 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (dd, J = 10.4, 1.6 Hz, 1H), 7.48 (dd, J = 8.2, 1.4 Hz, 1H), 7.40 - 7.35 (m, 1H), 5.20 (t, J = 7.1 Hz, 1H), 4.55 (s, 1H), 3.45 - 3.43 (m, 2H), 3.35 (d, J = 3.0 Hz, 6H), 2.87 - 2.81 (m, 2H), 2.57 - 2.51 (m, 1H), 1.88 (s, 1H).

[0154] Step 6: Preparation of 5-(4-bromo-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2- a]imidazole (11g)

[0155] 2-(4-bromo-2-fluorophenyl)-N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-pyrrol-5-amine (11f) (4.65 g, 13.41 mmol) was dispersed in hydrochloric acid (6 M, 50 mL) at room temperature and heated to 100 °C for 16 h. The reaction was cooled and concentrated and purified by reverse phase C18 column chromatography (mobile phase: 0.1% formic acid in water / acetonitrile) to give the target compound 5-(4-bromo-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole (11g). 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (dd, J = 10.3, 1.9 Hz, 1H), 7.49 (dd, J = 8.6, 1.7 Hz, 2H), 7.40 (d, J = 1.8 Hz, 1H), 7.17 (t, J = 8.3 Hz, 1H), 5.81 (dd, J = 9.1, 4.2 Hz, 1H), 3.20 - 3.13 (m, 3H), 2.60 - 2.51 (m, 1H).

[0156] Step 7: Preparation of N-(tert-butyl)-3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11h)

[0157] To a mixture of (2-(N-(tert-butyl)sulfamoyl)-5-isobutylthiophen-3-yl)boronic acid (1d) (0.70 g, 2.19 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added 5-(4-bromo-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (11g) (0.68 g, 2.41 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.16 g, 0.22 mmol) and potassium carbonate (0.91 g, 6.58 mmol) sequentially at room temperature under nitrogen. The reaction was heated to 110 °C for 2 hours under nitrogen and then cooled. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried, concentrated and the residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 10 / 1) to give the title compound N-(tert-butyl)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11h). LC-MS (ESI) calcd for C 24 H 30 FN3O2S2[M+H] + m / z 476.2, found 475.8. 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (dd, J = 11.6, 1.5 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.31 - 7.22 (m, 1H), 7.00 - 6.93 (m, 3H), 5.70 - 5.58 (m, 1H), 3.13 - 2.99 (m, 2H), 2.70 (d, J = 7.0 Hz, 2H), 2.48 - 2.36 (m, 2H), 1.96 - 1.79 (m, 1H), 0.97 (s, 9H), 0.93 (d, J = 6.6 Hz, 6H).

[0158] Step 8: Preparation of 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11i)

[0159] To a stirred solution of N-(tert-butyl)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-5-yl)-3-fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11h) (0.60 g, 1.26 mmol) in trifluoroacetic acid (5 mL) was added anisole (0.7 mL) at room temperature and the reaction was heated to 30 °C for 16 h. The reaction was concentrated and the crude product was purified by preparative HPLC (mobile phase: 0.1% formic acid in water / acetonitrile) to give the title compound 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11i). LC-MS (ESI) calcd for C 20 H 22 FN3O2S2[M+H] + m / z 420.1, found 420.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 2H), 7.52 (dd, J = 11.7, 1.5 Hz, 1H), 7.38 (dd, J = 8.0, 1.6 Hz, 1H), 7.00 (d, J = 1.2 Hz, 1H), 6.96 (s, 2H), 6.87 (t, J = 8.0 Hz, 1H), 5.65 (dd, J = 8.2, 4.6 Hz, 1H), 3.14 - 3.01 (m, 1H), 2.92 - 2.77 (m, 2H), 2.68 (d, J = 7.0 Hz, 2H), 2.48 - 2.39 (m, 1H), 1.95 - 1.81 (m, 1H), 0.93 (d, J = 6.6 Hz, 6H).

[0160] Step 9: Preparation of (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11i-A) and (S)-3-(4-(6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11i-B)

[0161] Compound 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophene-2-sulfonamide (11i) was separated by SFC (column: Chiralpak® AD-H (250mm*25mm, 10pm); mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (+0.1% 7.0 mol / L Ammonia in MeOH)) to give enantiomers (peak 1 and peak 2). (250mm*25mm, 10pm); mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (+0.1% 7.0 mol / L Ammonia in MeOH)).

[0162] Peak 1 is R configuration, i.e. (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11i-A), LC-MS (ESI) calcd for C 20 H 22 FN3O2S2[M+H] + m / z 420.1, found 420.3, SFC characterization, column: Chiralpak AD-H (100mm*3.0mm, 3.0μm); Mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (0.1%DEA), Retention time: 1.43min; ee: >98%.

[0163] Peak 2 is S configuration, i.e. (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11i-B), LC-MS (ESI) calcd for C 20 H 22 FN3O2S2[M+H] + m / z 420.1, found 420.3, SFC characterization, column: Chiralpak AD-H (100mm*3.0mm, 3.0μm); Mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (0.1%DEA), Retention time: 1.03min; ee: >99%.

[0164] Step 10: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophene-2-yl)sulfonyl)carbamic acid ethyl ester (11A) and (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophene-2-yl)sulfonyl)carbamic acid ethyl ester (11B)

[0165] To a stirred solution of (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11i-A) (0.02 g, 0.05 mmol) in dichloromethane (3 mL) was added ethyl chloroformate (0.05 g, 0.05 mmol) and N,N- diisopropylethylamine (0.02 g, 0.14 mmol) under ice water bath. The reaction was allowed to react at room temperature for 16 h. The reaction was concentrated and the crude product was purified by preparative HPLC (mobile phase: 0.1% formic acid in water / acetonitrile) to give the target product (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (11A). LC-MS (ESI) calcd for C 23 H 26 FN3O4S2[M+H] + m / z 492.1, found 491.7. 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 12.6 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 15.0 Hz, 2H), 7.03 (t, J = 8.1 Hz, 1H), 6.91 (s, 1H), 5.84 - 5.71 (m, 1H), 3.80 (q, J = 7.0 Hz, 2H), 3.18 - 3.03 (m, 3H), 2.66 (d, J = 7.0 Hz, 2H), 2.59 - 2.53 (m, 1H), 1.91 - 1.80 (m, 1H), 1.03 (t, J = 7.1 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H).

[0166] The target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (11B) was synthesized using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophene-2-sulfonamide (11i-B) as the starting material following the procedure 10 synthesis scheme of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (11A). LC-MS (ESI) calcd for C 23 H 26 FN3O4S2[M+H] +m / z 492.1, found 491.7.

[0167] Example 11. (R)-Butyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (12A) and (S)-butyl ((3-(4-(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl) carbamate (12B)

[0168] Synthetic Route:

[0169] Step 1. Preparation of (R)-butyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (12A) and (S)-butyl ((3-(4-(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl) carbamate (12B)

[0170] Following the synthetic protocol of Reference Example 10, Step 10, the target product (R)-butyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (12A) was obtained. LC-MS (ESI) calcd for C 25 H 30 FN3O4S2[M+H] + m / z 520.2, found 519.7. 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 11.3 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.28 (s, 1H), 7.24 (s, 1H), 7.03 (t, J = 8.1 Hz, 1H), 6.91 (s, 1H), 5.80 - 5.74 (m, 1H), 3.79 (t, J = 6.5 Hz, 2H), 3.20 - 3.12 (m, 1H), 3.11 - 3.02 (m, 2H), 2.66 (d, J = 7.0 Hz, 2H), 2.59 - 2.53 (m, 1H), 1.92 - 1.81 (m, 1H), 1.43 - 1.34 (m, 2H), 1.22 - 1.14 (m, 2H), 0.93 (d, J = 6.6 Hz, 6H), 0.83 (t, J = 7.3 Hz, 3H).

[0171] The target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (12B) was obtained using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophene-2-sulfonamide (11i-B) as the starting material, referring to the synthesis scheme of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (12A). LC-MS (ESI) calcd for C 25 H 30 FN3O4S2[M+H] + m / z 520.2, found 519.7. 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 12.7 Hz, 2H), 7.03 - 6.92 (m, 1H), 6.89 (s, 1H), 5.79 - 5.68 (m, 1H), 3.76 (s, 2H), 3.18 - 2.91 (m, 4H), 2.65 (d, J = 7.1 Hz, 2H), 1.92 - 1.77 (m, 1H), 1.44 - 1.34 (m, 2H), 1.27 - 1.14 (m, 3H), 0.93 (d, J = 6.6 Hz, 6H), 0.82 (t, J = 7.3 Hz, 3H).

[0172] Example 12. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid propyl ester (13A) and (S)-((3-(4-(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamic acid propyl ester (13B)

[0173] Synthetic route:

[0174] Step 1: Preparation of (R)-propyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (13A) and (S)-propyl ((3-(4-(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl) carbamate (13B)

[0175] The target product (R)-propyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (13A) was obtained according to the synthetic scheme of Reference Example 10 Step 10. LC-MS (ESI) calcd for C 24 H 28 FN3O4S2[M+H] + m / z 506.2, found 506.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 12.5 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 6.4 Hz, 2H), 6.85 - 6.78 (m, 2H), 5.63 (dd, J = 8.4, 4.8 Hz, 1H), 3.62 (t, J = 6.6 Hz, 2H), 3.13 - 3.01 (m, 1H), 2.96 - 2.77 (m, 2H), 2.61 (d, J = 6.9 Hz, 2H), 2.51 - 2.40 (m, 1H), 1.90 - 1.78 (m, 1H), 1.43 - 1.35 (m, 2H), 0.93 (d, J = 6.6 Hz, 6H), 0.77 (t, J = 7.4 Hz, 3H).

[0176] The target product (R)-propyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (13A) was obtained according to the synthetic scheme of Reference Example 10 Step 10. LC-MS (ESI) calcd for C 24 H 28 FN3O4S2[M+H] +m / z 506.2, found 506.4. 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 12.5 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.26 (s, 1H), 7.05 (t, J = 8.1 Hz, 1H), 6.91 (s, 1H), 5.81 - 5.74 (m, 1H), 3.75 (t, J = 6.5 Hz, 2H), 3.16 - 3.03 (m, 3H), 2.66 (d, J = 6.9 Hz, 2H), 1.87 (dt, J = 13.4, 6.8 Hz, 1H), 1.47 - 1.37 (m, 2H), 1.29-1.18 (m, 1H), 0.93 (d, J = 6.6 Hz, 6H), 0.77 (t, J = 7.4 Hz, 3H).

[0177] Example 13. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate cyclopropylmethyl ester (14A) and (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate cyclopropylmethyl ester (14B)

[0178] Synthetic Route:

[0179] Step 1: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate-2,2,2-trichloroethyl ester (14a-A)

[0180] Chloroformic acid-2,2,2-trichloroethyl ester (0.03 g, 0.12 mmol) was added slowly dropwise to a stirred solution of (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-5-yl)-3-fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11i-A) (0.05 g, 0.12 mmol) and N,N-diisopropylethylamine (0.05 g, 0.36 mmol) in dichloromethane (2 mL) at 0 °C. The reaction was then allowed to react at room temperature for 1 h before being quenched with water. The reaction was diluted with water and extracted with dichloromethane. The combined organic layers were dried and concentrated. The crude product was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 10 / 1) to give the target compound ((R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid-2,2,2- trichloroethyl ester (14a-A). LC-MS (ESI) calcd for C 23 H 23 Cl3FN3O4S2[M+H] + m / z 594.0; 596.0, found 594.

