Selective angiotensin II compounds

Abstract

The present invention provides pharmaceutical compounds of formula I wherein R1, R2, R3, R4, R5, R6, Y1, Y2, Y3, X and Z have the meanings given in the specification, which are useful in the treatment of autoimmune and / or fibrotic diseases, including interstitial lung diseases such as idiopathic pulmonary fibrosis and sarcoidosis. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to novel pharmaceutically useful compounds, in particular compounds that are angiotensin II (Ang II) agonists, more particularly agonists of the Ang II type 2 receptor (hereinafter referred to as the AT2 receptor), and especially compounds that selectively bind to this receptor. The present invention further relates to the use of such compounds as medicaments, pharmaceutical compositions containing them, and synthetic routes for their production. Background Art

[0002] Renin (a protease) cleaves its only known substrate (angiotensinogen) to form angiotensin I (AngI), which in turn 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 -lle 5 -His 6 -Pro 7 -Phe 8 ), and is the 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 seem to indicate that activation of the AT2 receptor has an effect opposite to that mediated by the AT1 receptor in the regulation of responses following Ang II receptor stimulation. The AT2 receptor has also been shown to be involved in apoptosis and inhibition of cell proliferation (de Gasparo M et al., Pharmacol. Rev. (2000); 52, 415-472). Recently, AT2 receptor agonists have been shown to have potential utility in the treatment and / or prevention of digestive tract disorders (such as dyspepsia and irritable bowel syndrome) and multiple organ failure (see International Patent Application WO 99 / 43339). The expected pharmacological effects of the agonism of the AT2 receptor are generally described in the paper of de Gasparo M et al. (see above).

[0004] The stimulatory effects of Ang II on vascular tone, cell growth, inflammation, and extracellular matrix synthesis are primarily coupled to AT1 receptors in any organ, whereas the function of AT2 receptors appears to be more prevalent in damaged tissues and exerts repair properties as well as antagonistic properties of AT1 receptors. For example, AT2 receptors have been shown to be important in reducing cardiomyocyte hypertrophy and fibrosis.

[0005] Interstitial lung disease (ILD) is a group of lung diseases that affect the interstitium and is characterized by scarring and / or thickening of the tissue surrounding the alveoli, and thus inhibits the breathing process.

[0006] ILD differs from obstructive airway diseases (for example, chronic obstructive airway disease (COPD) and asthma) in that it is typically characterized by narrowing (obstruction) of the bronchi and / or bronchioles. ILD may be caused by lung damage that triggers an abnormal healing response, but in some cases, the cause of these diseases is unknown. ILD can be triggered by chemicals (silicosis, asbestosis, certain medications), infections (for example, pneumonia), or other diseases (for example, 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 decreased lung function.

[0008] Sarcoidosis is a disease of unknown cause characterized by the accumulation of inflammatory cells into masses (granulomas) that typically begin in the lungs (as well as the skin and / or lymph nodes, but any organ can be affected). When sarcoidosis affects the lungs, symptoms include cough, wheezing, shortness of breath, and / or chest pain.

[0009] Treatment of sarcoidosis varies from patient to patient. In most cases, symptomatic treatment is with nonsteroidal anti-inflammatory drugs (NSAIDs), but patients with pulmonary symptoms are typically treated with glucocorticoids (eg, prednisone or prednisolone), antimetabolites, and / or monoclonal anti-tumor necrosis factor antibodies.

[0010] IPF is a lung disease of unknown cause that affects approximately 5 million people worldwide. Except for rare cases where lung transplantation is performed, there is no curative treatment option, resulting in chronic, irreversible progressive deterioration of lung function, and in most cases, leading to death within 2-5 years (median survival is 2.5 to 3.5 years). Although the overall prognosis of IPF is poor, it is difficult to predict the progression rate of individual patients. The risk factors for IPF include age, male sex, genetic susceptibility, and smoking history. The annual incidence rate is between 5-16 cases per 100,000 people, and the prevalence rate is between 13-20 cases per 100,000 people, which increases sharply with age (King JrTE et al., Lancet (2011); 378, 1949-1961; Noble PW et al., J.Clin.Invest. (2012); 122, 2756-2762). IPF is limited to the lungs and is difficult to treat with therapies directed against the immune system, which distinguishes it from pulmonary fibrosis associated with systemic diseases.

[0011] Patients with IPF typically present with chronic and progressive exertional dyspnea and cough. Lung imaging studies typically reveal traction bronchiectasis, interlobular thickening, and subpleural honeycombing. The diagnosis of IPF is likely when all three clinical manifestations are present and there is no evidence of systemic connective tissue disease or environmental exposure. The definitive diagnosis is usually made by lung biopsy and requires a multidisciplinary team of professionals, including a pulmonologist, radiologist, and pathologist experienced in interstitial lung disease.

[0012] IPF presents with distinct phenotypes with varying prognoses, defined as mild, moderate, and severe. Mild cases follow a steady or slowly progressive path, sometimes requiring patients to seek medical advice for several years. Accelerated IPF has a much more rapid progression rate, shorter survival, and affects a specific subset of patients, typically male smokers. Acute exacerbations of IPF are defined as rapid disease progression, and patients in this subgroup have a very poor prognosis, with a high short-term mortality rate. The etiology of IPF remains unclear, but it appears to be a disorder likely caused by an interaction of environmental and genetic factors, resulting in relentless fibroblast-driven tissue remodeling rather than normal repair; pathogenesis is primarily driven by fibrosis rather than inflammation. Accumulating evidence suggests that the disease is initiated through microinjury and apoptosis of alveolar epithelial cells, activating neighboring epithelial cells and attracting stem or progenitor cells that produce factors responsible for the expansion of fibroblast and myofibroblast populations in a tumor-like manner. Fibroblast foci secrete excess extracellular matrix, which damages 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 L. Symptoms appear 1 to 2 years before diagnosis, 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, such as anti-inflammatory, immunomodulatory, cytotoxic, general antifibrotic, antioxidant, anticoagulant, anti-chemokine, anti-angiogenic drugs, as well as RAS blockers, endothelin antagonists and sildenafil, all of which have essentially been shown to provide limited or no benefit (Rafii R et al., J. Thorac. Dis. (2013); 5, 48-73).

[0015] Current treatment for IPF involves supplemental oxygen. Medications used include pirfenidone or nintedanib, but have had limited success in slowing disease progression. Furthermore, both drugs often cause side effects, primarily gastrointestinal.

[0016] There are disadvantages associated with all of the above-mentioned ILD (and IPF) drug treatments, and there is a real clinical need for safer and / or more effective treatments.

[0017] Restoring the alveolar epithelium as a treatment for IPF is highly desirable, and stem cell therapy has been tested. Some preclinical studies have shown the potential of using pluripotent stem cells, which can differentiate into lung epithelial and endothelial cells, to repair lung injury and fibrosis.

[0018] Currently, lung transplantation is the only intervention that can substantially improve survival in IPF patients. However, complications such as infection and transplant rejection are not uncommon.

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

[0020] US patent application US2004 / 0167176 describes the preparation of tricyclic heterocycles useful as Ang II receptor agonists.

[0021] Selective AT2 receptor agonists with reduced CYP 450 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] In particular, International Patent Application WO 2002 / 096883 describes the preparation of imidazolyl, triazolyl, and tetrazolylthiophenesulfonamides and derivatives as AT2 receptor agonists. The compound described in this document (as Example 1) is compound C21 (N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide). C21 was selected from a group of approximately 20 related analogs as a selective AT2 receptor agonist for clinical development. It is currently under clinical development for the treatment of AT2 receptor-related disorders (including IPF) (see, for example, International Patent Application WO 2016 / 139475).

[0024] C21 has also been shown to have potential use in treating, among other things, stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer therapy-related cardiotoxicity, peripheral neuropathy, and systemic sclerosis (see, e.g., International Patent Applications WO 2004 / 046141, WO 2016 / 092329, WO 2016 / 107879, WO 2016 / 139475, WO 2017 / 221012, WO 2019 / 008393, and U.S. Patent Application US2012 / 035232).

[0025] During development, it was discovered that C21 has the following disadvantages: it is a potent inhibitor of several cytochrome P450 enzymes (CYPs), particularly CYP 2C9 and CYP 3A4, which may affect the metabolism of other drugs; and it is rapidly hydrolyzed to an inactive sulfonamide metabolite. Therefore, developing potent and selective AT2 agonists that are metabolically stable and / or exhibit less inhibition of CYP enzymes is a fundamental challenge.

[0026] We present here certain chemical compounds, as defined below, which are not only selective AT2 receptor agonists, but are also more potent than C21, have significantly improved stability to metabolic hydrolysis and / or exhibit less inhibition of CYP enzymes. DETAILED DESCRIPTION

[0027] In a first aspect of the present invention, there is provided a compound of formula I,

[0028]

[0029] in:

[0030] R 1 Represents H, halogen atom, -CN or C 1-7 Alkyl or C 1-7 Alkoxy, both of which are optionally substituted by one or more halogen atoms, hydroxyl groups, C 1-7 Alkyl, CF3 or OR 7 replace;

[0031] R 2 and R 3 independently represent H, a halogen atom, -CN or C 1-7 Alkyl or C 1-7 Alkoxy, both of which are optionally substituted by one or more halogen atoms, hydroxyl groups, C 1-7 Alkyl, CF3 or OR 7a replace;

[0032] R 4 Indicates C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6Alkoxy-C 1-6 alkyl, the alkyl portion of each of which is optionally substituted and / or terminated by one or more halogen atoms, -CN or -OH groups, or

[0033] R 4 Represents aryl, C 1-6 Alkyl aryl, C 1-3 Alkenyl aryl, heteroaryl, C 1-6 Alkyl heteroaryl or C 1-3 Alkenylheteroaryl, each of which is optionally substituted by one or more halogen, CF3, CF3O-, -CN, C 1-6 Alkyl and C 1-6 Alkoxy substitution;

[0034] R 5 Represents H, halogen atoms, hydroxyl groups, -CN, -NR 9a R 10a 、C 1-7 Alkyl, C 1-7 Alkoxy or C 1-6 Alkoxy-C 1-6 Alkyl, each of which is optionally substituted by one or more halogen atoms, hydroxyl, -CN, -NR 9b R 10b 、C 1-7 Alkyl or C 1-7 Alkoxy substitution;

[0035] R 6 、R 7 and R 7a independently represents H or C 1-6 an alkyl group, which is optionally substituted with one or more halogen atoms;

[0036] Y 1 Yes-CR 8 -, -N-, -NH-, O or S;

[0037] Y 2 Yes-CR 8 -、-CR 8 =CH-, -CH=CR 8 -、-CR 8 =CR 8 -, -N-, -NH-, O, or S; and

[0038] Y 3 Yes-CR 8 -,

[0039] R 8 Represents H, halogen atoms, hydroxyl groups, -CN, -NR 9c R 10c , or C1-7 Alkyl or C 1-7 Alkoxy, both of which are optionally substituted by one or more halogen atoms, hydroxyl, -CN, -NR 9d R 10d 、C 1-7 Alkyl or C 1-7 Alkoxy substitution;

[0040] The conditions are:

[0041] (a)Y 1 and Y 2 are different; and

[0042] (b) In Y 1 、Y 2 and Y 3 In the 8 At least one of the groups does not represent H or fluorine,

[0043] X and Z independently represent CH=CH, CR 11 , N, NH, O or S,

[0044] The conditions are:

[0045] (a) X and Z are different,

[0046] (b) When X represents CH=CH, then Z can only represent CR 11 ;and

[0047] (c) When Z represents CH=CH, then X can only represent CR 11 ;

[0048] R 11 Represents H, halogen atoms, hydroxyl groups, -CN, -NR 9e R 10e , or C 1-7 Alkyl or C 1-7 Alkoxy, both of which are optionally substituted by one or more halogen atoms, hydroxyl, amino, -CN, -NR 9f R 10f 、C 1-7 Alkyl or C 1-7 Alkoxy substituted; and

[0049] R 9a 、R 10a 、R 9b 、R 10b 、R 9c 、R 10c 、R 9d 、R 10d 、R 9e 、R 10e 、R9f and R 10f Each independently represents H or C 1-6 an alkyl group, which is optionally substituted by one or more halogen atoms,

[0050] or a pharmaceutically acceptable salt thereof,

[0051] These compounds and salts are hereinafter collectively referred to as "compounds of the present invention."

