Selective angiotensin II receptor ligands

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] TIFF2024511451000020.tif7463

Description

[Technical field]

[0001] The present invention relates to novel medicamentously useful compounds, particularly compounds which are angiotensin II (Ang II) agonists, more particularly agonists of the Ang II type 2 receptor (hereinafter AT2 receptor), especially agonists which selectively bind to that receptor. The invention further relates to the use of such compounds as medicaments, pharmaceutical compositions containing them, and synthetic routes to their preparation. [Background technology]

[0002] The protease renin cleaves its only known substrate (angiotensinogen) to form angiotensin I (Ang I), which then serves as a substrate for angiotensin converting enzyme (ACE) to form Ang II. The endogenous hormone Ang II is a linear octapeptide (Asp 1 -Arg 2 -Val 3 -Tyr 4 -Ile 5 -His 6 -Pro 7 -Phe 8 ), an active component of the renin-angiotensin system (RAS). Angiotensin II type 1 (AT1) receptors are expressed in most organs and are thought to be responsible for most of the pathological effects of Ang II.

[0003] Several studies in adult individuals appear to demonstrate that activation of the AT2 receptor has an effect opposing that mediated by the AT1 receptor in modulating responses following Ang II receptor stimulation. The AT2 receptor has also been shown to be involved in the inhibition of apoptosis and cell proliferation (de Gasparo M et al., Pharmacol. Rev. (2000); 52, 415-472). More recently, AT2 receptor agonists have been shown to be of potential utility in the treatment and / or prevention of disorders of the gastrointestinal tract, such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see International Patent Application No. 99 / 43339). The expected pharmacological effects of AT2 receptor agonism are generally described in 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 mediated by AT1 receptors in any organ, whereas AT2 receptor function appears to be more prevalent in damaged tissues, exerting reparative and opposing properties to AT1 receptors. For example, AT2 receptors have been shown to be important for myocyte hypertrophy and reduction of fibrosis.

[0005] Interstitial lung diseases (ILDs) are a group of lung diseases that affect the interstitium and are characterized by scarring and / or thickening of the tissue surrounding the alveoli, thereby impeding the breathing process.

[0006] ILDs differ from obstructive airway diseases (e.g., chronic obstructive airway disease (COPD) and asthma), which are usually characterized by narrowing (obstruction) of the bronchi and / or bronchioles. ILDs can be caused by injury to the lungs, triggering an abnormal healing response, although in some cases the cause of these diseases is unknown. ILDs may 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 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 collections of inflammatory cells that form masses (granulomas) and often begins in the lungs (as well as the skin and / or lymph nodes, although any organ may be affected.) When sarcoidosis affects the lungs, symptoms include coughing, wheezing, shortness of breath, and / or chest pain.

[0009] Treatment of sarcoidosis is patient-specific: most cases can be treated symptomatically with nonsteroidal anti-inflammatory drugs (NSAIDs), but patients with pulmonary manifestations often receive glucocorticoids (e.g., prednisone or prednisolone), antimetabolites, and / or monoclonal anti-tumor necrosis factor antibodies.

[0010] IPF is a lung disease of unknown etiology that affects approximately 5 million people worldwide. There are no curative treatment options, except for lung transplantation, which, in rare cases, leads to a chronic, irreversible, progressive deterioration of lung function and, in most cases, death within 2-5 years (median survival 2.5-3.5 years). The overall prognosis is poor in IPF, but it is difficult to predict the rate of progression in individual patients. Risk factors for IPF include age, male sex, genetic predisposition, and smoking history. The annual incidence is 5-16 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 distinct from pulmonary fibrosis, which is associated with systemic disease, in that it is confined to the lungs and is refractory to therapies that target the immune system.

[0011] Patients with IPF usually seek medical assistance due to chronic and progressive exertional dyspnea and cough. Pulmonary 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 diagnosis of IPF is highly likely. Definitive diagnosis is usually made by lung biopsy and requires a multidisciplinary team of expertise including pulmonologists, radiologists, and pathologists experienced in interstitial lung disease.

[0012] IPF presents different phenotypes with different prognoses defined as mild, moderate, and severe. Mild cases follow a stable or slowly progressive course, and patients may take years to seek medical advice. Rapid IPF shows a more rapid progression, shortens survival, and affects a subgroup of patients, usually male smokers. Acute exacerbations of IPF are defined as a rapid worsening of the disease, and this subpopulation of patients shows 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 that likely results in unabated tissue remodeling by fibroblasts rather than normal repair from an interplay of environmental and genetic factors, with a pathogenesis that is primarily fibrotic rather than inflammatory. Growing evidence suggests that the disease is initiated through microdamage and apoptosis of alveolar epithelial cells, activating neighboring epithelial cells and attracting stem or progenitor cells that produce factors involved in the expansion of fibroblast and myofibroblast populations in a tumor-like manner. Fibroblast nests secrete excessive amounts of extracellular matrix that destroys the lung parenchyma and ultimately leads to loss of lung function.

[0013] The average annual rate of decline in lung function (vital capacity) ranges from 0.13 to 0.21 liters. Symptoms precede diagnosis by 1 to 2 years, and radiographic signs may precede symptoms (Ley B et al., Am. J. Respir. Crit. Care Med. (2011);183,431-440).

[0014] Many therapeutic approaches have been tested in preclinical models and clinical trials, including anti-inflammatory, immunomodulatory, cytotoxic, general antifibrotic, antioxidant, anticoagulant, antichemokine, antiangiogenic drugs as well as RAS blockers, endothelin antagonists, and sildenafil, and have essentially been shown to provide limited or no benefit (Rafii R et al., J. Thorac. Dis. (2013);5,48-73).

[0015] Current treatments for IPF include supplemental oxygen. Medications used include pirfenidone or nintedanib, but they have limited effectiveness in slowing disease progression. Furthermore, both of these drugs generally cause side effects (mainly gastrointestinal).

[0016] There are drawbacks associated with all of the aforementioned pharmacological treatments for ILD (and IPF) and there is a compelling clinical need for safer and / or more effective treatments.

[0017] Restoring the alveolar epithelium is a highly desirable therapeutic effect in IPF, and therefore stem cell therapy is also being tested. Several preclinical studies have shown that the use of pluripotent stem cells can differentiate into pulmonary epithelial and endothelial cells, which may repair lung injury and fibrosis.

[0018] Currently, lung transplantation is the only intervention that substantially improves survival in patients with IPF, however complications such as infection and graft rejection are significant.

[0019] Therefore, the development of new therapeutic strategies for IPF is important. Therefore, a fundamental challenge for the future is to develop appropriate therapeutic approaches to reverse or halt the progression of the disease.

[0020] US Patent Application No. 2004 / 0167176 describes the preparation of tricyclic heterocycles useful as Ang II receptor agonists.

[0021] Selective AT2 receptor agonists with reduced CYP450 inhibition are 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, triazolyl, and tetrazolylthiophene sulfonamides and derivatives as AT2 receptor agonists. Among the compounds described in that document (as Example 1) is compound C21 (N-butyloxycarbonyl-3-(4-imidazol-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. WO 2016 / 139475).

[0024] C21 has also been indicated for potential use in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cardiotoxicity associated with cancer therapy, peripheral neuropathy, and systemic sclerosis, among others (see, e.g., International Patent Applications Nos. 2004 / 046141, 2016 / 092329, 2016 / 107879, 2016 / 139475, 2017 / 221012, 2019 / 008393, and U.S. Patent Application No. 2012 / 035232).

[0025] During development, C21 was found to be a potent inhibitor of several cytochrome P450 enzymes (CYPs), particularly CYP 2C9 and CYP 3A4, which potentially affect the metabolism of other drugs, and also has the drawback of being rapidly hydrolyzed to inactive sulfonamide metabolites. Therefore, it is a fundamental challenge to develop potent and selective AT2 agonists that are metabolically stable and / or have low inhibition of CYP enzymes.

[0026] Surprisingly, it has been found that certain chemically modified compounds, as defined below, are not only selective AT2 receptor agonists, but are also more potent, have significantly improved stability against metabolic hydrolysis and / or exhibit less inhibition of CYP enzymes compared to C21. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] In a first aspect of the invention, there is provided a compound of formula I, [ka] During the ceremony, R 1 (C optionally substituted with one or more fluorine atoms) 1-2 Alkyl, OR 7 or a fluorine atom, R 2 and R 3 each independently represents H or C optionally substituted by one or more halogen atoms; 1-6 represents an alkyl group, Y 1 , Y 2 , Y 3 , and Y 4 represents independently -CH-, -CF-, or -N-; R 4 But, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6alkyl, each of which the alkyl portion is optionally substituted with one or more halogen atoms; R 4 Aryl, C 1-6 Alkylaryl, C 1-3 Alkenylaryl, heteroaryl, C 1-6 alkylheteroaryl, or C 1-3 alkenylheteroaryl, each of which is halogen, -CF3, CF3O-, C 1-6 Alkyl, and C 1-6 Optionally substituted by one or more substituents selected from alkoxy; R 5 But H or C 1-6 alkyl, each of which is optionally substituted with one or more halogen atoms; R 6 C optionally substituted by one or more halogen atoms 2-4 represents an alkyl group, R 7 represents H or represents methyl optionally substituted by one or more fluorine atoms, or a pharma- ceutically acceptable salt thereof is provided. These compounds and salts are hereinafter referred to as "compounds of the invention."

[0028] For the purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

[0029] Compounds may be named according to the IUPAC nomenclature system, generated by the program Chemdoodle 8.1.0.

[0030] For the avoidance of doubt, those skilled in the art will understand that reference herein to a compound of a particular aspect of the invention (such as any aspect of the invention, which refers to a compound of formula I as defined herein above) includes reference to all embodiments and specific features thereof, which embodiments and specific features may be combined to form further embodiments and features of the invention.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0032] 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 or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (for example, by vacuum, lyophilization or filtration). Salts may also be prepared using techniques known to those skilled in the art, for example, by exchanging the counterion of the compound of the present invention in the form of a salt with another counterion using a suitable ion exchange resin.