[0181] Step 2: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl methyl ester (14A)

[0182] Cyclopropylmethanol (0.02 g, 0.30 mmol) was added to a solution of ((R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-2,2,2-trichloroethyl ester (14a-A) (0.04 g, 0.06 mmol) and N,N-diisopropylethylamine (0.04 g, 0.30 mmol) in acetonitrile (3 mL) at room temperature. The reaction was heated to 140 °C for 1 h before being quenched. The reaction was cooled, filtered, and concentrated. The crude product was purified by preparative high-performance liquid chromatography (mobile phase: ammonium bicarbonate in water / acetonitrile) to give the target product ((R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl methyl ester (14A). LC-MS (ESI) calcd for C 25 H 28 FN3O4S2[M+H] + m / z 518.2, found 518.1. 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.27 - 7.21 (m, 2H), 7.02 (s, 1H), 6.90 (s, 1H), 5.78 (s, 1H), 3.63 (d, J = 6.8 Hz, 2H), 3.24 - 2.93 (m, 4H), 2.66 (d, J = 7.0 Hz, 2H), 1.91 - 1.81 (m, 1H), 0.93 (d, J = 6.6 Hz, 7H), 0.45 - 0.38 (m, 2H), 0.13 (q, J = 4.5 Hz, 2H).

[0183] Using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11i-B) as the starting material, following the synthetic protocol of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-5-yl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate cyclopropylmethyl ester (14A), the target product (S)-((3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamate cyclopropylmethyl ester (14B) was obtained. LC-MS (ESI) calcd for C 25 H 28 FN3O4S2[M+H] + m / z 518.2, found 518.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 12.3 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 4.9 Hz, 2H), 7.00 - 6.91 (m, 1H), 6.88 (s, 1H), 5.77 - 5.65 (m, 1H), 3.59 (d, J = 7.0 Hz, 2H), 3.19 - 2.90 (m, 4H), 2.64 (d, J = 7.0 Hz, 2H), 1.94 - 1.78 (m, 1H), 0.97 - 0.89 (m, 7H), 0.45 - 0.34 (m, 2H), 0.16 - 0.08 (m, 2H).

[0184] Example 14. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl ester (15A) and (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl ester (15B)

[0185] Synthetic Route:

[0186] Step 1: Preparation of (4-nitrophenyl) carbamic acid cyclopropyl ester (15a)

[0187] Cyclopropanol (0.173 g, 2.98 mmol) was added slowly dropwise to a stirred solution of p-nitrophenyl chloroformate (0.50 g, 2.48 mmol) in dichloromethane (5 mL) at 0 °C, followed by the addition of pyridine (0.22 g, 2.73 mmol). The reaction was then stirred at room temperature for 1 hour before being quenched. Saturated aqueous ammonium chloride solution was added to the reaction, which was then extracted with dichloromethane. The combined organic layers were dried and concentrated, and the residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 10 / 1) to give the target compound (4-nitrophenyl) carbamic acid cyclopropyl ester (15a). 1 H NMR (400 MHz, DMSO-d6) δ 8.37 - 8.28 (m, 2H), 7.62 - 7.53 (m, 2H), 4.34 - 4.19 (m, 1H), 0.92 - 0.71 (m, 4H).

[0188] Step 2: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl ester (15A)

[0189] (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophene-2-sulfonamide (11i-A) (0.01 g, 0.02 mmol) and triethylamine (0.008 g, 0.079 mmol) in dichloromethane (2 mL) at 0 °C. The reaction was then heated to 40 °C and stirred for 16 h before being stopped. The reaction was cooled to room temperature, concentrated, and the resulting residue was separated by preparative high performance liquid chromatography (mobile phase: ammonium bicarbonate in water / acetonitrile) to give the target product (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl ester (15A). LC-MS (ESI) calcd for C 24 H 26 FN3O4S2[M+H] + m / z 504.1, found 504.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 11.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.27 (s, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.88 (s, 1H), 5.85 - 5.72 (m, 1H), 3.71 (s, 1H), 3.22 - 2.96 (m, 4H), 2.64 (d, J = 6.9 Hz, 2H), 1.93 - 1.78 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H), 0.48 - 0.44 (m, 2H), 0.38 - 0.29 (m, 2H).

[0190] The target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl ester (15B) was obtained using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophene-2-sulfonamide (11i-B) as the starting material, following the synthetic protocol for (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid cyclopropyl ester (15A). LC-MS (ESI) calcd for C 24 H 26 FN3O4S2[M+H] +m / z 504.1, found 504.4. 1 HNMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 11.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.12 (t, J = 8.1 Hz, 1H), 6.90 (s, 1H), 5.82 (d, J = 8.3 Hz, 1H), 3.75 (s, 1H), 3.25 - 3.09 (m, 4H), 2.66 (d, J = 7.1 Hz, 2H), 1.88 - 1.85 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H), 0.50 (d, J = 6.2 Hz, 2H), 0.37 (s, 2H).

[0191] Example 15. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)phenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (17A) and (S)-((3-(4-(6,7-dihydro- 5H-pyrrolo[l,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl) carbamate (17B)

[0192] Synthetic Route:

[0193] Step 1: Preparation of 2-isobutyl-3-methylthiophene (17b)

[0194] Zinc chloride (0.5 M in tetrahydrofuran, 254.50 mmol, 509 mL) was dissolved in dry tetrahydrofuran (120 mL) at room temperature, and isobutylmagnesium bromide (1 M in tetrahydrofuran, 226.00 mmol, 226 mL), 2-bromo-3-methyl-thiophene (17a) (25.00 g, 141.20 mmol) and bis(triphenylphosphine)palladium (3.60 g, 7.10 mmol) were added successively under nitrogen protection. The reaction was terminated after heating to 90 °C for 1 hour under nitrogen protection. The reaction solution was cooled and diluted with water, and extracted with ethyl acetate. The organic phase was combined, dried and concentrated. The obtained crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to give the target compound 2-isobutyl-3-methylthiophene (17b). 1 H NMR (400 MHz, CDC13) δ 7.02 (d, J = 5.1 Hz, 1H), 6.77 (d, J = 5.1 Hz, 1H), 2.59 (d, J = 7.2 Hz, 2H), 2.15 (s, 3H), 1.93 - 1.80 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H).

[0195] Step 2: Preparation of 5-isobutyl-4-methylthiophene-2-sulfonyl chloride (17c)

[0196] Dissolve 2-isobutyl-3-methylthiophene (17b) (15.20 g, 98.70 mmol) in dichloromethane (120 mL) at room temperature, add chlorosulfonic acid (35.60 g, 306.00 mmol) with stirring, and allow the reaction to proceed at room temperature for 1 hour. Dilute the reaction with water and extract with ethyl acetate. Combine, dry, and concentrate the organic phase. The resulting crude product is separated by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 15 / 1) to give the target compound 5-isobutyl-4-methylthiophene-2-sulfonyl chloride (17c). 1 H NMR (400 MHz, CDC13) δ 7.59 (s, 1H), 2.67 (d, J = 7.2 Hz, 2H), 2.20 (s, 3H), 2.01-1.86 (m, 1H), 0.99 (d, J = 6.6 Hz, 6H).

[0197] Step 3: Preparation of N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (17d)

[0198] Dissolve 5-isobutyl-4-methylthiophene-2-sulfonyl chloride (17c) (10.80 g, 42.90 mmol) in dichloromethane (100 mL) at room temperature, add N,N-diisopropylethylamine (11.10 g, 85.70 mmol) and tert-butylamine (4.70 g, 64.30 mmol). Warm the reaction to 40°C and allow it to proceed for 1 hour. Cool the reaction and dilute it with water. Extract with ethyl acetate. Combine, dry, and concentrate the organic phase. The resulting crude product is separated by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 20 / 1) to give the target compound N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (17d). 1 H NMR (400 MHz, CDC13) δ 7.29 (s, 1H), 2.60 (d, J = 7.2 Hz, 2H), 2.13 (s, 3H), 1.93-1.84 (m, 1H), 1.28 (s, 9H), 0.95 (d, J = 6.6 Hz, 6H).

[0199] Step 4: Preparation of (2-(N-(tert-butyl)sulfonamido)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (17e)

[0200] N-(tert-butyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (17d) (10.30 g, 35.60 mmol) was dissolved in dry tetrahydrofuran (150 mL) at room temperature. n-Butyllithium (2.5 M n-hexane solution, 42.8 mL, 107.00 mmol) was added dropwise slowly under nitrogen protection at -60 °C. After addition, the reaction was carried out for 0.5 h at -60 °C under nitrogen protection, and then triisopropyl borate (12.70 g, 67.70 mmol) was added. The reaction was terminated after 3 h. The reaction solution was quenched with saturated ammonium chloride and then diluted with water, and extracted with ethyl acetate. The organic phase was combined, dried, concentrated, and the obtained crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to give the target compound (2-(N-(tert-butyl)sulfonamido)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (17e). 1 H NMR (400 MHz, DMSO-d6) δ 2.61 (d, J = 7.2 Hz, 2H), 2.11 (s, 3H), 1.90 - 1.77 (m, 1H), 1.14 (s, 9H), 0.90 (d, J = 6.6 Hz, 6H).

[0201] Step 5: Preparation of N-(tert-butyl)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (17f)

[0202] (2-(N-(tert-butyl)sulfonamido)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (17e) (0.25 g, 0.75 mmol) was dispersed in 1,4-dioxane (12 mL) and water (8 mL) at room temperature, and then 5-(4-bromophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (1h) (0.22 g, 0.83 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.06 g, 0.08 mmol) and potassium carbonate (0.31 g, 2.25 mmol) were added successively under nitrogen protection. The reaction solution was then heated to 100 °C and terminated after 16 h of reaction under nitrogen protection. The reaction solution was cooled and diluted with water, and extracted with ethyl acetate. The organic phase was combined, dried, concentrated, and the obtained crude product was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give the target compound N-(tert-butyl)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (17f). LC-MS (ESI) calcd for C 25 H 33 N3O2S2[M+H] + m / z 472.2, found 472.2.1 H NMR (400 MHz, CDC13) δ 8.28 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 3H), 6.79 (s, 1H), 5.38 (t, J = 6.9 Hz, 1H), 3.23-3.08 (m, 3H), 2.69-2.55 (m, 3H), 1.97-1.86 (m, 1H), 1.90 (s, 3H), 1.09 (s, 9H), 0.99 (d, J = 6.6 Hz, 6H).

[0203] Step 6: Preparation of 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutyl-4-methylthiophene-2-sulfonamide (17g)

[0204] Anisole (0.3 mL) was added to a stirred solution of N-(tert-butyl)-3-(4-(6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (17f) (0.19 g, 0.40 mmol) in trifluoroacetic acid (2 mL) at room temperature. The reaction was heated to 30 °C for 16 h and then quenched. The reaction was concentrated and the crude product was purified by reverse phase C18 column chromatography (mobile phase: 0.1% formic acid in water / acetonitrile) to give the target compound 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4- methylthiophene-2-sulfonamide (17g). LC-MS (ESI) calcd for C 21 H 25 N3O2S2[M+H] + m / z 416.1, found 416.1.