[0052] Compounds of the invention that may be mentioned include those as defined above, but in which:

[0053] R 1 Indicates H, C 1-6 Alkyl, which is optionally substituted by one or more halogen atoms, CF3 or OR 7 replace;

[0054] R 2 and R 3 independently represents H or C 1-6 an alkyl group, which is optionally substituted with one or more halogen atoms;

[0055] R 4 Indicates C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy-C 1-6 alkyl, the alkyl portion of each of which is optionally substituted and / or terminated by one or more halogen atoms, -CN or -OH groups, or

[0056] R 4 Represents aryl, C 1-6 Alkyl aryl, C 1-3 Alkenyl aryl, heteroaryl, C 1-6 Alkyl heteroaryl or C 1-3 Alkenylheteroaryl, each of which is optionally substituted by one or more halogen, CF3, CF3O-, -CN, C 1-6 Alkyl and C 1-6 Alkoxy substitution;

[0057] R 5 Indicates C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, each of which is optionally

[0058] substituted by one or more halogen atoms;

[0059] R 6 and R 7 independently represents H or C 1-6an alkyl group, which is optionally substituted with one or more halogen atoms; and / or

[0060] R 8 represents H, a halogen atom, or represents C 1-3 Alkyl or C 1-3 alkoxy, both of which are optionally substituted by one or more halogen atoms.

[0061] For the purposes of interpreting this specification, the following definitions will apply and, where appropriate, terms used in the singular will also include the plural and vice versa.

[0062] The compounds were named according to the IUPAC nomenclature generated by the program ChemDraw Ultra 12.0.

[0063] For the avoidance of doubt, the skilled person will understand that references herein to compounds of a particular aspect of the invention (such as any aspect of the invention relating to compounds of formula I as defined hereinbefore) will include references to all embodiments thereof and specific features thereof, which may be combined to form further embodiments and features of the invention.

[0064] Unless defined otherwise, 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.

[0065] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can 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 the medium using standard techniques (e.g., in a vacuum, by freeze drying, or by filtering). Salts can also be prepared using techniques known to those skilled in the art, such as by exchanging the counterion of the compound of the present invention in salt form with another counterion (e.g., using a suitable ion exchange resin).

[0066] Specific acid addition salts that may be mentioned include carboxylates such as formates, acetates, trifluoroacetates, benzoates, oxalates, fumarates, maleates, and the like; sulfonates such as methanesulfonates, ethanesulfonates, toluenesulfonates, and the like; halide salts such as hydrochlorides, hydrobromides, and the like; sulfates and phosphates such as sulfates or phosphates, and the like.

[0067] Specific base addition salts that may be mentioned include salts formed with alkali metals (such as Li, Na and K salts), salts formed with alkaline earth metals (such as Mg and Ca salts) or salts formed with other metals (such as Al and Zn salts), and salts formed with amine bases (such as ammonia, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine). More particularly, base addition salts that may be mentioned include Mg salts, Ca salts, and most particularly K salts and Na salts.

[0068] Compounds of the present invention can exist as solids, and therefore the scope of the present invention includes all amorphous, crystalline and partially crystalline forms thereof, and can also exist as oils. Where compounds of formula I exist in crystalline and partially crystalline forms, such forms may include solvates, which are included within the scope of the present invention.

[0069] The compounds of the present invention may also be present in solution (ie, in a solution in a suitable solvent). For example, the compound of formula I may be present in aqueous solution, in which case the compound of the present invention may be present in the form of a hydrate.

[0070] The compounds of the present invention may contain double bonds and, unless otherwise specified, may therefore 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.

[0071] The compounds of the present invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the present invention (particularly those that are sufficiently stable to allow their separation).

[0072] The compounds of the present invention may also contain one or more asymmetric carbon atoms and, therefore, may exhibit optical and / or diastereoisomerism (i.e., exist as enantiomers or diastereoisomers). Conventional techniques (e.g., chromatography or fractional crystallization) may be used to separate diastereomers. Various stereoisomers (i.e., enantiomers) may be separated by separating racemic or other mixtures of the compounds using conventional (e.g., fractional crystallization or HPLC) techniques. Alternatively, the desired enantiomer or diastereomer can be obtained from an appropriate starting material by reacting the appropriate optically active starting material with a "chiral auxiliary" under conditions that will not cause racemization or epimerization (i.e., the "chiral pool" method), which can then be removed at an appropriate stage by derivatization (i.e., resolution, including dynamic resolution; for example, with a homochiral acid, followed by separation of diastereomeric derivatives by conventional means such as chromatography), or by reaction with an appropriate chiral reagent or chiral catalyst to obtain the desired enantiomer or diastereomer, all of which methods and processes can be carried out under conditions known to those skilled in the art. Unless otherwise indicated, all stereoisomers and mixtures thereof are included within the scope of the present invention.

[0073] As used herein, the term "halogen" when used herein includes fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Likewise, the term "halo" if and when used herein includes fluoro, chloro, bromo and iodo.

[0074] Unless otherwise stated, C is defined herein 1-7 Alkyl groups, such as C 1-6 Alkyl groups (e.g., C 1-4 Alkyl group), C 2-7 Alkyl groups, such as C 2-4 Alkyl groups, and C 1-7 Alkoxy groups, such as C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkyl aryl, C 1-3 Alkenylaryl, C 1-6 Alkyl heteroaryl and C 1-3 The alkyl portion of the alkenylheteroaryl group may be linear or, when there are a sufficient number (ie, at least two or three, where appropriate) of carbon atoms, branched and / or cyclic (e.g., to form a C 3-7 , such as C 3-6 When there are a sufficient number (ie, at least four) of carbon atoms, such groups may also be partially cyclic (eg, forming a C 4-7 , such as C 4-6Partial cycloalkyl groups). 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 there are a sufficient number of carbon atoms, such groups may also be polycyclic (e.g., bicyclic or tricyclic) and / or spirocyclic.

[0075] When a sufficient number (ie, a minimum of three) of carbon atoms are present, alkyl and alkoxy groups may be unsaturated and thus introduce double or triple bonds.

[0076] Specific alkyl groups that may be mentioned include straight chain (ie, non-branched and / or cyclic) alkyl groups. For example, C 1-7 Alkyl groups, such as C 1-6 Alkyl groups, and C 1-7 Alkoxy groups, such as 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.

[0077] For the avoidance of any doubt, C 1-7 Alkyl groups, such as C 1-6 Alkyl groups, and C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkyl aryl, C 1-3 Alkenylaryl, C 1-6 Alkyl heteroaryl and C 1-3 The point of attachment of the alkyl portion of an alkenylheteroaryl group is via the alkyl portion of such group.

[0078] For the avoidance of doubt, an alkoxy group is linked to the remainder of the molecule via the oxygen atom in the group and an alkoxyalkyl group is linked to the remainder of the molecule via the alkyl portion of the group.

[0079] Unless otherwise stated, alkoxy refers to an O-alkyl group, wherein the term "alkyl" has the meaning given above.

[0080] As used herein, references to heteroatoms will take their ordinary meaning as understood by those skilled in the art. Specific heteroatoms that may be mentioned include phosphorus, selenium, silicon, boron, oxygen, nitrogen, and sulfur (e.g., oxygen, nitrogen, and sulfur, such as oxygen and nitrogen).

[0081] As may be used herein, reference to a "heteroaryl" (which may also be referred to as a 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 comprise one, two or three rings, at least one of which is an aromatic ring (wherein the aromatic ring may or may not contain one or more heteroatoms). Where appropriate, substituents on the heteroaryl / heteroaromatic group may be located on any suitable atom (including heteroatoms) in the ring system (e.g., on a suitable N atom).

[0082] The point of attachment of the heteroaryl / heteroaromatic group may be via any atom in the ring system (including, where appropriate, a heteroatom). Bicyclic heteroaryl / heteroaromatic groups may comprise a benzene ring fused to one or more further aromatic or non-aromatic heterocycles, in which case the point of attachment of the polycyclic heteroaryl / heteroaromatic group may be via any ring including a benzene ring or a heteroaryl / heteroaromatic or heterocyclyl ring.

[0083] For the avoidance of doubt, it will be understood by the skilled artisan that the heteroaryl groups which may form part of the compounds of the present invention are those which are obtainable by chemical processes as known to those skilled in the art. Various heteroaryl groups are well known to those skilled in the art, such as pyridyl, pyrrolyl, furyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiazolyl, triazinyl, pyrimidinyl, furopyridyl, indolyl, azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolyl, isoquinolyl, quinazolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl and purinyl.

[0084] For the avoidance of doubt, oxides of heteroaryl / heteroaromatic groups are also included within the scope of the present invention (eg, N-oxides).

[0085] As mentioned above, heteroaryl includes polycyclic (e.g., bicyclic) groups in which one ring is aromatic (while the other rings may or may not be aromatic). Thus, other heteroaryl groups that may be mentioned include groups such as benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazolyl, 3,4-dihydrobenzo[1,4]oxazinyl, dihydrobenzothiophenyl, dihydroindole, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, and the like.

[0086] As used herein, the term "aryl" may refer to a C 6-14 (For example, C 6-10) aromatic groups. Such groups may be monocyclic or bicyclic and, when bicyclic, may be fully or partially aromatic. C 6-10 Aryl groups include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like (eg, phenyl, naphthyl, and the like).

[0087] An aromatic group can be depicted as a cyclic group containing a suitable number of double bonds to allow aromaticity.

[0088] The skilled person will appreciate that the aryl groups that may form part of the compounds of the present invention are those that are obtainable by chemical methods as known to those skilled in the art.

[0089] For the avoidance of doubt, the point of attachment of a substituent on an aryl group may be via any suitable carbon atom of the ring system.

[0090] The present invention also includes isotopically labeled compounds of the invention identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (or the most abundant atom found in nature). All isotopes of any particular atom or element specified herein are contemplated within the scope of the compounds of the present invention and their uses. Thus, 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.

[0091] In the case where the characteristics of two or more substituents in the compounds of the present invention may be the same, the actual characteristics of the corresponding substituents are not interdependent in any way. For example, where there are two or more halo groups, those groups may be the same or different (e.g., two chloro groups, or one fluoro group and one chloro group). Similarly, where there are two or more alkyl groups, the groups in question may be the same or different in terms of their number of carbon atoms and / or whether they are straight chain, branched, unsaturated or otherwise.

[0092] Further, when a substituent is itself optionally substituted with one or more substituents (e.g., butyl optionally substituted with one or more independently selected halo groups), 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).

[0093] Where a group is referred to herein as optionally substituted, it is specifically contemplated that such optional substituent may be absent (i.e., the reference to such optional substituent may be removed), in which case the optionally substituted group may be referred to as unsubstituted.

[0094] Unless otherwise indicated, substituents (whether optional or otherwise) may be located at any point on the group to which they may be attached. In this regard, alkyl and alkoxy groups (for example) that may be substituted with one or more substituents may also be end-capped (meaning located at, for example, the terminus of the alkyl or alkoxy chain) with such substituents.

[0095] For the avoidance of doubt, where the identity of two or more substituents in a compound of formula I may be identical, the actual identity of the respective substituents is not in any way interdependent. 2 and R 3 All C 1-6 In the case of alkyl, the C 1-6 The alkyl groups can be the same or different.

[0096] The skilled artisan will recognize that the compounds of the present invention that are the subject of the present invention include those that are available, i.e., those that can be prepared in a stable form. That is, the compounds of the present invention include those that are sufficiently stable to withstand isolation (e.g., isolation from a reaction mixture) to obtain a useful degree of purity.

[0097] Preferred compounds of the present invention include those wherein:

[0098] When R 1 Indicates H or C 1-6 When an alkyl group such as methyl, ethyl, propyl (e.g. isopropyl, cyclopropyl) or butyl (e.g. n-butyl or tert-butyl) is present, it is optionally substituted by one or more halogen atoms, CF3 or OR 7 replace;

[0099] R 2 and R 3 independently represents H or C 1-4 an alkyl group such as methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., n-butyl), optionally substituted with up to three halogen atoms (e.g., CH2CHClCH2CH2F or CH2CF3);

[0100] Y 1 Indicates -CR 8 -;

[0101] Y 2 Indicates -CR 8 -、-CR 8 =CH-, -CH=CR 8 -、-CR 8 =CR 8 -;

[0102] One of X or Z represents -CH=CH- and the other represents -CH-, or one of X or Z represents O or S and the other represents -CH- or N;

[0103] R 4 Indicates C 1-4 an alkyl group such as ethyl, propyl (eg, n-propyl or isopropyl), or butyl (eg, tert-butyl, isobutyl, or n-butyl), C 1-4 Alkoxy (e.g., methoxy, ethoxy), the alkyl portion of each of which is optionally substituted and / or terminated by one or more halogen atoms, -CN or -OH groups; aryl (e.g., phenyl), heteroaryl, C 1-3 Alkyl aryl or C 1-3 Alkylheteroaryl, each of which is optionally substituted by one or more halogens (such as F, Cl or Br), CF3, -CN, C 1-6 Alkyl (eg, methyl) and C 1-6 Alkoxy (e.g., methoxy) substitution;

[0104] R 5 Indicates C 1-4 an alkyl group (such as methyl, ethyl, propyl (eg, n-propyl), or butyl (eg, isobutyl));

[0105] R 6 and R 7 independently represents H, methyl, ethyl or propyl (eg n-propyl).

