Selective angiotensin II receptor ligand

Abstract

Pharmaceutical compounds of formula I are provided, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y 1 , Y 2 , Y 3 , and Y 4 has the meaning given in the description, and the compounds are useful in the treatment of autoimmune and / or fibrotic diseases, including interstitial lung diseases such as idiopathic pulmonary fibrosis and sarcoidosis. [Formula 1] TIFF2024511452000020.tif65166

Description

[Technical Field] 【0001】 The present invention relates to novel pharmaceutically useful compounds, specifically angiotensin II (Ang II) agonists, more specifically agonists of the Ang II type 2 receptor (hereinafter referred to as the AT2 receptor), and in particular compounds that selectively bind to the receptor. The present invention further relates to the use of such compounds as pharmaceuticals, pharmaceutical compositions containing them, and synthetic routes for their manufacture. [Background technology] 【0002】 The protease renin cleaves its only known substrate (angiotensinogen) to form angiotensin I (Ang I), which then acts as a substrate for angiotensin-converting enzyme (ACE) to form Ang II. The endogenous hormone Ang II is converted into a linear octapeptide (Asp). 1 -Arg 2 -Val 3 -Tyr 4 -Ile 5 -His 6 -Pro 7 -Phe 8 It is the active component of the renin-angiotensin system (RAS). The angiotensin II type 1 (AT1) receptor is expressed in most organs and is thought to be involved in most of the pathological effects of Ang II. 【0003】 Several studies in adult individuals suggest that AT2 receptor activation counteracts AT1 receptor-mediated effects in regulating the response to Ang II receptor stimulation. AT2 receptors have also been shown to be involved in inhibiting apoptosis and cell proliferation (de Gasparo M et al., Pharmacol. Rev. (2000); 52, 415-472). More recently, AT2 receptor agonists have shown potential usefulness in the treatment and / or prevention of gastrointestinal disorders such as dyspepsia, irritable bowel syndrome, and multiple organ failure (see International Patent Application No. 99 / 43339). The expected pharmacological effects of AT2 receptor agonism are generally described by de Gasparo M et al. (see above). 【0004】 The stimulatory effects of Ang II on vascular tone, cell proliferation, inflammation, and extracellular matrix synthesis are primarily linked to AT1 receptors in any organ, while the function of AT2 receptors appears to be more dominant in damaged tissue, exhibiting repair and counteracting properties of AT1 receptors. For example, AT2 receptors have been shown to be important in reducing myocyte hypertrophy and fibrosis. 【0005】 Interstitial lung disease (ILD) is a group of lung diseases that affect the interstitium, characterized by scarring and / or thickening of the tissue surrounding the alveoli, thereby inhibiting the respiratory process. 【0006】 Unlike obstructive airway diseases (e.g., chronic obstructive airway disease (COPD) and asthma), ILDs are typically characterized by narrowing (obstruction) of the bronchi and / or bronchioles. ILDs can be caused by damage to the lungs and trigger an abnormal healing response, although in some cases the cause of these diseases is unknown. ILDs can be caused by chemicals (silicosis, asbestosis, certain drugs), infections (e.g., pneumonia), or other diseases (e.g., rheumatoid arthritis, systemic sclerosis, myositis, or systemic lupus erythematosus). 【0007】 The most common intrapulmonary diseases (ILDs) are idiopathic pulmonary fibrosis (IPF) and sarcoidosis, both of which are characterized by chronic inflammation and reduced lung function. 【0008】 Sarcoidosis is a disease of unknown cause characterized by clusters of inflammatory cells that form lumps (granulomas), often beginning in the lungs (as well as the skin and / or lymph nodes, but any organ can be affected). When sarcoidosis affects the lungs, symptoms include cough, wheezing, shortness of breath, and / or chest pain. 【0009】 Treatment for sarcoidosis is patient-specific. In most cases, symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) is possible, but patients with pulmonary symptoms often require glucocorticoids (e.g., prednisone or prednisolone), antimetabolites, and / or monoclonal antitumor necrosis factor antibodies. 【0010】 IPF is a lung disease of unknown cause affecting approximately 5 million people worldwide. While rare, there are no curative treatment options other than lung transplantation, leading to a chronic, irreversible, and progressive deterioration of lung function, and in most cases, death within 2–5 years (median survival time 2.5–3.5 years). The overall prognosis for IPF is poor, but predicting the rate of progression in individual patients is difficult. Risk factors for IPF include age, male sex, genetic predisposition, and smoking history. The annual incidence is 5–16 cases per 100,000 people, and the prevalence is 13–20 cases per 100,000 people, increasing dramatically with age (King Jr TE et al., Lancet (2011); 378, 1949–1961; Noble PW et al., J. Clin. Invest. (2012); 122, 2756–2762). IPF is confined to the lungs and is refractory to immune system-targeted therapies, thus distinguishing it from pulmonary fibrosis, which is associated with systemic disease. 【0011】 Patients with interstitial lung disease (IPF) typically seek medical assistance due to chronic and progressive exertional dyspnea and cough. Lung imaging classically reveals traction bronchiectasis, thickened interlobar septa, and subpleural honeycombing. When all three signs are present and there is no evidence of systemic connective tissue disease or environmental exposure, the likelihood of a diagnosis of IPF is very high. Definitive diagnosis is usually made by lung biopsy and requires an interdisciplinary team of experts, including pulmonologists, radiologists, and pathologists with experience in interstitial lung disease. 【0012】 IPF exhibits different phenotypes with varying prognoses, defined as mild, moderate, and severe. Mild cases follow a stable or slowly progressive path, so patients may take several years to seek medical advice. Rapid IPF shows more rapid progression, shortens survival time, and affects a subgroup of patients, typically male smokers. Acute exacerbations of IPF are defined as a rapid deterioration of the disease, and patients in this subgroup have a very poor outcome, with a high mortality rate in the short run. The cause of IPF is unknown, but it appears to be a disorder likely resulting from the interaction of environmental and genetic factors, causing unrelenting tissue remodeling by fibroblasts rather than normal repair, and the pathogenesis is primarily fibrotic rather than inflammatory. There is growing evidence suggesting that the disease initiates via micro-injury and apoptosis of alveolar epithelial cells, inducing stem cells or progenitor cells that activate adjacent epithelial cells and produce factors involved in the expansion of fibroblast and myofibroblast populations in a tumor-like manner. Fibroblast foci secrete excessive amounts of extracellular matrix, which destroys the lung parenchyma and ultimately leads to loss of lung function. 【0013】 The average annual rate of decline in lung function (vital capacity) is in the range of 0.13 to 0.21 liters. Symptoms precede diagnosis by 1 to 2 years, and X-ray signs may precede symptoms ((Ley B et al., Am.J.Respir.Crit.Care Med.(2011);183,431-440). 【0014】 Many treatment approaches, including anti-inflammatory drugs, immunomodulators, cytotoxic drugs, common antifibrotic drugs, antioxidants, anticoagulants, antichemokines, anti-angiogenic drugs, as well as RAS blockers, endothelin antagonists, and sildenafil, have been tested in preclinical models and clinical trials, and have generally shown to provide limited or no benefit ((Rafii R et al., J. Thorac. Dis. (2013); 5, 48-73). 【0015】 Current treatment for IPF includes oxygen therapy. Drugs used include pirfenidone and nintedanib, but these have limited effect in slowing disease progression. Furthermore, both of these drugs generally cause side effects (primarily gastrointestinal). 【0016】 There are drawbacks associated with all of the aforementioned drug treatments for ILD (and IPF), and there is a pressing clinical need for safer and / or more effective treatments. 【0017】 Repairing alveolar epithelium is highly desirable as a therapeutic effect in IPF, and therefore stem cell therapy is also being investigated. Several preclinical studies have shown that pluripotent stem cells can differentiate into lung epithelial and endothelial cells, thereby potentially repairing lung damage and fibrosis. 【0018】 Currently, lung transplantation is the only intervention that substantially improves the survival of IPF patients. However, complications such as infection and graft rejection are highly likely. 【0019】 Therefore, the development of new treatment strategies for IPF is crucial. Thus, the fundamental challenge for the future is to develop appropriate therapeutic approaches that can reverse or halt disease progression. 【0020】 U.S. Patent Application No. 2004 / 0167176 describes the preparation of a tricyclic heterocycle useful as an Ang II receptor agonist. 【0021】 A selective AT2 receptor agonist with reduced CYP450 inhibition is described in Mahalingam et al., Bioorg. Med. Chem. (2010); 18, 4570-4590. 【0022】 A transesterification method for the synthesis of AT2 receptor ligands with improved stability in human liver microsomes is described in Wannberg et al., Bioorg. Med. Chem. Lett. (2018); 28, 519-522. 【0023】 Specifically, International Patent Application No. 2002 / 096883 describes the preparation of imidazolyl, triazollyl, and tetrazolylthiophenesulfonamides and derivatives as AT2 receptor agonists. Among the compounds described in that document (as Example 1), is compound C21 (N-butyloxycarbonyl-3-(4-imidazole-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide). C21 was selected for clinical development from a group of about 20 related analogues as a selective AT2 receptor agonist. It is currently in clinical development for the treatment of AT2 receptor-related disorders, including IPF (see, for example, International Publication No. 2016 / 139475). 【0024】 C21 has also been shown to have potential uses in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cardiotoxicity associated with cancer treatment, peripheral neuropathy, and systemic sclerosis (see, for example, International Patent Applications 2004 / 046141, 2016 / 092329, 2016 / 107879, 2016 / 139475, 2017 / 221012, 2019 / 008393, and U.S. Patent Application 2012 / 035232). 【0025】 C21 has been found during development to be a potent inhibitor of several cytochrome P450 enzymes (CYPs), particularly both CYP 2C9 and CYP 3A4, which can potentially affect the metabolism of other drugs, and also has the drawback of being rapidly hydrolyzed to an inactive sulfonamide metabolite. Therefore, it is a fundamental challenge to develop a potent and selective AT2 agonist that is metabolically stable and / or has less inhibition of CYP enzymes. 【0026】 Surprisingly, certain chemically modified compounds defined below have been found to be not only selective AT2 receptor agonists, but also more potent, have significantly improved stability against metabolic hydrolysis compared to C21, and / or exhibit less inhibition of CYP enzymes. 