[0033] Particular acid addition salts that may be mentioned include carboxylates such as formates, acetates, trifluoroacetates, benzoates, oxalates, fumarates, maleates, sulfonates such as methanesulfonates, ethanesulfonates, toluenesulfonates, halide salts such as hydrochlorides, hydrobromides, sulfates and phosphates, etc.

[0034] Particular base addition salts which may be mentioned include salts formed with alkali metals (such as Li, Na and K salts), alkaline earth metals (such as Mg and Ca salts) or other metals (such as Al and Zn salts), amine bases (such as ammonia, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, etc.) More particularly, the base addition salts which may be mentioned include Mg salts, Ca salts, and most particularly K salts and Na salts.

[0035] The compounds of the present invention may exist as solids, and therefore the scope of the present invention includes all amorphous, crystalline, and partially crystalline forms thereof, 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 within the scope of the present invention.

[0036] The compounds of the present invention may also be present in solution (i.e. in a solution in a suitable solvent). For example, the compounds of formula I may be present in aqueous solution, in which case the compounds of the present invention may be present in the form of hydrates.

[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 about 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 invention may also exhibit tautomerism, and all tautomers and mixtures thereof (especially those with sufficient stability to allow their isolation) are included within the scope of the invention.

[0039] The compounds of the present invention may also contain one or more asymmetric carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism (i.e., may exist in enantiomeric or diastereomeric forms). Diastereomers may be separated using conventional techniques, for example, chromatography or fractional crystallization. The various stereoisomers (i.e., enantiomers) can be isolated by separating racemic or other mixtures of the compounds using conventional, for example, fractional crystallization or HPLC techniques. Alternatively, the desired enantiomer or diastereomer can be obtained from suitable optically active starting materials under conditions that will not cause racemization or epimerization (i.e., the "chiral pool" method), by reaction of the appropriate starting materials with a "chiral auxiliary" that can be subsequently removed at a suitable stage, by derivatization (i.e., resolution, including kinetic resolution, for example, treatment with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography), or by reaction with a suitable chiral reagent or chiral catalyst, all of which methods and processes may 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 iodo.

[0041] Unless otherwise specified, C as defined herein 1-6 Alkyl groups (e.g., C 1-2 Alkyl group), C 2-4 Alkyl groups, and C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylaryl, C 1-3 Alkenylaryl, C 1-6 Alkylheteroaryl, and C 1-3The alkyl portion of the alkenylheteroaryl group can be linear or, when there is a sufficient number (i.e., a minimum of 2 or 3, as appropriate) of carbon atoms, can be branched and / or cyclic (e.g., C 3-6 When there is a sufficient number (i.e., a minimum of four) of carbon atoms, such groups may also be part cyclic (e.g., C 4-6 (which may form a partial cycloalkyl group). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Similarly, partial cyclic alkyl groups (which may also be referred to as "partial cycloalkyl" groups) that may be mentioned include cyclopropylmethyl. When a sufficient number of carbon atoms are present, such groups may also be polycyclic (e.g., bicyclic or tricyclic) and / or spirocyclic.

[0042] The alkyl and alkoxy groups, when there is a sufficient number (ie, a minimum of three) of carbon atoms, may be unsaturated and thus incorporate double or triple bonds.

[0043] Particular alkyl groups that may be mentioned include linear (i.e., not branched and / or cyclic) alkyl groups. For example, 1-6 Alkyl groups, and C 1-6 The alkyl portion of the alkoxy group includes, but is not limited to, n-butyl, sec-butyl, isobutyl, tert-butyl; propyl, such as n-propyl, 2-methylpropyl, or isopropyl; ethyl; and methyl.

[0044] For the avoidance of any doubt, C 1-6 Alkyl groups and C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylaryl, C 1-3 Alkenylaryl, C 1-6 Alkylheteroaryl, and C 1-3 The point of attachment of the alkenylheteroaryl group to the alkyl portion of such group is through the alkyl portion of such group.

[0045] For the avoidance of doubt, alkoxy groups are bonded to the remainder of the molecule through the oxygen atom of the group, and alkoxyalkyl groups are bonded to the remainder of the molecule through the alkyl moiety of the group.

[0046] Unless otherwise specified, alkoxy refers to an O-alkyl group, where the term "alkyl" has the meaning given above.

[0047] As used herein, references to heteroatoms shall take their ordinary meaning as understood by those of ordinary skill in the art. Particular heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen and sulfur (e.g., oxygen, nitrogen and sulfur, such as oxygen and nitrogen).

[0048] As may be used herein, reference to a "heteroaryl" (which may also be referred to as heteroaromatic) ring or group may refer to a heteroaromatic group containing one or more heteroatoms (such as one or more heteroatoms selected from oxygen, nitrogen, and / or sulfur). Such heteroaryl groups may contain one, two, or three rings, at least one of which is aromatic (which aromatic ring may or may not contain one or more heteroatoms). Substituents on the heteroaryl / heteroaromatic group, where appropriate, may be located on any suitable atom in the ring system that contains a heteroatom (e.g., on a suitable N atom).

[0049] The point of attachment of the heteroaryl / heteroaromatic group may be via any atom of the ring system including (where appropriate) a heteroatom. Bicyclic heteroaryl / heteroaromatic groups may contain a benzene ring fused to one or more further aromatic or non-aromatic heterocyclic rings, in which case the point of attachment of the polycyclic heteroaryl / heteroaromatic group may be via the benzene ring or any ring comprising the heteroaryl / heteroaromatic or heterocyclic ring.

[0050] For the avoidance of doubt, those skilled in the art will understand that the heteroaryl groups which may form part of the compounds of the present invention are those which are chemically obtainable, as known to those skilled in the art. A variety of heteroaryl groups, such as pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolylthiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, and purinyl, will be known to those skilled in the art.

[0051] For the avoidance of doubt, oxides (eg, N-oxides) of heteroaryl / heteroaromatic groups are also encompassed within the scope of the present invention.

[0052] As mentioned above, heteroaryl includes polycyclic (e.g., bicyclic) groups in which one ring is aromatic (the other may or may not be aromatic).Other heteroaryl groups that may be mentioned thus include benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazole, 3,4-dihydrobenzo[1,4]oxazinyl, dihydrobenzothiophenyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, thiochromanyl, and other groups.

[0053] As used herein, the term aryl refers to C 6-14 (For example, C 6-10 ) aromatic groups. Such groups may be monocyclic or bicyclic, and if bicyclic, may be either fully aromatic or partially aromatic. 6-10Aryl groups include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like (eg, phenyl, naphthyl, and the like).

[0054] An aromatic group may be represented as a cyclic group containing a suitable number of double bonds therein to permit aromaticity.

[0055] Those skilled in the art will recognize that the aryl groups that may form part of the compounds of the present invention are chemically available, as known to those skilled in the art.

[0056] For the avoidance of doubt, the point of attachment of substituents on an aryl group may be via any suitable carbon atom of the ring system.

[0057] The present invention also includes isotopically labeled compounds of the present invention, in which one or more atoms are actually replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or most abundantly found in nature), but are the same as described herein.All isotopes of any specific atom or element specified herein are contemplated within the scope of the compounds of the present invention.Therefore, 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 the hydrogen isotope deuterium.

[0058] In the case where the identity of two or more substituents in the compound of the present invention may be the same, the actual identity of each substituent is in no way mutually dependent.For example, in the situation where two or more halo groups are present, those groups may be the same or different (e.g., two chloro groups, or a fluoro group and a chloro group).Similarly, when two or more alkyl groups are present, the groups in question may be the same or different in terms of their number of carbon atoms and / or in terms of whether they are linear, branched, unsaturated, or otherwise.

[0059] Further, when a substituent is itself specified as being optionally substituted with one or more substituents (e.g., butyl optionally substituted with one or more groups independently selected from halo), these substituents may be located on the same or different atoms, where possible. Such optional substituents may be present in any suitable number thereof (e.g., the relevant group may be substituted with one or more such substituents, such as one such substituent).

[0060] Where a group is referred to herein as being optionally substituted, it is specifically contemplated that such optional substituents may be absent (i.e., reference to such optional substituents may be omitted), in which case the optionally substituted group may be referred to as unsubstituted.

[0061] Unless otherwise specified, substituents (whether optional or not) may be located at any point on the group to which they may be attached. In this regard, alkyl and alkoxy groups (for example) which may be substituted by one or more substituents may also be terminated by such a substituent (i.e., meaning located at the end of the alkyl or alkoxy chain).

[0062] For the avoidance of doubt, where the identities of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are in no way interdependent. For example, R 2 and R 3 Both are C 1-6 In the case of alkyl, the C in question 1-6 The alkyl groups can be the same or different.

[0063] Those of skill in the art will appreciate that the compounds of the invention that are the subject of the present invention include those that are available, i.e., that can be prepared in a stable form, i.e., compounds of the present invention include compounds that are sufficiently robust to survive isolation, e.g., isolation to a useful degree of purity from a reaction mixture.

[0064] Preferred compounds of the present invention include R 1 represents a methyl or ethyl group, which is optionally substituted by up to three fluorine atoms (e.g., CH2CF3), R 2 and R 3 independently represents H or C optionally substituted by up to three halogen atoms; 1-4 represents an alkyl group (such as methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., n-butyl)) (e.g., CH2CHClCH2CH2F or CH2CF3); Y 1 represents -CH-, -CF-, or -N-; Y 2 represents -CH- or -CF-; Y 3 represents -CH-; Y 4 represents -CH- or -N-; R 4 But, C 1-4 Alkyl groups (such as ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., tert-butyl, isobutyl, or n-butyl), etc.); 1-4 Alkoxy-C 1-4 Alkyl (e.g. methoxyethyl), phenyl, C 1-3 Alkylaryl or C 1-3 each of which is optionally substituted or terminated with up to three halogen atoms (such as F); R 5 represents H or C 1-4 represents an alkyl group (such as methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., isobutyl), R 6 represents ethyl, propyl (eg, n-propyl), or butyl (eg, n-butyl) optionally substituted by one or more halogens.

[0065] More preferred compounds of the present invention include R1 Methyl, OR 7 or a fluorine atom, R 2 and R 3 each independently represents H or methyl; Y 1 , Y 2 , Y 3 , and Y 4 represents independently -CH- or -CF-; R 5 represents H, methyl, ethyl, n-propyl, n-butyl, or isobutyl; R 6 represents n-propyl, n-butyl, or isobutyl, optionally substituted or more preferably terminated by up to three fluorine atoms; R 7 represents H or methyl.