[0205] Step 7: Preparation of (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutyl-4-methylthiophene-2-sulfonamide (17h-A) and (S)-3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (17h-B)

[0206] Compound 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4- methylthiophene-2-sulfonamide (17g) was subjected to SFC (column: Chiralpak IC, 250 mm x 4.6 mm, 5 pm; mobile phase: 0.1% formic acid in methanol) to give (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4- methylthiophene-2-sulfonamide (17h-A) and (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (17h-B). (250mm*25mm, 10pm); Mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (+0.1% 7.0 mol / L Ammonia in MeOH)) to give enantiomers (peak 1 and peak 2).

[0207] wherein peak 1 is R configuration, i.e. (R)-3-(4-(6,7-dihydro-5H-pyrrolo[l,2- a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (17h-A), LC-MS (ESI) calcd for C 21 H 25 N3O2S2[M+H] + m / z 416.1, found 416.1, SFC characterization, column: (100mm*3.0mm, 3.0pm); Mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (0.1% DEA), retention time 1.36 min; ee: >97%.

[0208] peak 2 is S configuration, i.e. (S)-3-(4-(6,7-dihydro-5H-pyrrolo[l,2- a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (17h-B), LC-MS (ESI) calcd for C 21 H 25 N3O2S2[M+H] + m / z 416.1, found 416.1, SFC characterization, column: (100mm*3.0mm, 3.0pm); Mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (0.1% DEA), retention time 0.97 min; ee: >99%.

[0209] Step 8: Preparation of (R)-ethyl ((3-(4-(6,7-dihydro-5H-pyrrolo[l,2- a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophene-2-yl)sulfonyl)carbamate (17A) and (S)-ethyl ((3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4- methylthiophene-2-yl)sulfonyl)carbamate (17B)

[0210] Ethyl chloroformate (0.01 g, 0.06 mmol) was added dropwise to a solution of (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4- methylthiophene-2-sulfonamide (17h-A) (0.02 g, 0.06 mmol) and N,N- diisopropylethylamine (0.02 g, 0.17 mmol) in dichloromethane (1.5 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 1 h before being quenched. The reaction was concentrated and the crude product was separated by preparative HPLC (0.1 % formic acid in water / acetonitrile) to give the desired product (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (17A). LC-MS (ESI) calcd for C 24 H 29 N3O4S2[M+H] + m / z 488.2, found 488.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.13 (s, 1 H), 7.07 (s, 1 H), 5.57 - 5.48 (m, 1 H), 3.87 (q, J = 7.0 Hz, 2H), 3.12 - 2.92 (m, 4H), 2.66 (d, J = 7.1 Hz, 2H), 1.89 - 1.81 (m, 1 H), 1.80 (s, 3H), 1.05 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 6.6 Hz, 6H).

[0211] The procedure of step 8 of synthesis scheme for (R)-((3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (17A) was used to synthesize (S)-((3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (17B) using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (17h-B) as the starting material. LC-MS (ESI) calcd for C 24 H 29 N3O4S2[M+H] + m / z 488.2, found 488.2.

[0212] Example 16. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (18A) and (S)-((3-(4-(6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (18B)

[0213] Synthetic Route:

[0214] Step 1: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (18A) and (S)-((3-(4-(6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (18B)

[0215] Following the synthetic protocol of Reference Example 15, Step 8, the target product (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4- methylthiophen-2-yl)sulfonyl)carbamate (18A) was obtained. LC-MS (ESI) calcd for C 25 H 31 N3O4S2[M+H] + m / z 502.2, found 502.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.09 (s, 1H), 7.04 (s, 1H), 5.53 - 5.46 (m, 1H), 3.77 (t, J = 6.5 Hz, 2H), 3.18 - 2.80 (m, 4H), 2.64 (d, J = 7.1 Hz, 2H), 1.88 - 1.81 (m, 1H), 1.79 (s, 3H), 1.48 - 1.40 (m, 2H), 0.95 (d, J = 6.6 Hz, 6H), 0.79 (t, J = 7.4 Hz, 3H).

[0216] The target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid propyl ester (18B) was obtained using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4- methylthiophene-2-sulfonamide (17h-B) as the raw material, referring to the synthesis scheme of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4- methylthiophen-2-yl)sulfonyl)carbamic acid propyl ester (18A). 25 H 31 N3O4S2[M+H] + m / z 502.2, found 502.4. 1H NMR (400 MHz, DMSO-d6) δ 7.26 - 7.18 (m, 4H), 7.13 (s, 1H), 7.07 (s, 1H), 5.57 - 5.46 (m, 1H), 3.80 (t, J = 6.6 Hz, 2H), 3.16 - 2.87 (m, 4H), 2.66 (d, J = 7.1 Hz, 2H), 1.92 - 1.77 (m, 4H), 1.51 - 1.39 (m, 2H), 0.95 (d, J = 6.6 Hz, 6H), 0.79 (t, J = 7.4 Hz, 3H).

[0217] Example 17. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4- methylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (19A) and (S)-((3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (19B)

[0218] Synthetic route:

[0219] Step 1. Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (19A) and (S)-((3-(4-(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4-methylthiophen-2- yl)sulfonyl)carbamic acid butyl ester (19B)

[0220] The target product (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (19A) was obtained by reference to the synthetic scheme of Step 8 of Reference Example 15. LC-MS (ESI) calcd for C 26 H 33 N3O4S2[M+H] + m / z 516.2, found 516.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.08 (s, 1H), 7.04 (s, 1H), 5.53 - 5.45 (m, 1H), 3.81 (t, J = 6.3 Hz, 2H), 3.14 - 2.84 (m, 4H), 2.64 (d, J = 7.1 Hz, 2H), 1.91 - 1.80 (m, 1H), 1.79 (s, 3H), 1.46 - 1.36 (m, 2H), 1.26 - 1.19 (m, 2H), 0.95 (d, J = 6.4 Hz, 6H), 0.84 (t, J = 7.2 Hz, 3H).

[0221] The target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (19B) was obtained by reference to the synthetic scheme of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid propyl ester (19A) using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutyl-4- methylthiophene-2-sulfonamide (17h-B) as the starting material. LC-MS (ESI) calcd for C 26 H 33 N3O4S2[M+H] + m / z 516.2, found 516.2.

[0222] Example 18. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid ethyl ester (20A) and (S)-((3-(4-(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4-methylthiophen-2- yl)sulfonyl)carbamic acid ethyl ester (20B)

[0223] Synthesis route:

[0224] Step 1: Preparation of N-(tert-butyl)-3-(4-(6,7-dihydro-5H-pyrrolo[l,2- a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (20a)

[0225] Compound 5-(4-bromo-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole (llg) (0.50 g, 1.78 mmol) was dissolved in 1,4-dioxane (20 mL) and water (4 mL) at room temperature, (2-(N-(tert-butyl)sulfamoyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid (l7e) (0.77 g, 2.31 mmol), [l,l'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.13 g, 0.18 mmol) and potassium carbonate (0.74 g, 5.33 mmol) were added under argon protection. The reaction was then heated to 120 °C and stirred for 3 hours under nitrogen protection before termination. The reaction was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic phase was dried, concentrated and the resulting crude product was separated by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 5 / 1) to give the target compound N-(tert-butyl)-3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (20a). LC-MS (ESI) calcd for C 25 H 32 FN3O2S2[M+H] + m / z 490.2, found 490.1.

[0226] Step 2: Preparation of 3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (20b)

[0227] N-(tert-butyl)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (20a) (0.75 g, 1.53 mmol) was dissolved in trifluoroacetic acid (8 mL) at room temperature, and anisole (3 mL) was added with stirring. The reaction was then allowed to react at 35 °C under nitrogen protection for 16 hours and terminated. The reaction was cooled to room temperature and concentrated. The resulting residue was diluted with water and extracted with ethyl acetate. The organic phase was combined, dried, concentrated, and the resulting crude product was purified by reverse phase C18 column chromatography (mobile phase: 0.1% formic acid in water / acetonitrile) to give the target compound 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (20b). LC-MS (ESI) calcd for C 21 H 24 FN3O2S2[M+H] + m / z 434.1, found 434.1.

[0228] Step 3: Preparation of (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (20c-A) and (S)-3-(4-(6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene- 2-sulfonamide (20c-B)

[0229] The racemic 3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutyl-4-methylthiophene-2-sulfonamide (20b) was separated by SFC (column: (250 mm*25 mm, 10 μm); mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (+0.1% 7.0 mol / L Ammonia in MeOH)) to give enantiomers (peak 1 and peak 2).

[0230] Peak 1 is R configuration, i.e., (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)- 3-fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (20c-A), LC-MS (ESI) calcd for C 21 H 24 FN3O2S2[M+H] + m / z 434.1, found 434.1, SFC characterization, column: (100 mm*3.0 mm, 3.0 pm); mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (0.1% DEA), retention time 1.09 min; ee: >98%.

[0231] Peak 2 is S configuration, i.e. (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (20c-B), LC-MS (ESI) calcd for C 21 H 24 FN3O2S2[M+H] + m / z 434.1, found 434.0, SFC characterization, column: (100 mm*3.0 mm, 3.0 pm); mobile phase: Phase A: Supercritical CO2; Phase B: MeOH (0.1% DEA), retention time 0.81 min; ee: >99%.

[0232] Step 4: Preparation of (R)-ethyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophene-2-yl)sulfonyl)carbamate (20A) and (S)-ethyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4- methylthiophene-2-yl)sulfonyl)carbamate (20B)

[0233] (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4- methylthiophene-2-sulfonamide (20c-A) (0.02 g, 0.05 mmol) and N,N-diisopropylethylamine (0.02 g, 0.14 mmol) were dissolved in anhydrous dichloromethane (1 mL) at 0 °C, and ethyl chloroformate (0.01 g, 0.06 mmol) was added dropwise under nitrogen protection and stirring. The reaction was then terminated after 16 hours of reaction at room temperature and under nitrogen protection. The reaction was concentrated, and the obtained crude product was separated by high performance liquid preparation chromatography (mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile = 65 / 35) to obtain the target product (R)-ethyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4- methylthiophene-2-yl)sulfonyl)carbamate (20A). LC-MS (ESI) calcd for C 24 H28 FN3O4S2[M+H] + m / z 506.2, found 506.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.23 - 7.08 (m, 3H), 7.03 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 5.77 - 5.67 (m, 1H), 3.97 - 3.76 (m, 2H), 3.19 - 3.08 (m, 1H), 3.05 - 2.87 (m, 2H), 2.65 (d, J = 7.2 Hz, 2H), 1.93 - 1.75 (m, 4H), 1.28 - 1.19 (m, 1H), 1.05 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 6.6 Hz, 6H).

[0234] The target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)aminoformic acid ethyl ester (20B) was synthesized according to the procedure of Step 4 of (R)-((3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4-methylthiophen-2- yl)sulfonyl)aminoformic acid ethyl ester (20A) using (S)-3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4-methylthiophene-2- sulfonamide (20c-B) as the starting material. LC-MS (ESI) calcd for C 24 H 28 FN3O4S2[M+H] + m / z 506.2, found 506.1.