[0106] More preferred compounds of the present invention include those wherein:

[0107] R 1 represents H, methyl, ethyl, isopropyl, cyclopropyl or tert-butyl, which is optionally substituted by halogen, CF3 or OR 7 replace;

[0108] R 2 and R 3 independently represents H or methyl;

[0109] Y 1 represents -CH-;

[0110] Y 2 Indicates -CH=CH-;

[0111] Y 3 Indicates -CR 8 -;

[0112] X represents -CH=CH-, O or S;

[0113] Z represents -CH- or N;

[0114] R 4 Indicates C 1-4 Alkoxy (e.g., methoxy, ethoxy), the alkyl portion of which is optionally substituted and / or terminated with one or more F, Cl, Br, -CN, or -OH groups; or R 4 represents a heteroaryl group selected from the groups thiazole, oxazole, isoxazole, pyridine, pyridazine, triazine, pyrazine and more preferably pyrimidine, each of which is optionally substituted by one or more F, Cl, Br, CF3, -CN, Me or methoxy;

[0115] R 5 represents a methyl, ethyl, n-propyl, n-butyl or isobutyl group;

[0116] R 6 represents H or methyl;

[0117] R 7 Indicates H;

[0118] R 8 represents halogen or methyl, which is optionally substituted by one or more halogens.

[0119] Particularly preferred compounds of the present invention include those wherein:

[0120] R 1 represents methyl, which is optionally substituted by one or more fluoro groups, or represents 2-hydroxypropan-2-yl;

[0121] R 2 and R 3 All represent H;

[0122] X represents -CH=CH- or S;

[0123] Z represents -CH-;

[0124] R 4 represents a heteroaryl group selected from the groups oxazole, pyridine and more preferably pyrimidine, each of which is optionally substituted by one or more F, Cl, Br, CF3, -CN, methyl or methoxy;

[0125] R 5 represents a methyl, ethyl, n-propyl, n-butyl or isobutyl group;

[0126] R 6 represents H or methyl;

[0127] Y 3 It represents -CCl-, -C(methyl)- or -C(CF3)-.

[0128] Preferred compounds of the present invention include those wherein:

[0129] R 1 represents methyl, trifluoromethyl or 2-hydroxypropan-2-yl;

[0130] Y 1 represents -CH-;

[0131] Y 2 Indicates -CH=CH-;

[0132] R 4 represents pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 5-methylpyrimidin-2-yl, 5-trifluoromethylpyrimidin-2-yl, 4,5-dimethyloxazol-2-yl, pyridin-2-yl;

[0133] R 5 represents n-butyl or isobutyl;

[0134] R 6 Indicates H.

[0135] Further preferred compounds of the present invention include those wherein:

[0136] Y 3 Indicates -CR 8 -;

[0137] R 5 represents isobutyl;

[0138] R 7 Indicates H;

[0139] R 8 represents chlorine, bromine or iodine, or represents methyl, which is optionally substituted by one or more fluorine groups.

[0140] Further preferred compounds of the present invention include those wherein

[0141] R 1 represents a methyl group;

[0142] Y 3 represents -CCl-;

[0143] R 4 represents a methoxy group;

[0144] R 8 represents chlorine, methyl or trifluoromethyl.

[0145] Preferred compounds of the present invention include those wherein:

[0146] When X represents S and Z represents -CH-, then R 1 represents methyl, trifluoromethyl or 2-hydroxypropan-2-yl;

[0147] When X represents -CH=CH- and Z represents -CH-, then R 1 Represents a methyl group.

[0148] Further preferred compounds of the present invention include those wherein:

[0149] When X represents S and Z represents -CH-, then R 1 represents methyl, trifluoromethyl, 2-hydroxyprop-2-yl or isopropyl;

[0150] When X represents -CH=CH- and Z represents -CH-, then R 1 represents a methyl or isopropyl group.

[0151] Thus, preferred compounds of the present invention that may be mentioned include:

[0152] 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyridin-2-yl)thiophene-2-sulfonamide, 5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(pyridin-2-yl)thiophene-2-sulfonamide,

[0153] 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyridin-2-yl)-[1,1'-biphenyl]-2-sulfonamide,

[0154] 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(5-fluoropyrimidin-2-yl)-5-isobutylthiophene-2-sulfonamide,

[0155] 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(4,5-dimethyloxazol-2-yl)-5-isobutylthiophene-2-sulfonamide,

[0156] 3-(3-chloro-4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide,

[0157] 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-(trifluoromethyl)pyrimidin-2-yl)thiophene-2-sulfonamide,

[0158] 5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)thiophene-2-sulfonamide,

[0159] 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-methylpyrimidin-2-yl)thiophene-2-sulfonamide,

[0160] 3'-chloro-5-isobutyl-N-(5-methoxypyrimidin-2-yl)-4'-((2-methyl-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide,

[0161] 5-isobutyl-3'-methyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide,

[0162] 3-(3-chloro-4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide,

[0163] 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide,

[0164] 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-methoxythiophene-2-sulfonamide,

[0165] 2-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide,

[0166] 5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]-3-(trifluoromethyl)phenyl]-N-pyrimidin-2-yl-thiophene-2-sulfonamide, 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide and

[0167] 3-[3-Chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiophene-2-sulfonamide.

[0168] IUPAC names were generated by the program ChemDraw Ultra 12.0.

[0169] More preferred compounds of the present invention include the compounds of the Examples described below.

[0170] Compounds of formula I can be prepared according to techniques well known to those skilled in the art, for example as described below.

[0171] According to a further aspect of the present invention, there is provided a method for preparing a compound of formula I, wherein the method comprises making a compound of formula II,

[0172]

[0173] where R 1 、R 2 、R 3 、R 5 、R 6 、Y 1 、Y 2 、Y 3 , X and Z are as defined above, reacted with a compound of formula III or a salt thereof,

[0174] L 1 R 4 III

[0175] where R 4 As defined above and L 1 for a suitable leaving group (e.g., a halo group such as chloro or bromo), for example, in the presence of a palladium catalyst (e.g., palladium acetate), a suitable ligand (e.g., 1,1-bis(diphenylphosphino)ferrocene), a suitable solvent (e.g., toluene, acetonitrile, dimethylformamide, dioxane, water) and / or a suitable base (e.g., potassium carbonate, triethylamine, 4-dimethylaminopyridine, potassium tert-butoxide, sodium tert-butoxide, N,N'-dimethylethylenediamine, pyrrolidinylpyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or mixtures thereof) at about room temperature or higher (e.g., up to 80°C-140°C), in the presence of lithium chloride.

[0176] Compounds of formula I may alternatively be prepared according to a process comprising reacting a compound of formula II as defined above with a compound of formula III as defined above, for example under microwave irradiation at about room temperature or higher (e.g., up to 90° C.-140° C.) in the presence of a suitable solvent (e.g., toluene, acetonitrile, dimethylformamide, dioxane, dichloromethane, such as toluene, acetonitrile, dimethylformamide, dioxane) and / or a suitable base (e.g., potassium carbonate, triethylamine, 4-dimethylaminopyridine, pyridine, diisopropylethylamine, such as potassium carbonate, triethylamine, 4-dimethylaminopyridine), optionally in the presence of copper(I) iodide and / or a suitable base (e.g., N,N′-dimethylethylenediamine, pyrrolidinylpyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or mixtures thereof).

[0177] The compound of formula II can be prepared by making a compound of formula IV,

[0178]

[0179] Among them, X, Z, R 5 and R 6 As defined above, or an N-protected derivative thereof, and L 2 represents a suitable cross-coupling group, which is reacted with a compound of formula V to prepare,

[0180]

[0181] where R 1 、R 2 、R 3 、Y 1 、Y 2 and Y 3 As defined above and L 3 represents a suitable cross-coupling group.

[0182] The above coupling reaction can be a palladium-catalyzed C-H activation, which means that L 2 and L 3One of the represents one of the suitable cross-coupling groups, ie H, and the other represents other groups (eg a halogen group such as iodine or bromine). Standard C—H activation conditions can be applied to the reaction, including, for example, the presence of an appropriate coupling catalyst system (e.g., a palladium catalyst such as palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, 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 hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or diisopropylamine) and a suitable solvent system (e.g., toluene, ethanol, n-butanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane, or a mixture thereof). The reaction can be carried out at temperatures above room temperature (e.g., at the reflux temperature of the solvent system used). The reaction can be carried out under microwave irradiation at temperatures above room temperature.

[0183] The above coupling reaction can also be a Suzuki reaction and can therefore be carried out under standard Suzuki conditions, which means that L 2 and L 3 One of the represents a suitable Suzuki cross-coupling group (or 'partner'), i.e., one of boronic acid (-B(OH)2) or boronic acid MIDA ester (e.g., 5-methyl-3,7-dioxo-2,8-dioxa-5-azonia-1-boranebicyclo[3.3.0]octan-1-yl) and a halide group (such as iodine or bromine) and the other represents another group. Standard Suzuki conditions can be applied to the reaction, including, for example, the presence of an appropriate coupling catalyst system (e.g., a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II) dichloromethane complex, 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 hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or diisopropylamine) and a suitable solvent system (e.g., toluene, ethanol, n-butanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane, or a mixture thereof). The reaction can be carried out at temperatures above room temperature (e.g., at the reflux temperature of the solvent system used). The reaction can be carried out under microwave irradiation at temperatures above room temperature.

[0184] If a protected form of the compound of formula IV is used, the reaction can be followed by deprotection of the SO NH- group under standard conditions (e.g., as described below). The reaction of the compound of formula IV with the compound of formula V can also be followed by reaction of the intermediate thus formed with a suitable acid to form an acid addition salt, or more preferably an N-protected form thereof. Suitable acid addition salts include fumarate, trifluoroacetate, and oxalate.

[0185] Alternatively, the compound of formula II may be prepared by making a compound of formula VI,

[0186]

[0187] where R 1 、R 2 and R 3 As defined above, reacted with a compound of formula VII to prepare

[0188]

[0189] where R 5 、R 6 、Y 1 、Y 2 、Y 3 , X and Z are as defined above and L 4 Represents a suitable leaving group (such as, in particular, bromine) or its N-protected derivative, for example, at about room temperature or below room temperature in the presence of a suitable base (e.g., pyridine) and a suitable organic solvent (e.g., toluene). If the protected form of the compound of formula VII is adopted, then the reaction can be followed by deprotection of the SO NH-group under standard conditions (e.g., as described below). In addition, the compound of formula II can be prepared in this way, for example, according to or similar to the method described in, in particular, British patent application GB 2281298.

[0190] Compounds of formula V may be prepared by standard techniques, for example by reacting a compound of formula VI as defined hereinbefore with a compound of formula VIII,

[0191]

[0192] Among them L 3 、L 4 、Y 1 、Y 2 and Y 3As defined above, for example in the presence of a suitable base (e.g., sodium hydride, potassium carbonate, potassium hydroxide, such as sodium hydride or potassium carbonate) and a suitable solvent (e.g., dimethylformamide, acetonitrile, dimethyl sulfoxide, such as dimethylformamide or acetonitrile), at room temperature, below room temperature (e.g., 0°C) or above room temperature (e.g., at the reflux temperature of the solvent system used), such as at room temperature or below room temperature.

[0193] Compounds of formula VII are known in the art. For example, they can be prepared according to or in analogy to the methods described in, inter alia, US Pat. No. 5,312,820, UK Patent Application GB 2281298 and / or International Patent Application WO 02 / 096883.

[0194] Compounds of formula IV are known in the art. For example, they can be prepared according to or analogously to the methods described, inter alia, in International Patent Application WO 02 / 096883.

[0195] Compounds of formula III, VI and VIII are commercially available, are known in the literature, or can be obtained by methods analogous to those described herein, or can be prepared by conventional synthetic procedures from readily available starting materials according to standard techniques using appropriate reagents and reaction conditions.

[0196] Those skilled in the art will recognize that in the processes described above and below, functional groups of intermediate compounds may need to be protected by protecting groups.