[0066] Particularly preferred compounds of the present invention include R 1 represents methyl, R 2 and R 3 But both represent H, Y 1 represents -CH- or -CF-; Y 2 , Y 3 , and Y 4 are all -CH-, R 4 represents ethyl, n-propyl, or n-butyl, optionally terminated by up to three fluorine atoms; methoxyethyl; benzyl; 2-methylfuryl, 2-methylthiophenyl, or 2-methylpyridyl, R 5 represents H, R 6 However, examples thereof include isobutyl.

[0067] Thus, preferred compounds of the invention that may be mentioned are: Furan-2-ylmethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonyl]urea, Thiophene-2-ylmethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl] -2-thienyl]sulfonylurea, 2-Methoxyethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonylurea, pyridin-2-ylmethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonylurea, 1-[[3-[4-[(2-tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-pyridylmethyl)urea, 1-[[3-[4-[(2-tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-ethyl-urea, or 1-[[3-[4-[(2-tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-thienylmethyl)urea.

[0068] IUPAC names can be generated from the program Chemdoodle 8.1.0.

[0069] More preferred compounds of the present invention include the compounds of the Examples described below.

[0070] Compounds of formula I may be made according to techniques well known to those skilled in the art, for example as described below.

[0071] According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I, the process comprising: (i) A compound of formula II [ka] In the formula, R 1 , R 2 , R 3 , R 6 , Y 1 , Y 2 , Y 3 , and Y 4 is as defined hereinabove, and L is C 1-6 A compound of formula II, which represents an alkyl or aryl group (such as phenyl), and a compound of formula III or a salt thereof, NHR 4 R 5 III In the formula, R 4 and R 5 with a compound of formula III, or a salt thereof, wherein: (ii)R 5 In the case of compounds of formula I, where represents H, compounds of formula IV, [ka] In the formula, R 1 , R 2 , R 3 , R 6 , Y 1 , Y 2 , Y 3 and Y 4 is as defined hereinbefore, and a compound of formula V, R 4 -N=C=OV In the formula, R 4is as defined herein above, for example, optionally in the presence of 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 mixtures thereof), and a suitable solvent (e.g., pyridine, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, acetonitrile, or mixtures thereof) at about room temperature or above room temperature (e.g., up to 60-70° C.). (iii)R 5 In the case of a compound of formula I, wherein represents H, a compound of formula IV as defined hereinbefore and a compound of formula VI, [ka] In the formula, R 4 is as defined hereinabove, and X 1 is a suitable leaving group (e.g., halo (e.g., chloro or bromo), -OC 1-6 Alkyl or -OC 1-6 Reaction with a compound of formula VI which is aryl (e.g., -OPh), for example, includes reaction 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]undec-7-ene, or mixtures thereof) and a suitable solvent (e.g., acetonitrile, pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, or toluene) at above room temperature under microwave irradiation.

[0072] A compound of formula II is a compound of formula IV as defined hereinbefore and a compound of formula VII, [ka] In the formula, X 1a and X 1b Each of X is defined hereinabove. 1 and may be prepared, for example, by reaction with a compound of formula VII, which may be the same or different, in the presence of a suitable base as defined herein above and a suitable solvent (e.g., pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, acetonitrile, or toluene) at below, at about, or above room temperature (e.g., 0° C., or up to 50-70° C.).

[0073] The compound of formula IV is a compound of formula VIII, [ka] In the formula, R 6 is as defined hereinbefore or an N-protected derivative thereof, X 2 represents a suitable cross-coupling group, and a compound of formula IX, [ka] In the formula, R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , and Y 4 is as defined hereinabove, and X 3 can be prepared by reaction with a compound of formula IX, which 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 can be carried out by reacting X 2 and X 3represents any one of the suitable Suzuki cross-coupling groups (or "partners"), i.e., a boronic acid (-B(OH)2) or a boronic ester (e.g., a MIDA derivative or a pinacol ester), and a halo group, such as iodo or bromo, and the other represents the other group. Standard Suzuki conditions can be applied to this reaction, including, for example, the presence of a suitable coupling catalyst system (e.g., a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane, Pd(PPh3)4, or Pd(OAc)2 / ligand (wherein the ligand can be, for example, PPh3, P(o-Tol)3, or 1,1'-bis(diphenylphosphino)ferrocene)) and a suitable base (e.g., sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or di-iso-propylamine), as well as a suitable solvent system (e.g., toluene, ethanol, n-butanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane, or mixtures thereof). The reaction can be carried out at room temperature or above (e.g., at the reflux temperature of the solvent system used). This reaction can be carried out under microwave irradiation above room temperature.When a protected version of the compound of formula VIII is used, this reaction can be followed by deprotection of the SO2NH group, for example under standard conditions as described below.The reaction of the compound of formula VIII with the compound of formula IX can also be followed by reacting the intermediate thus formed with a suitable acid to form an acid addition salt, or more preferably, its N-protected version.Suitable acid addition salts include fumarate, trifluoroacetate and oxalate.

[0074] Alternatively, the compound of formula IV is a compound of formula X, [ka] In the formula, R 1 , R2 , and R 3 is as defined hereinbefore, and a compound of formula XI, [ka] In the formula, R 6 , X 1 , Y 1 , Y 2 , Y 3 , and Y 4 is as defined hereinabove (X 1 may be specifically represented by bromo) or its N-protected derivative, for example in the presence of a suitable base (e.g. pyridine) and a suitable organic solvent (e.g. toluene) at about or below room temperature. If a protected version of the compound of formula XI is used, this reaction may be followed by deprotection of the SO2NH group, for example under standard conditions as described below. Furthermore, the compound of formula IV may be prepared in this way, for example according to or analogously to the processes described, inter alia, in British Patent Application No. 2281298.

[0075] Compounds of formula IX can be prepared by standard techniques, for example by reacting a compound of formula X, as defined hereinbefore, with a compound of formula XII, [ka] In the formula, X 1 , X 3 , Y 1 , Y 2 , Y 3 , and Y 4 can be prepared by reaction with a compound of formula XII, which is as defined hereinbefore, for example under conditions similar to those described hereinbefore for the preparation of a compound of formula IV.

[0076] Compounds of formula XI are known in the art. For example, they can be prepared according to or analogously to the processes described, inter alia, in U.S. Patent No. 5,312,820, British Patent Application No. 2281298, and / or International Patent Application No. 02 / 096883.

[0077] Compounds of formula VIII are known in the art. For example, they can be prepared according to or analogously to the processes described, inter alia, in International Patent Application No. WO 02 / 096883.

[0078] Compounds of formula III, V, VI, VII, X, and XII are either commercially available, known in the literature, or can be obtained from readily available starting materials using suitable reagents and reaction conditions according to standard techniques, either by analogy with the processes described herein, or by conventional synthetic procedures.

[0079] It will be appreciated by those skilled in the art that in the processes described above and below, the functional groups of intermediate compounds may need to be protected by protecting groups.

[0080] Functional groups that are desirable to be protected include sulfonamide, amide, amino, and aldehyde. Suitable protecting groups for sulfonamide, amide, and amino include tert-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), or tert-butyl. Suitable protecting groups for aldehyde include alcohols such as methanol or ethanol, and diols such as 1,3-propanediol, or preferably 1,2-ethanediol (thus forming a cyclic acetal). Protection and deprotection of functional groups can be carried out before or after the reaction in the scheme mentioned above.

[0081] Protective groups can be applied and removed according to techniques well known to those skilled in the art and 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 dictate the need and type of protecting groups, as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3rd edition, TW Greene & P. ​​GMWutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference.

[0082] Medical and pharmaceutical uses As described herein, the compounds of the invention, and thus compositions and kits comprising same, are useful because they have pharmacological activity and / or are metabolized in the body following oral or parenteral administration to form compounds that have pharmacological activity.

[0083] Thus, according to a further aspect of the invention there is provided a compound of the invention as defined below for use as a pharmaceutical (or for use as a medicament).

[0084] In particular, the compounds of the invention are agonists of the AT2 receptor and are therefore expected to be useful in conditions where there is a deficiency in endogenous production of Ang II and / or where increased activity of the AT2 receptor is desirable or required.

[0085] More specifically, the compounds of the invention are agonists of the AT2 receptor and, in particular, selective agonists of its sub-receptors (vs. the AT1 receptor), as can be demonstrated, for example, in the tests described below.

[0086] AT2 receptor agonists include those that fully activate AT2 receptors and those that partially activate AT2 receptors.Therefore, the compounds of the present invention can selectively bind to AT2 receptors and exhibit agonist activity at AT2 receptors.A compound that "selectively binds" to AT2 receptors includes that the affinity ratio (AT2:AT1) of related compounds at a given concentration is at least 50:1, such as at least 100:1, preferably at least 1000:1.

[0087] Compounds of the invention are further expected to be useful in conditions where AT2 receptors are expressed and their stimulation is desirable or required.

[0088] In this regard, the compounds of the invention are indicated 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.

[0089] The compounds of the invention may also exhibit thromboxane receptor activity. In this regard, the compounds of the invention may have an inhibitory effect on platelet activation and / or aggregation (hence, for example, an antithrombotic effect) and / or may reduce vasoconstriction and / or bronchoconstriction in a therapeutic manner.

[0090] The compounds of the invention are further indicated in the treatment of stress-related disorders and / or in improving microcirculatory and / or mucosal protective mechanisms.

[0091] Thus, the compounds of the invention may be characterized as set forth above and are expected to be useful in the treatment of disorders, for example, of the gastrointestinal tract, cardiovascular system, respiratory tract, kidney, eye, female reproductive (ovulatory) system, and central nervous system (CNS).

[0092] Gastrointestinal disorders that may be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastroesophageal reflux, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), liver disorders (such as hepatitis), gallbladder disease, multiple organ failure (MOF) and sepsis.Other gastrointestinal disorders that may be mentioned include xerostomia, gastritis, gastroparesis, hyperacidity, biliary disorders, coeliosis, Crohn's disease, ulcerative colitis, diarrhea, constipation, colitis, anorexia, vomiting, nausea, dyspepsia and Sjogren's syndrome.