[0235] Example 19. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)aminoformic acid propyl ester (21A) and (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)aminoformic acid propyl ester (21B)

[0236] Synthetic Route:

[0237] Step 1: Preparation of (R)-propyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (21A) and (S)-propyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4- methylthiophen-2-yl)sulfonyl)carbamate (21B)

[0238] Following the synthetic protocol of Reference Example 18, Step 4, the target product (R)-propyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (21A) was obtained. LC-MS (ESI) calcd for C 25 H 30 FN3O4S2[M+H] + m / z 520.2, found 520.0. 1 H NMR (400 MHz, DMSO-d6) δ 7.21 - 7.07 (m, 3H), 7.03 (d, J = 9.2 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 5.76 - 5.68 (m, 1H), 3.78 (s, 2H), 3.17 - 3.07 (m, 1H), 3.01 - 2.95 (m, 2H), 2.65 (d, J = 7.2 Hz, 2H), 1.95 - 1.73 (m, 4H), 1.49 - 1.37 (m, 2H), 1.26 - 1.19 (m, 1H), 0.95 (d, J = 6.6 Hz, 6H), 0.79 (t, J = 7.4 Hz, 3H).

[0239] Following the synthetic protocol of Reference Example 18, Step 4, the target product (R)-propyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (21A) was obtained. LC-MS (ESI) calcd for C 25 H 30 FN3O4S2[M+H] +m / z 520.2, found 520.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.19 - 7.08 (m, 3H), 7.03 (d, J = 7.9 Hz, 1H), 7.00 - 6.92 (m, 1H), 5.77 - 5.68 (m, 1H), 3.78 (d, J = 6.6 Hz, 2H), 3.18 - 3.05 (m, 1H), 3.03 - 2.86 (m, 2H), 2.65 (d, J = 7.0 Hz, 2H), 1.94 - 1.75 (m, 4H), 1.51 - 1.37 (m, 2H), 0.95 (d, J = 6.6 Hz, 6H), 0.79 (t, J = 7.4 Hz, 3H).

[0240] Example 20. (R)-Butyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (22A) and (S)-butyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4- methylthiophen-2-yl)sulfonyl)carbamate (22B)

[0241] Synthetic Route:

[0242] Step 1: Preparation of (R)-butyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (22A) and (S)-butyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutyl-4- methylthiophen-2-yl)sulfonyl)carbamate (22B)

[0243] Following the synthetic protocol of Reference Example 18, Step 4, the target product (R)-butyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamate (22A) was obtained. LC-MS (ESI) calcd for C 26 H 32 FN3O4S2[M+H] + m / z 534.2, found 534.2. 1H NMR (400 MHz, DMSO-d6) δ 7.15 (d, J = 11.5 Hz, 1H), 7.10 (s, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.97 - 9.90 (m, 1H), 5.76 - 5.66 (m, 1H), 3.80 (s, 2H), 3.17 - 3.05 (m, 1H), 3.02 - 2.87 (m, 2H), 2.64 (d, J = 7.1 Hz, 2H), 1.90 - 1.75 (m, 4H), 1.44 - 1.34 (m, 2H), 1.33 - 1.11 (m, 3H), 0.95 (d, J = 6.6 Hz, 6H), 0.83 (t, J = 7.4 Hz, 3H).

[0244] The target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)aminoformic acid butyl ester (22B) was synthesized using (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophene-2-sulfonamide (20c-B) as the starting material referring to the synthesis scheme of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutyl-4-methylthiophen-2-yl)sulfonyl)carbamic acid butyl ester (22A). LC-MS (ESI) calcd for C 26 H 32 FN3O4S2[M+H] + m / z 534.2, found 534.2.

[0245] Example 21. ((3-(4-((R)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid (2,2-difluorocyclopropyl)methyl ester (24A)

[0246] Synthesis route:

[0247] Step 1. Preparation of ((3-(4-((R)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid (2,2-difluorocyclopropyl)methyl ester (24A)

[0248] (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-2,2,2-trichloroethyl ester (6a-A) (0.03 g, 0.04 mmol) was dissolved in acetonitrile (1 mL) at room temperature, N,N- diisopropylethylamine (0.03 g, 0.26 mmol) and (2,2-difluorocyclopropyl)methanol (0.02 g, 0.22 mmol) were added with stirring. After stirring at 100 °C for 1.5 h, the reaction was terminated. The cooled reaction was filtered, and the filtrate was separated by high performance liquid preparative chromatography (mobile phase: ammonia solution / acetonitrile) to give (2,2-difluorocyclopropyl)methyl ((3-(4-((R)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (24A). LC-MS (ESI) calcd for C 25 H 27 F2N3O4S2[M+H] + m / z 536.2, found 536.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 8.1 Hz, 2H), 7.38 (s, 1H), 7.32 - 7.18 (m, 3H), 6.84 (s, 1H), 5.60 (t, J = 6.9 Hz, 1H), 3.94 (s, 1H), 3.75 - 3.61 (m, 1H), 3.22 - 2.98 (m, 3H), 2.64 (d, J = 7.0 Hz, 2H), 2.00 - 1.78 (m, 2H), 1.59 - 1.46 (m, 1H), 1.33 - 1.25 (m, 2H), 0.94 (d, J = 6.6 Hz, 6H).

[0249] Using (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-2,2,2-trichloroethyl ester (6a-B) as the starting material, the synthesis scheme of (2,2-difluorocyclopropyl)methyl ((3-(4-((R)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (24A) was referred to, to give the target product (2,2-difluorocyclopropyl)methyl ((3-(4-((S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (24B). LC-MS (ESI) calcd for C 25 H 27 F2N3O4S2[M+H]+ m / z 536.2, found 536.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 8.1 Hz, 2H), 7.38 (s, 1H), 7.32 - 7.21 (m, 3H), 6.88 (s, 1H), 5.60 (t, J = 6.9 Hz, 1H), 3.94 (s, 1H), 3.75 - 3.61 (m, 1H), 3.22 - 3.10 (m, 3H), 2.64 (d, J = 7.0 Hz, 2H), 2.00 - 1.78 (m, 2H), 1.59 - 1.46 (m, 1H), 1.33 - 1.25 (m, 2H), 0.94 (d, J = 6.6 Hz, 6H).

[0250] Example 22. (R)-isopropyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (25)

[0251] Synthesis route:

[0252] Step 1: Preparation of (R)-isopropyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (25)

[0253] (R)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2- sulfonamide (1j-A) (0.02 g, 0.05 mmol) and N,N-diisopropyl ethylamine (0.03 g, 0.23 mmol) were dissolved in anhydrous dichloromethane (1 mL) at room temperature, and isopropyl chloroformate (0.01 g, 0.07 mmol) was added dropwise slowly at 0 °C. The reaction was terminated after 16 hours at room temperature. The reaction was concentrated, and the residue was separated by high performance liquid chromatography (mobile phase: ammonia / acetonitrile) to give (R)-isopropyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (25). LC-MS (ESI) calcd for C 24 H 29 N3O4S2[M+H] + m / z 488.2, found 487.9. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 7.7 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 6.96 (s, 1H), 6.92 (s, 1H), 6.78 (s, 1H), 5.41 - 5.37 (m, 1H), 4.48 - 4.44 (m, 1H), 3.05 - 2.70 (m, 3H), 2.61 (d, J = 6.7 Hz, 2H), 2.50 - 2.35 (m, 1H), 1.91 - 1.78 (m, 1H), 0.97 (d, J = 6.2 Hz, 6H), 0.93 (d, J = 6.6 Hz, 6H).

[0254] Example 23. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-2-methoxyethyl ester (26)

[0255] Synthetic Route:

[0256] Step 1: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-2-methoxyethyl ester (26)

[0257] (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamic acid-2,2,2-trichloroethyl ester (6a-A) (0.03 g, 0.04 mmol) was dissolved in acetonitrile (1 mL) at room temperature, and N,N-diisopropylethylamine (0.03 g, 0.26 mmol) and ethylene glycol monomethyl ether (0.02 g, 0.22 mmol) were added with stirring. After heating to 100 °C in a microwave and stirring for 1.5 h, the reaction was terminated. The cooled reaction was filtered. The filtrate was separated by high performance liquid preparative chromatography (mobile phase: ammonia / acetonitrile) to give (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-2-methoxyethyl ester (26). LC-MS (ESI) calcd for C 24 H 29 N3O5S2[M+H] + m / z 504.2, found 504.3. 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 8.4 Hz, 2H), 7.37 - 7.13 (m, 4H), 6.86 (s, 1H), 5.57 (t, J = 6.4 Hz, 1H), 3.91 - 3.85 (m, 2H), 3.37 - 3.32 (m, 2H), 3.23 - 3.00 (m, 3H), 3.20 (s, 3H), 2.66 (d, J = 7.0 Hz, 2H), 2.58 - 2.50 (m, 1H), 1.94 - 1.79 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H).

[0258] Example 24. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-2-cyclopropylethyl ester (27)

[0259] Following the synthetic protocol of Reference Example 23, (R)-((3-(4-(6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid-2- cyclopropylethyl ester (27) was obtained. LC-MS (ESI) calcd for C 26 H 31 N3O4S2[M+H] + m / z 514.2, found 514.4. 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.2 Hz, 2H), 7.25 - 7.16 (m, 4H), 6.88 (s, 1H), 5.57 - 5.53 (m, 1H), 3.86 (t, J = 6.6 Hz, 2H), 3.15 - 2.95 (m, 3H), 2.67 (d, J = 7.0 Hz, 2H), 2.52 - 2.47 (m, 1H), 1.90 - 1.84 (m, 1H), 1.32 (q, J = 6.7 Hz, 2H), 0.94 (d, J = 6.6 Hz, 6H), 0.65 - 0.52 (m, 1H), 0.35 - 0.31 (m, 2H), 0.05 - 0.00 (m, 2H).

[0260] Example 25. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid (1-methylcyclopropyl)methyl ester (28)

[0261] Synthetic Route:

[0262] Step 1: Preparation of (4-nitrophenyl) carbonic acid (1-methylcyclopropyl)methyl ester (28a)

[0263] To a stirred solution of (1-methylcyclopropyl)methanol (0.18 g, 2.09 mmol) in dry dichloromethane (2 mL) at 0 °C was added p-nitrophenyl chloroformate (0.84 g, 4.18 mmol) and pyridine (0.83 g, 10.44 mmol) successively. The reaction was stirred at room temperature for 16 h before it was quenched. The resulting reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 20 / 1) to give (4-nitrophenyl) carbonic acid (1-methylcyclopropyl)methyl ester (28a). 1 H NMR (400 MHz, CDC13) δ 8.33-8.24 (m, 2H), 7.45-7.34 (m, 2H), 4.10 (s, 2H), 1.22 (s, 3H), 0.58 (t, J = 5.3 Hz, 2H), 0.48 (t, J = 5.3 Hz, 2H).