【Mode for Carrying Out the Invention】 【0027】 In a first aspect of the present invention, a compound of formula I, 【Chemical Formula】 wherein, R 1 represents C 7 alkyl optionally substituted by one or more fluorine atoms and / or OR 1-4 , R 2 and R 3 each independently represents H or C 1-6 alkyl optionally substituted by one or more halogen atoms, Y 1 , Y 2 , Y 3 , and Y 4 each independently represents -CH-, -CF-, or -N-, R 4 is C 1-7 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6Representing alkyl, each of these alkyl portions is substituted and / or terminated by at least one -OH group and optionally substituted with one or more halogen atoms. R 5 However, C represents H, or is optionally substituted with one or more halogen atoms. 1-6 Represents alkyl, R 6 However, C is optionally substituted by one or more halogen atoms. 2-4 Represents alkyl, R 7 However, a compound that represents H, or a methyl atom optionally substituted with one or more fluorine atoms, Or a pharmaceutically acceptable salt thereof is provided. These compounds and salts are hereinafter referred to as "the compounds of the present invention." 【0028】 For the purposes of interpreting this specification, the following definitions apply, and where appropriate, terms used in the singular also include the plural form, and vice versa. 【0029】 The compounds are named according to the IUPAC nomenclature generated by the program Chemdoodle8.1.0. 【0030】 To avoid any doubt, those skilled in the art will understand that any reference herein to compounds of a particular aspect of the present invention (such as any aspect of the present invention, referring to compounds of formula I as defined herein) includes references to all embodiments and their specific features, and that further embodiments and features of the present invention may be formed by combining those embodiments and specific features. 【0031】 Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention pertains. 【0032】 Examples of pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example, by reacting the free acid or free base form of the compound of the present invention with one equivalent or more of a suitable acid or base in an optional solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (e.g., by vacuum, freeze-drying, or filtration). Salts may also be prepared using techniques known to those skilled in the art, for example, by exchanging the counterions of the compound of the present invention in salt form with other counterions using a suitable ion exchange resin. 【0033】 Specific acid addition salts that may be mentioned include carboxylates such as formate, acetate, trifluoroacetate, benzoate, oxalate, fumarate, and maleate; sulfonates such as methanesulfonate, ethanesulfonate, and toluenesulfonate; halogenated salts such as hydrochloride and hydrobromide; and sulfates and phosphates such as sulfates and phosphates. 【0034】 Specific base addition salts that may be mentioned include salts formed with alkali metals (such as Li salts, Na salts, and K salts), alkaline earth metals (such as Mg salts and Ca salts), or other metals (such as Al salts and Zn salts), or amine bases (such as ammonia, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, and tromethamine). More specifically, base addition salts that may be mentioned include Mg salts, Ca salts, and most specifically, K salts and Na salts. 【0035】 The compounds of the present invention may exist as solids, and therefore the scope of the invention includes all amorphous, crystalline, and partially crystalline forms, and may also exist as oils. When the compounds of formula I exist in crystalline and partially crystalline forms, such forms may include solvates, which are also included in the scope of the present invention. 【0036】 The compounds of the present invention may also exist in solution (i.e., in solution in a suitable solvent). For example, the compound of formula I may exist in aqueous solution, in which case the compounds of the present invention may exist in the form of a hydrate. 【0037】 The compounds of the present invention may contain double bonds and, therefore, unless otherwise indicated, may exist as E (entgegen) and Z (zusammen) geometric isomers for each individual double bond. Unless otherwise specified, all such isomers and mixtures thereof are included within the scope of the present invention. 【0038】 The compounds of the present invention may also exhibit tautomerism. All tautomers and mixtures thereof (in particular those that are stable enough to allow their isolation) are included within the scope of the present invention. 【0039】 The compounds of the present invention may also contain one or more chiral carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism (i.e., may exist in enantiomer or diastereomer forms). Diastereomers may be separated using conventional techniques, e.g., chromatography or fractional crystallization. Various stereoisomers (i.e., enantiomers) can be isolated by separating racemic or other mixtures of the compound using conventional techniques, e.g., fractional crystallization or HPLC techniques. Alternatively, the desired enantiomer or diastereomer may be obtained from appropriately optically active starting material (i.e., the "chiral pool" method), by derivatization (i.e., decomposition including dynamic decomposition, e.g., treatment with a homochiral acid followed by separation of the diastereomer derivative by conventional means such as chromatography), or by reaction with an appropriate chiral reagent or chiral catalyst, under conditions that will not cause racemization or epimerization, and all of these methods and processes can be carried out under conditions known to those skilled in the art. Unless otherwise specified, all stereoisomers and mixtures thereof are included within the scope of the present invention. 【0040】 As used herein, the term “halogen” includes fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Similarly, the term “halo” includes fluoro, chloro, bromo, and iodine as used herein. 【0041】 Unless otherwise specified, C as defined herein 1-6 Alkyl alkyl groups (for example, C 1-4 (Alkyl alkyl group), C 2-4 Alkyl groups, and C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 The alkyl portion of an alkyl group can be a straight chain, or it can be a branched chain and / or cyclic structure if there are a sufficient number of carbon atoms (i.e., at least two or three as needed) (e.g., C 3-6 (It can form a cycloalkyl group). If there are a sufficient number of carbon atoms (i.e., at least four), such a group can also be a subcyclic group (e.g., C 4-6 (They can form partial cycloalkyl groups). For example, cycloalkyl groups that can be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Similarly, a partially cyclic alkyl group (which can also be called a “partially cycloalkyl” group) that can be mentioned is cyclopropylmethyl. If a sufficient number of carbon atoms are present, such groups can also be polycyclic (e.g., bicyclic or tricyclic) and / or spirocyclic. 【0042】 Alkyl and alkoxy groups can be unsaturated if a sufficient number (i.e., at least three) of carbon atoms are present, and therefore can incorporate double or triple bonds. 【0043】 Specific alkyl groups that may be mentioned include linear (i.e., not branched and / or cyclic) alkyl groups. For example, C 1-6 Alkyl alkyl groups, and C 1-6Examples of alkyl groups in the alkoxy group include, but are not limited to, n-butyl, sec-butyl, isobutyl, tert-butyl; propyl such as n-propyl, 2-methylpropyl, or isopropyl; ethyl; and methyl. 【0044】 To avoid any doubt, C 1-6 Alkyl and C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 The bonding site between an alkylaryl group and the alkyl moiety is via the alkyl moiety of such a group. 【0045】 To avoid any ambiguity, an alkoxy group is bonded to the rest of the molecule via the oxygen atom of its group, and an alkoxyalkyl group is bonded to the rest of the molecule via the alkyl portion of its group. 【0046】 Unless otherwise specified, alkoxy refers to an O-alkyl group in which the term "alkyl" has the above meaning. 【0047】 The present invention also includes isotope-labeled compounds of the present invention in which one or more atoms are actually replaced by atoms having atomic masses or mass numbers different from those commonly found in nature (or most abundantly found in nature), but which are identical to those described herein. All isotopes of any particular atom or element identified herein are intended to be within the range of compounds of the present invention. Accordingly, the compounds of the present invention also include deuterated compounds, i.e., compounds of the present invention in which one or more hydrogen atoms are replaced by hydrogen isotopes. 【0048】 If two or more substituents in the compound of the present invention may be identical, the actual identity of each substituent is never interdependent. For example, in the presence of two or more halo groups, these groups may be identical or different (e.g., two chloro groups, or a fluoro group and a chloro group). Similarly, in the presence of two or more alkyl groups, the groups in question may be identical or different with respect to the number of carbon atoms they have and / or whether they are linear, branched, unsaturated, or otherwise. 【0049】 Furthermore, if the substituent itself is specified to be optionally substituted by one or more substituents (e.g., butyl optionally substituted by one or more groups independently selected from the halo), these substituents may, if possible, be located on the same or different atoms. Such optionally substituted substituents may be present in any preferred number (e.g., the group in question may be substituted by one or more such substituents, such as one such substituent). 【0050】 Where a group is referred to herein as being optionally substituted, it is particularly intended that such optional substituents may be absent (i.e., references to such optional substituents may be omitted), in which case the optionally substituted group may be referred to as unsubstituted. 【0051】 Unless otherwise specified, substituents (whether optional or not) can be located at any point on the group to which they can be attached. In this regard, alkyl and alkoxy groups (for example) that can be substituted by one or more substituents can also be terminated by such substituents (i.e., meaning located at the end of an alkyl or alkoxy chain). 【0052】 To avoid any doubt, if two or more substituents in a compound of formula I may be identical, then the actual identity of each substituent is never interdependent. For example, R 2 and R 3 Both are C 1-6In the case of alkyl, the C in question 1-6 The alkyl groups may be the same or different. 【0053】 Those skilled in the art will understand that the compounds of the present invention, which are the subject of this invention, include those that are readily available, i.e., those that can be prepared in a stable form. That is, the compounds of the present invention include compounds that are robust enough to survive isolation, for example, isolation from a reaction mixture to a useful purity. 【0054】 Preferred compounds of the present invention include: R 1 However, C 1-4 When representing an alkyl group, it refers to methyl, ethyl, propyl (e.g., isopropyl), or butyl (e.g., n-butyl or tert-butyl) (e.g., CH2CHClCH2CH2F or CH2CF3) which are optionally substituted with up to three fluorine atoms. R 2 and R 3 However, independently, H is represented, or C is optionally substituted by up to three halogen atoms. 