[0093] Disorders of the airways that may be mentioned include asthma, obstructive pulmonary diseases (such as chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension, and inflammatory disorders such as adult respiratory distress syndrome.

[0094] Renal disorders that may be mentioned include renal failure, nephritis, and renal hypertension.

[0095] Eye disorders that may be mentioned include diabetic retinopathy, early onset retinopathy, and retinal microangiogenesis.

[0096] Disorders of the female reproductive system that may be mentioned include ovulatory dysfunction.

[0097] Cardiovascular disorders that may be mentioned include hypertension, cardiac hypertrophy, heart failure (including heart failure with preserved ejection fraction), atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial lesions, post-balloon dilation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina, cardiac arrhythmias, intermittent cloudicates, pre-eclampsia, myocardial infarction, reinfarction, ischemic lesions, erectile dysfunction, and neointimal proliferation.

[0098] Diseases of the CNS that may be mentioned include cognitive dysfunction, dysfunction of food intake (hunger / satiety) and thirst, stroke, cerebral hemorrhage, cerebral embolism and infarction, multiple sclerosis (MS), Alzheimer's disease, and Parkinson's disease.

[0099] The compounds of the invention may also be useful in regulating growth metabolism and proliferation, for example in the treatment of aging, hypertrophic disorders, prostatic hyperplasia, autoimmune disorders (e.g., arthritis such as rheumatoid arthritis, or systemic lupus erythematosus), psoriasis, obesity, nerve cell regeneration, ulcer healing, inhibition of adipose tissue hyperplasia, stem cell differentiation and proliferation, fibrotic disorders, cancer (e.g., of or in the gastrointestinal tract (including the esophagus or stomach), prostate, breast, liver, kidney, as well as lymphoma, lung cancer, ovarian cancer, pancreatic cancer, hematological malignancies, and the like), apoptosis, tumors (in general), and hypertrophy, diabetes, neurological lesions, and organ rejection.

[0100] The compounds of the invention are also useful in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophies, cancer therapy-related cardiotoxicity, peripheral neuropathy, and particularly systemic sclerosis.

[0101] The compounds of the invention are particularly indicated in the treatment and / or prevention of ILDs such as sarcoidosis or fibrosis, more particularly pulmonary fibrosis and especially IPF, as well as conditions which may induce an ILD, such as systemic sclerosis, rheumatoid arthritis, myositis or systemic lupus erythematosus, or conditions which are associated with an ILD, such as pulmonary hypertension and / or pulmonary arterial hypertension.

[0102] The compounds of the invention are particularly useful in the treatment of pulmonary fibrosis, particularly IPF.

[0103] According to a further aspect of the invention there is provided a method of treatment of pulmonary fibrosis, in particular IPF, which comprises administering to a human suffering from such a condition a therapeutically effective amount of a compound of the invention.

[0104] In the treatment of pulmonary fibrosis, including IPF, the compounds of the present invention may have anti-fibrotic effects, involving reduction of fibrosis and prevention of further deposition of extracellular matrix. The compounds of the present invention may reduce lung scarring / wound healing, and may also have anti-apoptotic effects, thereby preventing the apoptosis of alveolar endothelial cells, which is an initiator of the development of pulmonary fibrosis. The compounds of the present invention may also have anti-proliferative effects, thus reducing the 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.

[0105] In addition, the compounds of the present invention may also be useful in the treatment or prevention of any fibrotic condition of one or more internal organs characterized by excessive accumulation of fibrous connective tissue, and / or in the treatment or prevention of fibrosis and the morbidity and mortality that may be associated therewith. Such fibrosis may be associated with acute inflammatory conditions such as acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), multiorgan inflammation, injury and / or failure that may be caused by internal or external trauma (e.g., injury) or by infectious disease.

[0106] Thus, such conditions may result from sepsis or septic shock caused by viral, bacterial, or fungal infections (e.g., viral airway infections). Furthermore, acute lung injury, ARDS, and especially SARS, may be caused by viruses such as coronaviruses, including novel SARS coronavirus 2 (SARS-CoV-2), which may result in internal tissue damage and / or dysfunction of relevant internal (e.g., mucosal) 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 may also result in 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.

[0107] 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.

[0108] In an alternative embodiment of the invention, there is provided the use of a compound of formula I, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament 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.

[0109] "Diseases or conditions in which activation of the AT2 receptor is desirable or required, but inhibition of CYP is undesirable" include diseases or conditions, such as those mentioned below, that are known to be treatable by activation of the AT2 receptor, but existing treatments for such conditions may include administration of other therapeutic agents that are metabolized by CYP. Thus, such diseases or conditions may include conditions in which inhibition of at least one CYP enzyme is not required, advantageous, and / or undesirable, or in which such inhibition is or may be harmful to the patient.

[0110] Particular diseases or conditions in which activation of AT2 receptors is desirable or required, but inhibition of CYP enzymes is undesirable, are interstitial lung disease (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 disease (e.g., diabetic nephropathy), pulmonary hypertension, pulmonary arterial hypertension, preeclampsia, and / or infarction (e.g., myocardial infarction and stroke).Accordingly, the compounds of the present invention are particularly useful for treating interstitial lung disease such as IPF, autoimmune diseases such as rheumatoid arthritis, chronic kidney disease such as diabetic nephropathy, pulmonary hypertension including pulmonary arterial hypertension, and / or infarction such as myocardial infarction.

[0111] According to a further aspect of the invention there is provided a method of treatment of a disease or condition in which activation of the AT2 receptor is desirable or required but inhibition of CYP enzymes is undesirable (such as pulmonary fibrosis, particularly IPF), the method comprising administering to a human suffering from the relevant condition a therapeutically effective amount of a compound of the invention.

[0112] The compounds of the invention are indicated in both the therapeutic, palliative and / or diagnostic treatment, as well as the prophylactic treatment (including preventing and / or arresting the deterioration and / or worsening of the condition) of any of the above conditions.

[0113] The compounds of the present invention are typically administered orally, intravenously, subcutaneously, buccally, rectally, dermal, intranasal, intratracheal, intrabronchial, by other parenteral routes, or via inhalation or pulmonary routes, or any combination thereof, in a pharma- ceutically acceptable dosage form, in a solution, in a suspension, in an emulsion (including nanosuspensions), or in a liposomal formulation.Additional methods of administration include, but are not limited to, intraarterial, intramuscular, intraperitoneal, intraportal, intradermal, epidural, intrathecal, or any combination thereof.

[0114] In some embodiments, the compounds of the invention may be administered singly (e.g., separately) and / or sequentially and / or simultaneously in parallel (e.g., concurrently) using different routes of administration, but are preferably administered via 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, etc. Administration via inhalation is preferably performed by using a nebulizer, thus delivering the compounds of the invention to small lung tissues, including the alveoli and bronchioles, preferably without causing irritation or coughing in the subject being treated.

[0115] Preferably, administration of a therapeutically effective amount of a compound of the invention is carried out by a combination of routes of administration, including via inhalation and orally, either separately (e.g., about 2 hours or more apart from each other), sequentially (e.g., within about 2 hours of each other), or simultaneously (e.g., concurrently), to achieve an effective dosage.

[0116] In some embodiments, methods are provided for treating diseases or conditions in which activation of the AT2 receptor is desired or required (and such diseases or conditions in which inhibition of CYP enzymes is undesirable), including pulmonary fibrosis, specifically IPF, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention via a combination of routes of administration, either separately, sequentially, or simultaneously, preferably via inhalation and orally, to achieve a therapeutically effective amount or dosage.

[0117] Such combinations of administration routes, preferably via inhalation and orally, may be presented as separate formulations of the compounds of the invention optimized for each administration route.

[0118] Such formulations may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0119] Thus, according to a further aspect of the invention there is provided a pharmaceutical formulation comprising a compound of the invention in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier.

[0120] The compounds of the present invention may be administered in combination with other AT2 agonists known in the art, such as C21, as well as in combination with AT1 receptor antagonists known in the art, and / or in combination with inhibitors of angiotensin-converting enzyme (ACE). Non-limiting but illustrative examples of AT1 receptor antagonists that can be used according to the embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, pratosartan, ripiasartan, saprisartan, tasosartan, telmisartan, valsartan, and / or combinations thereof. Non-limiting, but illustrative examples of ACE inhibitors that may be used in accordance with the embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, alacepril, ceronapril, delepril, moveltipril, and / or combinations thereof.

[0121] Other active ingredients that may be administered in combination with the compounds of the invention include disodium cromoglycate; endothelin receptor antagonists such as bosentan, ambrisentan, sitaxsentan, macitentan; PDE5 inhibitors such as sildenafil and tadalafil; prostacyclin (epoprostenol) and its analogs such as iloprost and treprostinil; other biologics including interferon gamma-1b, etanercept, infliximab, and adalimumab; and methotrexate. Further active ingredients under development that may be co-administered with the compounds of the invention include pamrevlumab (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, Respirant), SMO4646 (wnt-signal inhibitor, United Therapeutics), KD25 (Rho-associated kinase inhibitor, Kadmon). Holdings), BG00011 (integrin antagonist, Biogen), PLN-74809 (integrin antagonist, Pilant Therapeutics), saracatinib (src kinase inhibitor, AstraZeneca), PAT-1251 (lysyl oxidase inhibitor 2, PharmAkea), ABM-125 (IL-25MAB, Abeome) and TA5-115 (multikinase inhibitor, Otsuka).

[0122] 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 therapy for treating various conditions, including those mentioned herein above.Since the compounds of the present invention show minimal CYP enzyme inhibition, such combinations are particularly advantageous when the other therapeutic agents used for use in the relevant condition are themselves metabolized by CYP enzymes.

[0123] Therefore, when the condition to be treated is interstitial lung disease, such as IPF, systemic sclerosis, or fibrotic disease known in the art, the compound of the present invention is 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 compound of the present invention is with pirfenidone or its pharmaceutically acceptable salt, and the compound is known to be metabolized by CYP enzymes, such as CYP1A.

[0124] Furthermore, when 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 treatments, such as irbesartan and / or torsemide, which are known to be metabolized by CYP enzymes, such as CYP2C9.