[0197] The functional group of expectation protection comprises sulfonamido, amido, amino and aldehyde.Suitable protecting group of sulfonamido, amido and amino comprises tert-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc) or tert-butyl.Suitable protecting group of aldehyde comprises alcohol, such as methyl alcohol or ethanol and glycol (such as 1,3-propylene glycol or preferably 1,2-ethylene glycol) (therefore forming cyclic acetal).The protection of functional group and deprotection can be carried out before or after the reaction in the above scheme.

[0198] Protecting groups can be applied or removed according to techniques well known to those skilled in the art or as described hereinafter. For example, standard deprotection techniques can be used to chemically convert protected compounds / intermediates as described herein into unprotected compounds. The chemical types involved will determine the demand and type of protecting groups and the order in which the synthesis is completed. The use of protecting groups is fully described in the following document: "Protective Groups in Organic Synthesis", 3rd edition, TW Greene and PGM Wutz, Wiley-Interscience (1999), which is incorporated herein by reference.

[0199] Medical and pharmaceutical uses

[0200] As described herein, the compounds of the present invention, and therefore compositions and kits comprising these compounds, are useful because they are pharmacologically active and / or are metabolized in vivo following oral or parenteral administration to form a pharmacologically active compound.

[0201] Thus, according to a further aspect of the present invention, there is provided a compound of the invention as hereinbefore defined for use as (or in) a medicament.

[0202] In particular, the compounds of the present invention are agonists of the AT2 receptor.Thus, the compounds of the present invention are expected to be useful in those conditions in which endogenous production of Ang II is insufficient and / or increased AT2 receptor activity is desired or required.

[0203] More particularly, the compounds of the present invention are agonists of the AT2 receptor, and in particular selective (relative to the AT1 receptor) agonists of this subreceptor, as can be demonstrated, for example, by the test described hereinafter.

[0204] AT2 receptor agonists include agonists that fully activate the AT2 receptor and agonists that partially activate the AT2 receptor. Therefore, the compounds of the present invention can selectively bind to the AT2 receptor and exhibit agonist activity to the AT2 receptor. Compounds that "selectively bind" to the AT2 receptor include having an affinity ratio (AT2:AT1) of at least 50:1, such as at least 100:1, preferably at least 1000:1, to the relevant compound at a given concentration.

[0205] The compounds of the present invention are further expected to be useful in those conditions in which AT2 receptors are expressed and their stimulation is desired or required.

[0206] In this regard, the compounds of the invention are useful in treating disorders characterized by vasoconstriction, fibrosis, increased cell growth and / or differentiation, increased myocardial contractility, increased cardiovascular hypertrophy and / or fluid and electrolyte retention, as well as skin disorders and musculoskeletal disorders.

[0207] The compounds of the present invention may also exhibit thromboxane receptor activity. In this regard, the compounds of the present invention may have an inhibitory effect on platelet activation and / or aggregation (thus having, for example, an antithrombotic effect) and / or may therapeutically reduce vasoconstriction and / or bronchoconstriction.

[0208] The compounds of the present invention are further suitable for treating stress-related disorders, and / or improving microcirculation and / or mucosal protective mechanisms.

[0209] Thus, the compounds of the invention are expected to be useful for the treatment of disorders which may be characterized as indicated above and are, for example, disorders of the gastrointestinal tract, cardiovascular system, respiratory tract, kidneys, eyes, female reproductive (ovulatory) system and central nervous system (CNS).

[0210] 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), pancreatitis, 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 tract disorders, celiac disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, colic, dysphagia, vomiting, nausea, dyspepsia and Sjögren's syndrome.

[0211] Respiratory diseases that may be mentioned include inflammatory disorders such as asthma, obstructive lung diseases (such as chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension and adult respiratory distress syndrome.

[0212] Renal disorders that may be mentioned include renal failure, nephritis and renal hypertension.

[0213] Eye disorders that may be mentioned include diabetic retinopathy, retinopathy of prematurity and retinal microvascularization.

[0214] Disorders of the female reproductive system that may be mentioned include ovulatory dysfunction.

[0215] Cardiovascular diseases 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, stenosis after balloon dilatation, angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmias, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic lesions, erectile dysfunction and neointimal proliferation.

[0216] CNS disorders that may be mentioned include cognitive dysfunction, food intake (hunger / satiety) and thirst dysfunction, stroke, cerebral hemorrhage, cerebral embolism and cerebral infarction, multiple sclerosis (MS), Alzheimer's disease and Parkinson's disease.

[0217] The compounds of the present invention can also be used to regulate growth metabolism and proliferation, for example, for the treatment of aging, hypertrophic disorders, prostate hyperplasia, autoimmune diseases (e.g., arthritis, such as rheumatoid arthritis or systemic lupus erythematosus), psoriasis, obesity, neuronal regeneration, ulcer healing, inhibition of adipose tissue proliferation, stem cell differentiation and proliferation, fibrotic diseases, cancer (e.g., cancer in the gastrointestinal tract (including the esophagus or stomach), prostate, breast, liver, kidney or cancer itself, as well as lymphoma, lung cancer, ovarian cancer, pancreatic cancer, hematological malignancies, etc.), apoptosis, tumors (general) and hypertrophy, diabetes, neuronal diseases and organ rejection.

[0218] The compounds of the invention may also be useful in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cardiotoxicity associated with cancer therapy, peripheral neuropathy, and, in particular, systemic sclerosis.

[0219] The compounds of the present invention are particularly useful in treating and / or preventing ILD, such as sarcoidosis or fibrosis, more particularly pulmonary fibrosis (and particularly IPF), as well as conditions that may cause ILD (such as systemic sclerosis, rheumatoid arthritis, myositis or systemic lupus erythematosus) or otherwise be associated with ILD (such as pulmonary hypertension and / or arterial pulmonary hypertension).

[0220] The compounds of the present invention are particularly useful in the treatment of pulmonary fibrosis, in particular IPF.

[0221] Term " IPF " should be understood as not only including prototype IPF (it is well-known progressive fibrosis ILD, it is characterized by accelerated respiratory failure, frequent disease aggravation and early death), but also including illness ' progressive fibrosis ILD ' (PF-ILD), some of which individuals develop the progressive phenotype similar to IPF (see, for example, Flaherty et al., N.Engl.J.Med., 381,1718 (2019) and Wells, Lancet, 9,437 (2021)).PF-ILD phenotype is usually by disease (such as connective tissue disease, such as rheumatoid arthritis, scleroderma, dermatomyositis / polymyositis, related ILD (CTD-ILD), fibrosis hypersensitivity pneumonitis (fHP), pneumoconiosis such as asbestosis, silicosis), sarcoidosis, idiopathic nonspecific interstitial pneumonia (NSIP) and the ILD that cannot be classified cause. Regardless of the disease trigger, PF-ILD shares similar risk factors to prototypical IPF and progresses through similar mechanisms, such as self-sustaining dysregulated cellular repair, fibroblast proliferation, and alveolar dysfunction, and can be targeted together in a similar manner. To avoid unnecessary repetition, the conditions IPF and PF-ILD will be referred to collectively as 'IPF' below.

[0222] According to a further aspect of the present invention there is provided a method of treating pulmonary fibrosis (and in particular IPF) which comprises administering to a human suffering from such a condition a therapeutically effective amount of a compound of the invention.

[0223] In the treatment of pulmonary fibrosis (including IPF), the compounds of the present invention can have an anti-fibrotic effect, reduce fibrosis and prevent further deposition of extracellular matrix. The compounds of the present invention can reduce lung scarring / wound healing and also have an anti-apoptotic effect, thereby preventing the apoptosis of alveolar endothelial cells (this apoptosis is the initiating factor of pulmonary fibrosis development). The compounds of the present invention can also have an anti-proliferative effect, thereby reducing the cancer-like proliferation of fibroblasts and myofibroblasts in pulmonary fibrosis. The compounds of the present invention can also improve the vascular remodeling in pulmonary fibrosis, thereby reducing secondary pulmonary hypertension. Finally, the compounds of the present invention can show anti-inflammatory, anti-growth factor (e.g., transforming growth factor β) and / or anti-cytokine effects.

[0224] In addition, the compounds of the present invention can also be used to treat or prevent any fibrotic condition of one or more internal organs characterized by excessive accumulation of fibrous connective tissue, and / or for treating or preventing fibrosis and the morbidity and mortality associated therewith. Such fibrosis may be associated with acute inflammatory conditions such as acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), and multi-organ inflammation, injury, and / or failure, which may be caused by internal or external trauma (e.g., injury) or infection.

[0225] Therefore, such illness may be caused by sepsis or septic shock caused by viral, bacterial or fungal infection (for example, viral respiratory infection). In addition, acute lung injury, ARDS (particularly SARS) may be caused by viruses (such as coronavirus, including novel SARS coronavirus 2 (SARS-CoV-2)), which may cause internal tissue damage and / or related internal (for example, mucosa) tissue (such as respiratory epithelium) dysfunction, thereby causing virus-induced pneumonia, impaired lung function, respiratory dysfunction, distress and / or failure. Such tissue damage may also cause severe fibrosis. For example, the SARS disease (coronavirus disease 2019 or COVID-19) known to be caused by novel coronavirus SARS-CoV-2 causes fibrosis in many cases.

[0226] The compounds of the present invention are particularly useful for treating diseases or conditions in which activation of the AT2 receptor is desired or necessary, but inhibition of one or more CYP enzymes is undesirable.

[0227] In an alternative embodiment of the present invention, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of diseases and conditions in which activation of the AT2 receptor is desired or required, but in which inhibition of CYP enzymes is undesirable.

[0228] "Diseases and conditions in which activation of the AT2 receptor is desirable or necessary, but in which inhibition of CYP enzymes is undesirable" include diseases or conditions that are known to be treatable by activation of the AT2 receptor, such as those mentioned below, but in which existing treatments for such conditions may include the 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 undesirable, beneficial, and / or desirable, or conditions in which such inhibition is harmful or would be harmful to the patient.

[0229] Particular diseases and conditions in which activation of the AT2 receptor is desired or required, but in which inhibition of CYP enzymes is not desired, are interstitial lung diseases (e.g., pulmonary fibrosis, IPF, systemic sclerosis, and sarcoidosis), autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, and inflammatory bowel disease), chronic kidney disease (e.g., diabetic nephropathy), pulmonary hypertension, arterial pulmonary hypertension, and / or infarction (e.g., myocardial infarction and stroke). The compounds of the present invention are particularly useful for treating interstitial lung diseases, such as IPF; autoimmune diseases, such as rheumatoid arthritis; chronic kidney disease, such as diabetic nephropathy; pulmonary hypertension, including pulmonary hypertension; and / or infarction, such as myocardial infarction.

[0230] According to a further aspect of the invention, there is provided a method of treating certain diseases and conditions in which activation of the AT2 receptor is desired or required but in which inhibition of CYP enzymes is not desired, such as pulmonary fibrosis, in particular IPF, which method comprises administering to a human suffering from the relevant condition a therapeutically effective amount of a compound of the invention.

[0231] The compounds of the present invention are suitable for the therapeutic, palliative and / or diagnostic treatment, as well as the prophylactic treatment (including prevention and / or elimination of worsening and / or exacerbation) of any of the following conditions.

[0232] The compounds of the present invention will generally be administered in a pharmaceutically acceptable dosage form (in solution, in a suspension, in an emulsion (including nanosuspensions), or in a liposomal formulation) orally, intravenously, subcutaneously, orally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, or via inhalation or pulmonary route, or any combination thereof. Additional methods of administration include, but are not limited to, intraarterial, intramuscular, intraperitoneal, intraportal, intradermal, epidural, intrathecal administration, or any combination thereof.

[0233] In some embodiments, the compounds of the present invention can be administered separately (e.g., separately), and / or sequentially, and / or in parallel at the same time (e.g., simultaneously) using different routes of administration, but are preferably administered by known pharmaceutical formulations including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions or emulsions for parenteral or intramuscular administration or via inhalation, and the like. Administration by inhalation is preferably accomplished by using a nebulizer, thereby delivering the compounds of the present invention to small lung tissues (including alveoli and bronchioles), preferably without causing irritation or coughing in the subject being treated.

[0234] Preferably, administration of a therapeutically effective amount of a compound of the invention is carried out separately (e.g., about 2 hours or more apart from each other), sequentially (e.g., within about 2 hours of each other), or in parallel at the same time (e.g., simultaneously) by a combination of routes of administration, including via inhalation and oral administration, to achieve an effective dose.

[0235] In some embodiments, a method of treating a disease or condition in which activation of the AT2 receptor is desired or required (as well as such diseases or conditions in which inhibition of CYP enzymes is undesirable), including pulmonary fibrosis and particularly IPF, is provided, comprising administering to a patient in need of such therapy a therapeutically effective amount of a compound of the invention, either separately, sequentially, or in parallel at the same time, preferably via inhalation and oral administration, by a combination of routes of administration so as to achieve an effective amount or dose.