1-4 This represents an alkyl group (methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., n-butyl)) (e.g., CH2CHClCH2CH2F or CH2CF3), Y 1 , Y 2 , Y 3 , and Y 4 However, independently, it represents -CH- or -CF-, R 4 However, C which is substituted and / or terminated as described above in this specification. 2-7 Alkyl alkyl group, or more preferably, C 2-6 Alkyl group (ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., tert-butyl, isobutyl, or n-butyl), or cyclohexylmethyl group, or more preferably cyclopentylmethyl, cyclobutylmethyl, or cyclobutylethyl group, etc.) R 5 However, it represents H, or C1-4 Represents an alkyl group (methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., isobutyl)), R 6 However, examples include those representing ethyl, propyl (e.g., n-propyl), or butyl (e.g., n-butyl or isobutyl). 【0055】 A more preferred compound of the present invention is: R 1 However, this represents methyl, ethyl, isopropyl, or tert-butyl. R 2 and R 3 However, it independently represents H or methyl, Y 1 , Y 2 , Y 3 , and Y 4 At least one of them (for example, one or two) represents -CF-, and the rest represent -CH-, R 4 However, it represents cyclohexylmethyl, or more preferably ethyl, n-propyl, n-butyl, or isobutyl, each of which is substituted and / or terminated by one -OH group. R 5 However, this represents H, methyl, ethyl, n-propyl, n-butyl, or isobutyl. R 6 However, examples include those representing n-propyl, n-butyl, or isobutyl. 【0056】 Particularly preferred compounds of the present invention include: R 1 However, this represents ethyl, isopropyl, or tert-butyl. R 2 and R 3 However, both represent H, Y 1 and Y 2 However, both represent -CH-, or Y 1 and Y 2 One or both of them represent -CF-, Y 3 and Y4 However, both represent -CH, R 4 However, it represents cyclohexylmethyl, or more preferably ethyl, n-propyl, or isobutyl substituted and / or terminated by one -OH group, R 5 However, it represents H, R 6 However, one example is isobutyl. 【0057】 Therefore, particularly preferred compounds of the present invention that may be mentioned include: 1-[[3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea, 1-[[3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(3-hydroxypropyl)urea, 1-[[3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxy-2-methylpropyl)urea, 1-[[3-[2-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea, 1-[[3-[3,5-difluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea, 1-[[3-[4-[(2-tert-butylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea, 1-[[3-[4-[(2-tert-butylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxy-2-methyl-propyl)urea, 1-[[3-[4-[(2-Ethylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea, 1-[[3-[4-[(2-Ethylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-[(1-hydroxycyclohexyl)methyl]urea, 1-[[3-[3-Fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea, can be mentioned. 【0058】 The IUPAC name was generated from the program Chemdoodle 8.1.0. 【0059】 More preferable compounds of the present invention include the compounds of the examples described below. 【0060】 The compound of formula I can be prepared according to techniques well known to those skilled in the art as described, for example, below. 【0061】 According to a further aspect of the present invention, a process for the preparation of a compound of formula I is provided, the process comprising (i) a compound of formula II, wherein 【Chemical formula】 wherein R 1 , R 2 , R 3 , R 6 , Y 1 , Y[[ID=四十一]] 2 , Y 3 , and Y 4 [[ID=四十六]]are as defined above in the text of this specification, and L represents a C 1-6 alkyl or aryl group (such as phenyl), a compound of formula II, and a compound of formula III or a salt thereof, wherein NHR 4 R 5 III wherein R4 and R 5 is a reaction with a compound of formula III or a salt thereof as defined in the foregoing of this specification, for example, in the presence of a suitable solvent such as toluene, acetonitrile, or dioxane, and / or a suitable base such as triethylamine, 4-dimethylaminopyridine, or potassium carbonate, at approximately room temperature or above room temperature (e.g., up to 90 - 110 °C). (ii) In the case of a compound of formula I where R 5 represents H, it is a compound of formula IV, 【Chemical formula】 wherein R 1 , R 2 , R 3 , R 6 , Y 1 , Y 2 , Y 3 and Y 4 are as defined in the foregoing of this specification, is a reaction with a compound of formula V, R 4 -N=C=O V wherein R 4 is as defined in the foregoing of this specification, which is a reaction in the presence of, for example, optionally copper(I) chloride or boron trifluoride etherate, and / or a suitable base (e.g., pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, di-isopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or a mixture thereof), and a suitable solvent (e.g., pyridine, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, acetonitrile, or a mixture thereof), at approximately room temperature or above room temperature (e.g., up to 60 - 70 °C). (iii) In the case of a compound of formula I where R 5 represents H, it is a compound of formula IV as defined in the foregoing of this specification, and a compound of formula VI, 【Chemical formula】 In the formula, R 4 However, as defined above in this specification, X 1 However, suitable leaving groups (e.g., halo (e.g., chloro or bromo), -OC) 1-6 Alkyl, or -OC 1-6 Reactions with compounds of formula VI, which are aryl (e.g., OPh), include, for example, reactions under microwave irradiation above room temperature in the presence of a suitable base (e.g., sodium bicarbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, di-isopropylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, or mixtures thereof) and a suitable solvent (e.g., acetonitrile, pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, or toluene). 【0062】 The compound of formula II is the compound of formula IV as defined above in this specification, and the compound of formula VII, [ka] In the formula, X 1a and X 1b However, both are X as defined above in this specification. 1 A reaction with a compound of formula VII, which may be the same or different, can be prepared, for example, by a reaction below room temperature, near room temperature, or above room temperature (e.g., 0°C, or up to 50-70°C) in the presence of a suitable base and a suitable solvent (e.g., pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, acetonitrile, or toluene) as defined above herein. 【0063】 The compound of formula IV is the compound of formula VIII, [ka] In the formula, R 6However, either as defined above in this specification, or an N-protected derivative thereof, X 2 However, the compound of formula VIII and the compound of formula IX represent suitable cross-coupling groups, [ka] In the formula, R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , and Y 4 However, as defined above in this specification, X 3 However, it can be prepared by reaction with a compound of formula IX that represents a suitable cross-coupling group. The above coupling reaction is preferably a Suzuki reaction and can therefore be carried out under standard Suzuki conditions, which is X 2 and X 3One of the groups represents one of the preferred Suzuki cross-coupling groups (or "partners"), namely a boronic acid (-B(OH)2) or boronic acid ester (e.g., a MIDA derivative or pinacol ester), and a halo group such as iodine or bromo, while the other group represents another group. Standard Suzuki conditions can be applied to this reaction, and these conditions include, for example, a suitable coupling catalyst system (e.g., a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane, Pd(PPh3)4, or Pd(OAc)2 / ligand (where the ligand can be, for example, PPh3, P(o-Tol)3, or 1,1'-bis(diphenylphosphino)ferrocene)), a suitable base (e.g., sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, or di-isopropylamine), and a suitable solvent system (e.g., toluene, ethanol, n-butanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane, or mixtures thereof). This reaction can be carried out above room temperature (e.g., at the reflux temperature of the solvent system used). This reaction can be carried out under microwave irradiation above room temperature. If a protected version of the compound of formula VIII is used, the SO2NH- group may be deprotected following this reaction under standard conditions, for example, as described below. Following the reaction of the compound of formula VIII with the compound of formula IX, the intermediate thus formed may also be reacted with a suitable acid to form an acid addition salt, or more preferably its N-protected version. Suitable acid addition salts include fumarates, trifluoroacetates, and oxalates. 【0064】 Alternatively, the compound of formula IV is the compound of formula X, [ka] In the formula, R 1 , R2 , and R 3 However, a compound of formula X and a compound of formula XI, as defined above in this specification, [ka] In the formula, R 6 , X 1 , Y 1 , Y 2 , Y 3 , and Y 4 However, as defined above in this specification (X 1 Specifically, the compounds can be prepared by a reaction with a compound of formula XI (which may represent bromo) or an N-protected derivative thereof, for example, at approximately room temperature or below room temperature in the presence of a suitable base (e.g., pyridine) and a suitable organic solvent (e.g., toluene). If a protected version of the compound of formula XI is used, this reaction may be followed by deprotection of the SO2NH group under standard conditions, for example, as described below. Furthermore, the compounds of formula IV can thus be prepared, for example, in accordance with or similar to the process described in, in particular, UK Patent Application No. 2281298. 【0065】 The compound of formula IX is obtained by standard techniques, for example, from the compound of formula X as defined above herein, and the compound of formula XII, [ka] In the formula, X 1 , X 3 , Y 1 , Y 2 , Y 3 , and Y 4 However, it can be prepared by a reaction with the compound of formula XII, as defined above in this specification, for example, by a reaction under the same conditions as those described above in this specification with respect to the preparation of the compound of formula IV. 【0066】 Compounds of formula XI are known in the art. For example, they can be prepared in accordance with or similar to the processes described in, in particular, U.S. Patent No. 5,312,820, UK Patent Application No. 2281298, and / or International Patent Application No. 02 / 096883. 【0067】 Compounds of formula VIII are known in the art. For example, they can be prepared, in particular, by the process described in or similar to that described in International Patent Application No. 02 / 096883. 【0068】 The compounds of formulas III, V, VI, VII, X, and XII can be obtained from readily available starting materials using appropriate reagents and reaction conditions, either commercially available, known in the literature, or by analogy using the processes described herein or by conventional synthetic procedures, according to standard techniques. 【0069】 Those skilled in the art will understand that in the processes described above and below, it may be necessary to protect the functional groups of the intermediate compound with protecting groups. 