[0125] When the condition being treated is pulmonary hypertension, the compounds of the invention are preferably administered in combination with one or more other drugs also used in such treatment, such as selexipag and / or sildenafil, which are known to be metabolized by CYP enzymes, such as CYP3A4.

[0126] When the condition to be treated or prevented is a 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 pharma- ceutically acceptable salts thereof, which are known to be metabolized by CYP enzymes, such as CYP1A, CYP2CP and / or CYP3A4.

[0127] 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 treatment, including, but not limited to, steroidal anti-inflammatory drugs (NSAIDs) such as loxane, celecoxib, meloxicam or analogues thereof (e.g., piroxicam) or indomethacin, which are compounds known to be metabolized by CYP enzymes such as CYP1A, CYP2CP, CYP2C19 and / or CYP3A4; or drugs such as tizanidine, cyclophosphamide, cyclosporine, deflazacort and / or hydrocortisone, riluzole, or pharma- ceutically acceptable salts thereof.

[0128] Therefore, the compounds of the present invention are particularly useful for treating diseases or conditions where activation of AT2 receptor is desirable or required, but CYP enzyme inhibition is undesirable, and therefore can be administered in combination with one or more of the other therapeutic agents mentioned hereinabove, 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 CYP pathway and are useful or may be useful, to treat diseases including those mentioned hereinabove.Most preferably, the compounds of the present invention are administered in combination with pirfenidone to treat interstitial lung disease, such as IPF.

[0129] Therapeutic agents that may be used in conjunction with the compounds of the invention include various standard of care treatments for viral infections, including antibody therapies (e.g., LY-CoV555 / LY-CoV016 (bamlanivimab and etesevimab), LY-CoV555 (bamlanivimab, Eli Lilly), REGN-COV2 (casirivimab and imdevimab), REGN3048-3051, TZLS-501, SNG001 (Synairgen), eculizumab (Soliris; Alexion Pharmaceuticals), ravulizumab (Ultomiris; Alexion Pharmaceuticals), lenzilumab, leronlimab, tocilizumab (Actemra; Roche), sarilumab (Kevzara; Regeneron Pharmaceuticals), and others). Pharma; and Octagam (Octapharma); antiviral drugs (e.g., oseltamivir, remdesivir, favipiravir, molnupiravir, simeprevir, daclatasvir, sovosbuvir, 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 Pharma), anti-inflammatories (e.g., NSAIDs such as ibuprofen, ketorolac, naproxen), chloroquine, hydroxychloroquine, interferons (e.g., interferon beta (interferon beta-1a), tocilizumab (Actemra), lenalidomide, pomalidomide, and thalidomide), analgesics (e.g., paracetamol or opioids), antifungals (e.g., dextromethorphan), vaccinations (e.g., INO-4800 from Inovio Pharmaceuticals and Beijing Advaccine Biotechnology, when available), COVID-19 convalescent plasma (CCP), and / or passive antibody therapy with antibodies derived from the blood of people who have recovered from SARS-CoV or SARS-CoV-2 infection.

[0130] Further therapeutic agents that may be mentioned include antifibrotic drugs (eg nintedanib, in particular pirfenidone), vitamins (eg vitamins B, C and D) and mucolytic agents such as acetylcysteine ​​and ambroxol.

[0131] Other therapeutic agents that may be used in conjunction with the compounds of the invention, or pharma- ceutically acceptable salts thereof, according to the invention include corticosteroids, including both natural and synthetic corticosteroids.

[0132] Naturally occurring corticosteroids that may be mentioned include cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, progesterone, as well as naturally occurring precursors and intermediates in the biosynthesis of corticosteroids, and other derivatives of naturally occurring corticosteroids, such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, 18-hydroxycortisol, 1 ... Examples of such hormones include cyto-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.

[0133] Among the synthetic corticosteroids that may be mentioned are cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, tixocortol and tixocortol pivalate, prednisolone, methylprednisolone, prednisone, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolone, fluprednisolone, loteprednol, prednicarbate and triam. those of the hydrocortisone type (group A), such as cinolone; acetonides and related substances (group B), such as amcinonide, budesonide, desonide, fluocinolone setonide, fluocinonide, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formocortal, fludroxycortide, flunisolid and fluocinolone acetonide; beclomethasone, betamethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, fluocortolone, halometasone, mometasone and mometasone furoate (Beta)methasone type (group C) such as alclometasone and alclometasone dipropionate, clobetasol and clobetasol propionate, clobetasone and clobetasone butyrate, clocortolone, desoximetasone, diflorasone, diflocortolone, flucloron, flumethasone, fluocortin, fluprednidene and fluprednidene acetate, fluticasone, fluticasone furoate and fluticasone propionate, meprednisone, paramethasone, prednylidene, rimexolone and eurobetasol; ); progesterone-type drugs, such as flugestone, fluorometholone, medrysone, and prevedilone acetate; and progesterone derivatives (progestins), such as chlormadinone acetate, cyproterone acetate, medrogestone, medroxyprogesterone acetate, megestrol acetate, and segesterone acetate; and other corticosteroids, such as cortivazol and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androsta-1,4,6-trien-3-one.

[0134] Preferred corticosteroids include cortisone, prednisone, prednisolone, methylprednisolone, and especially dexamethasone.

[0135] Further therapeutic agents that may be used in combination with the compounds of the present invention, or pharma- ceutically acceptable salts thereof, include H2 receptor blockers, anticoagulants, antiplatelet agents, as well as statins, antibacterial agents and antiallergic / antiasthmatic agents.

[0136] H2 receptor blockers that may be mentioned include famotidine. Anticoagulants that may be mentioned include heparin and low molecular weight heparins (e.g. bemiparin, nadroparin, reviparin, enoxaparin, parnaparin, certoparin, dalteparin, tinzaparin), direct acting oral anticoagulants (e.g. dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betrixaban, darexaban, otamixaban, retaxaban, erivaxaban, hirudin, lepirudin and bivalirudin), coumarin type vitamin K antagonists (e.g. coumarin, acenocoumarol, phenprocoumon, atromentin and phenindione) and synthetic pentasaccharide inhibitors of factor Xa (e.g. fondaparinux, idraparinux and idrabiotaparinux). Antiplatelet drugs that may be mentioned include irreversible cyclooxygenase inhibitors (e.g., aspirin 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., vorapaxal), glycoprotein IIB / IIIA inhibitors (e.g., abciximab, eptifibatide and tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), and thromboxane inhibitors (e.g., terutroban, ramatroban, seratrodast and picotamide). Statins that may be mentioned include atorvastatin, simvastatin and rosuvastatin. Antibacterial agents that may be mentioned include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam and teicoplanin. Antiallergic / antiasthmatic drugs that may be mentioned include chlorpheniramine, levocetirizine and montelukast.

[0137] Thus, the subject may also be receiving (and / or may already be receiving) any one or more of the other therapeutic agents mentioned above, meaning receiving prescribed doses of one or more of these other therapeutic agents prior to, in addition to, and / or after treatment with a compound of the invention, or a pharma- ceutically acceptable salt thereof.

[0138] When the compounds of the present invention are "combined" with other therapeutic agents mentioned hereinabove, the active ingredients may be administered together in the same formulation or separately (simultaneously or sequentially) in different formulations.

[0139] Such combination products provide for administration of a compound of the invention in conjunction with another therapeutic agent and therefore may be presented as separate formulations, at least one of which contains a compound of the invention and at least one of which contains the other therapeutic agent, or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation containing a compound of the invention and the other therapeutic agent).

[0140] therefore, (1) A pharmaceutical formulation comprising a compound of the present invention; a therapeutic agent selected from those described above (e.g., known to be metabolized by a CYP enzyme); and a pharma- ceutically acceptable excipient (e.g., an adjuvant, diluent, or carrier), hereinafter referred to as a "combination preparation"; (2) A kit of parts comprising the following components: (A) a pharmaceutical formulation comprising a compound of the invention in admixture with a pharma- ceutically acceptable adjuvant, diluent, or carrier; and (B) a pharmaceutical formulation comprising a therapeutic agent selected from those described above (e.g., one known to be metabolized by a CYP enzyme) in admixture with a pharma- ceutically acceptable adjuvant, diluent, or carrier; There is further provided a kit-of-parts, in which components (A) and (B) are each provided in a form suitable for administration in conjunction with the other.

[0141] In a further aspect of the present invention, there is provided a process for the preparation of a combination preparation as defined herein above, comprising bringing into association a compound of the present invention, another anti-inflammatory agent, a therapeutic agent, with at least one (e.g., pharma- ceutically acceptable) excipient.

[0142] In a further aspect of the present invention, there is provided a process for the preparation of the kit-of-parts as defined herein above, the process comprising combining components (A) and (B). As used herein, reference to combining shall mean that the two components are suitable for administration in conjunction with each other.

[0143] Thus, with regard to the process for the preparation of a kit-of-parts as defined herein above by "combining" two components with each other, the two components of the kit-of-parts are (i) may be provided as separate formulations (i.e., independent of each other) and then combined for use in conjunction with each other in a combination therapy; or (ii) They may be packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

[0144] therefore, (I) one of components (A) and (B) as defined herein, (II) instructions for using the component in conjunction with the other of the two components.

[0145] Depending on the patient being treated and the route of administration, the compounds of the present invention may be administered in varying doses. Although the dose will vary from patient to patient, a suitable daily dose ranges from 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, etc., or any range or value therein), administered in single or multiple doses. More preferred daily doses are in the range of about 0.1 to about 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, etc., or any range or value therein). Particularly preferred daily doses range from about 0.3 to about 100 mg per patient.

[0146] Individual doses of the compounds of the invention can range from about 0.1 to about 100 mg (e.g., 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, etc., or any range or value therein).

[0147] In any event, a physician or person skilled in the art can determine the actual dosage that will 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 exemplary of the average case, and there can, of course, be individual cases where higher or lower dosage ranges are merited, and such are within the scope of this invention.

[0148] The advantage of using the compounds of the present invention separately and / or sequentially and / or simultaneously in parallel via a combination of administration routes is to produce a tailored treatment for the patient in need of treatment, potentially preventing and / or reducing side effects, and also to tailor the correct dosage level of the therapeutically effective amount of the compounds of the present invention.