[0236] Such combinations of administration routes, preferably via inhalation and oral administration, can be presented as separate formulations of the compounds of the invention optimized for each route of administration.

[0237] Such formulations may be prepared according to standard and / or accepted pharmaceutical practice.

[0238] Therefore, according to a further aspect of the present invention, there is provided a pharmaceutical formulation comprising a compound of the present invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0239] The compounds of the present invention can be combined with other AT2 agonists known in the art (such as C21), as well as with AT1 receptor antagonists known in the art, and / or with inhibitors of angiotensin converting enzyme (ACE). Illustrative but non-limiting examples of AT1 receptor antagonists that can be used in accordance with the embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, mifasartan, olmesartan, pomisartan, pratosartan, ripiasartan, sapsartan, tasosartan, telmisartan, valsartan, and / or combinations thereof. Illustrative but non-limiting examples of ACE inhibitors that can be used in accordance with the embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, alacepril, cilopril, dilepril, movipril, and / or combinations thereof.

[0240] Other active ingredients that can be administered in combination with the compounds of the present invention include disodium cromolyn; endothelin receptor antagonists such as bosentan, ambrisentan, sitaxsentan, and 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 can 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, Respivant), SMO4646 (wnt signaling 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-25 MAB, Abeome), and TA5-115 (multi-kinase inhibitor, Otsuka).

[0241] In a further aspect of the invention, the compounds of the present invention are particularly useful when combined with other therapeutic agents in combination therapy to treat various conditions (including those mentioned above). Since the compounds of the present invention exhibit minimal CYP enzyme inhibition, such combinations are particularly advantageous when the other therapeutic agents used for the relevant conditions are themselves metabolized by CYP enzymes.

[0242] Therefore, when the condition to be treated is an interstitial lung disease known in the art (such as IPF), systemic sclerosis or fibrotic disease, the compounds of the present invention are preferably administered in combination with a galectin-3 inhibitor, a lysophosphatidic acid receptor 1 (LPA1) antagonist, an autotaxin (ATX) inhibitor, a recombinant human pentraxin-2 protein or an established therapy for such treatment (including but not limited to pirfenidone and / or nintedanib). Preferably, the combination of the compounds of the present invention is a combination with pirfenidone or a pharmaceutically acceptable salt thereof (which is known to be metabolized by a CYP enzyme such as CYP1A).

[0243] Further, when the condition to be treated is chronic kidney-related disease, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatment, such as irbesartan and / or torsemide, which are known to be metabolized by CYP enzymes such as CYP2C9.

[0244] When the condition to be treated is pulmonary hypertension, the compounds of the invention are preferably administered in combination with one or more other drugs also used in such treatments, such as celecoxib and / or sildenafil, which are known to be metabolized by CYP enzymes such as CYP3A4.

[0245] When the condition to be treated or prevented is myocardial infarction and / or stroke-related diseases, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatments (such as propranolol, warfarin, clopidogrel, atorvastatin, cilostazol, lidocaine and / or simvastatin, or pharmaceutically acceptable salts thereof, which are known to be metabolized by CYP enzymes such as CYP1A, CYP2CP and / or CYP3A4).

[0246] When the condition to be treated is an autoimmune disease such as rheumatoid arthritis, multiple sclerosis or psoriasis, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatments (including but not limited to nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen, celecoxib, meloxicam or its analogs (e.g., piroxicam) or indomethacin; or drugs such as tizanidine, cyclophosphamide, cyclosporine, deflazacort and / or hydrocortisone, riluzole, or pharmaceutically acceptable salts thereof, which are known to be metabolized by CYP enzymes such as CYP1A, CYP2CP, CYP2C19 and / or CYP3A4).

[0247] Therefore, the compounds of the present invention are particularly useful for treating diseases or conditions in which activation of the AT2 receptor is desired or required but inhibition of CYP enzymes is not desired, and therefore can be administered in combination with one or more of the other therapeutic agents metabolized, useful, or potentially useful by the CYP enzyme pathways mentioned above to treat the disease (including those mentioned above), including pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam, torasemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, celecoxib, sildenafil, and / or simvastatin. Most preferably, the compounds of the present invention are administered in combination with pirfenidone to treat interstitial lung disease (such as IPF).

[0248] Therapeutic agents that can be used in combination with the compounds of the present invention include standard treatments for viral infections applied in various ways, including antibody therapies (e.g., LY-CoV555 / LY-CoV016 (banivimab and etezvir), LY-CoV555 (banivimab, Eli Lilly), REGN-COV2 (carevimab and idevimab), REGN3048-3051, TZLS-501, SNG001 (Synairgen), eculizumab (Soliris; Alexion Pharmaceuticals), reslizumab (Ultomiris; Alexion Pharmaceuticals), renzlumab, lelizumab, tocilizumab (Actemra; Roche), sarrelumab (Kevzara; Regeneron Pharma) and Octagam (Octapharma)), antiviral drugs (e.g., oseltamivir, remdesivir, favipiravir, monoprevir, semideprevir, daclatasvir, sofosbuvir, ribavirin, arbidol, lopinavir, ritonavir, lopinavir / ritonavir (Kaletra; AbbVie Deutschland GmbH Co. KG), teicoplanin, baricitinib (Olumiant; Eli Lilly and Company), Lilly), ruxolitinib (Jakavi; Novartis), tofacitinib (Xeljanz; Pfizer), the TMPRSS2 inhibitor 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 galisvir (BiocrystPharma), anti-inflammatory agents (e.g., NSAIDs such as ibuprofen, ketorolac, naproxen, etc.), chloroquine, hydroxychloroquine, interferons (e.g., interferon beta (interferon beta-1a), tocilizumab (Actemra), lenalidomide, pomalidomide, and thalidomide), analgesics (e.g., acetaminophen or opioids), cough suppressants (e.g., dextromethorphan), vaccinations (e.g., INO-4800 by Inovio Pharmaceuticals and Beijing Advaccine Biotechnology, if available), COVID-19 convalescent plasma (CCP), and / or passive antibody therapy using antibodies from the blood of people who have recovered from SARS-CoV or SARS-CoV-2 infection.

[0249] Further therapeutic agents that may be mentioned include antifibrotic drugs (eg nintedanib and in particular pirfenidone), vitamins (eg vitamin B, vitamin C and vitamin D) and mucolytics (such as acetylcysteine ​​and ambroxol).

[0250] Other therapeutic agents that may be used in combination with the compounds according to the present invention or their pharmaceutically acceptable salts according to the present invention include corticosteroids.Corticosteroids include naturally occurring corticosteroids and synthetic corticosteroids.

[0251] 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-hydroxy-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.

[0252] Synthetic corticosteroids that may be mentioned include those of the hydrocortisone type (group A), such as cortisone acetate, hydrocortisone pyruvate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate, hydrocortisone valerate, tixocortol and tixocortol pivalate, prednisolone, methylprednisolone, prednisone, chloroprednisolone, chloroprednisolone, difluprednate, fludrocortisone, fluocinolone acetonide, fluperone,

[0253] Fluprednisolone, loteprednol, prednicarbate, and triamcinolone; acetonides and related substances (Group B), such as amcinonide, budesonide, desonide, fluocinolone, fluocinolone acetate, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formocort, flurandrenolide, flunisolide, and fluocinolone acetate; (β) betamethasones (Group C), such as beclomethasone, betamethasone, betamethasone dipropionate, and betamethasone valerate, dexamethasone, flucortolone, halometasone, mometasone, and mometasone furoate, alclometasone, and alclometasone dipropionate, clobetasol, and clobetasol propionate, clobetasone, and clobetasone butyrate, clocortolone, desoximetasone, and diflorasone , diflucortolone, fluclorololone, flumethasone, fluocortidine, flupredniidine and flupredniidine acetate, fluticasone, fluticasone furoate and fluticasone propionate, methylprednisone, paramethasone, prednisone, rimexolone and ulebetasol; progesterone drugs such as flugestrel, fluorometholone, medroxyprogesterone acetate and acetoxypregnenolone, and progesterone derivatives (progestogens) such as chlormadinone acetate, cyproterone acetate, medrogestone, medroxyprogesterone acetate, megestrol acetate and norgestrel acetate; and other corticosteroids such as cortivazole and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androsta-1,4,6-trien-3-one.

[0254] Preferred corticosteroids include cortisone, prednisone, prednisolone, methylprednisolone, and especially dexamethasone.

[0255] Furthermore, therapeutic agents that may be used in combination with the compounds of the present invention or pharmaceutically acceptable salts thereof include H2 receptor blockers, anticoagulants, antiplatelet drugs, as well as statins, antimicrobials, and anti-allergy / anti-asthma drugs.

[0256] 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, parparin, certoparin, dalteparin, tinzaparin); direct-acting oral anticoagulants (e.g., dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betrixaban, darixaban, otamixaban, ritoxaban, ilibaxiban, hirudin, lepirudin, and bivalirudin); coumarin vitamin K antagonists (e.g., coumarin, acenocoumarol, phenprocoumon, atomycin, and phenindione) and synthetic pentasaccharide inhibitors of factor Xa (e.g., fondaparinux sodium, idraparinux, and biotinylated idraparinux sodium). 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., vorapaxar); glycoprotein IIB / IIIA inhibitors (e.g., abciximab, eptifibatide, and tirofiban); adenosine reuptake inhibitors (e.g., dipyridamole); and thromboxane inhibitors (e.g., trutroban, ramatroban, serostat, and picotamide). Statins that may be mentioned include atorvastatin, simvastatin, and rosuvastatin. Antimicrobial agents that may be mentioned include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam, and teicoplanin. Anti-allergy / anti-asthma drugs that may be mentioned include chlorpheniramine, levocetirizine, and montelukast.

[0257] Thus, the subject may also (and / or may have already) received one or more of any of the other therapeutic agents described above, which means receiving prescribed doses of one or more of those other therapeutic agents before, in addition to and / or after treatment with the compound of the invention or a pharmaceutically acceptable salt thereof.

[0258] When the compounds of the present invention are "combined" with other therapeutic agents as described hereinabove, the active ingredients may be administered together in the same formulation, or administered separately (simultaneously or sequentially) in different formulations.

[0259] Such combination products provide for the combined administration of a compound of the invention and the other therapeutic agent and, therefore, can be presented as separate formulations, wherein at least one of those formulations contains the compound of the invention and at least one contains the other therapeutic agent; or can be presented (i.e., formulated) as a combined preparation (i.e., presented in a single formulation including the compound of the invention and the other therapeutic agent).

[0260] Therefore, it is further provided that:

[0261] (1) a pharmaceutical preparation comprising a compound of the present invention; a therapeutic agent selected from those described above (e.g., a therapeutic agent known to be metabolized by a CYP enzyme); and a pharmaceutically acceptable excipient (e.g., an adjuvant, diluent, or carrier), which preparation is hereinafter referred to as a "combination preparation"; and

[0262] (2) A multi-component kit comprising the following components:

[0263] (A) a pharmaceutical preparation comprising a compound of the present invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and

[0264] (B) a pharmaceutical formulation comprising a therapeutic agent selected from those described above (e.g., a therapeutic agent known to be metabolized by a CYP enzyme) in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier,

[0265] Components (A) and (B) are each provided in a form suitable for combined administration with the other.

[0266] In a further aspect of the invention, there is provided a process for preparing a combined preparation as defined above, which comprises bringing together a compound of the invention, the other therapeutic agent and at least one (eg pharmaceutically acceptable) excipient.

[0267] In a further aspect of the invention there is provided a method for preparing a kit of parts as hereinbefore defined, the method comprising bringing components (A) and (B) together. As used herein, reference to combining shall mean that the two components are suitable for administration in conjunction with each other.

[0268] Thus, with respect to the method for preparing a kit of parts as defined hereinbefore, bringing two components "into association" with one another comprises that the two components of the kit of parts may:

[0269] (i) are provided as separate formulations (i.e., independent of each other) which are subsequently brought together for use in conjunction with each other in a combination therapy; or

[0270] (ii) The separate components are packaged and presented together as a "combination pack" for use in conjunction with each other in a combination therapy.

[0271] Therefore, there is further provided a kit of parts comprising:

[0272] (I) one of components (A) and (B) as defined herein; and

[0273] (II) Instructions for combining one of the two components with the other component.