【0070】 Functional groups that are desirable to protect include sulfonamides, amides, aminos, and aldehydes. Suitable protecting groups for sulfonamides, amides, and aminos include tert-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), or tert-butyl. Suitable protecting groups for aldehydes include alcohols such as methanol or ethanol, and diols such as 1,3-propanediol, or preferably 1,2-ethanediol (which thus forms a cyclic acetal). Protection and deprotection of functional groups may be carried out before or after the reactions in the schemes mentioned above. 【0071】 Protecting groups can be applied and removed according to techniques well known to those skilled in the art and the techniques described below. For example, the protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemical reaction involved will determine the need and type of protecting group, as well as the sequence for achieving the synthesis. The use of protecting groups is fully described in “Protective Groups in Organic Synthesis”, 3rd edition, TW Greene & P. ​​G.M. Wutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference. 【0072】 Medical and pharmaceutical use As described herein, the compounds of the present invention, and therefore compositions and kits containing them, are useful because they are pharmaceutically active and / or metabolized in the body after oral or parenteral administration to form pharmaceutically active compounds. 【0073】 Therefore, according to further aspects of the present invention, compounds of the present invention, as defined below, are provided for use as pharmaceuticals (or for use as agents). 【0074】 Specifically, the compounds of the present invention are agonists of the AT2 receptor. Therefore, the compounds of the present invention are expected to be useful in conditions in which the endogenous production of Ang II is deficient, and / or in conditions in which an increase in AT2 receptor activity is desirable or required. 【0075】 More specifically, the compounds of the present invention are agonists of the AT2 receptor, and in particular, selective agonists of its subreceptors (against the AT1 receptor), as can be demonstrated, for example, in the tests described below. 【0076】 Examples of AT2 receptor agonists include those that completely activate the AT2 receptor and those that partially activate it. Therefore, the compounds of the present invention can selectively bind to the AT2 receptor and exhibit agonist activity at the AT2 receptor. Compounds that "selectively bind" to the AT2 receptor include having an affinity ratio (AT2:AT1) of at least 50:1, preferably at least 1000:1, of the related compound at a given concentration. 【0077】 The compounds of the present invention are further expected to be useful in conditions in which AT2 receptors are expressed and their stimulation is desirable or required. 【0078】 In this regard, the compounds of the present invention are needed in the treatment of conditions characterized by vasoconstriction, fibrosis, increased cell proliferation and / or differentiation, increased myocardial contractility, increased cardiovascular hypertrophy, and / or increased fluid and electrolyte retention, as well as skin and musculoskeletal disorders. 【0079】 The compounds of the present invention may also exhibit thromboxane receptor activity. In this regard, the compounds of the present invention may have an inhibitory effect on platelet activation and / or aggregation (and therefore, for example, an antithrombotic effect), and / or may reduce vasoconstriction and / or bronchoconstriction in a therapeutic manner. 【0080】 The compounds of the present invention are further required in the treatment of stress-related disorders and / or in the improvement of microcirculation and / or mucosal protective mechanisms. 【0081】 Therefore, the compounds of the present invention may be characterized as described above and are expected to be useful in the treatment of disorders of the gastrointestinal tract, cardiovascular system, airway, kidneys, eyes, female reproductive (ovulation) system, and central nervous system (CNS), for example. 【0082】 Gastrointestinal disorders that may be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, indigestion (including non-ulcerative indigestion), gastroesophageal reflux, irritant bowel syndrome (IBS), inflammatory bowel disease (IBD), liver disorders (such as hepatitis), gallbladder disorders, multiple organ failure (MOF), and sepsis. Other gastrointestinal disorders that may be mentioned include xerostomia, gastritis, gastroparesis, hyperacidity, biliary disorders, coelicitis, Crohn's disease, ulcerative colitis, diarrhea, constipation, colitis, loss of appetite, vomiting, nausea, indigestion, and Sjögren's syndrome. 【0083】 Airway disorders that may be mentioned include asthma, obstructive pulmonary disease (such as chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension, and inflammatory disorders such as adult respiratory distress syndrome. 【0084】 Possible kidney disorders include renal failure, nephritis, and renal hypertension. 【0085】 Eye disorders that may be mentioned include diabetic retinopathy, premature retinopathy, and retinal microangiopathy. 【0086】 One possible female reproductive system disorder to mention is ovulation dysfunction. 【0087】 Cardiovascular disorders that may be mentioned include hypertension, cardiac hypertrophy, heart failure (including heart failure with maintained ejection fraction), atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial lesions, post-balloon stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina, cardiac arrhythmias, intermittent claudication, pre-eclampsia, myocardial infarction, reinfarction, ischemic lesions, erectile dysfunction, and neointimal hyperplasia. 【0088】 CNS disorders that may be mentioned include cognitive impairment, impaired food intake (hunger / satiety) and thirst, stroke, cerebral hemorrhage, cerebral embolism and cerebral infarction, multiple sclerosis (MS), Alzheimer's disease, and Parkinson's disease. 【0089】 The compounds of the present invention may also be useful in regulating growth metabolism and proliferation, for example, in the treatment of aging, hypertrophic disorders, benign prostatic hyperplasia, autoimmune disorders (e.g., arthritis such as rheumatoid arthritis, or systemic lupus erythematosus), psoriasis, obesity, nerve cell regeneration, ulcer healing, suppression of adipose tissue hyperplasia, stem cell differentiation and proliferation, fibrous disorders, cancer (e.g., of or within the gastrointestinal tract (including the esophagus or stomach)), prostate, breast, liver, kidney, and lymphoma, lung cancer, ovarian cancer, pancreatic cancer, hematological malignancies, etc.), apoptosis, tumors (in general), as well as hypertrophy, diabetes, neurological lesions, and organ rejection. 【0090】 The compounds of the present invention are also useful in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer treatment-related cardiotoxicity, peripheral neuropathy, and specifically, systemic sclerosis. 【0091】 The compounds of the present invention are particularly necessary in the treatment and / or prevention of sarcoidosis or fibrosis, more specifically pulmonary fibrosis and IPF and other interstitial lung diseases (ILDs), as well as conditions that can induce ILDs, such as systemic sclerosis, rheumatoid arthritis, myositis, or systemic lupus erythematosus, or conditions associated with ILDs, such as pulmonary hypertension and / or pulmonary arterial hypertension. 【0092】 The compounds of the present invention are particularly useful in the treatment of pulmonary fibrosis, specifically IPF. 【0093】 A further aspect of the present invention provides a method for treating pulmonary fibrosis, particularly IPF, comprising administering a therapeutically effective amount of the compound of the present invention to a person suffering from such a condition. 【0094】 In the treatment of pulmonary fibrosis, including IPF, the compounds of the present invention may have anti-fibrotic effects, including reduction of fibrosis and prevention of further deposition of extracellular matrix. The compounds of the present invention may reduce pulmonary scarring / wound healing and have anti-apoptotic effects, thereby preventing apoptosis of alveolar endothelial cells, which are initiating factors in the development of pulmonary fibrosis. The compounds of the present invention may also have antiproliferative effects, and therefore reduce cancer-like proliferation of fibroblasts and myofibroblasts in pulmonary fibrosis. The compounds of the present invention may also improve vascular remodeling in pulmonary fibrosis, thereby reducing secondary pulmonary hypertension. Finally, the compounds of the present invention may exhibit anti-inflammatory, anti-growth factor (e.g., transforming growth factor beta), and / or anti-cytokine effects. 【0095】 In addition, the compounds of the present invention may also be useful in the treatment or prevention of any fibrous condition of one or more viscera characterized by an excessive accumulation of fibrous connective tissue, and / or in the treatment or prevention of fibrosis, and in the morbidity and mortality that may be associated therewith. Such fibrosis may be associated with injuries and / or dysfunctions that may be caused by acute inflammatory conditions such as acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), multi-organ inflammation, internal or external trauma (e.g., injury), or infection. 【0096】 Therefore, such conditions can result from sepsis or septic shock caused by viral, bacterial, or fungal infections (e.g., viral respiratory tract infections). Furthermore, acute lung injury, ARDS, and SARS in particular can be caused by viruses such as coronaviruses, including novel SARS coronavirus 2 (SARS-CoV-2), which can lead to internal tissue damage and / or dysfunction of associated internal (e.g., mucous membrane) tissues such as the respiratory epithelium, thus resulting in virus-induced pneumonia, low lung function, respiratory dysfunction, dyspnea, and / or respiratory failure. Such tissue damage can also lead to severe fibrosis. For example, SARS disease (coronavirus disease 2019 or COVID-19), caused by the novel coronavirus SARS-CoV-2, is known to often result in fibrosis. 【0097】 The compounds of the present invention are particularly useful in the treatment of diseases or conditions in which activation of the AT2 receptor is desirable or required, but inhibition of one or more CYP enzymes is undesirable. 【0098】 An alternative embodiment of the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a drug for use in the treatment of a disease or condition in which activation of the AT2 receptor is desirable or required, but inhibition of CYP enzymes is undesirable. 【0099】 "Diseases or conditions in which AT2 receptor activation is desirable or required, but CYP inhibition is undesirable" include diseases or conditions known to be treatable by AT2 receptor activation, such as those mentioned below, but existing treatments for such conditions may include the administration of other therapeutic agents metabolized by CYP. Thus, such diseases or conditions may include conditions in which inhibition of at least one CYP enzyme is not required, unfavorable, and / or undesirable, or in which such inhibition is or may be harmful to the patient. 