[0149] The kit-of-parts described herein may include two or more formulations containing suitable amounts / doses of the compounds of the invention and / or two or more formulations containing suitable amounts / doses of other therapeutic agents to provide for repeated administration. When two or more formulations (containing any active compound) are present, such formulations may be the same or different with respect to the dose, chemical composition and / or physical form of any compound.

[0150] "Administration in conjunction with" in reference to the kit of parts described herein includes sequential, separate and / or simultaneous administration of each formulation containing a compound of the invention and another therapeutic agent over the course of treatment of the relevant condition.

[0151] Thus, with respect to a combination product according to the invention, the term "administration in conjunction with" includes administration of the two components of the combination product (a compound of the invention and another therapeutic agent) together, or sufficiently close in time (optionally repeatedly) to permit a greater beneficial effect to the patient over the course of treatment of the relevant condition than if either a formulation containing the compound of the invention or a formulation containing the other agent were administered alone (optionally repeatedly) over the same course of treatment in the absence of the other component. The determination of whether a combination provides a greater beneficial effect with respect to and over the course of treatment of a particular condition depends on the condition being treated or prevented, but can be routinely accomplished by one of ordinary skill in the art.

[0152] Furthermore, in the context of the kit-of-parts according to the invention, the term "in conjunction with" includes that one or the other of the two formulations may be administered (optionally repeatedly) before, after and / or simultaneously with the administration of the other component. As used in this context, the terms "co-administered" and "administered simultaneously with" include administration of individual doses of the relevant compound of the invention and the other anti-inflammatory agent within 48 hours (e.g. 24 hours) of each other.

[0153] The pharmaceutical compositions / formulations, combination products and kits described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0154] Therefore, in a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition / formulation as defined hereinbefore, which comprises combining certain compounds of the present invention as defined hereinbefore with one or more pharma- ceutically acceptable excipients (e.g., adjuvants, diluents and / or carriers).

[0155] In a further aspect of the present invention, there is provided a process for the preparation of a combination product or kit-of-parts as defined hereinabove, the process comprising combining certain compounds of the present invention as defined hereinabove with other therapeutic agents useful in the treatment of the relevant disease or disorder, and at least one pharma- ceutically acceptable excipient.

[0156] Subjects suitable for treatment with the formulations of the present invention include, but are not limited to, mammalian subjects, particularly human subjects.

[0157] When used herein with respect to a particular value (such as an amount), the term "about" (or similar terms such as "approximately") will be understood as indicating that such value may vary by up to 10% (specifically up to 5%, such as up to 1%) of the defined value. In each case, it is contemplated that such terms may be replaced with the notation "±10%" or the like (or by indicating a particular amount of variation calculated based on the relevant value). It is also contemplated that in each case, such terms may be omitted.

[0158] The compounds of the present invention have the advantage that they are more potent than metabolic hydrolysis and / or are stable to metabolic hydrolysis and / or do not inhibit the CYP enzymes mentioned herein above.

[0159] The compounds described herein, whether for use in the treatment of IPF or not, may have the advantage that they may be more effective, less toxic, longer acting, more potent, have fewer side effects, be more readily absorbed, and / or have a superior pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or have other useful pharmacological, physical or chemical properties than compounds known in the prior art. Such effects may be assessed clinically, objectively, and / or subjectively by a health care professional, a subject being treated, or an observer.

[0160] The present invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention.

[0161] In case of discrepancy between the nomenclature and any compound depicted in the figures, the latter takes precedence (unless contradicted by any experimental details that may be provided and / or clear from the context).

[0162] Experimental procedure The starting materials and intermediates used in the synthesis of the compounds described herein are either commercially available or can be prepared by methods described herein or known in the art.

[0163] Experiments were generally performed under an inert atmosphere (nitrogen or argon), especially when oxygen- or moisture-sensitive reagents or intermediates were used.

[0164] Mass spectrometry data are reported from liquid chromatography-mass spectrometry (LC-MS). Chemical shifts for NMR data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvents used.

[0165] In syntheses referring to general procedures, reaction conditions (such as reaction length or temperature) may vary. Reactions were generally followed by thin layer chromatography or LC-MS and work-up as required. Purification may vary between experiments. Solvents and ratios of solvents used in eluents / gradients were generally chosen according to appropriate R f and / or retention times were selected to provide. Some products were purified using supercritical fluid chromatography on a reversed-phase column using, for example, a solvent combination of mobile phase A: CO2 and B: MeOH / H2O / NH3. Some compounds were purified using preparative HPLC, flash column chromatography, or a manual C18 reversed-phase column with H2O / MeCN polarity. EXAMPLES

[0166] Example 1 Furan-2-ylmethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonyl]urea (a) 1-[(4-bromophenyl)methyl]-2-tert-butyl-imidazole To a stirred solution of 2-tert-butyl-1H-imidazole (0.497 g, 4.0 mmol, 1 equiv) in DMF (0.27 M) was added NaH (0.184 g, 8.0 mmol, 2 equiv) at 0° C. After 20 min, 1-bromo-4-(bromomethyl)benzene (1.05 g, 4.2 mmol, 1.05 equiv) was added. The resulting mixture was warmed to ambient temperature and stirred overnight, then quenched with water (15 mL). The product was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The title compound was obtained as a solid in 99% yield (1.16 g, 0.396 mmol).

[0167] (b) 5-Bromo-N-(tert-butyl)thiophene-2-sulfonamide 5-Bromothiophene-2-sulfonyl chloride (1 mmol, 1 equiv.) was dissolved in DCM (2 mL), tert-butylamine (1.1 mmol, 1.1 equiv.) was added and the reaction mixture was stirred for 2-4 h. The subtitled product was isolated by flash column (20% EtOAc in isohexane) as a colourless solid.

[0168] (c) N-tert-butyl-5-isobutylthiophene-2-sulfonamide The subtitled products were prepared according to Methods A and B below.

[0169] Method A: Zinc chloride (1.9M in 2-methyltetrahydrofuran) was added to a dry vial and capped. Iso-butylmagnesium chloride (2.0M in THF) was added slowly and the mixture was stirred for 15 minutes. 5-Bromo-N-(tert-butyl)thiophene-2-sulfonamide (from step (b) above) and Pd(tBu3P)2 were dissolved in dry THF (0.75 mL) and added to the vial. The reaction mixture was heated at 80° C. under microwave irradiation for 30 minutes.

[0170] Method B: Pd(OAc)2 was combined with Xantphos in degassed THF under nitrogen. After stirring for 5 min, the solution was transferred to another vessel containing 5-bromo-N-(tert-butyl)thiophene-2-sulfonamide and iso-butylzinc bromide under nitrogen. The sealed vessel was heated at 80° C. for 18 h.

[0171] In both Methods A and B, upon cooling to room temperature, the reaction mixture was filtered and the solid washed with DCM. The solvent was removed by rotary evaporation and the subtitle compound was purified by column chromatography (20% EtOAc in isohexane) as a colourless solid.

[0172] (d) N-(tert-butyl)-5-isobutyl-3-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiophene-2-sulfonamide N-tert-Butyl-5-isobutylthiophene-2-sulfonamide (1.00 g, 3.65 mmol; from step (c) above) was dissolved in dry THF and transferred to a dry 3-neck round bottom flask. The flask was evacuated three times and placed under an inert atmosphere. The mixture was cooled to -78°C and n-BuLi (7.59 mL, 19.0 mmol, 4.74 equiv) was added dropwise. The mixture was stirred at -78°C for 30 min, then transferred to an ice bath and stirred at 0°C for 45 min to give an orange solution. The mixture was again placed in a dry ice bath and tri-isopropyl borate (2.53 mL, 10.9 mmol) was added over 5 min using a syringe. The solution was stirred for 15 min, then returned to the ice bath and stirred for 1 h, during which time the formation of a white precipitate was observed.

[0173] To the now white opaque solution was added 2M HCl (aq; 20 mL) and the solution was stirred for 15 min. Partial evaporation of the mixture was performed to remove most of the THF present. The remaining mixture was diluted with water (10 mL) and extracted with DCM (3×25 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure.

[0174] The crude boronic acid was dissolved in DMSO (2 mL) and toluene (30 mL). Methyliminodiacetic acid (0.748 g, 5.09 mmol eq.) was added and the mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature over 1 h.

[0175] The mixture was diluted with EtOAc (100 mL) and then washed with 0.1 M aqueous HCl (3×50 mL). The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by FCC (10-100% ethyl acetate in isohexane) to give the product as a pale yellow amorphous solid (1.56 g, 77% yield). 1 H NMR(400MHz,chloroform-d) δ 6.87(d,J=0.8Hz,1H),5.20(s,1H),3.98(m,4H),2.82(s,3H),2.66(d,J=7.6Hz,2H),1.89(m,1H),1.25(s,9H),0.93(d,J=6.6Hz,6H).

[0176] (e) 3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfonamide N-(tert-butyl)-5-isobutyl-3-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiophene-2-sulfonamide (from step (d) above; 0.451 g, 1.05 mmol), KCO (0.415 g, 3.00 mmol, 3 equiv), 1-[(4-bromophenyl)methyl]-2-tert-butyl-imidazole (see step (a) above; 0.293 g, 1.0 mmol), and Pd(PPh) (57.8 g, 0.50 mmol, 0.05 equiv) were suspended in degassed toluene (6 mL), ethanol (2 mL), and water (1 mL). The resulting reaction mixture was stirred at 120° C. for 60 min under microwave irradiation and cooled to ambient temperature, then water (10 mL) was added and the reaction mixture was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by FCC (0-10% MeOH in CH2Cl2) to give the subtitle compound as a pale yellow amorphous solid (0.364 g, 75% yield, 90% purity after two steps). 1 H-NMR(400MHz,chloroform-d) δ 7.53(d,J=7.8Hz,2H),7.31(s,1H),7.19-6.93(m,3H),6.69(s,1H),5.76(s,br.,2H),5 .46(s,2H),2.61(d,J=7.0Hz,2H),2.12-1.78(m,1H),1.49(s,9H),0.92(d,J=6.6,6H).