[0274] According to patient to be treated and route of administration, the compounds of the present invention can be used in different dosages. Although dosage varies from patient to patient, when using in single dose or multiple dose, suitable daily dosage is in the range of about 0.1 mg to about 1000 mg per patient (for example, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg etc., or any range or value therein). More preferred daily dosages are in the range of about 0.1 mg to about 250 mg per patient (e.g., 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg, 75 mg, 80 mg, 8 ...

[0014] The preferred daily dosage is preferably in the range of about 0.3 to about 100 mg per patient. The preferred daily dosage is preferably in the range of about 0.3 to about 100 mg per patient.

[0275] A single dose of a compound of the invention can be in the range of about 0.1 mg to about 100 mg (e.g., 0.3 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, etc., or any range or value therein).

[0276] In any case, the physician or technician will be able to determine the actual dosage that is most suitable for an individual patient, which dosage may vary with the condition to be treated, and the age, weight, sex and response of the particular patient to be treated. The above dosages are examples of general situations; of course, there may be individual cases where higher or lower dosage ranges are required, and this is within the scope of the present invention.

[0277] The benefit of using the compounds of the present invention via a combined route of administration, separate and / or sequential and / or in parallel at the same time, is to produce a customized treatment for the patient in need of such therapy, with the possibility of preventing and / or reducing side effects, and also to adjust the correct dosage level of a therapeutically effective amount of the compound of the present invention.

[0278] The kits of parts described herein may include more than one formulation comprising an appropriate amount / dose of a compound of the invention, and / or more than one formulation comprising an appropriate amount / dose of another therapeutic agent, so as to provide for repeated administration. If there is more than one formulation (comprising any one active compound), such formulations may be identical, or may differ in the dosage, chemical composition, and / or physical form of any one compound.

[0279] With respect to the kits of parts described herein, "combined administration" includes sequential, separate and / or simultaneous administration of corresponding formulations comprising the compound of the present invention and the other therapeutic agent during the treatment of the relevant condition.

[0280] Thus, with respect to the combination products according to the present invention, the term "administered in conjunction" includes the administration of the two components of the combination product (the compound of the present invention and the other therapeutic agent) together (optionally repeatedly), or sufficiently close in time to produce a beneficial effect on the patient during the treatment of the relevant condition that is greater than when the formulation containing the compound of the present invention or the formulation containing the other agent is administered alone (optionally repeatedly) in the absence of the other component during the same treatment. Determining whether a combination provides a greater beneficial effect with respect to a particular condition or during the treatment of a particular condition will depend on the condition to be treated or prevented, but can be routinely accomplished by a skilled person.

[0281] Further, in the context of a kit of parts according to the present invention, the term "in combination" includes that one or the other of the two formulations can be administered before, after and / or at the same time (optionally repeatedly) as the other component. When used in this context, the terms "simultaneous administration" and "administered at the same time" include administering individual doses of the relevant compound of the present invention and the other anti-inflammatory agent within 48 hours (e.g., 24 hours) of each other.

[0282] Pharmaceutical compositions / formulations, combination products and kits as described herein may be prepared according to standard and / or accepted pharmaceutical practice.

[0283] Therefore, in a further aspect of the present invention, there is provided a process for preparing a pharmaceutical composition / formulation as defined above, which comprises combining certain compounds of the present invention as defined above with one or more pharmaceutically acceptable excipients (e.g., adjuvants, diluents and / or carriers).

[0284] In a further aspect of the invention, there is provided a method for preparing a combination product or a kit of parts as defined above, which method comprises combining certain compounds of the invention as defined above with other therapeutic agents useful for treating relevant diseases or conditions and at least one pharmaceutically acceptable excipient.

[0285] Subjects suitable for treatment with the formulations of the present invention include, but are not limited to, mammalian subjects, particularly human subjects.

[0286] When used herein with respect to specific values ​​(such as amounts), the term "about" (or similar terms, such as "approximately") will be understood to indicate that such value may vary by up to 10% (particularly, up to 5%, such as up to 1%) from the defined value. It is contemplated that such terms in each instance may be replaced with the notation "±10%" or the like (or by indicating the variance of the specific amount calculated based on the relevant value). It is also contemplated that such terms in each instance may be deleted.

[0287] The compounds of the present invention have the advantage that they are more potent than the aforementioned CYP enzymes, and / or are stable to metabolic hydrolysis, and / or do not inhibit the aforementioned CYP enzymes.

[0288] The compounds of the present invention may also have the following advantages: whether for the treatment of IPF or other uses, they may be more effective, less toxic, have a longer duration of action, be more potent, produce fewer side effects, be more easily absorbed, and / or have better pharmacokinetic characteristics (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 can be assessed clinically, objectively and / or subjectively by healthcare professionals, treatment subjects or observers.

[0289] Examples

[0290] The present invention will be further described with reference to the following examples, but these examples are not intended to limit the scope of the invention.

[0291] In the event of a discrepancy between the name and any compound depicted graphically, the latter shall prevail (unless contradicted by any experimental details that may be given, or unless clear from the context).

[0292] Experimental procedures

[0293] The starting materials and intermediates used in the synthesis of the compounds described herein are commercially available or can be prepared by the methods described herein or by methods known in the art.

[0294] Experiments were generally performed under an inert atmosphere (nitrogen or argon), particularly when oxygen- or moisture-sensitive reagents or intermediates were used. Unless otherwise noted, experiments were performed in oven-dried glassware using standard techniques for handling air- and moisture-sensitive materials.

[0295] All solvents and chemicals purchased were used without further purification. Microwave heating reactions were carried out in Biotage vials sealed with septa, and controlled irradiation of 2450 MHz with a power of 0 W to 400 W was produced using a Biotage single-mode microwave reactor equipped with a built-in online infrared sensor. The reaction was monitored by thin layer chromatography (TLC), performed on Merck silica gel 60F-254 plates, and visualized using UV light (λ = 254 nm). Automated flash column chromatography (FCC) was performed on a Biotage Isolera Dalton 2000 instrument using commercial silica gel cartridges. Manual FCC was performed using commercial silica gel cartridges. Analytical HPLC / ESI-MS was performed using UV detection (214, 254, and 280 nm) and electrospray ionization (ESI) MS on a C18 column (50 × 3.0 mm, 2.6 μm particle size, The pore size was 0.50 nm (0.84 nm) using a gradient of acetonitrile in 0.05% HCOOH as the mobile phase (flow rate 1.5 mL / min). High resolution molecular mass (HRMS) was determined on a mass spectrometer equipped with an ESI source and a 7-T hybrid linear ion trap (LTQ). Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance III HD or Bruker Avance Neo instrument. The spectra were recorded at 400 MHz, 101 MHz, 126 MHz, and 376 MHz, respectively. 1 H. 13 C and 19 F NMR spectra. Chemical shifts (δ) are reported in ppm and referenced to trimethylsilane ( 1 H:CDCl3-d is at 7.26ppm, MeOD-d4: 3.31ppm pentad, acetone d6: 2.09ppm, septet; DMSO-d6 is at 2.50ppm septet, 13C:CDCl3: 77.16 ppm, triplet; MeOD-d4: 49.00 ppm, septet; acetone-d6: 29.84 ppm, septet; DMSO-d6: 39.52 ppm, septet). Recorded using proton decoupling. 13 C NMR and 19 F NMR spectrum. Data are reported as follows: chemical shift δ / ppm, integral (only 1 H), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br. = broad, m = multiplet, or a combination thereof; unless otherwise indicated, 13 C signals are all single peaks), the coupling constant J is in Hertz (Hz), and is assigned. Used where appropriate 1 H COSY, HSQC, and HMBC were used to facilitate structural assignment. All final compounds were ≥95% pure as determined by HPLC (UV at 254 nm) and NMR. Mass spectral data were reported by liquid chromatography-mass spectrometry (LC-MS). Chemical shifts for NMR data are expressed in parts per million (ppm, δ) referenced to residual peaks in the deuterated solvent used.

[0296] For syntheses following the general procedure, reaction conditions (such as reaction length or temperature) may vary. In general, the reactions are followed by thin layer chromatography or LC-MS analysis and, when appropriate, by post-processing. Purification may vary between experiments: in general, the solvents and solvent ratios used for the eluent / gradient are selected to provide the appropriate R f Some products were purified using supercritical fluid chromatography (e.g., on a reverse phase column using a solvent combination with mobile phases A: CO2 and B: MeOH / H2O / NH3). Some compounds were purified using preparative HPLC, flash column chromatography, or a manual C18 reverse phase column with H2O / MeCN polarity.

[0297] Examples

[0298] Example 1

[0299] 3-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiophene-2-sulfonyl Amide

[0300] (a) 1-[(4-Bromo-2-chloro-phenyl)methyl]-2-methyl-imidazole

[0301] 2-Methylimidazole (1.64 g, 20 mmol) and KCO (5.53 g, 40 mmol) were dissolved in acetonitrile (50 ml). After 30 minutes, 4-bromo-2-chlorobenzyl bromide (2.84 g, 10 mmol) was added. The reaction was stirred at room temperature for 3 days. The solid material was filtered off. The solvent was evaporated. The remaining solid was washed with water overnight. 2.4 g of solid was isolated, with a yield of 84%. 1 H-NMR (CDCl3): 2.36 (s, 3H), 5.11 (s, 2H), 6.54 (d, 1H), 6.85 (s, 1H), 7.03 (s, 1H), 7.37 (d, 1H), 7.62 (s, 1H). MS (M+H): 285.07, calculated value: 284.9794.

[0302] (b) 3-[3-Chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-thiophene-2-sulfonamide

[0303] 1-[(4-Bromo-2-chloro-phenyl)methyl]-2-methyl-imidazole (prepared according to step (a) above; 240 mg, 840 μmol), N-tert-butyl-5-isobutyl-thiophene-2-sulfonamide (268 mg, 840 μmol), K2CO3 (348 mg, 2521 μmol) and Pd(PPh3)4 (24 mg, 21 μmol) were added to dioxane (10 ml) and water (1 ml). The reaction was heated to 90°C under a nitrogen atmosphere overnight. Water and ethyl acetate were added. The organic layer was dried, filtered and the solvent was evaporated. The crude material was dissolved in CH2Cl2 (5 ml). BCl3 was added at room temperature. After 3 hours, ethyl acetate (25 ml) and water (10 ml) were added. NH3(aq) (3 ml) was added. The organic layer was dried, filtered and the solvent was evaporated. Methanol-ethyl acetate chromatography, 10-90. The product was isolated in an amount of 175 mg, a yield of 49%. 1 H-NMR (CDCl3): 0.98 (d, 6H), 1.92 (m, 1H), 2.04 (s, 3H), 2.68 (d, 2H), 5.17 (s, 2H), 6.74 (m, 2H), 6.88 (s, 1H), 7.00 (s, 1H), 7.47 (d, 1H), 7.66 (s, 1H). MS (M+H): 423.93, calculated value 424.0920.

[0304] (c) 3-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiophene- 2-Sulfonamide

[0305] 3-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-thiophene-2-sulfonamide (prepared according to step (b) above; 212 mg, 0.5 mmol), 2-bromopyrimidine (119 mg, 0.75 mmol), palladium(II) acetate (2.8 mg, 12.5 μmol), 1,1-bis(diphenylphosphino)ferrocene (6.9 mg, 12.5 μmol), LiCl (42 mg, 1.0 mmol) and potassium tert-butoxide (185 mg, 1.65 mmol) were dissolved in dioxane (10 ml). The reaction was heated to 80° C. under a nitrogen atmosphere and continued overnight. Water (10 ml) and CH Cl (10 ml) were added. The organic layer was dried, filtered and the solvent evaporated. The product was purified using HPLC in an amount of 14 mg and isolated as a CF COOH salt. 1 H-NMR (CD3OD): 0.98 (d, 6H), 1.93 (m, 1H), 2.38 (s, 3H), 2.72 (d, 2H), 5.28 (s, 2H), 6.77 (s, 1H), 6.84 (d, 1H), 6.91 (t, 1H), 6.94 (d, 1H), 7.07 (d, 1H), 7.35 (m, 1H), 7.46 (d, 1H), 8.33 (d, 2H). MS (M+H): 502.0, calculated value 502.1138.

[0306] Example 2

[0307] 3-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-(2-pyridyl)thiophene-2-sulfonyl Amide

[0308] The title compound was prepared using a procedure analogous to that described in Example 1 above, except that 3-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-thiophene-2-sulfonamide (prepared according to step (b) of Example 1 above; 212 mg, 0.5 mmol) and 2-bromopyridine (118 mg, 0.75 mmol) were used. The product was isolated as the CF3COOH salt in an amount of 18 mg. 1 H-NMR (CD3OD): 0.97 (d, 6H), 1.91 (m, 1H), 2.70 (m, 5H), 5.47 (s, 2H), 6.82 (s, 1H), 6.87 (t, 1H), 7.15-7.25 (m, 2H), 7.41 (s, 1H), 7.46-7.53 (m, 2H), 7.63 (d, 1H), 7.76 (t, 1H), 7.84 (s, 1H). MS (M+H): 501.0, calculated value 501.1186.