【0100】 Certain diseases or conditions in which AT2 receptor activation is desirable or required, but CYP enzyme inhibition is undesirable, include interstitial lung diseases (e.g., pulmonary fibrosis, IPF, systemic sclerosis, and sarcoidosis), autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, and inflammatory bowel disease), chronic kidney diseases (e.g., diabetic nephropathy), pulmonary hypertension, pulmonary arterial hypertension, pre-eclampsia, and / or infarctions (e.g., myocardial infarction and stroke). Therefore, the compounds of the present invention are particularly useful in the treatment of interstitial lung diseases such as IPF, autoimmune diseases such as rheumatoid arthritis, chronic kidney diseases such as diabetic nephropathy, pulmonary hypertension including pulmonary arterial hypertension, and / or infarctions such as myocardial infarction. 【0101】 A further aspect of the present invention provides a method for treating a disease or condition (specifically IPF, such as pulmonary fibrosis) in which activation of the AT2 receptor is desirable or required, but inhibition of CYP enzymes is undesirable, the method comprising administering a therapeutically effective amount of the compound of the present invention to a person suffering from the relevant condition. 【0102】 The compounds of the present invention are required in both therapeutic, palliative, and / or diagnostic treatment, as well as prophylactic treatment (including preventing and / or inhibiting deterioration and / or worsening of the condition) of any of the above conditions. 【0103】 The compounds of the present invention are typically administered orally, intravenously, subcutaneously, buccally, rectally, through the skin, intranasally, intratracheally, intrabronchally, by other parenteral routes, or by inhalation, pulmonary routes, or any combination thereof, in pharmaceutically acceptable dosage forms, in solutions, suspensions, emulsions (including nanosuspensions), or liposomal formulations. Additional methods of administration include, but are not limited to, intra-arterial, intramuscular, intraperitoneal, intra-portal, intradermal, epidural, intrathecal, or any combination thereof. 【0104】 In some embodiments, the compounds of the present invention may be administered alone (e.g., separately), and / or sequentially, and / or simultaneously and in parallel (e.g., concurrently) using different routes of administration, but preferably by known pharmaceutical formulations, including tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions, or emulsions for parenteral or intramuscular administration or by inhalation. Administration by inhalation is preferably carried out using a nebulizer, and thus preferably delivers the compounds of the present invention to small lung tissues, including alveoli and bronchioles, without causing irritation or coughing in the target being treated. 【0105】 Preferably, the administration of a therapeutically effective dose of the compound of the present invention is carried out by achieving an effective dose via inhalation and orally, either separately (e.g., about 2 hours or more apart from each other), consecutively (e.g., within about 2 hours of each other), or simultaneously (e.g., concurrently) depending on the combination of administration routes. 【0106】 In some embodiments, methods are provided for treating diseases or conditions in which AT2 receptor activation is desired or required (and in which inhibition of CYP enzymes is undesirable), including pulmonary fibrosis, specifically IPF. The method involves administering a therapeutically effective amount of the compound of the present invention to a patient in need of such treatment, either separately, sequentially, or simultaneously in parallel, via a combination of administration routes, preferably by inhalation and orally, in order to achieve a therapeutically effective dose or dosage. 【0107】 Such combinations of administration routes can be presented as separate formulations of the compound of the present invention optimized for each administration route, preferably via inhalation and orally. 【0108】 Such formulations may be prepared in accordance with standard and / or acceptable pharmaceutical regulations. 【0109】 Accordingly, according to a further aspect of the present invention, a pharmaceutical formulation is provided comprising the compound of the present invention mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. 【0110】 The compounds of the present invention may be administered in combination with other AT2 agonists known in the art, such as C21, and in combination with AT1 receptor antagonists known in the art, and / or in combination with angiotensin-converting enzyme (ACE) inhibitors. Non-limiting but exemplary examples of AT1 receptor antagonists that can be used according to the embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, platosartan, ripiasartan, saprisartan, tasosartan, telmisartan, valsartan, and / or combinations thereof. Non-limiting but exemplary examples of ACE inhibitors that can be used according to the embodiment include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, alacepril, seronapril, delepril, movertipril, and / or combinations thereof. 【0111】 Other active ingredients that can be administered in combination with the compounds of the present invention include disodium cromoglycate; endothelin receptor antagonists such as bosentan, ambrisentan, cytaxentan, and macitentan; PDE5 inhibitors such as sildenafil and tadalafil; prostacyclins (epoprostenol) and their analogs such as iloprost and treprostinil; other biological agents including interferon-gamma-1b, etanercept, infliximab, and adalimumab; and methotrexate. Further active ingredients under development that can be administered co-administered with the compounds of the present invention include pamrebulumab (anti-CTGF, Fibrogen), GLPG1690 (autotaxin inhibitor, Galapagos), TD139 (galectin-3 inhibitor, Galecto), PRM-151 (recombinant pentraxin-2, Promedior), BBT-877 (autotaxin inhibitor, Boehringer / Bridge), CC-90001 (JNK inhibitor, Celgene), PBI-4050 (dual GPR40 agonist / GPR84 antagonist, Prometic), BMS-986020 (lysophosphatidic acid receptor antagonist, BMS), RVT-1601 (mast cell stabilizer, Respivant), SMO4646 (wnt-signaling inhibitor, United Therapeutics), and KD25 (Rho-related kinase inhibitor, Kadmon). Examples include Biogen Holdings, BG00011 (integrin antagonist), Pilant Therapeutics (integrin antagonist), Salacatinib (src kinase inhibitor), AstraZeneca, Pharmakea (lysyl oxidase inhibitor 2), Abeome (IL-25MAB), and Otsuka (multikinase inhibitor). 【0112】 In a further aspect of the present invention, the compounds of the present invention find particular utility when combined with other therapeutic agents in combination therapies for treating a variety of conditions, including those referenced above herein. Since the compounds of the present invention exhibit minimal CYP enzyme inhibition, such combinations are particularly advantageous when the other therapeutic agents used for use in the relevant conditions are themselves metabolized by CYP enzymes. 【0113】 Therefore, when the condition being treated is an interstitial lung disease such as IPF, systemic sclerosis, or fibrous disease, which are known in the art, the compounds of the present invention are preferably administered in combination with established therapies for such treatment, including but not limited to galectin-3 inhibitors, lysophosphatidic acid receptor 1 (LPA1) antagonists, autotaxin (ATX) inhibitors, recombinant human pentraxin-2 protein, or pirfenidone and / or nintedanib. Preferably, the combination of the compounds of the present invention is with pirfenidone or a pharmaceutically acceptable salt thereof, the compounds being known to be metabolized by CYP enzymes such as CYP1A. 【0114】 Furthermore, if the condition being treated is a chronic kidney-related disease, the compounds of the present invention are preferably administered in combination with one or more other drugs used in such treatment, such as irbesartan and / or torsemide, which are known to be metabolized by CYP enzymes such as CYP2C9. 【0115】 When the condition being treated is pulmonary hypertension, the compounds of the present invention are preferably administered in combination with one or more other drugs, such as selexipag and / or sildenafil, which are also used in such treatments, and these compounds are known to be metabolized by CYP enzymes such as CYP3A4. 【0116】 When the condition being treated or prevented is myocardial infarction and / or stroke-related disease, the compounds of the present invention are preferably administered in combination with one or more other drugs used in such treatment, such as propranolol, warfarin, clopidogrel, atorvastatin, cilostazol, lidocaine and / or simvastatin, or pharmaceutically acceptable salts thereof, which are known to be metabolized by CYP enzymes such as CYP1A, CYP2CP and / or CYP3A4. 【0117】 When the condition being treated is an autoimmune disease such as rheumatoid arthritis, multiple sclerosis, or psoriasis, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatments, including but not limited to drugs such as tizanidine, cyclophosphamide, cyclosporine, deflazacort, and / or hydrocortisone, riluzole, or pharmaceutically acceptable salts thereof. 【0118】 Therefore, the compounds of the present invention are particularly useful for treating diseases or conditions in which AT2 receptor activation is desirable or required, but CYP enzyme inhibition is undesirable, and can therefore be administered in combination with one or more of the other therapeutic agents mentioned above herein, including pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil and / or simvastatin, which are metabolized via the CYP pathway and are useful or may be useful, to treat diseases including those mentioned above herein. Most preferably, the compounds of the present invention are administered in combination with pirfenidone to treat interstitial lung diseases such as IPF. 【0119】 Therapeutic agents that may be used in conjunction with the compounds of the present invention include standard treatments applicable to various viral infections, including antibody therapies (e.g., LY-CoV555 / LY-CoV016 (bamuranivimab and etesevimab), LY-CoV555 (bamuranivimab, Eli Lilly), REGN-COV2 (casiribimab and imdevimab), REGN3048-3051, TZLS-501, SNG001 (Synairgen), eculizumab (Soliris; Alexion Pharmaceuticals), ravulizumab (Ultomiris; Alexion Pharmaceuticals), renzilumab, leronlimab, tocilizumab (Actemra; Roche), sarilumab (Kevzara; Regeneron)). Includes antiviral drugs (e.g., oseltamivir, remdesivir, faviravir, mornupiravir, simeprevir, daclatasvir, sofosbuvir, ribavirin, umifenovir, lopinavir, ritonavir, lopinavir / ritonavir (Kaletra; AbbVie Deutschland GmbH Co.)).KG), teicoplanin, baricitinib (Olumiant; Eli Lilly), ruxolitinib (Jakavi; Novartis), tofacitinib (Xeljanz; Pfizer), TMPRSS2 inhibitors, camostat, or camostat mesylate, Actemra (Roche), AT-100 (rhSP-D), MK-7110 (CD24Fc; Merck), OYA1 (OyaGen9), BPI-002 (BeyondSpring), NP-120 (Ifenprodil; Algernon Pharmaceuticals), and galidesivir (Biocryst This includes passive antibody therapy with antibodies derived from the blood of people who have recovered from SARS-CoV or SARS-CoV-2 infection, as well as anti-inflammatory agents (e.g., NSAIDs such as ibuprofen, ketrolac, and naproxen), chloroquine, hydroxychloroquine, interferons (e.g., interferon beta (interferon beta-1a), tocilizumab (Actemra), lenalidomide, pomalidomide, and thalidomide), analgesics (e.g., paracetamol or opioids), antifungal agents (e.g., dextromethorphan), vaccines (e.g., INO-4800 from Inovio Pharmaceuticals and Beijing Advaccine Biotechnology (if available)), COVID-19 convalescent plasma (CCP), and / or antibodies derived from the blood of people who have recovered from SARS-CoV or SARS-CoV-2 infection. 