[0177] (f) furan-2-ylmethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]-phenyl]-2-thienyl]sulfonyl]urea 3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-sulfon-amide (from step (f) above; 0.12 mmol, 1 equiv.) and copper(I) chloride (0.02 mmol, 15 mol%) were dissolved in dry DMF at room temperature and 2-(isocyanatomethyl)furan (0.35 mmol, 2.5 equiv.) was added under argon atmosphere and the reaction mixture was stirred for 24 h. After the reaction was complete, the crude mixture was poured into 0.1 N aqueous HCl, diluted with ethyl acetate (25 mL) and the organic and aqueous phases were separated. The aqueous phase was extracted twice with ethyl acetate (20 mL) and the combined organic phases were washed with brine (20 mL), dried over MgSO4 and the solvent was evaporated in vacuo to give the crude product. The crude product was purified by preparative HPLC (20-90% acetonitrile in water) to give the product as a white amorphous solid (36 mg, 56% yield). 1 H-NMR(400MHz,acetonitrile-d3) δ 7.51(d,J=8.2Hz,2H),7.40(d,J=1.0Hz,1H),7.12(d,J=8.2Hz,2H),6.90(brs,2H),6.85(brs,1H),6.35(dd,J=3.2,1.9Hz,1H),6. 22-6.11(m,2H),5.42(s,2H),4.20(d,J=5.7Hz,2H),2.75(d,J=7.1Hz,2H),1.97-1.95(m,1H),1.42(s,9H),1.01(d,J=6.6Hz,6H). 13 C-NMR (101MHz, acetonitrile-d3) δ 154.4, 153.2, 142.5, 138.0, 137.9, 134.6, 130.1, 130.0, 126.9, 126.8, 124.6, 123.2, 111.1, 110.9, 108.1, 107.3, 51.2, 39.1, 37.0, 33.8, 30.9, 29.5, 22.0. HRMS (ESI): C 28 H 35 N4O4S2 + [M+H] + Calculated value: 555.2094; measured value: 555.2107.

[0178] In acetonitrile-d3 (top) 1When H NMR was measured, it was observed that one of the proton peaks was captured by the acetonitrile solvent residual peak (peak at 1.97-1.95 (m, 1H)). Therefore, 1 1 H NMR is also measured in MeOD. 1 H-NMR (400MHz, methanol-d4) δ 7.46(brs,2H),7.38(d,J=1.8Hz,1H),7.19(brs,2H),7.03(brs,2H),6.77(s,1H),6.32(dd,J=3.2,1.8Hz,1H),6.15(d,J=3. 1Hz,1H), 5.57(s,2H),4.16(s,2H),2.73(d,J=7.0Hz,2H),1.94(dt,J=13.4,6.7Hz,1H),1.49(s,9H),1.01(d,J=6.6Hz,6H).

[0179] Example 2 Thiophen-2-ylmethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonylurea The title compound was prepared using a process similar to that described in Example 1 above, except that 2-(isocyanatomethyl)thiophene (0.30 mmol, 2.5 equiv.) was used in the final step. The crude product was purified by preparative HPLC (20-90% acetonitrile in water) to give the product as a white amorphous solid (31 mg, 47% yield). 1 H-NMR(400MHz,acetonitrile-d3) δ 7.52(d,J=7.8Hz,2H),7.23(dd,J=5.1,1.3Hz,1H),7.07(d,J=8.3Hz,2H),6.99(brs,2H),6.91(dd,J=5.1,3.4Hz,1H),6.90-6.84(m ,2H),6.83(s,1H),5.43(s,2H),4.33(d,J=5.7Hz,2H),2.71(d,J=7.1Hz,2H),1.95-1.86(m,1H),1.41(s,9H),0.98(d,J=6.6Hz,6H). 13C-NMR (101MHz, acetonitrile-d3) δ 154.2, 154.0, 149.5, 144.0, 143.3, 137.3, 135.3, 134.7, 130.1, 129.9, 127.2, 127.0, 125.9, 125.3, 123.6, 123.5, 51.4, 39.1, 38.7, 33.9, 30.9, 29.3, 22.0. HRMS (ESI): C 28 H 35 N4O3S3 + [M+H] + Calculated value 571.1866; measured value 571.1864.

[0180] Example 3 2-Methoxyethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonylurea The title compound was prepared using a process similar to that described in Example 1 above, except that 1-isocyanato-2-methoxyethane (0.29 mmol, 2.5 equiv.) was used in the final step. The crude product was purified by preparative HPLC (20-90% acetonitrile in water) to give the product as a white amorphous solid (31 mg, 47% yield). 1 H-NMR(400MHz,acetonitrile-d3) δ 7.55(d,J=8.2Hz,2H),7.18(d,J=7.9Hz,2H),6.99(d,J=1.6Hz,1H),6.96(d,J=1.5Hz,1H),6.87(s,1H),6.14(brs,1H),5.46(s,2H),3 .34(t,J=5.5Hz,2H),3.29(s,3H),3.19(q,J=5.5Hz,2H),2.77(d,J=7.0Hz,2H),2.01-1.98(m,1H),1.45(s,9H),1.01(d,J=6.6Hz,6H). 13 C-NMR (101 MHz, acetonitrile-d3) δ 154.3, 153.0, 150.1, 144.6, 144.2, 137.6, 134.6, 134.4, 130.1, 127.1, 123.8, 123.5, 71.4, 58.4, 51.4, 39.9, 39.1, 33.9, 30.9, 29.3, 22.0. HRMS (ESI): C26 H 37 N4O4S2 + [M+H] + Calculated value: 533.2251; measured value: 533.2252.

[0181] Example 4 Pyridin-2-ylmethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonylurea Sulfonamide (0.18 mmol, 1 equiv.), N-(2-pyridylmethyl)phenylcarbamate (0.28 mmol, 1.5 equiv.; synthesized as described in Org. Biomol. Chem., 2017, 15, 4992), and DBU (0.28 mmol, 1.5 equiv.) were dissolved in acetonitrile and the reaction mixture was heated under MW for 1 h. After completion of the reaction as indicated by TLC, the solvent was evaporated under reduced pressure. The residue was then dissolved in ethyl acetate and extracted with 0.1 N HCl. The aqueous phase was extracted twice with ethyl acetate (20 mL), the combined organic phase was washed with brine (20 mL), dried over MgSO4, and the solvent was evaporated in vacuum to give the crude product. The crude product was purified on a manual C-18 reverse column with water-acetonitrile polarity (20-90% acetonitrile in water) to give the product as a white amorphous solid (60 mg, 57% yield). 1 H-NMR(400MHz,DMSO-d6) δ 8.48(d,J=4.2Hz,1H),7.73(td,J=7.7,1.8Hz,1H),7.55(d,J=8.0Hz,2H), 7.26(dd,J=7.0,5.1Hz,1H),7.14(d,J=7.8Hz,1H),7.09-7.07(m,3H),6.9 2(d,J=9.2Hz,2H),6.84(brs,1H),5.45(s,2H),4.25(d,J=5.5Hz,2H),2.7 0(d,J=7.1Hz,2H),1.92-1.82(m,1H),1.32(s,9H),0.93(d,J=6.6Hz,6H). 13C-NMR(101MHz,DMSO-d6) δ 163.5,158.2,153.7,152.2,149.3,149.2,144.0,138.4,137.2,133.6,130.0,129 .7,126.4,125.0,123.3,122.65,121.3,50.5,44.9,38.6,33.6,30.3,30.0,22.5. HRMS(ESI):C 29 H 36 N5O3S2 + [M+H] + Calculated value: 566.2254; measured value: 566.2267.

[0182] Example 5 1-[[3-[4-[(2-Tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-pyridylmethyl)urea (a) 1-(4-bromo-2-fluorobenzyl)-2-(tert-butyl)-1H-imidazole The subtitle compound was prepared using a process similar to that described in Example 1, step (a) above, except that 2-tert-butyl-1H-imidazole (1.02 g, 8.21 mmol) and 4-bromo-1-(bromomethyl)-2-fluoro-benzene (2.20 g, 8.21 mmol) were used instead. The crude product was purified by FCC (30% ethyl acetate in isohexane) to give the product as a pale yellow amorphous solid (2.56 g, 39% yield). 1 H-NMR (400 MHz, chloroform-d) δ 7.24 (dd, J = 9.5, 1.9 Hz, 1H), 7.21-7.16 (m, 1H), 6.93 (d, J = 1.4 Hz, 1H), 6.67 (d, J = 1.4 Hz, 1H), 6.55 (t, J = 8.1 Hz, 1H), 5.25 (s, 2H), 1.35 (s, 9H). 13C-NMR (101 MHz, chloroform-d) δ 159.4 (d, J = 251.2 Hz), 154.6, 129.2 (d, J = 4.5 Hz), 128.0 (d, J = 3.7 Hz), 126.9, 124.0 (d, J = 14.4 Hz), 122.0 (d, J = 9.3 Hz), 121.6, 119.1 (d, J = 24.1 Hz), 44.7 (d, J = 4.9 Hz), 33.5, 29.8. 19 F-NMR (376 MHz, chloroform-d) δ −115.61 (t, J = 8.7 Hz).

[0183] (b) 3-(4-((2-(Tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophene-2-sulfonamide The subtitle compound was prepared using a process similar to that described above in Example 1, step c. 1 H-NMR(400MHz,chloroform-d) δ 7.48-7.31(m,3H),7.15-6.97(m,2H),6.72(s,1H),5.78(s,br.,2H),5.48(s,2H),2. 64(d,J=7.0Hz,2H),1.98-1.81(m,J=6.7Hz,1H),1.56(s,9H),0.96(d,J=6.6Hz,6H). 13 C-NMR (101 MHz, chloroform-d) δ 159.9 (d, J = 248.9 Hz), 152.8, 148.7, 141.1, 138.2 (d, J = 8.4 Hz), 136.7, 129.2, 129.1, 126.2, 122.9, 120.7 (d, J = 14.3 Hz), 119.7, 117.0 (d, J = 21.9 Hz), 46.8 (d, J = 3.4 Hz), 39.2, 33.9, 30.6, 28.7, 22.3. 19 F-NMR (376 MHz, chloroform-d) δ −75.39.