[0309] Example 3

[0310] 5-isobutyl-3-[3-methyl-4-[(2-methylimidazol-1-yl)methyl]phenyl]-N-(2-pyridyl)thiophene-2-yl Sulfonamide

[0311] (a) 1-[(4-Bromo-2-methyl-phenyl)methyl]-2-methyl-imidazole

[0312] The title compound was prepared using a similar method to that described in step (a) of Example 1 above, except that 4-bromo-1-methylbromo-2-toluene (736 mg, 2.8 mmol) and 2-methylimidazole (458 mg, 5.6 mmol) were used. The subtitle compound was obtained in an amount of 500 mg with a yield of 68%. 1 H-NMR (CDCl3): 2.30 (s, 3H), 2.39 (s, 3H), 4.99 (s, 2H), 6.59 (d, 1H), 6.76 (s, 1H), 7.01 (s, 1H), 7.32 (d, 1H), 7.41 (s, 1H). MS (M+H): 265.13, calculated value 265.0340.

[0313] (b) 5-Isobutyl-3-[3-methyl-4-[(2-methylimidazol-1-yl)methyl]phenyl]-thiophene-2-sulfonamide

[0314] The subtitle compound is prepared by a similar method to the method described in Example 1 above, step (b), except that 1-[(4-bromo-2-methyl-phenyl) methyl]-2-methyl-imidazole (330 mg, 1.24 mmol) and N-tert-butyl-5-isobutyl-thiophene-2-sulfonamide (397 mg, 1.24 mmol) are used. The subtitle compound of the amount of 465 mg is obtained, and productive rate is 93%. 1 H-NMR (CDCl3): 1.00 (d, 6H), 1.94 (m, 1H), 2.36 (s, 3H), 2.41 (s, 3H), 2.69 (d, 2H), 5.10 (s, 2H), 6.73-6.77 (m, 2H), 6.80 (s, 1H), 7.01 (s, 1H), 7.39 (m, 1H), 7.48 (s, 1H). MS (M+H): 404.17, calculated value 404.1466.

[0315] (c) 5-Isobutyl-3-[3-methyl-4-[(2-methylimidazol-1-yl)methyl]phenyl]-N-(2-pyridyl)thiazolyl Phenyl-2-sulfonamide

[0316] The title compound was prepared by a method analogous to that described in step (c) of Example 1, except using 5-isobutyl-3-[3-methyl-4-[(2-methylimidazol-1-yl)methyl]phenyl]thiophene-2-sulfonamide (175 mg, 0.434 mmol) and 2-bromopyridine (103 mg, 0.650 mmol). The title compound was obtained as the CF3COOH salt in an amount of 18 mg.1 H-NMR (CD3OD): 0.98 (d, 6H), 1.91 (m 1H), 2.20 (s, 3H), 2.63 (s, 3H), 2.71 (d, 2H), 5.35 (s, 2H), 6.75 (s, 1H), 6.82 (b, 1H), 6.87 (t, 1H), 7.14 (b, 1H), 7.24 (b, 2H), 7.32 (d, 1H), 7.47 (d, 1H), 7.75 (b, 1H), 7.87 (b, 1H). MS (M+H): 481.0, calculated value 481.1732.

[0317] Example 4

[0318] Compounds of the present invention

[0319] The following compounds were prepared according to the aforementioned experimental techniques:

[0320] 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyridin-2-yl)-[1,1'-biphenyl]-2-sulfonamide,

[0321] 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(5-fluoropyrimidin-2-yl)-5-isobutylthiophene-2-sulfonamide,

[0322] 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(4,5-dimethyloxazol-2-yl)-5-isobutylthiophene-2-sulfonamide,

[0323] 3-(3-chloro-4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide,

[0324] 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-(trifluoromethyl)pyrimidin-2-yl)thiophene-2-sulfonamide,

[0325] 5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)thiophene-2-sulfonamide,

[0326] 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-methylpyrimidin-2-yl)thiophene-2-sulfonamide,

[0327] 3'-chloro-5-isobutyl-N-(5-methoxypyrimidin-2-yl)-4'-((2-methyl-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide,

[0328] 5-isobutyl-3'-methyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide,

[0329] 3-(3-chloro-4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide,

[0330] 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide and 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-methoxythiophene-2-sulfonamide.

[0331] Example 5

[0332] (2-[3-Chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide

[0333] (a) 2-[3-Chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-benzenesulfonamide

[0334] 1-[(4-Bromo-2-chloro-phenyl)methyl]-2-methyl-imidazole (571 mg, 2 mmol), [2-(tert-butylsulfamoyl)-5-isobutyl-phenyl]boronic acid (930 mg, 3 mmol), K2CO3 (829 mg, 6 mmol) and Pd(PPh3)4 (86 mg, 75 μmol) were added to dioxane (30 ml) and water (3 ml). The reaction was heated to 90°C under a nitrogen atmosphere overnight. Water and ethyl acetate were added. The organic layer was dried, filtered and the solvent was evaporated. The crude material was dissolved in CF3COOH (20 ml). The solution was heated to 45°C overnight. The excess acid was evaporated. The crude material was dissolved between ethyl acetate and Na2CO3(aq). The organic layer was dried, filtered and the solvent was evaporated. Ethyl acetate chromatography. 320 mg of product was isolated with a yield of 38%. 1H-NMR (CDCl3): 0.95 (d, 6H), 1.93 (m, 1H), 2.41 (s, 3H), 2.58 (d, 2H), 5.22 (s, 2H), 6.74 (d, 1H), 6.91 (s, 1H), 7.04 (s, 1H), 7.09 (d, 1H), 7.33 (m, 2H), 7.58 (d, 1H), 8.08 (d, 1H). MS (M+H): 417.9, calculated value 418.1356.

[0335] (b) (2-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonyl Amide

[0336] 2-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-benzenesulfonamide (220mg, 526μmol), 2-bromopyrimidine (126mg, 790μmol), palladium (II) acetate (12mg, 53μmol), 1,1-bis(diphenylphosphino)ferrocene (29mg, 53μmol), LiCl (45mg, 1053μmol) and potassium tert-butoxide (195mg, 1737μmol) were dissolved in dioxane (15ml). The reaction was refluxed under a nitrogen atmosphere for 3 hours. Ethyl acetate (10ml) was added and the mixture was filtered. The solvent was evaporated. The product was purified by supercritical fluid chromatography in an amount of 3.3mg. 1 H-NMR (CD3OD): 0.92 (d, 6H), 1.91 (m, 1H), 2.38 (s, 3H), 2.57 (d, 2H), 5.26 (s, 2H), 6.78 (d, 1H), 6.82 (b, 1H), 6.91 (s, 1H), 7.00 (s, 1H), 7.07 (s, 1H), 7.17 (d, 1H), 7.25 (s, 1H), 7.35 (d, 1H), 8.13 (d, 1H), 8.28 (b, 2H). MS (M+H): 496.1, calculated value 496.1574.

[0337] Example 6

[0338] 5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]-3-(trifluoromethyl)phenyl]-N-pyrimidin-2-yl- Thiophene-2-sulfonamide

[0339] 5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]-3-(trifluoromethyl)phenyl]thiophene-2-sulfonamide (183 mg, 400 μmol), 2-bromopyrimidine (95 mg, 600 μmol), palladium (II) acetate (9 mg, 40 μmol), 1,1-bis(diphenylphosphino)ferrocene (22 mg, 40 μmol), LiCl (34 mg, 800 μmol) and potassium tert-butoxide (148 mg, 1320 μmol) were dissolved in dioxane (15 ml). The reaction was heated to reflux for 3 hours under a nitrogen atmosphere. Ethyl acetate (10 ml) was added and the solid was filtered off. The product was purified by supercritical fluid chromatography in an amount of 3.2 mg. 1 H-NMR (CD3OD): 0.90 (d, 6H), 1.83 (m, 1H), 2.23 (s, 3H), 2.60 (d, 2H), 5.30 (s, 2H), 6.50 (b, 1H), 6.63-6.69 (m, 2H), 6.85 (s, 1H), 6.99 (s, 1H), 7.81-7.85 (m, 2H), 8.09 (d, 2H). MS (M+H): 536.1, calculated value 536.1402.

[0340] Example 7

[0341] 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonyl amine

[0342] (a) 1-[(4-Bromo-2-chloro-phenyl)methyl]-2-isopropyl-imidazole

[0343] 2-Isopropylimidazole (3.30 g, 30 mmol) and K2CO3 (8.29 g, 60 mmol) were dissolved in acetonitrile (75 ml). After 15 minutes, 4-bromo-2-chloro-1-bromomethylbenzene (4.26 g, 15 mmol) was added. The reaction was stirred at room temperature for three days. The solid material was filtered off and the solvent was evaporated. The crude product was washed with water. The isolated crystalline product was dried under vacuum. Quantity: 3.69 g, yield: 78%. 1 H-NMR (CDCl3): 1.28 (d, 6H), 2.88 (sep, 1H), 5.11 (s, 2H), 6.46 (d, 1H), 6.77 (s, 1H), 7.05 (s, 1H), 7.33 (d, 1H), 7.59 (s, 1H). MS (M+H): 313.1, calculated value 313.0107.

[0344] (b) 2-[3-Chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-benzenesulfonamide

[0345] 1-[(4-bromo-2-chloro-phenyl)methyl]-2-isopropylimidazole (586 mg, 1.87 mmol), [2-(tert-butylsulfamoyl)-5-isobutyl-phenyl]boronic acid (585 mg, 1.87 mmol), K2CO3 (774 mg, 5.60 mmol) and Pd(PPh3)4 (54 mg, 47 μmol) were added to dioxane (20 ml) and water (2 ml). The reaction was heated to 90°C under a nitrogen atmosphere and continued overnight. Water and diethyl ether were added. The organic layer was dried, filtered and the solvent was evaporated. The crude material was dissolved in CF3COOH (10 ml). The solution was stirred for three days. The excess acid was evaporated. The crude material was dissolved between ethyl acetate and NaHCO3 (aq). The organic layer was dried, filtered and the solvent was evaporated. Ethyl acetate chromatography. 589 mg of product was isolated with a yield of 71%. 1 H-NMR (CDCl3): 0.92 (d, 6H), 1.30 (d, 6H), 1.90 (sep, 1H), 2.54 (d, 2H), 2.94 (sep, 1H), 5.23 (s, 2H), 6.68 (d, 1H), 6.83 (s, 1H), 7.02-7.07 (m, 2H), 7.27-7.31 (m, 2H), 7.55 (s, 1H), 8.04 (d, 1H). MS (M+H): 446.2, calculated value 446.1669.

[0346] (c) 2-[3-Chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonyl Amide

[0347] By 2-[3-chloro-4-[(2-isopropylimidazole-1-yl)methyl]phenyl]-4-isobutyl-benzenesulfonamide (437mg, 980μmol), 2-bromopyrimidine (312mg, 1961μmol), palladium acetate (II) (44mg, 196μmol), 1,1-bis(diphenylphosphino)ferrocene (109mg, 196μmol), LiCl (83mg, 1961μmol) and potassium tert-butoxide (220mg, 1961μmol) are dissolved in dioxane (10ml).The reaction is heated to reflux for 3 hours under a nitrogen atmosphere.Ethyl acetate (10ml) is added and solid is filtered off.Supercritical fluid chromatography is used to purify the product in an amount of 8.5mg. 1H-NMR (CD3OD): 0.91 (d, 6H), 1.27 (d, 6H), 1.90 (sep, 1H), 2.56 (d, 2H), 3.10 (sep, 1H), 5.27 (s, 2H), 6.73 (d, 1H), 6.85 (s, 1H), 6.90-7.03 (m, 4H), 7.09 (m, 1H), 7.20 (s, 1H), 7.38 (d, 1H), 8.15 (d, 1H), 8.34 (b, 2H). MS (M+H): 524.3, calculated value 524.1887.