【0120】 Further therapeutic agents that may be mentioned include antifibrotic drugs (e.g., nintedanib, especially pirfenidone), vitamins (e.g., vitamins B, C, and D), and mucolytics such as acetylcysteine ​​and ambroxol. 【0121】 Other therapeutic agents that can be used in conjunction with the compounds of the present invention or pharmaceutically acceptable salts thereof include corticosteroids. Corticosteroids include both natural and synthetic corticosteroids. 【0122】 Naturally occurring corticosteroids that may be mentioned include cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, progesterone, as well as naturally occurring precursors and intermediates in corticosteroid biosynthesis, and other naturally occurring derivatives of corticosteroids, such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, and 18-hydrocortisone. Examples include C-11-deoxycorticosterone, 18-hydroxycorticosterone, 21-deoxycortisone, 11β-hydroxypregnenolone, 11β,17α,21-trihydroxypregnenolone, 17α,21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 21-hydroxypregnenolone, 11-ketoprogesterone, 11β-hydroxyprogesterone, 17α-hydroxyprogesterone, and 18-hydroxyprogesterone. 【0123】 Synthetic corticosteroids that may be mentioned include cortisone acetate, hydrocortisone acetate, hydrocortisone acetate, hydrocortisone buteplat, hydrocortisone butyrate, hydrocortisone valerate, thixocortol and thixocortol pivalate, prednisolone, methylprednisolone, prednisone, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolon, fluprednisolone, loteprednol, prednicarbate and triam Hydrocortisone-type substances (Group A) such as cinolone; acetonides and related substances (Group B) such as amcinonide, budesonide, desonide, fluocinolone cetonide, fluocinonide, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formocortal, fludroxycortide, flunisolid, and fluocinolone acetonide; beclomethasone, betamethasone, betamethasone dipropionate, and betamethasone valerate, dexamethasone, fluocortone, halomethasone, mometasone, and mometasone floeate (Group C) (beta)methasone-type drugs such as alclomethasone and alclomethasone dipropionate, clobetasol and clobetasol propionate, clobetasol and clobetasol butyrate, crocoltrone, desoxymethasone, diflorasone, diflocortrone, flurolon, flumetasone, fluocortin, flupredniden and flupredniden acetate, fluticasone, fluticasone furoate and fluticasone propionate, meprednisone, paramethasone, prednilidene, rimexolone and eurobetasol. Examples include progesterone-type progestins such as flugestone, fluorometholone, medrisone, and prevediolone acetate; progesterone derivatives (progestins) such as chlormadinone acetate, cyproterone acetate, medroguestone, medroxyprogesterone acetate, megestrol acetate, and segesterone acetate; and other corticosteroids such as cortibazole and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androsta-1,4,6-trien-3-one. 【0124】 Preferred corticosteroids include cortisone, prednisone, prednisolone, methylprednisolone, and especially dexamethasone. 【0125】 Furthermore, therapeutic agents that may be used in combination with the compounds of the present invention or pharmaceutically acceptable salts thereof include H2 receptor blockers, anticoagulants, antiplatelet agents, as well as statins, antibacterial agents, and antiallergic / antiasthmatic agents. 【0126】 Possible H2 receptor blockers to mention include famotidine. Possible anticoagulants to mention include heparin and low molecular weight heparins (e.g., bemiparin, nadroparin, reviparin, enoxaparin, parnaparin, sertoparin, dalteparin, tinzaparin), direct-acting oral anticoagulants (e.g., dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betrixaban, dalexaban, otamichaban, retaxaban, eribaxaban, hirudin, repirudine, and bivalirudine), coumarin vitamin K antagonists (e.g., coumarin, asenocumarol, fenprocumone, atromentin, and phenindione), and factor Xa synthesis pentasaccharide inhibitors (e.g., fondaparinux, hydrabarinux, and hydraviotaparinux). Antiplatelet agents that may be mentioned include irreversible cyclooxygenase inhibitors (e.g., spirin and triflusal), adenosine diphosphate receptor inhibitors (e.g., cangrelor, clopidogrel, prasugrel, ticagrelor and ticlopidine), phosphodiesterase inhibitors (e.g., cilostazol), protease-activated receptor 1 antagonists (e.g., borapaxal), glycoprotein IIB / IIIA inhibitors (e.g., absiximab, eptifivatide and tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), and thromboxane inhibitors (e.g., tertroban, ramatroban, seratrodast and picotamide). Statins that may be mentioned include atorvastatin, simvastatin and rosuvastatin. Antimicrobial agents that may be mentioned include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam, and teicoplanin. Antiallergic / antiasthmatic agents that may be mentioned include chlorpheniramine, levocetirizine, and montelukast. 【0127】 Therefore, the subject may also be receiving (and / or already receiving) one or more of the other therapeutic agents described above, which means receiving one or more prescribed doses of these other therapeutic agents before, in addition to, and / or after, treatment with the compound of the present invention or a pharmaceutically acceptable salt thereof. 【0128】 When the compounds of the present invention are “combined” with other therapeutic agents referred to in the foregoing specification, the active ingredients may be administered together in the same formulation or separately (simultaneously or sequentially) in different formulations. 【0129】 Such combination products provide administration of the compound of the present invention in combination with other therapeutic agents, and therefore, at least one of these formulations may be presented as separate formulations, or as a combination preparation (i.e., formulated) (i.e., as a single formulation containing the compound of the present invention and the other therapeutic agent). 【0130】 therefore, (1) A pharmaceutical preparation comprising the compound of the present invention; a therapeutic agent selected from the above (for example, one known to be metabolized by a CYP enzyme); and a pharmaceutically acceptable excipient (for example, an adjuvant, diluent, or carrier), hereinafter referred to as the "combination preparation," (2) A kit of parts comprising the following components: (A) A pharmaceutical preparation comprising the compound of the present invention mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, and (B) A pharmaceutical preparation comprising a therapeutic agent selected from the above (for example, one known to be metabolized by CYP enzymes) mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, A kit of parts is further provided, wherein components (A) and (B) are provided in forms suitable for administration together with the other. 【0131】 In a further aspect of the present invention, a process for preparing a combination formulation as defined above in this specification is provided, comprising associating a compound of the present invention, another anti-inflammatory agent, or therapeutic agent with at least one (e.g., pharmaceutically acceptable) excipient. 【0132】 In a further aspect of the present invention, a process for preparing a kit of parts as defined above in this specification is provided, the process comprising combining components (A) and (B). As used herein, the reference to combining would mean that the two components are suitable for administration together with each other. 【0133】 Therefore, with respect to the process for preparing the kit of parts as defined above in this specification by "combining" two components with each other, the two components of the kit of parts are: (i) They may be provided as separate formulations (i.e., independently of each other) and then combined for use in combination therapy, or (ii) may be packaged and presented together as separate components in a “combination pack” for use in combination therapy. 【0134】 therefore, (I) one of components (A) and (B) as defined herein, (II) A kit of parts is further provided, including instructions for using component (II) in combination with the other of the two components. 【0135】 Depending on the patient being treated and the route of administration, the compounds of the present invention may be administered in varying doses. While the dose will vary from patient to patient, a preferred daily dose is in the range of about 0.1 to about 1000 mg per patient (e.g., 0.1, 0.5, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 mg, or any range or value within that range), administered as a single or multiple dose. A more preferred daily dose is in the range of approximately 0.1 to approximately 250 mg per patient (e.g., 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 mg, or any range or value within that range). A particularly preferred daily dose is in the range of approximately 0.3 to 100 mg per patient. 【0136】 The individual doses of the compounds of the present invention may range from about 0.1 to about 100 mg (for example, 0.3, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg, or any range or value within that range). 【0137】 In any case, a physician or a person skilled in the art can determine the actual dosage that would be most suitable for an individual patient, which is likely to vary with the condition being treated, as well as the age, weight, sex, and response of the particular patient being treated. The dosages mentioned above are examples of average cases, and naturally, there may be individual cases where a higher or lower dosage range is appropriate, and such cases are within the scope of the present invention. 【0138】 The advantages of using the compounds of the present invention separately, and / or sequentially, and / or simultaneously in parallel, through a combination of administration routes, are to produce a treatment tailored for patients in need, which may prevent and / or reduce side effects, and to adjust the correct dosage level of the therapeutically effective amount of the compounds of the present invention. 【0139】 The kit of parts described herein may comprise two or more formulations containing an appropriate amount / dose of the compound of the present invention, and / or two or more formulations containing an appropriate amount / dose of another therapeutic agent to provide repeated doses. If two or more formulations (containing any of the active compounds) exist, such formulations may be identical or different in terms of the dose, chemical composition and / or physical form of any of the compounds. 【0140】 The “combined administration” of kits of parts as described herein includes the administration of each formulation comprising the compound of the present invention and other therapeutic agents sequentially, separately, and / or simultaneously over the course of treatment of the relevant condition. 