[0264] Step 2: Preparation of (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid (1-methylcyclopropyl)methyl ester (28)

[0265] Referring to the synthetic scheme of Reference Example 2, Step 2, (R)-((3-(4-(6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid (1- methylcyclopropyl)methyl ester (28) was obtained. LC-MS (ESI) calcd for C 26 H 31 N3O4S2[M+H] + m / z 514.2, found 514.3. 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.1 Hz, 2H), 7.27 - 7.16 (m, 3H), 7.13 (s, 1H), 6.87 (s, 1H), 5.58 - 5.48 (m, 1H), 3.62 (s, 2H), 3.16 - 2.91 (m, 3H), 2.66 (d, J = 7.1 Hz, 2H), 1.93 - 1.77 (m, 1H), 1.21 - 1.13 (m, 1H), 0.95 (s, 3H), 0.94 (d, J = 6.6 Hz, 6H), 0.34 (t, J = 4.6 Hz, 2H), 0.22 (t, J = 4.9 Hz, 2H).

[0266] Example 26. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid isobutyl ester (29)

[0267] Referring to the synthetic scheme of Example 2, Step 2, (R)-((3-(4-(6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid isobutyl ester (29) was obtained. LC-MS (ESI) calcd for C 25 H 31 N3O4S2[M+H] + m / z 502.2, found 502.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.1 Hz, 2H), 7.27 - 7.16 (m, 3H), 7.13 (s, 1H), 6.87 (s, 1H), 5.58 - 5.48 (m, 1H), 3.62 (s, 2H), 3.16 - 2.91 (m, 3H), 2.66 (d, J = 7.1 Hz, 2H), 1.93 - 1.77 (m, 1H), 1.21 - 1.13 (m, 1H), 0.95 (s, 3H), 0.94 (d, J = 6.6 Hz, 6H), 0.34 (t, J = 4.6 Hz, 2H), 0.22 (t, J = 4.9 Hz, 2H).

[0268] Example 27. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-1-methylcyclopropyl ester (30)

[0269] Reference the synthetic scheme of Example 25, Step 1 and Step 2 to obtain (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2- yl)sulfonyl)alanine-1-methylcyclopropyl ester (30). LC-MS (ESI) calcd for C 25 H 29 N3O4S2[M+H] + m / z 500.2, found 500.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 8.2 Hz, 2H), 7.22 - 7.17 (m, 3H), 7.11 (s, 1H), 6.87 (s, 1H), 5.57 - 5.48 (m, 1H), 3.13 - 2.91 (m, 3H), 2.67 (d, J = 6.9 Hz, 2H), 2.50 - 2.45 (m, 1H), 1.95 - 1.76 (m, 1H), 1.30 (s, 3H), 0.94 (d, J = 6.6 Hz, 6H), 0.56 - 0.37 (m, 4H).

[0270] Example 28. (R)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)alanine-sec-butyl ester (31)

[0271] Reference the synthetic scheme of Example 2, Step 2 to obtain (R)-((3-(4-(6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)alanine-sec- butyl ester (31). LC-MS (ESI) calcd for C 25 H 31 N3O4S2[M+H] + m / z 502.2, found 502.3. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 7.09 (s, 1H), 7.03 (s, 1H), 6.86 (s, 1H), 5.54 - 5.42 (m, 1H), 4.46 - 4.33 (m, 1H), 3.15 - 2.82 (m, 3H), 2.66 (d, J = 7.0 Hz, 2H), 2.49 - 2.38 (m, 1H), 1.94 - 1.77 (m, 1H), 1.41 - 1.28 (m, 2H), 0.98 (d, J = 6.1 Hz, 3H), 0.94 (d, J = 6.6 Hz, 6H), 0.72 (t, J = 7.4 Hz, 3H).

[0272] Example 29. Butyl ((3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (32)

[0273] Synthetic Route:

[0274] Step 1: Preparation of 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid (32a)

[0275] To a stirred solution of bromobenzene (15.00 g, 95.54 mmol) in anhydrous 1,2- dichloroethane (300 mL) was added dry aluminium trichloride (50.95 g, 382.14 mmol) at room temperature. The reaction was stirred at room temperature for 1 h under nitrogen atmosphere. To the mixture was added 2,2-dimethylsuccinic anhydride (24.48 g, 191.07 mmol) dropwise. The reaction was then heated to 70 °C and stirred for 16 h before it was quenched by slow addition of ice water. The resulting mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue of the crude product was separated by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 5 / 1 ~ 1 / 1) to give 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid (32a). The product was used directly in the next step without further purification.

[0276] Step 2: Preparation of methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate (32b)

[0277] To a solution of 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid (32a) (7.70 g, 27.00 mmol), potassium carbonate (11.20 g, 81.01 mmol) and iodomethane (7.67 g, 54.01 mmol) was added dimethyl sulfoxide (130 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then quenched by adding water. The reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 15 / 1) to give methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate (32b). LC-MS (ESI) calcd for C 13 H 15 BrO3[M+H] + m / z 299.0; 301.0, found 301.3.

[0278] Step 3: Preparation of methyl 4-(4-bromophenyl)-4-(hydroxyimino)-2,2-dimethylbutanoate (32c)

[0279] To a solution of methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate (32b) (3.00 g, 10.03 mmol), hydroxylamine hydrochloride (1.74 g, 25.07 mmol) and sodium acetate (2.47 g, 30.08 mmol) was added methanol / water (40 mL / 14 mL) at room temperature. The reaction mixture was then heated to 80 °C and stirred for 2 hours under nitrogen atmosphere, then quenched. The reaction mixture was concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 10 / 1) to give methyl 4-(4-bromophenyl)-4-(hydroxyimino)-2,2-dimethylbutanoate (32c). LC-MS (ESI) calcd for C 13 H 16 BrNO3[M+H] + m / z 314.0; 316.0, found 314.3.

[0280] Step 4: Preparation of 5-(4-bromophenyl)-3,3-dimethylpyrrolidin-2-one (32d)

[0281] Methyl 4-(4-bromophenyl)-4-(hydroxyimino)-2,2-dimethylbutanoate (32c) (1.00 g, 3.18 mmol) was dissolved in acetic acid (20 mL) at room temperature, and zinc powder (2.08 g, 31.83 mmol) was added portionwise with stirring. The reaction was then heated to 80 °C and stirred for 16 h under nitrogen before being quenched. The resulting reaction was cooled and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 10 / 1) to give 5-(4-bromophenyl)-3,3-dimethylpyrrolidin-2-one (32d). 1 H NMR (400 MHz, CDC13) δ 7.50 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 5.65 (br s, 1H), 4.66 (dd, J = 15.5, 7.9 Hz, 1H), 2.38 (dd, J = 12.8, 7.0 Hz, 1H), 1.79 (dd, J = 12.8, 8.6 Hz, 1H), 1.25 (s, 3H), 1.22 (s, 3H).

[0282] Step 5: Preparation of 2-(4-bromophenyl)-5-methoxy-4,4-dimethyl-3,4-dihydro-2H-pyrrole (32e)

[0283] To a stirred solution of 5-(4-bromophenyl)-3,3-dimethylpyrrolidin-2-one (32d) (0.80 g, 2.98 mmol) in dry dichloromethane (10 mL) was added trimethylsulfoxonium tetrafluoroborate (0.88 g, 5.96 mmol) slowly at 0 °C under nitrogen. The reaction was then stirred at room temperature for 16 h under nitrogen before being quenched. The reaction was extracted with dichloromethane after the addition of saturated aqueous sodium bicarbonate solution. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 2-(4-bromophenyl)-5-methoxy-4,4-dimethyl-3,4-dihydro-2H-pyrrole (32e). The crude product was used directly in the next step without further purification. LC-MS (ESI) calcd for C 13 H 16 BrNO[M+H] + m / z 282.0; 284.0, found 284.2.

[0284] Step 6: Preparation of 2-(4-bromophenyl)-N-(2,2-dimethoxyethyl)-4,4-dimethyl-3,4-dihydro-2H-pyrrol-5-amine (32f)

[0285] Aminoacetaldehyde dimethyl acetal (0.42 g, 3.99 mmol) was added to a stirred solution of 2-(4-bromophenyl)-5-methoxy-4,4-dimethyl-3,4-dihydro-2H-pyrrole (32e) (0.75 g, 2.66 mmol) in ethanol (10 mL) at room temperature, and the reaction was then heated to 85 °C and stirred for 16 h before being terminated. The cooled reaction was concentrated, and the residue was separated by column chromatography on silica gel (eluent: dichloromethane / methanol = 10 / 1) to give 2-(4-bromophenyl)-N-(2,2-dimethoxyethyl)-4,4-dimethyl-3,4-dihydro-2H-pyrrole-5-amine (32f). LC-MS (ESI) calcd for C 16 H 23 BrN2O2[M+H] + m / z 355.1; 357.1, found 357.3.

[0286] Step 7: Preparation of 5-(4-bromophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[l,2- a]imidazole (32g)

[0287] N-(2,2-dimethoxyethyl)-4,4-dimethyl-3,4-dihydro-2H-pyrrole-5-amine (32f) (0.67 g, 1.89 mmol) was dispersed in hydrochloric acid (6 M, 10 mL) at room temperature, and the reaction was then heated to 100 °C and stirred for 16 h under nitrogen before being terminated. The cooled reaction was concentrated, and the residue was separated by column chromatography on silica gel (eluent: dichloromethane / methanol = 20 / 1) to give 5-(4-bromophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole (32g). 1 H NMR (400 MHz, CDC13) δ 7.58 - 7.44 (m, 2H), 7.10 (d, J = 1.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 1.2 Hz, 1H), 5.21 (t, J = 7.6 Hz, 1H), 2.83 (dd, J = 13.0, 7.4 Hz, 1H), 2.33 (dd, J = 13.2, 7.6 Hz, 1H), 1.48 (s, 3H), 1.39 (s, 3H).

[0288] Step 8: Preparation of N-(tert-butyl)-3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[l,2- a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (32h)

[0289] To a stirred solution of N-(tert-butyl)-3-(4-(7,7-dimethyl-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (32h) (0.11 g, 0.23 mmol) in trifluoroacetic acid (3 mL) was added anisole (0.5 mL) at room temperature. The reaction mixture was then heated to 30 °C and stirred for 16 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 10:1) to give 3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophene-2-sulfonamide (32i). LC-MS (ESI) calcd for C 26 H 35 N3O2S2[M+H] + m / z 486.2, found 486.3.

[0290] Step 9: Preparation of 3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophene-2-sulfonamide (32i)

[0291] To a stirred solution of N-(tert-butyl)-3-(4-(7,7-dimethyl-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene-2-sulfonamide (32h) (0.11 g, 0.23 mmol) in trifluoroacetic acid (3 mL) was added anisole (0.5 mL) at room temperature. The reaction mixture was then heated to 30 °C and stirred for 16 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 10:1) to give 3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophene-2-sulfonamide (32i). LC-MS (ESI) calcd for C 22 H 27 N3O2S2[M+H] + m / z 430.2, found 430.1.