[0348] Example 8

[0349] 3-[3-Chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiophene-2-yl Sulfonamide

[0350] (a) 3-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-thiophene-2-sulfonamide

[0351] The title compound was prepared using a procedure analogous to that described above for 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-benzenesulfonamide in Example 7, except that 1-[(4-bromo-2-chloro-phenyl)methyl]-2-isopropyl-imidazole (627 mg, 2 mmol) and N-tert-butyl-5-isobutyl-thiophene-2-sulfonamide (638 mg, 2 mmol) were used. Quantity 431 mg, 48% yield. 1 H-NMR (CDCl3): 0.98 (d, 6H), 1.44 (d, 6H), 1.91 (sep, 1H), 2.68 (d, 2H), 3.30 (sep, 1H), 5.34 (s, 2H), 6.74 (s, 1H), 7.02 (d, 1H), 7.26 (s, 1H), 7.42 (s, 1H), 7.57 (d, 1H), 7.66 (s, 1H). MS (M+H): 452.1, calculated value 452.1233.

[0352] (b) 3-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiol Phenyl-2-sulfonamide

[0353] The title compound was prepared using a procedure analogous to that described above for 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide in Example 7, except that 3-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-thiophene-2-sulfonamide (203 mg, 449 μmol) was used in an amount of 0.5 mg.

[0354] Bioassay

[0355] The biological activity of the exemplary compounds as described herein above was assessed (and compared to C21) using the following bioassay.

[0356] Metabolic stability

[0357] Human liver microsomes at a concentration of 0.5 mg / mL in PBS were incubated at 37°C for 70 minutes with or without 1 mM NADPH. The test compound was added 10 minutes later to a final concentration of 1 μM. Samples were taken out at 0, 5, 15, and 60 minutes and added to a test tube containing acetonitrile to stop the reaction, and terfenadine was added as an internal standard. After centrifugation at 10,000 × g for 5 minutes, the supernatant was diluted 1:1 with 1% formic acid. The samples were separated on a reversed-phase column and detected by triple quadrupole MSMS (Agilant 6540). Using terfenadine as an internal standard, the concentration of the parent compound at different time points was measured by an external standard curve, and the initial metabolic rate in the presence or absence of NADPH was calculated.

[0358] <![CDATA[T 1 / 2 , without NaDPH [min]]]> <![CDATA[T 1 / 2 , with NaDPH [min]]]> C21 30 35 Example 1 >60 minutes >60 Example 2 >60 60 Example 3 >60 53

[0359] Asterisks (*) indicate the average of data obtained from two runs.

[0360] Binds to AT1 and AT2 receptors

[0361] Binding of compounds to human recombinant AT2 and AT1 receptors was evaluated using radioscintillation assays according to Eurofins protocols ITEM26 and ITEM24.

[0362] In short, for IC 50 For measurement, the recombinant protein was incubated with the test compound (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 hours. The Ki value for the AT2 receptor was determined using a seven-point dose-response curve. 125 I(sar1,IIe8)-AT-II is used as a ligand for the AT1 receptor and 125 ICGP42112A was used as a ligand for the AT2 receptor. The percentage inhibition of control specific binding was calculated as 100 - (measured specific binding / control specific binding) × 100.

[0363]

[0364]

[0365] Asterisks (*) indicate the average of data obtained from two runs.

[0366] CYP inhibition

[0367] The inhibitory effects of 10 μM compounds on the major cytochrome P450 isoforms (CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A4 & 5) were evaluated 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.

[0368] At the end of the incubation, the formation of metabolites was monitored by HPLC-MS / MS as peak area responses.

[0369]

[0370] abbreviation

[0371] The following abbreviations may be used herein.

[0372] DCM dichloromethane

[0373] DMF dimethylformamide

[0374] EtOAc

[0375] FCC flash column chromatography

[0376] MeCN Acetonitrile

[0377] MeOH methanol

[0378] MW microwave

[0379] NMR Nuclear Magnetic Resonance

Claims

1. A compound of formula I, in: R 1 Represents H, halogen atom, -CN or C 1-7 Alkyl or C 1-7 Alkoxy, both of which are optionally substituted by one or more halogen atoms, hydroxyl groups, C 1-7 Alkyl, CF3 or OR 7 replace; R 2 and R 3 independently represent H, a halogen atom, -CN or C 1-7 Alkyl or C 1-7 Alkoxy, both of which are optionally substituted by one or more halogen atoms, hydroxyl groups, C 1-7 Alkyl, CF3 or OR 7a replace; R 4 Indicates C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy-C 1-6 alkyl, the alkyl portion of each of which is optionally substituted and / or terminated by one or more halogen atoms, -CN or -OH groups, or R 4 Represents aryl, C 1-6 Alkyl aryl, C 1-3 Alkenyl aryl, heteroaryl, C 1-6 Alkyl heteroaryl or C 1-3 Alkenylheteroaryl, each of which is optionally substituted by one or more halogen, CF3, CF3O-, -CN, C 1-6 Alkyl and C 1-6 Alkoxy substitution; R 5 Represents H, halogen atoms, hydroxyl groups, -CN, -NR 9a R 10a 、C 1-7 Alkyl, C 1-7 Alkoxy or C 1-6 Alkoxy-C 1-6 Alkyl, each of which is optionally substituted by one or more halogen atoms, hydroxyl, -CN, -NR 9b R 10b 、C 1-7 Alkyl or C 1-7 Alkoxy substitution; R 6 、R 7 and R 7a independently represents H or C 1-6 alkyl, which is optionally substituted by one or more halogen atoms; Y 1 Yes-CR 8 -, -N-, -NH-, O or S; Y 2 Yes-CR 8 -、-CR 8 =CH-, -CH=CR 8 -、-CR 8 =CR 8 -, -N-, -NH-, O, or S; and Y 3 Yes-CR 8 -, R 8 Represents H, halogen atoms, hydroxyl groups, -CN, -NR 9c R 10c , or C 1-7 Alkyl or C 1-7 Alkoxy, both of which are optionally substituted by one or more halogen atoms, hydroxyl, -CN, -NR 9d R 10d 、C 1-7 Alkyl or C 1-7 Alkoxy substitution; The conditions are: (a)Y 1 and Y 2 are different; and (b) In Y 1 、Y 2 and Y 3 In the 8 At least one of the groups does not represent H or fluorine, and X and Z independently represent CH=CH, CR 11 , N, NH, O or S, The conditions are: (a) X and Z are different, (b) When X represents CH=CH, then Z can only represent CR 11 ;and (c) When Z represents CH=CH, then X can only represent CR 11 ; R 11 Represents H, halogen atoms, hydroxyl groups, -CN, -NR 9e R 10e , or C 1-7 Alkyl or C 1-7 Alkoxy, both of which are optionally substituted by one or more halogen atoms, hydroxyl, amino, -CN, -NR 9f R 10f 、C 1-7 Alkyl or C 1-7 Alkoxy substituted; and R 9a 、R 10a 、R 9b 、R 10b 、R 9c 、R 10c 、R 9d 、R 10d 、R 9e 、R 10e 、R 9f and R 10f Each independently represents H or C 1-6 an alkyl group, which is optionally substituted by one or more halogen atoms, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein: R 1 Indicates H or C 1-6 Alkyl, which is optionally substituted with halogen, CF3 or OR 7 replace; R 2 and R 3 independently represents H or C 1-6 an alkyl group, which is optionally substituted with one or more halogen atoms; R 4 Indicates C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy-C 1-6 alkyl, the alkyl portion of each of which is optionally substituted and / or terminated by one or more halogen atoms, -CN or -OH groups, or R 4 Represents aryl, C 1-6 Alkyl aryl, C 1-3 Alkenyl aryl, heteroaryl, C 1-6 Alkyl heteroaryl or C 1-3 Alkenylheteroaryl, each of which is optionally substituted by one or more halogen, CF3, CF3O-, -CN, C 1-6 Alkyl and C 1-6 Alkoxy substitution; R 5 Indicates C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, each of which is optionally substituted by one or more halogen atoms; R 6 and R 7 independently represents H or C 1-6 an alkyl group, which is optionally substituted with one or more halogen atoms; and / or R 8 represents H, a halogen atom, or represents C 1-3 Alkyl or C 1-3 alkoxy, both of which are optionally substituted by one or more halogen atoms.

3. The compound according to any one of claim 1 or claim 2, wherein R 1 represents H, methyl, ethyl, isopropyl, cyclopropyl or tert-butyl, which is optionally substituted by halogen, CF3 or OR 7 replace.

4. A compound according to any one of the preceding claims, wherein R 2 and R 3 represents H or methyl.

5. A compound according to any one of the preceding claims, wherein R 4 represents a heteroaryl group, which is optionally substituted by one or more halogen atoms, CF3, -CN, Me or methoxy.

6. The compound according to any one of claims 1 to 4, wherein R 4 Indicates C 1-4 Alkoxy groups, the alkyl portion of which is optionally substituted and / or terminated with one or more F, Cl, Br, -CN or -OH groups.

7. A compound according to any one of the preceding claims, wherein R 5 represents a methyl group, an ethyl group, an n-propyl group, an n-butyl group or an isobutyl group.

8. A compound according to any one of the preceding claims, wherein R 6 represents H or methyl.

9. A compound according to any one of the preceding claims, wherein Y 1 Indicates -CH-, Y 2 represents -CH=CH-, and / or Y 3 Indicates -CR 8 -.

10. A compound according to any one of the preceding claims, wherein R 8 represents halogen or methyl, which is optionally substituted by one or more halogens.

11. A compound according to any one of the preceding claims, wherein X represents -CH=CH-, O or S, and / or Z represents -CH- or N.

12. A compound according to any one of the preceding claims, which is: 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyridin-2-yl)thiophene-2-sulfonamide, 5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(pyridin-2-yl)thiophene-2-sulfonamide, 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyridin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(5-fluoropyrimidin-2-yl)-5-isobutylthiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(4,5-dimethyloxazol-2-yl)-5-isobutylthiophene-2-sulfonamide, 3-(3-chloro-4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-(trifluoromethyl)pyrimidin-2-yl) Thiophene-2-sulfonamide, 5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-methylpyrimidin-2-yl)thiophene-2-sulfonamide, 3'-chloro-5-isobutyl-N-(5-methoxypyrimidin-2-yl)-4'-((2-methyl-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide, 5-isobutyl-3'-methyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, 3-(3-chloro-4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-methoxythiophene-2-sulfonamide, 2-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide, 5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]-3-(trifluoromethyl)phenyl]-N-pyrimidin-2-yl-thiophene-2-sulfonamide, 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide and 3-[3-Chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiophene-2-sulfonamide.

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

14. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 11 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

15. A compound according to any one of claims 1 to 11 for use in the treatment of autoimmune diseases, viral respiratory infections and / or pneumonia caused therefrom, fibrotic diseases, chronic kidney disease, pulmonary hypertension, heart failure, preeclampsia and / or myocardial infarction.

16. 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 infections and / or pneumonia caused thereby, fibrotic diseases, chronic kidney disease, pulmonary hypertension, heart failure and / or myocardial infarction.

17. A method for treating autoimmune diseases, viral respiratory infections and / or pneumonia caused thereby, fibrotic diseases, chronic kidney disease, pulmonary hypertension, heart failure, preeclampsia and / or myocardial infarction, the method comprising administering to a patient in need of such treatment a compound according to any one of claims 1 to 11.

18. The compound for use according to claim 15, the use according to claim 16 or the method of treatment according to claim 17, wherein the disease is an interstitial lung disease.

19. The compound for use, use or method of treatment according to claim 18, wherein the interstitial lung disease is idiopathic pulmonary fibrosis or sarcoidosis.

20. The compound for use according to claim 15, the use according to claim 16 or the method of treatment according to claim 17, wherein the autoimmune disease is rheumatoid arthritis or systemic sclerosis.

21. The compound for use according to claim 15, the use according to claim 16 or the method of treatment according to claim 17, wherein the chronic kidney disease is diabetic nephropathy.

22. The compound for use according to claim 15, the use according to claim 16 or the method of treatment according to claim 17, wherein the pulmonary hypertension is arterial pulmonary hypertension.

23. The compound for use according to claim 15, the use according to claim 16 or the method of treatment according to claim 17, wherein the heart failure is heart failure with preserved ejection fraction.

24. The compound for use according to claim 15, the use according to claim 16 or the method of treatment according to claim 17, wherein the viral respiratory tract infection results in viral-induced pneumonia.

25. The compound for use according to claim 15, the use according to claim 16 or the method for treatment according to claim 17, wherein the interstitial lung disease is progressive fibrosing ILD or pulmonary fibrosis.

26. A process for preparing a compound of formula I according to any one of the preceding claims, said process comprising reacting a compound of formula II, where R 1 、R 2 、R 3 、R 5 、R 6 , X, Z, Y 1 、Y 2 and Y 3 As claimed in any one of claims 1 to 11, reacting with a compound of formula III, L 1 R 4 III where R 4 According to any one of claims 1, 5 or 6, and L 1 represents a suitable leaving group.

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