【0141】 Therefore, with respect to the combination products according to the present invention, the term "administered in combination with ~" means administering the two components of the combination product (the compound of the present invention and the other therapeutic agent) together, or in sufficiently close time intervals (optionally repeated) to enable a greater beneficial effect to the patient over the course of treatment of the relevant condition than administering either the formulation containing the compound of the present invention or the formulation containing the other agent alone (optionally repeated) over the same course of treatment in the absence of the other component. The determination of whether the combination provides a greater beneficial effect with respect to the treatment of a particular condition and over the course of treatment depends on the condition being treated or prevented, but can be conventionally achieved by those skilled in the art. 【0142】 Furthermore, in the context of the kit of parts according to the present invention, the term “in conjunction with ~” includes the fact that one or the other of the two formulations may (optionally and repeatedly) be administered before, after, and / or simultaneously with the administration of the other components. When used in this context, the terms “co-administered” and “administered simultaneously with ~” include the fact that individual doses of the relevant compounds of the present invention and other anti-inflammatory agents are administered within 48 hours (e.g., 24 hours) of each other. 【0143】 The pharmaceutical compositions / formulations, combination products and kits described herein may be prepared in accordance with standard and / or acceptable pharmaceutical practices. 【0144】 Accordingly, further embodiments of the present invention provide a process for preparing a pharmaceutical composition / formulation as defined above herein, the process comprising combining a particular compound of the present invention as defined above herein with one or more pharmaceutically acceptable excipients (e.g., adjuvants, diluents, and / or carriers). 【0145】 In further aspects of the present invention, a process is provided for the preparation of a combination product or kit of parts as defined above herein, the process comprising combining a particular compound of the present invention as defined above herein with another therapeutic agent useful for the treatment of a related disease or disorder, and at least one pharmaceutically acceptable excipient. 【0146】 Suitable subjects for treatment with the formulation of the present invention include, but are not limited to, mammals, specifically humans. 【0147】 Where used herein in reference to a particular value (such as a quantity), the term “about” (or similar terms such as “approximately”) will be understood to indicate that such a value may vary by up to 10% (specifically, up to 5%, such as up to 1%) of the defined value. In each case, such a term may be replaced by notation such as “±10%” (or by indicating the variation of a particular quantity calculated based on the relevant value). In each case, such a term may also be omitted. 【0148】 The compounds of the present invention have the advantages of being more potent than metabolic hydrolysis, and / or stable to metabolic hydrolysis, and / or not inhibiting the CYP enzymes referred to herein. 【0149】 The compounds described herein, whether or not they are intended for use in the treatment of IPF, may have advantages over compounds known in the prior art, such as being more effective, less toxic, longer-acting, potent, having fewer side effects, being easily absorbed, and / or having a superior pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or possessing other useful pharmacological, physical, or chemical properties. Such effects may be evaluated clinically, objectively, and / or subjectively by healthcare professionals, patients, or observers. 【0150】 The present invention may be further described by reference to the following embodiments, which are not intended to limit the scope of the invention. 【0151】 In the event of any inconsistency between the nomenclature and any compound depicted in the figures, the latter shall prevail (unless it contradicts any experimental details that may be provided and / or is not evident from the context). 【0152】 Experimental Procedure The starting materials and intermediates used in the synthesis of the compounds described herein are commercially available or can be prepared by the methods described herein or by methods known in the art. 【0153】 Experiments were generally conducted under an inert atmosphere (nitrogen or argon), especially when using reagents or intermediates that were sensitive to oxygen or moisture. 【0154】 Mass spectrometry data from liquid chromatography-mass spectrometry (LC-MS) have been reported. The chemical shifts in the NMR data are expressed in parts per million (ppm, δ), referring to the residual peaks from the deuterated solvent used. 【0155】 In synthesis referring to general procedures, reaction conditions (such as reaction length or temperature) may vary. Generally, thin-layer chromatography or LC-MS was performed after the reaction, and workup was carried out as needed. Purification may vary between experiments. Generally, the ratio of solvent to the solvent used for the eluent / gradient is appropriate. f Selected to provide and / or retention time. Some products were purified using supercritical fluid chromatography on a reversed-phase column using, for example, mobile phase A: CO2 and solvent combination B: MeOH / H2O / NH3. Some compounds were purified using preparative HPLC, flash column chromatography, or manual C18 reversed-phase column with H2O / MeCN polarity. [Examples] 【0156】 Example 1 1-[[3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea (a) N-tert-butyl-3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide 1-[(4-bromo-2-fluorophenyl)methyl]-2-methylimidazole (2.5 g, 9.3 mmol; prepared by reacting 2-methylimidazole with 4-bromo-1-(bromomethyl)-2-fluorobenzene; both commercially available), 5-isobutyl-2-(tert-butylaminosulfonyl)-3-thiopheneboronic acid (3.0 g, 9.3 mmol; prepared as described in International Patent Application No. 2002 / 096883), K2CO3 (3.9 g, 27.9 mmol), and Pd(PPh3)4 (268 mg, 232 μmol) were added to dioxane (120 mL) and water (12 mL). The reaction mixture was heated overnight at 95°C under a nitrogen atmosphere. Most of the solvent was evaporated. Water (50 mL) was added, and the product was extracted with diethyl ether (2 × 50 mL). Chromatography from HCl-MeOH yielded 3.9 g of the subtitle product in 90% yield. 1 H-NMR(CDCl3):0.96(d,6H),1.05(s,9H),1.90(m,1H),2.40(s,3H),2.67(d,2H),5.12 (s,2H),6.71(s,1H),6.88(s,1H),6.95(m,1H),6.97(s,1H),7.20(d,1H),7.30(d,1H). 【0157】 (b) 3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide N-tert-butyl-3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide (4 g, 8.6 mmol; see step (a) above) was dissolved in dichloromethane (50 mL). Boron trichloride (26 mL, 1 M in dichloromethane) was added, and the solution was stirred at room temperature for 2 hours. Na2CO3 (saturated, 20 mL) was added, and the product was extracted with ethyl acetate (40 mL). The secondary product was obtained by chromatography from ethylacetate-MeOH in 1.72 g, in 49% yield. 1H-NMR(CDCl3):0.98(d,6H),1.92(m,1H),2.39(s,3H),2.68(d,2H),5.12(s,2H) ,6.74(s,1H),6.87(s,1H),6.91(t,1H),6.94(s,1H),7.32(d,1H),7.39(d,1H). 【0158】 (c)1-[[3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea 3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide (450 mg, 1.1 mmol; see step (b) above), diphenyl carbonate (355 mg, 1.66 mmol), and K2CO3 (305 mg, 2.21 mmol) were dissolved in acetonitrile (30 ml), and the reaction mixture was heated at 60°C for 4 hours. The solution was filtered, and the solvent was evaporated. The crude material and 3-aminoethanol (672 mg, 11 mmol) were dissolved in dioxane (15 mL). The reaction mixture was heated at 60°C overnight. The solvent was evaporated. The product was purified to a volume of 88 mg using supercritical fluid chromatography. 1 H-NMR(CD3OD):0.96(d,6H),1.91(m,1H),2.68(s,3H),2.69(d,2H),3.14(t,2H),3.49 (t,2H),5.29(s,2H),6.71(s,1H),7.24-7.38(b,5H),MS(M+H): Experimental value 495.20, Calculated value 495.61. 【0159】 Example 2 1-[[3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(3-hydroxypropyl)urea The title compound was prepared using a process similar to that described in Example 1 above, except that 3-aminopropanol was used in the final step. 1H-NMR(CDCl3):0.97(d,6H),1.57(m,2H),1.92(m,1H),2.68(s,3H),2.69(d,2H),3 .19(t,2H),3.49(t,2H),5.26(s,2H),6.72(s,1H),6.96(s,1H),7.18-7.35(b,4H). MS(M+H): Experimental value 509.20, Calculated value 509.64. 【0160】 Example 3 1-[[3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxy-2-methylpropyl)urea The title compound was prepared using a process similar to that described in Example 1 above, except that 1-amino-2-methylpropan-2-ol was used in the final step. 1 H-NMR(CD3OD):0.98(d,6H),1.07(s,6H),1.89(m,1H),2.38(s,2H),2.66(d,2H),2.72(s,3H) ,5.21(s,2H),6.76(s,1H),6.84(s,1H),7.04(t,1H),7.05(s,1H),7.46(d,1H),7.56(d,1H). 【0161】 Example 4 1-[[3-[2-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea The title compound was prepared using a process similar to that described in Example 1 above, except that 1-[(4-bromo-3-fluorophenyl)methyl]-2-methylimidazole was used in the first step. 1 H-NMR(CDCl3):0.87(d,6H),1.84(m,1H),2.59(d,2H),3.09(t,2H),3.24(s,3H),3 .44(t,2H),5.18(s,2H),6.60(s,1H),6.86(d,1H),6.91(d,1H),7.18-7.35(b,3H). MS(M+H): Experimental value 495.20, Calculated value 495.61. 【0162】 Example 5 1-[[3-[3,5-difluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea The same procedure as in Example 1, but using 1-[(4-bromo-2,6-fluorophenyl)methyl]-2-methylimidazole in the first step instead. 1 H-NMR(CDCl3):0.97(d,6H),1.92(m,1H),2.70(d,2H),2.78(s,3H),3.16(t,2H),3.53(t,2H),5.30(s,2H),6.70(s,1H),7.10-7.32(b,4H). MS(M+H): Experimental value 513.00 Calculated value 513.60. 【0163】 Example 6 1-[[3-[4-[(2-tert-butylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea 3-[4-[(2-tert-butylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutylthiophene-2-sulfonamide (148 mg, 330 μmol; prepared as described in step (b) of Example 1, except that 2-tert-butylimidazole was used in step (a)), diphenyl carbonate (106 mg, 495 μmol), and K2CO3 (91 mg, 660 μmol) were dissolved in acetonitrile (15 ml), and the reaction was heated overnight at 50°C under a nitrogen atmosphere. The solid was filtered off, and the solvent was evaporated. The crude material and 2-aminoethanol (61 mg, 1 mmol) were dissolved in dioxane (10 ml). The reaction was heated overnight at 60°C under a nitrogen atmosphere. The solvent was evaporated. The product was purified to an amount of 86 mg using HPLC and isolated as the CF3COOH salt. 1H-NMR(CDCl3):0.98(d,6H),1.62(s,9H),1.90(m,1H),2.69(d,2H),3.16(d,2H),3. 53(t,2H),5.52(s,2H),6.77(s,1H),7.18(t,1H),7.29(d,1H),7.33-7.40(m,3H)). MS(M+H): 538.0, calculated value: 537.2. 