[0184] (c) 1-[[3-[4-[(2-Tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-pyridylmethyl)urea 3-(4-((2-(Tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophene-2-sulfonamide (450 mg, 330 μmol; from step (b) above), diphenyl carbonate (106 mg, 495 μmol), and K2CO3 (91 mg, 660 μmol) were dissolved in acetonitrile (15 ml) and the reaction was heated at 60° C. under nitrogen overnight. The solids were filtered off and the solvent evaporated. The crude material and 2-aminomethylpyridine (108 mg, 1 mmol) were dissolved in dioxane (10 ml). The reaction was heated at 70° C. overnight. The solvent was evaporated and the product was purified using HPLC in an amount of 18 mg and isolated as the CF3COOH-salt. 1 H-NMR(CD3OD):0.85(d,6H),1.44(s,9H),1.90(m,1H),2.68(d,2H),4.32(s,2H),5.49(s,2H),6.82(s,1H),6 .92(m,1H),6.97(s,1H),6.99(s,1H),7.23-7.28(b,2H),7.42(d,1H),7.59(d,1H),7.72(d,1H),8.41(d,1H). MS[M+H]:584.0, calculated value 584.2.

[0185] Example 6 1-[[3-[4-[(2-Tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-ethyl-urea 3-[4-[(2-tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-thiophene-2-sulfonamide (201 mg, 397 μmol; prepared as in Example 1 from step (b) above), ethyl isocyanate (94 μl, 1192 μmol), and BF3-etherate (169 mg, 1192 μmol) were dissolved in acetonitrile (20 ml). After 4 h at room temperature, LC / MS showed little conversion to the product. Further ethyl isocyanate (94 μl, 1192 μmol) was added and the reaction was stirred overnight. The solvent was evaporated and the product was purified using HPLC in an amount of 84 mg and isolated as the CF3COOH-salt.1 H-NMR(CDCl3):0.98(d,6H),1.04(t,3H),1.63(s,9H),1.93(m,1H),2.70(d,2H),3 .14(m,2H),5.51(s,2H),6.76(s,1H),7.11(t,1H),7.23(s,1H),7.27-7.35(b,3H). MS[M+H]:521.0, calculated value 521.2.

[0186] Example 7 1-[[3-[4-[(2-Tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-thienylmethyl)urea The title compound was prepared by a process similar to that described in Example 5 above, except that 2-aminomethylthiophene (113 mg, 1000 μmol) was used. The product was isolated in 70 mg yield as the CF3COOH-salt. 1 H-NMR(CDCl3):0.99(d,6H),1,61(s,9H),1.93(m,1H),2.69(d,2H),4.42(d, 2H),5.47(s,2H),6.72(s,1H),6.87(m,2H),7.04(b,2H),7.15(d,1H),7.21(m 2H),7.32(d,1H). MS[M+H]:589.0, calculated value 589.2.

[0187] Biological assays The biological activity of the example compounds described herein above was evaluated (and compared to C21) using the following biological assays.

[0188] metabolic stability Pooled human liver microsomes in PBS at a concentration of 0.5 mg / mL were incubated with or without 1 mM NADPH at 37° C. for 70 min. After 10 min, test compounds were added to a final concentration of 1 uM. Samples were removed at 0, 5, 15, and 60 min and added to a test tube containing acetonitrile to stop the reaction with terfenadine used as an internal standard. After centrifugation at 10 000×g for 5 min, the supernatant was diluted 1:1 with 1% formic acid. Samples were separated on a reversed-phase column and detected by a triple quadrupole MSMS (Agilant model 6540). The concentration of the parent compound at different time points was measured with an external standard curve using terfenadine as an internal standard to calculate the initial metabolic rate in the presence or absence of NADPH. [Table 1]

[0189] Binding to AT1 and AT2 receptors Compounds were evaluated for binding to human recombinant AT2 and AT1 receptors using a radiometric scintillation assay according to Eurofins protocols ITEM26 and ITEM24.

[0190] Briefly, IC 50 For the measurements, recombinant proteins were incubated 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 at 37 °C for 2-4 h. Ki values ​​for the AT2 receptor were determined using a 7-point dose-response curve. 125 I(sar1, IIe8)-AT-II was used as a ligand for the AT2 receptor. 125 ICGP 42112A was used. The inhibition percentage of control specific binding was calculated according to 100-(measured specific binding / control specific binding) x 100. [Table 2] An asterisk (*) denotes the median mean of data from duplicate runs.

[0191] 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 amodiaquine, CYP2C9 diclofenac, CYP2C19 omeprazole, CYP2D6 dextromethorphan, CYP3A midazolam and testosterone.

[0192] At the end of the incubation, metabolite formation was monitored by HPLC-MS / MS as peak area response. [Table 3] [Table 4]

[0193] Abbreviation The following abbreviations may be used herein: DBU 1,8-diazabicyclo(5.4.0)undec-7-ene DCM Dichloromethane DMF Dimethylformamide DMSO Dimethyl sulfoxide EtOAc Ethyl acetate FCC Flash Column Chromatography HPLC High Performance Liquid Chromatography HRMS high resolution mass spectrometry MeCN Acetonitrile MeOH Methanol MW Microwave NMR nuclear magnetic resonance rt room temperature TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography

Claims

1. A compound of formula I, 【Chemistry 1】 During the ceremony, R １ (optionally substituted with one or more fluorine atoms) １－２ Alkyl, OR ７ or a fluorine atom, R ２ and R ３ each independently represents H or C optionally substituted by one or more halogen atoms; １－６ represents an alkyl group, Y １ , Y ２ , Y ３ , and Y ４ each independently represents -CH-, -CF-, or -N-; R ４ But, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkoxy-C １－６ alkyl, the alkyl portion of which is optionally substituted with one or more halogen atoms; R ４ is aryl, C １－６ Alkylaryl, C １－３ Alkenylaryl, heteroaryl, C １－６ alkylheteroaryl, or C １－３ alkenylheteroaryl, each of which is selected from the group consisting of halogen, -CF ３ , C.F. ３ O-, C １－６ Alkyl, and C １－６ Optionally substituted by one or more substituents selected from alkoxy; R ５ But H or C １－６ alkyl, each of which is optionally substituted with one or more halogen atoms; R ６ C optionally substituted with one or more halogens ２－４ represents alkyl, R ７ represents H or represents methyl optionally substituted by one or more fluorine atoms, or a pharma- ceutically acceptable salt thereof.

2. R １ C optionally substituted with up to three fluorine atoms １－２ Alkyl or OR ７ 2. The compound according to claim 1 , wherein

3. R １ 2. The compound of claim 1, wherein represents methyl.

4. R ２ and R ３ A compound according to any one of claims 1 to 3, wherein both represent H.

5. R ４ But, C １－４ Alkyl or C １－４ Alkoxy-C １－４ Alkyl group, phenyl; １－３ Alkylaryl; or C １－３ The compound according to any one of claims 1 to 4, which represents alkylheteroaryl, each of which is optionally substituted by one or more halogen atoms.

6. R ５ A compound according to any one of claims 1 to 5, wherein represents H, methyl, ethyl, n-propyl, n-butyl or isobutyl.

7. R ６ A compound according to any one of claims 1 to 6, wherein represents n-propyl, n-butyl or isobutyl.

8. R ７ A compound according to any one of claims 1 to 7, wherein represents H or methyl.

9. Y １ represents -CF- or -CH; Y ２ , Y ３ , and Y ４ The compound according to any one of claims 1 to 8, wherein all represent -CH-.

10. furan-2-ylmethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonyl]urea, Thiophen-2-ylmethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl] -2-thienyl]sulfonylurea, 2-methoxyethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonylurea, pyridin-2-ylmethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonylurea, 1-[[3-[4-[(2-tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-pyridylmethyl)urea, 1-[[3-[4-[(2-tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-ethyl-urea, or 2. The compound of claim 1 which is 1-[[3-[4-[(2-tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-thienylmethyl)urea.

11. The compound of claim 10 which is pyridin-2-ylmethyl-3-[[5-isobutyl-3-[4-[(2-tert-butyl-imidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonylurea.

12. A compound according to any one of claims 1 to 11 for use as a medicament.

13. A pharmaceutical formulation comprising a compound as defined in any one of claims 1 to 11 in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier.

14. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 for use in the treatment of autoimmune diseases, viral respiratory tract infections and / or resulting pneumonia, fibrotic diseases, chronic kidney disease, pulmonary hypertension, heart failure and / or myocardial infarction.

15. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of autoimmune diseases, viral respiratory tract infections and / or resulting pneumonia, fibrotic diseases, chronic kidney diseases, pulmonary hypertension, heart failure and / or myocardial infarction.

16. 16. The pharmaceutical composition of claim 14 or the use of claim 15, wherein the disease is an interstitial lung disease.

17. 17. The pharmaceutical composition or use of claim 16, wherein the interstitial lung disease is idiopathic pulmonary fibrosis or sarcoidosis.

18. 16. The pharmaceutical composition of claim 14 or the use of claim 15, wherein the autoimmune disease is rheumatoid arthritis or systemic sclerosis.

19. 16. The pharmaceutical composition of claim 14 or the use of claim 15, wherein the chronic kidney disease is diabetic nephropathy.

20. 16. The pharmaceutical composition of claim 14 or the use of claim 15, wherein the pulmonary hypertension is pulmonary arterial hypertension.

21. 16. The pharmaceutical composition of claim 14 or the use of claim 15, wherein the heart failure is with preserved ejection fraction.

22. A process for the preparation of a compound according to any one of claims 1 to 11, said process comprising: (i) 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 is as defined in any one of claims 1 to 10, and L is C １－６ a compound of formula II, which represents alkyl or aryl, and a compound of formula III, NER ４ R ５ --- In the formula, R ４ and R ５ with a compound of formula III, wherein (ii) R ５ represents H; in compounds of formula I, 【Chemistry 3】 In the formula, R １ , R ２ , R ３ , R ６ , Y １ , Y ２ , Y ３ , and Y ４ is as defined in any one of claims 1 to 10, and a compound of formula V, R ４ -N=C=O V or a compound of formula VI, 【Chemistry 4】 In the formula, X １ is a suitable leaving group, and in each case, R ４ is as defined in any one of claims 1 to 10 with a compound of formula VI.

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