[0292] Step 10: Preparation of butyl ((3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (32)

[0293] To a stirred solution of 3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophene-2-sulfonamide (32i) (0.020 g, 0.047 mmol) in dichloromethane (1 mL) was added butyl chloroformate (0.013 g, 0.090 mmol) and triethylamine (0.024 g, 0.237 mmol) under ice water bath. The reaction was stirred at room temperature for 2 hours before it was terminated. The reaction was concentrated and the residue was separated by high performance liquid chromatography-preparative (mobile phase: 10 mmol ammonium bicarbonate in water / acetonitrile) to give the target compound butyl ((3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (32). LC-MS (ESI) calcd for C 27 H 35 N3O4S2[M+H] + m / z 530.2, found 530.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 7.7 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.21 (s, 1H), 7.01 (s, 1H), 6.90 (s, 1H), 5.59 (t, J = 7.5 Hz, 1H), 3.81 (t, J = 6.2 Hz, 2H), 2.91 (dd, J = 12.8, 7.4 Hz, 1H), 2.67 (d, J = 7.0 Hz, 2H), 2.42 - 2.29 (m, 1H), 1.92 - 1.80 (m, 1H), 1.43 - 1.33 (m, 8H), 1.25 - 1.16 (m, 2H), 0.94 (d, J = 6.6 Hz, 6H), 0.82 (t, J = 7.3 Hz, 3H).

[0294] Example 30. Preparation of propyl ((3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (33)

[0295] Synthetic Route:

[0296] Step 1: Preparation of (S)-((3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)alanine tert-butyl ester (31)

[0297] To a stirred solution of 3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5- yl)phenyl)-5-isobutylthiophene-2-sulfonamide (32i) (0.020 g, 0.047 mmol) in dichloromethane (1 mL) was added propyl chloroformate (0.011 g, 0.089 mmol) followed by triethylamine (0.024 g, 0.237 mmol) under ice water bath. The reaction was stirred at room temperature for 2 hours before it was terminated. The reaction was directly concentrated and the residue was separated by high performance liquid chromatography-preparative (mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile) to give the target compound (S)-((3-(4-(7,7-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)alanine tert-butyl ester (31). LC-MS (ESI) calcd for C 26 H 33 N3O4S2[M+H] + m / z 516.2, found 516.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.21 (s, 1H), 7.01 (s, 1H), 6.89 (s, 1H), 5.59 (t, J = 7.5 Hz, 1H), 3.78 - 3.74 (m, 2H), 2.91 (dd, J = 12.9, 7.2 Hz, 1H), 2.67 (d, J = 6.8 Hz, 2H), 2.40 - 2.35 (m, 1H), 1.89 - 1.85 (m, 1H), 1.47 - 1.38 (m, 5H), 1.34 (s, 3H), 0.94 (d, J = 6.6 Hz, 6H), 0.77 (t, J = 7.4 Hz, 3H).

[0298] Example 31. (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)alanine-2-methoxyethyl ester (34)

[0299] Synthetic Route:

[0300] Step 1: Preparation of (4-nitrophenyl)carbonic acid-2-methoxyethyl ester (34a)

[0301] Referring to the synthetic scheme of Step 1 of Reference Example 25, (4-nitrophenyl)carbonic acid-2-methoxyethyl ester (34a) was obtained. 1 HNMR (400 MHz, CDC13) δ 8.35-8.19 (m, 2H), 7.44-7.31 (m, 2H), 4.51-4.37 (m, 2H), 3.77-3.65 (m, 2H), 3.44 (s, 3H).

[0302] Step 2: Preparation of (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid-2-methoxyethyl ester (34)

[0303] (S)-3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophene-2-sulfonamide (l li-B) (0.020 g, 0.072 mmol), (4-nitrophenyl)carbonic acid-2-methoxyethyl ester (34a) (0.023 g, 0.095 mmol) and triethylamine (0.024 g, 0.238 mmol) were sequentially dissolved in acetonitrile (1 mL) under ice water bath. The microwave tube was sealed, heated to 70 °C by microwave and terminated after stirring overnight. The cooled reaction was concentrated, and the resulting residue was separated by high performance liquid chromatography-preparative (mobile phase: ammonium bicarbonate aqueous solution / acetonitrile) to give the target compound (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid-2-methoxyethyl ester (34). LC-MS (ESI) calcd for C 24 H 28 FN3O5S2[M+H] + m / z 522.2, found 522.6. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 12.3 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.39 - 7.21 (m, 2H), 7.12 - 6.98 (m, 1H), 6.89 (s, 1H), 5.83 - 5.71 (m, 1H), 3.88 - 3.84 (s, 2H), 3.35 - 3.26 (m, 2H), 3.20 (s, 3H), 3.18 - 3.02 (m, 3H), 2.65 (d, J = 7.0 Hz, 2H), 2.60 - 2.54 (m, 1H), 1.94 - 1.76 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H).

[0304] Example 32. (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid-3-fluoropropyl ester (35)

[0305] Referring to the synthetic scheme of Step 1 and Step 2 of Reference Example 31, (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-3-fluoropropyl ester (35) was obtained. LC-MS (ESI) calcd for C 24 H 27 F2N3O4S2[M+H] + m / z 524.2, found 524.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.77 - 7.73 (m, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 7.13 - 7.02 (m, 1H), 6.90 (s, 1H), 5.84 - 5.78 (m, 1H), 4.43 (t, J = 6.0 Hz, 1H), 4.32 (t, J = 6.0 Hz, 1H), 3.87 - 3.83 (m, 2H), 3.20 - 3.11 (m, 3H), 2.65 (d, J = 6.8 Hz, 2H), 2.58 - 2.50 (m, 1H), 1.93 - 1.68 (m, 3H), 0.93 (d, J = 6.6 Hz, 6H).

[0306] Example 33. (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid-2,2-difluoropropyl ester (36)

[0307] Referring to the synthetic scheme of Reference Example 31, Step 1 and Step 2, (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-2,2-difluoropropyl ester (36) was obtained. LC-MS (ESI) calcd for C 24 H 26 F3N3O4S2[M+H] + m / z 542.1, found 542.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 12.6 Hz, 1H), 7.55 (d, J = 9.5 Hz, 2H), 7.44 (s, 1H), 7.16 (t, J = 8.1 Hz, 1H), 6.87 (s, 1H), 5.86 (t, J = 7.6 Hz, 1H), 3.96 (t, J = 13.1 Hz, 2H), 3.26 - 3.14 (m, 3H), 2.66 - 2.60 (m, 3H), 1.96 - 1.72 (m, 1H), 1.50 (t, J = 19.2 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H).

[0308] Example 34. (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-4,4,4-trifluorobutyl ester (37)

[0309] Referring to the synthetic scheme of Reference Example 31, Step 1 and Step 2, (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-4,4,4-trifluorobutyl ester (37) was obtained. LC-MS (ESI) calcd for C 25 H 27 F4N3O4S2[M+H] + m / z 574.2, found 574.2. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 11.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.33 (s, 1H), 7.09 (t, J = 8.2 Hz, 1H), 6.90 (s, 1H), 5.84 - 5.78 (m, 1H), 3.82 (t, J = 5.9 Hz, 2H), 3.30 - 3.03 (m, 3H), 2.64 (d, J = 7.0 Hz, 2H), 2.59 - 2.50 (m, 1H), 2.25 - 2.09 (m, 2H), 1.92 - 1.78 (m, 1H), 1.69 - 1.58 (m, 2H), 0.93 (d, J = 6.6 Hz, 6H).

[0310] Example 35. (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate-4-fluorobutyl ester (38)

[0311] Referring to the synthetic scheme of Step 1 and Step 2 of Reference Example 31, (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate-4-fluorobutyl ester (38) was obtained. LC-MS (ESI) calcd for C 25 H 29 F2N3O4S2[M+H] + m / z 538.2, found 538.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 11.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.33 (s, 1H), 7.09 (t, J = 8.2 Hz, 1H), 6.90 (s, 1H), 5.84 - 5.78 (m, 1H), 3.82 (t, J = 5.9 Hz, 2H), 3.30 - 3.03 (m, 3H), 2.64 (d, J = 7.0 Hz, 2H), 2.59 - 2.50 (m, 1H), 2.25 - 2.09 (m, 2H), 1.92 - 1.78 (m, 1H), 1.69 - 1.58 (m, 2H), 0.93 (d, J = 6.6 Hz, 6H).

[0312] Example 36. (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid-3,3,3- trifluoropropyl ester (39)

[0313] Following the synthetic protocol of Reference Example 31, Step 1 and Step 2, (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-3,3,3-trifluoropropyl ester (39) was obtained. LC-MS (ESI) calcd for C 24 H 25 F4N3O4S2[M+H] + m / z 560.1, found 560.3. 1 H NMR (400 MHz, CDC13) δ 7.70 (d, J = 11.3 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.96 (s, 1H), 6.78 (s, 1H), 6.67 (s, 1H), 5.50 (t, J = 7.2 Hz, 1H), 4.30 - 4.24 (m, 1H), 4.14 - 4.08 (m, 1H), 3.58 - 3.31 (m, 2H), 3.26 - 3.07 (m, 1H), 2.80 - 2.75 (m, 1H), 2.74 (d, J = 6.6 Hz, 2H), 2.40 - 2.25 (m, 2H), 2.00 - 1.90 (m, 1H), 1.00 (t, J = 6.6 Hz, 6H).

[0314] Example 37. (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamic acid-3,3- difluoropropyl ester (40)

[0315] Following the synthetic protocol of Reference Example 31, Step 1 and Step 2, (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamic acid-3,3,3-trifluoropropyl ester (39) was obtained. LC-MS (ESI) calcd for C 24 H 26 F3N3O4S2[M+H] + m / z 542.1, found 542.3. 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 12.6 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.05 (t, J = 8.2 Hz, 1H), 6.88 (s, 1H), 6.11 - 5.76 (m, 2H), 3.84 (t, J = 6.3 Hz, 2H), 3.20 - 3.05 (m, 3H), 2.63 (d, J = 6.6 Hz, 2H), 2.60 - 2.50 (m, 1H), 2.05 - 1.93 (m, 2H), 1.90 - 1.80 (m, 1H), 0.93 (d, J = 6.6 Hz, 6H).

[0316] Example 38. (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate-4,4-difluorobutyl ester (41)

[0317] Referring to the synthetic scheme of Step 1 and Step 2 of Reference Example 31, (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3-fluorophenyl)-5-isobutylthiophen-2- yl)sulfonyl)carbamate-4,4-difluorobutyl ester (41) was obtained. LC-MS (ESI) calcd for C 25 H 28 F3N3O4S2[M+H] + m / z 556.2, found 556.4. 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 12.4 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 7.08 (t, J = 8.1 Hz, 1H), 6.90 (s, 1H), 6.05 (tt, J = 56.9, 4.4 Hz, 1H), 5.80 (t, J = 6.6 Hz, 1H), 3.82 (t, J = 6.2 Hz, 2H), 3.19 - 3.08 (m, 3H), 2.65 (d, J = 7.0 Hz, 2H), 2.60 - 2.53 (m, 1H), 1.92 - 1.65 (m, 3H), 1.61 - 1.47 (m, 2H), 0.93 (d, J = 6.6 Hz, 6H).