【0164】 Example 7 1-[[3-[4-[(2-tert-butylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxy-2-methyl-propyl)urea The title compound was prepared by a process similar to that described in Example 6, except that 1-amino-2-methylpropan-2-ol (89 mg, 1000 μmol) was used. The product was isolated as the CF3COOH salt in a yield of 133 mg. 1 H-NMR(CDCl3):0.98(d,6H),1.11(s,6H),1,63(s,9H),1.88(m,1H),2.70(d,2H) ,3.08(d,2H),5.50(s,2H),6.76(s,1H),7.18(t,1H),7.31(m,2H),7.42(m,2H). MS(M+H): 566.0, calculated value: 565.2. 【0165】 Example 8 1-[[3-[4-[(2-ethylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea The title compound was prepared by a process similar to that described in Example 6, except that 3-[4-[(2-ethylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutylthiophene-2-sulfonamide (211 mg, 500 μmol) and 2-aminoethanol (92 mg, 1500 μmol) were used. The product was isolated as the CF3COOH salt in a yield of 58 mg. 1H-NMR(CDCl3):0.86(d,6H),1.25(t,3H),1,80(m,1H),2.57(d,2H),2.84(q,2H) ,3.04(t,2H),3.38(t,2H),5.17(s,2H),6.60(s,1H),7.15(m,2H),7.24(m,3H). MS(M+H): 508.9, calculated value: 509.2. 【0166】 Example 9 1-[[3-[4-[(2-ethylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-[(1-hydroxycyclohexyl)methyl]urea The title compound was prepared by a process similar to that described in Example 6, except that 3-[4-[(2-ethylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutylthiophene-2-sulfonamide (211 mg, 500 μmol) and 1-aminomethyl-t-cyclohexanol (HCl salt) (248 mg, 1500 μmol) were used. The product was isolated as CF3COOH salt in a yield of 50 mg. MS(M+H): 577.0, calculated value: 577.2. 【0167】 Example 10 1-[[3-[3-fluoro-4-[(2-isopropylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea The title compound was prepared by a process similar to that described in Example 6, except that 3-[3-fluoro-4-[(2-isopropylimidazole-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide (218 mg, 500 μmol) and 2-aminoethanol (92 mg, 1500 μmol) were used. The product was isolated as the CF3COOH salt in a yield of 145 mg. 1H-NMR(CDCl3):0.97(d,6H),1.46(d,6H),1,92(m,1H),2.68(d,2H),3.17(q, 2H), 3.45 (m, 1H), 3.54 (t, 2H), 5.35 (s, 2H), 6.73 (s, 1H), 7.25-7.45 (m, 5H). MS(M+H): 523.0, calculated value: 523.2. 【0168】 Biological assays The biological activity of the example compounds described herein was evaluated using the following biological assays (and compared with C21). 【0169】 metabolic stability Human liver microsomes pooled in PBS at a concentration of 0.5 mg / mL were incubated at 37°C for 70 minutes with or without 1 mM NADPH. After 10 minutes, the test compound was added to a final concentration of 1 μM. Samples were removed at 0, 5, 15, and 60 minutes, added to test tubes containing acetonitrile, and the reaction was stopped using terfenadine, which was used as an internal standard. After centrifugation at 10,000 × g for 5 minutes, the supernatant was diluted 1:1 with 1% formic acid. The samples were separated using a reversed-phase column and detected by triple quadrupole MSMS (Agilant model 6540). The concentrations of the parent compound at different time points were measured on an external standard curve using terfenadine as an internal standard, and the initial metabolic rates in the presence or absence of NADPH were calculated. [Table 1] 【0170】 Binding to AT1 and AT2 receptors The compounds were evaluated for binding to human recombinant AT2 and AT1 receptors using radiometric scintillation assays according to Eurofins protocols ITEM26 and ITEM24. 【0171】 In short, IC 50For the measurements, recombinant proteins were incubated at 37°C for 2–4 hours with test compounds at concentrations of 1, 10, 100, and 1000 nM for the AT2 receptor, and 1 and 10 μM for the AT1 receptor. The Ki value of the AT2 receptor was determined using a 7-point dose-response curve. As a ligand for the AT1 receptor... 125 I(sar1,IIe8)-AT-II is used as a ligand for the AT2 receptor. 125 ICGP 42112A was used. The inhibition rate of control-specific binding was calculated according to 100 - (measured specific binding / control-specific binding) × 100. [Table 2] The asterisk (*) represents the median mean of the data obtained from two runs. 【0172】 CYP inhibition Compounds were evaluated at 10 μM for inhibition of major cytochrome P450 isoforms (CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A4&5) using isoform-specific substrates incubated with human liver microsomes (Eurofins protocol ITEMG232). The following substrates were used: CYP1A phenacetin, CYP2B6 bupropion, CYP2C8 paclitaxel and amodiaquin, CYP2C9 diclofenac, CYP2C19 omeprazole, CYP2D6 dextromethorphan, CYP3A midazolam and testosterone. 【0173】 At the end of incubation, metabolite formation was monitored as a peak area response by HPLC-MS / MS. [Table 3] [Table 4] 【0174】 Abbreviation The following abbreviations may be used in this specification. DCM Dichloromethane HCl ethyl acetate HPLC (High-Performance Liquid Chromatography) MeCN acetonitrile MeOH methanol NMR nuclear magnetic resonance MS mass spectrometry rt room temperature

Claims

[Claim 1] A compound of formula I, 【Chemistry 1】 During the ceremony, R １ However, by one or more fluorine atoms and / or OR ７ C is optionally replaced by １－４ Represents alkyl, R ２ and R ３ However, each independently represents H, or C is optionally substituted by one or more halogen atoms. １－６ Represents alkyl, Y １ 、 Y ２ 、 Y ３ 、 and Y ４ each independently represents -CH-, -CF-, or -N- R ４ However, C １－７ Alkyl, C １－６ Alkoxy, C １－６ Alkoxy-C １－６ Representing alkyl groups, each of these alkyl groups is substituted and / or terminated by at least one -OH group and optionally substituted with one or more halogen atoms. R ５ However, C represents H, or is optionally substituted with one or more halogen atoms. １－６ Represents alkyl, R ６ However, C is optionally substituted with one or more halogen atoms. ２－４ Represents alkyl, R ７ However, a compound that represents H, or a methyl atom optionally substituted with one or more fluorine atoms, or a pharmaceutically acceptable salt thereof. [Claim 2] R １ The compound according to claim 1, wherein the compound represents methyl, ethyl, isopropyl, or tert-butyl, which is optionally substituted with one or more fluorine atoms. [Claim 3] R ２ and R ３ The compound according to claim 1 or 2, wherein H or methyl is independently represented. [Claim 4] R ４ The compound according to any one of claims 1 to 3, wherein is ethyl, n-propyl, n-butyl, isobutyl, or methylcyclohexyl, each of which is substituted and / or terminated by one -OH group. [Claim 5] R ５ The compound according to any one of claims 1 to 4, wherein H represents methyl, ethyl, n-propyl, n-butyl, or isobutyl. [Claim 6] R ６ The compound according to any one of claims 1 to 5, wherein n-propyl, n-butyl, or isobutyl is represented. [Claim 7] R ７ A compound according to any one of claims 1 to 6, wherein H is represented. [Claim 8] Y １ However, it represents -CH- or -CF-, Y ２ However, it represents -CH or -CF-, Y ３ However, it represents -CH-, Y ４ The compound according to any one of claims 1 to 7, wherein -CH- is represented. [Claim 9] 1-[[3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea, 1-[[3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(3-hydroxypropyl)urea, 1-[[3-[3-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxy-2-methyl-propyl)urea, 1-[[3-[2-fluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea, or 1-[[3-[3,5-difluoro-4-[(2-methylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea, 1-[[3-[4-[(2-tert-butylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea, 1-[[3-[4-[(2-tert-butylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxy-2-methyl-propyl)urea, 1-[[3-[4-[(2-ethylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea, 1-[[3-[4-[(2-ethylimidazole-1-yl)methyl]-3-fluorophenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-[(1-hydroxycyclohexyl)methyl]urea, The compound according to claim 1, wherein the compound is 1-[[3-[3-fluoro-4-[(2-isopropylimidazole-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-hydroxyethyl)urea. [Claim 10] A compound according to any one of claims 1 to 9 for use as a pharmaceutical. [Claim 11] A pharmaceutical preparation comprising a compound according to any one of claims 1 to 9 in a mixture with a pharmaceutically acceptable adjuvant, diluent, or carrier. [Claim 12] A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 for use in the treatment of autoimmune diseases, viral respiratory infections and / or pneumonia resulting therefrom, fibrotic diseases, chronic kidney disease, pulmonary hypertension, heart failure, and / or myocardial infarction. [Claim 13] The pharmaceutical composition according to claim 12, wherein the disease is interstitial lung disease. [Claim 14] The pharmaceutical composition according to claim 13, wherein the interstitial lung disease is idiopathic pulmonary fibrosis or sarcoidosis. [Claim 15] The pharmaceutical composition according to claim 12, wherein the autoimmune disease is rheumatoid arthritis or systemic sclerosis. [Claim 16] The pharmaceutical composition according to claim 12, wherein the chronic kidney disease is diabetic nephropathy. [Claim 17] The pharmaceutical composition according to claim 12, wherein the pulmonary hypertension is pulmonary arterial hypertension. [Claim 18] The pharmaceutical composition according to claim 12, wherein the heart failure is a state in which the ejection fraction is maintained. [Claim 19] Use of the compound according to any one of claims 1 to 9 for the manufacture of agents for the treatment of autoimmune diseases, viral respiratory infections and / or pneumonia resulting therefrom, fibrotic diseases, chronic kidney disease, pulmonary hypertension, heart failure, and / or myocardial infarction. [Claim 20] The use according to claim 19, wherein the disease is interstitial lung disease. [Claim 21] The use according to claim 20, wherein the interstitial lung disease is idiopathic pulmonary fibrosis or sarcoidosis. [Claim 22] The use according to claim 19, wherein the autoimmune disease is rheumatoid arthritis or systemic sclerosis. [Claim 23] The use according to claim 19, wherein the chronic kidney disease is diabetic nephropathy. [Claim 24] The use according to claim 19, wherein the pulmonary hypertension is pulmonary arterial hypertension. [Claim 25] The use according to claim 19, wherein the heart failure is in a state in which the ejection fraction is maintained. [Claim 26] A process for preparing a compound of formula I as defined in any one of claims 1 to 9, wherein the process comprises: A compound of formula II, 【Chemistry 2】 In the formula, R １ , R ２ , R ３ , R ６ , Y １ , Y ２ , Y ３ , and Y ４ However, as defined in any one of claims 1 to 9, L is C １－６ A compound of formula II and a compound of formula III, representing alkyl or aryl, \.R ４ R ５ ΙΙΙ In the formula, R ４ and R ５ However, a reaction with a compound of formula III as defined in any one of claims 1 to 9, or (ii) R ５ However, in the compound represented by formula I, which represents H, it is the compound of formula IV, 【Transformation 3】 In the formula, R １ , R ２ , R ３ , R ６ , Y １ , Y ２ , Y ３ , and Y ４ However, a compound of formula IV and a compound of formula V, as defined in any one of claims 1 to 9. R ４ -N=C=O V Or a compound of formula VI, 【Chemistry 4】 In the formula, X １ However, the preferred leaving group is selected from halogen, -O-C1-6 alkyl, or -O-aryl, and in each case, R ４ A process comprising a reaction with a compound of formula VI, as defined in any one of claims 1 to 9.

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