[0318] Example 39. (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate-2-(1- methylcyclopropyl)ethyl ester (42)

[0319] Following the synthetic protocol of Reference Example 31, Step 1 and Step 2, the target product (S)-((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate-2-(1- methylcyclopropyl)ethyl ester (42) was obtained. LC-MS (ESI) calcd for C 27 H 32 FN3O4S2[M+H] + m / z 546.2, found 546.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 11.2 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.35 - 7.16 (m, 2H), 7.03 (t, J = 8.0 Hz, 1H), 6.91 (s, 1H), 5.82 - 5.71 (m, 1H), 3.89 (t, J = 7.0 Hz, 2H), 3.17 - 3.05 (m, 3H), 2.66 (d, J = 7.0 Hz, 2H), 2.60 - 2.50 (m, 1H), 1.94 - 1.78 (m, 1H), 1.36 (t, J = 7.1 Hz, 2H), 0.95 (s, 3H), 0.93 (d, J = 6.8 Hz, 6H), 0.23 - 0.19 (m, 2H), 0.17 - 0.13 (m, 2H).

[0320] Example 40. ((3-(4-((S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (2- methylcyclopropyl)methyl ester (43)

[0321] Following the synthetic protocol of Reference Example 31, Step 1 and Step 2, the target product ((3-(4-((S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)-3- fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (2- methylcyclopropyl)methyl ester (43) was obtained. LC-MS (ESI) calcd for C 26 H 30 FN3O4S2[M+H] + m / z 532.2, found 532.1.1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 12.1 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.28 (s, 1H), 7.24 (s, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.91 (s, 1H), 5.84 - 5.72 (m, 1H), 3.64 (d, J = 7.1 Hz, 2H), 3.20 - 3.03 (m, 3H), 2.66 (d, J = 7.0 Hz, 2H), 2.59 - 2.50 (m, 1H), 1.90 - 1.79 (m, 1H), 0.95 (d, J = 7.2 Hz, 6H), 0.93 (s, 3H), 0.71 - 0.52 (m, 2H), 0.35 - 0.26 (m, 1H), 0.21 - 0.13 (m, 1H).

[0322] Example 41. (S)-((3,3-difluorobutoxy)carbonyl)((3-(4-(6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)amide sodium salt (44)

[0323] Synthesis route:

[0324] Step 1: Preparation of benzoic acid 3-oxobutyl ester (44a)

[0325] To a stirred solution of 4-hydroxybutan-2-one (1.00 g, 11.35 mmol) in dichloromethane (10 mL) was added pyridine (1.9 mL, 22.70 mmol) and benzoyl chloride (1.6 mL, 13.62 mmol) sequentially at -78 °C. The reaction was then stirred at room temperature for 16 hours before being quenched. The reaction was diluted with water and extracted with dichloromethane. The combined organic layers were dried, filtered and concentrated. The crude residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 20 / 1) to give the target compound, benzoic acid 3-oxobutyl ester (44a). 1 H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.88 (m, 2H), 7.72 - 7.58 (m, 1H), 7.55 - 7.48 (m, 2H), 4.45 (t, J = 6.2 Hz, 2H), 2.94 (t, J = 6.2 Hz, 2H), 2.17 (s, 3H).

[0326] Step 2: Preparation of benzoic acid 3,3-difluorobutyl ester (44b)

[0327] To a stirred solution of 3-oxobutanoic acid benzyl ester (44a) (1.70 g, 8.84 mmol) in dichloromethane (20 mL) was added diethylamine sulfide trifluoride (DAST, 3.5 mL, 26.53 mmol) dropwise at 0 °C. The reaction was terminated after stirring at room temperature for 16 h. The reaction was diluted with water and extracted with dichloromethane. The organic phases were combined, dried, filtered and concentrated. The residue was separated by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 20 / 1) to give the target compound 3,3-difluorobutanoic acid benzyl ester (44b). 1 H NMR (400 MHz, DMSO-d6) δ 8.01 - 7.93 (m, 2H), 7.70 - 7.64 (m, 1H), 7.58 - 7.50 (m, 2H), 4.45 (dd, J = 8.1, 4.5 Hz, 2H), 2.48 - 2.34 (m, 2H), 1.70 (t, J = 19.2 Hz, 3H).

[0328] Step 3: Preparation of 3,3-difluorobutan-1-ol (44c)

[0329] To a stirred solution of 3,3-difluorobutanoic acid benzyl ester (44b) (0.35 g, 1.63 mmol) in diethyl ether (5 mL) was added sodium methoxide / methanol solution (25 wt%, 0.71 g, 3.28 mmol) at room temperature. The reaction was terminated after stirring at room temperature for 2 h. The reaction was diluted with water and extracted with dichloromethane. The organic phases were combined, dried, filtered and concentrated to give the target compound 3,3-difluorobutan-1-ol (44c) (0.17 g, crude). The product was used in the next step without further purification.

[0330] Step 4: Preparation of 3,3-difluorobutyl (4-nitrophenyl) carbonate (44d)

[0331] To a stirred solution of 3,3-difluorobutan-1-ol (44c) (0.17 g, 1.54 mmol) in dichloromethane (2 mL) was added pyridine (0.4 mL, 2.31 mmol) and p-nitrophenyl chloroformate (0.37 g, 1.85 mmol) successively at 0 °C. The reaction was terminated after stirring at room temperature for 16 h. The reaction was diluted with water and extracted with dichloromethane. The organic phases were combined, dried, filtered and concentrated. The residue was separated by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 20 / 1) to give the target compound 3,3-difluorobutyl (4-nitrophenyl) carbonate (44e). 1H NMR (400 MHz, DMSO-d6) δ 8.36 - 8.28 (m, 2H), 7.60 - 7.53 (m, 2H), 4.42 (t, J = 6.4 Hz, 2H), 2.46 - 2.36 (m, 2H), 1.68 (t, J = 19.2 Hz, 3H).

[0332] Step 5: Preparation of (S)-3,3-difluorobutyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-5-yl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamate (44)

[0333] (S)-3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5-isobutylthiophene- 2-sulfonamide (1j-B) (0.05 g, 0.12 mmol) and triethylamine (0.04 g, 0.37 mmol) were dissolved in acetonitrile (1 mL) at 0 °C, and 3,3-difluorobutyl (4-nitrophenyl) carbonate (44d) (0.07 g, 0.25 mmol) was added. The reaction was stirred at 70 °C for 16 h before it was terminated. The resulting reaction was concentrated, and the residue was separated by high performance liquid preparation chromatography (mobile phase: acetonitrile / ammonium bicarbonate aqueous solution) to give the target product (S)-3,3-difluorobutyl ((3-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-5-yl)phenyl)-5- isobutylthiophen-2-yl)sulfonyl)carbamate (44). LC-MS (ESI) calcd for C 25 H 29 F2N3O4S2[M+H] + m / z 538.2, found 538.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 7.5 Hz, 2H), 6.78 (s, 1H), 5.38 (dd, J = 7.8, 5.3 Hz, 1H), 3.80 (t, J = 6.7 Hz, 2H), 3.08 - 2.97 (m, 1H), 2.95 - 2.74 (m, 2H), 2.61 (d, J = 7.0 Hz, 2H), 2.45 - 2.35 (m, 1H), 2.11 - 1.94 (m, 2H), 1.93 - 1.75 (m, 1H), 1.54 (t, J = 19.3 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H).

[0334] In order to illustrate the beneficial effects of the present application, the following biological test examples are provided.

[0335] Biological test

[0336] Test Example 1: AT2R binding assay

[0337] The purpose of this assay is to evaluate the ability of compounds to bind to AT2R in vitro.

[0338] Prepare assay buffer 1X TLB (Cisbio, Cat# LABMED), 4X Buloxibutid (CAS: 477775-14-7) and test compound working solution, and 4X Tag-lite angiotensin receptor red agonist (Cisbio, Cat# L0007RED). Thaw one vial of AT2R labeled cells in a 37°C water bath for about 1-2 min until all ice is melted, quickly transfer the thawed cells to 5 mL of 1X TLB, mix gently and centrifuge at 200g for 5 min. Discard the supernatant, resuspend the cells with 1 mL of 1X TLB, mix well, add 1.7 mL of 1X TLB, mix well and let it stand at room temperature. Add 10 μL of cells to a 384-well plate (Greiner, Cat# 784075), centrifuge at 200g for 3 s. Add 5 μL of 4X compound working solution to the 384-well plate. Add 5 μL of 4X Tag-lite angiotensin receptor red agonist to all the assay wells. Let the reaction plate stand at room temperature for 1 h, centrifuge at 200g for 60 s at room temperature, and collect data using Envision HTRF detector.

[0339] Inhibition rate calculation:

[0340] % inhibition = 100 - (Signal cmpd -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC ) x 100.

[0341] Calculate the IC 50 of the compound using GraphPad nonlinear fit formula:

[0342] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope)).

[0343] X: compound concentration log value; Y: % inhibition.

[0344] The AT2R binding results of some examples are shown in Table 1.

[0345] Table 1 Binding of compounds to AT2R

[0346] The above results show that the compounds of the present application have strong AT2R binding activity.

[0347] Test Example 2: CYP enzyme inhibition study of some compounds

[0348] The inhibitors, probe substrates and reaction times of each subenzyme are shown in Table 2. Commercially available mixed human liver microsomes were used, with the liver microsomal concentration of dextromethorphan, midazolam being 0.1 mg / mL; phenacetin and testosterone liver microsomal concentration being 0.2 mg / mL. The probe substrates, specific inhibitors and working solutions of the compounds to be tested were diluted to the corresponding concentrations for use, and a mixed solution containing liver microsomes, MgCl2, substrates, specific inhibitors and the compounds to be tested was prepared, 50 μL of 4 mM NADP solution was added to start the reaction, the reaction time is shown in the table, after incubation, 600 μL of ice ACN working solution containing IS was added to terminate the reaction, after centrifugation, LC-MS / MS detection was performed.

[0349] Table 2 Inhibitors, probe substrates and reaction times of each subenzyme

[0350] At different concentration points of the compounds to be tested or positive inhibitors, the percentage of residual activity was obtained from the amount of characteristic metabolite of the probe substrate and the amount of metabolite generated in the absence of the compounds to be tested or positive inhibitors. If a significant decrease in metabolite production is found at the highest concentration setting point, the half-inhibitory concentration (IC 50 ) will be calculated using the log(inhibitor) vs. response--Variable slope formula of GraphPad Prism software:

[0351] Y = Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*Hillslope))

[0352] X: Log(concentration of the compound to be tested or positive inhibitor);

[0353] Y: percentage of residual activity;

[0354] Top and Bottom: respectively refer to the theoretical maximum and minimum percentage of residual activity;

[0355] Hillslope: slope coefficient or slope.

[0356] If there is no significant decrease in the amount of metabolic product produced at the highest concentration set point (percentage of residual enzyme activity > 50%), the half-inhibitory concentration (IC 50 ) cannot be accurately calculated, and the IC 50 is reported to be greater than the highest concentration tested.

[0357] CYP450 enzyme inhibition results of some compounds in Table 3

[0358] Note: CYP3A4 (T) is the CYP3A4 enzyme inhibition experiment when the probe substrate is testosterone (Testosterone); CYP3A4 (M) is the CYP3A4 enzyme inhibition experiment when the probe substrate is midazolam (Midazolam).

[0359] The results of the study, as shown in Table 3, indicate that the compounds in the present application have weaker inhibition of CYP enzymes compared to the Xanthium compounds, indicating a lower likelihood of drug-drug interactions occurring in the human body and higher safety.

[0360] Test Example 3: AT2R-CHO cell NO release test

[0361] The purpose of this test is to evaluate the effect of the compound on the amount of NO released by AT2R-CHO cells in vitro.

[0362] AT2R-CHO cells were implanted in a 96-well plate (3603 black-bottomed wells), F12K + 10% FBS, 5000 cells / 100 μL / well, 37°C, 5% CO2 incubation for 36 hours. The well culture medium was washed once, 50 μL / well, and then the DAF-FM probe was added to the cells, with a final probe concentration of 5 μM in the well, and incubated at 37°C, 5% CO2 for 30 min. The culture medium was discarded, 90 μL of optimization solution was added, and then 10 μL of diluted compound was added, and incubated at 37°C, 5% CO2 for 15 min. The culture medium was discarded, the cells were washed once with PBS, and fixed with 50 μL / well (containing DAPI) 4% paraformaldehyde. High-content imaging system scanning, data collection.

[0363] Activation rate calculation:

[0364] Relative activation % = (Sample-DMSO) / DMSO*100

[0365] The EC 50 of the compound was calculated using the GraphPad nonlinear fitting formula:

[0366] Y = Bottom + (Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0367] X: log value of compound concentration; Y: % Relative activation.

[0368] The in vitro data of some examples are shown in Table 4:

[0369] Table 4 In vitro activation data of AT2R-CHO of some compounds

[0370] The above results show that the compounds of the present application have stronger AT2R agonistic activity in vitro compared with the Xiazhen compound, and have stronger efficacy in treating / preventing AT2R-mediated diseases, which is beneficial to reduce the clinical dosage, reduce the risk of side effects and exert the efficacy.

[0371] Test Example 4: Efficacy of compounds on bleomycin-induced pulmonary fibrosis rats

[0372] The purpose of this test is to evaluate the in vivo efficacy of the compounds on bleomycin-induced pulmonary fibrosis rats.

[0373] After the animals were purchased and acclimated, they were randomly divided into groups according to body weight. The animals were divided into 5 groups, 12 animals in each group, namely the model control group, the positive control drug Buloxibutid group (10 mg / kg, bid), the test compound 5B group (10 mg / kg, bid), the test compound 12B group (10 mg / kg, bid), and the test compound 44 group (10 mg / kg, bid). Another 3 animals were used as a normal control group. After the rats were weighed, they were anesthetized by isoflurane inhalation, and after the animals lost the righting reflex, they were suspended on the upper incisors and fixed on the operating board with the abdomen facing upwards, ensuring adequate light to show the vocal cords. A sterile pad-equipped surgical forceps was used to gently stretch the tongue to the corner of the mouth, exposing the vocal cords in the direction of the mandible. A delivery device needle loaded with 100 μL of bleomycin was inserted through the vocal cord nodule, and a bleomycin aerosol solution was quickly sprayed. After that, the delivery device was removed, and the animals were placed back in the cage after they woke up. The control animals were given an equal amount of sterile normal saline. One day after the operation, the animals in each group were given the appropriate solvent or test substance orally for 12 consecutive days, twice a day. After the administration period ended, the animals were euthanized under deep CO2 anesthesia, and the lungs were removed and injected with 10% formalin solution through the bronchus. After the bronchus was ligated when the pleura was flat, the lung tissue was fixed and taken longitudinally from the lung apex to the lung base for pathological examination (HE staining, Sirius red staining). HE-stained sections were observed under an optical microscope (x100) for lung tissue pathology and image collection, and the lung fibrosis score was determined according to the Ashcroft scoring standard. The higher the score, the more severe the lung fibrosis. The right lung sections after embedding were stained with Sirius red, and the lung tissue pathology was observed under an optical microscope (x100) and the images were collected. The fibrosis ratio was obtained by collecting the red collagen area using Image pro plus 6.0 software. Fibrosis ratio = red collagen area / lung tissue area x 100%.

[0374] Table 5 Effect of test substances on HE staining and Sirius red staining of lung fibrosis model rats after 12 consecutive days of oral gavage administration (Mean ± SD, n = 3 for the normal control group, and n = 12 for the other groups)

[0375] ### P < 0.001 vs. the normal control group; ** P < 0.01, * P < 0.05 vs. the model control group.

[0376] The research results show that, compared with the Buloxibutid group with the same administration dose of 10 mg / kg to the SD rats, the test compound of the application such as 5B, 12B and 44 can better reduce the collagen deposition to reduce the proportion of lung tissue fibrosis and reduce the inflammatory cell infiltration of lung tissue to reduce the development degree of pulmonary fibrosis in the lung fibrosis model rats, and has a better treatment / prevention effect on the pulmonary fibrosis of the SD rats induced by bleomycin.

[0377] The above detailed description is further detailed for the purpose, technical solutions and beneficial effects of the present application, and it should be understood that the above is only a specific embodiment of the present application and is not used to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made on the basis of the technical solutions of the present application shall be included in the protection scope of the present application.

Claims

1. A compound of Formula I: ###0001### or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug thereof. R 1 is selected from ethyl, n-propyl, i-propyl, n-butyl, i-butyl or cyclopropylmethyl; X is selected from O or S; Y is selected from CR 10 or N, R 10 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-5 cycloalkyl, C 3-5 halocycloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; L is selected from O; R 2 selected from C 1-6 alkyl or C 3-7 cycloalkyl, wherein said C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more hydrogen, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, halophenyl, 5- to 6-membered heteroaromatic ring group, or OR 11 wherein said C 1-6 alkyl and C 3-7 cycloalkyl are each optionally substituted with one or more hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl; R 11 selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 halocycloalkyl, or C 3-7 cycloalkyl; Ring A is selected from a phenyl ring; R 3 selected from halogen, cyano or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more halogen; n = 0, 1 or 2; R 4 and R 5 are selected from hydrogen, fluorine or methyl; R 6 and R 7 are selected from hydrogen, fluorine or methyl; R 8 and R 9 are selected from hydrogen, fluorine or methyl.

2. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug thereof, wherein X is selected from S. Y is selected from CR 10 , R 10 is selected from hydrogen, fluorine, methyl or trifluoromethyl.

3. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug thereof, wherein R 3 is selected from fluoro, cyano, or methyl.

4. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug thereof, wherein n is selected from 0 or 1.

5. The compound of claim 1, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound of Formula I is represented by Formula I-1: wherein R 1 is selected from ethyl, n-propyl, i-propyl, n-butyl, i-butyl or cyclopropylmethyl; L is selected from O; R 2 selected from C 1-6 alkyl or C 3-7 cycloalkyl, wherein said C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more hydrogen, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, halophenyl, 5- to 6-membered heteroaromatic ring group, or OR 11 wherein said C 1-6 alkyl and C 3-7 cycloalkyl are each optionally substituted with one or more hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl; R 11 selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 halocycloalkyl or C 3-7 cycloalkyl; Ring A is selected from a phenyl ring; R 3 selected from halogen, cyano or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more halogen; n = 0, 1 or 2; R 4 and R 5 are selected from hydrogen, fluorine or methyl; R 6 and R 7 are selected from hydrogen, fluorine or methyl; R 8 and R 9 are selected from hydrogen, fluorine or methyl; R 10 is selected from hydrogen, fluorine, methyl or trifluoromethyl.

6. The compound of claim 1, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof. The compound of formula I is represented by formula I-2: wherein R 1 is selected from ethyl, n-propyl, i-propyl, n-butyl, i-butyl or cyclopropylmethyl; R 2 selected from C 1-6 alkyl or C 3-7 cycloalkyl, wherein said C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more hydrogen, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, halophenyl, 5- to 6-membered heteroaromatic ring group, or OR 11 group, wherein said C 1-6 alkyl and C 3-7 cycloalkyl are each optionally substituted with one or more hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; R 11 selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 halocycloalkyl, or C 3-7 cycloalkyl; R 3 selected from halogen, cyano or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more halogen; n = 0, 1 or 2; R 4 and R 5 is selected from hydrogen, fluorine or methyl; R 6 and R 7 is selected from hydrogen, fluorine or methyl; R 8 and R 9 is selected from hydrogen, fluorine or methyl; R 10 is selected from hydrogen, fluorine, methyl or trifluoromethyl.

7. The compound of claim 1, or a stereoisomer, or a pharmaceutically acceptable salt or a prodrug thereof, wherein the compound of Formula I is represented by Formula I-3: wherein R 2 is selected from C 1-4 linear alkyl or cyclopropyl, wherein said C 1-4 linear alkyl can be substituted by one or more fluorine, methyl, ethyl, cyclopropyl, phenyl, pyridine or OR 11 group, said cyclopropyl and phenyl can be substituted by one or more halogen or methyl; said R 11 is hydrogen, C 1-3 alkyl or C 3-5 cycloalkyl; R 3 is fluorine, chlorine, bromine, cyano, C 1-3 alkyl or C 1-3 fluoroalkyl; n = 0, 1 or 2; R 6 and R 7 is selected from hydrogen, fluorine or methyl; R 10 is hydrogen, methyl or trifluoromethyl.

8. The compound of claim 1, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound of Formula I is represented by Formula I-4: wherein R 2 is selected from C 1-4 straight-chain alkyl or cyclopropyl, wherein the C 1-4 straight-chain alkyl can be substituted by one or more fluorine, methyl, ethyl, cyclopropyl, phenyl, pyridine or OR 11 group, the cyclopropyl and phenyl can be substituted by one or more fluorine or methyl; R 11 is methyl; R 3 is fluorine; n = 0 or 1 ; R 6 and R 7 are simultaneously hydrogen or methyl; R 10 is hydrogen or methyl.

9. The compound according to any one of claims 1-8, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug thereof, selected from any of the following compounds:

10. A pharmaceutical composition, wherein, The compounds, stereoisomers, or pharmaceutically acceptable salts thereof, as described in any one of claims 1-9, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

11. Use of a compound of any one of claims 1-9, solvate, metabolite, co-crystal or prodrug thereof, or a composition of the foregoing, for the manufacture of a medicament for the treatment / prevention of an AT2R mediated disease.

12. The use of claim 11, wherein the disease comprises at least one of esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia, gastroesophageal reflux, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, liver disease, gallbladder disease, multiple organ failure, sepsis, xerostomia, gastritis, gastric neoplasm, gastric acid hypersecretion, biliary tract disease, abdominal disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, angina pectoris, dysphagia, nausea, vomiting, Sjogren's syndrome, inflammatory disease, asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, renal failure, nephritis, renal hypertension, diabetic retinopathy, retinopathy of prematurity, retinal microangiopathy, ovulation mechanism disorder, hypertension, cardiac hypertrophy, heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial damage, post-balloon dilation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic damage, erectile dysfunction, neointimal hyperplasia, cognitive dysfunction, feeding dysfunction, thirst, stroke, cerebral hemorrhage, cerebral embolism, cerebral infarction, hypertrophic disorder, prostatic hyperplasia, autoimmune disease, psoriasis, obesity, nerve regeneration, ulcer, inhibition of adipose tissue hypertrophy, stem cell differentiation and proliferation, cancer, apoptosis, tumor, hyperplasia diabetes, nerve damage, or organ rejection.

13. The use of claim 12, wherein the disease comprises at least one of asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, idiopathic pulmonary fibrosis.

Images