New compound

Abstract

Provided are compounds, pharmaceutical formulations, and processes for preparing compounds that are useful in the treatment of autoimmune and / or fibrotic diseases, including interstitial lung diseases such as idiopathic pulmonary fibrosis and sarcoidosis. The present invention provides 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

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

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

[0003] Several studies in adults appear to indicate that activation of the AT2 receptor has the opposite effect to that mediated by the AT1 receptor in regulating responses following Ang II receptor stimulation. The AT2 receptor has also been shown to be involved in the inhibition of apoptosis and cell proliferation (de Gasparo M et al., Pharmacol. Rev. (2000); 52, 415-472). More recently, AT2 receptor agonists have been shown to be potentially useful in the treatment and / or prevention of gastrointestinal disorders such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see International Patent Application No. 99 / 43339). The expected pharmacological effects of AT2 receptor agonism are generally described in de Gasparo M et al. (see above).

[0004] The stimulatory effects of Ang II on vascular tone, cell proliferation, inflammation, and extracellular matrix synthesis are primarily related to AT1 receptors in all organs, whereas AT2 receptor function is more prevalent in injured tissues, exerting reparative and opposing properties to AT1 receptors. For example, AT2 receptors have been shown to be important in relation to muscle hypertrophy and reduced fibrosis.

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

[0006] ILD differs from obstructive airway diseases (e.g., chronic obstructive airway disease (COPD) and asthma), which are typically characterized by narrowing (obstruction) of the bronchi and / or bronchioles. ILD can be caused by lung injury that triggers an abnormal healing response, but in some cases, the cause of these diseases is unknown. ILD can be caused by chemicals (silicosis, asbestosis, certain drugs), infections (e.g., pneumonia), or other diseases (e.g., rheumatoid arthritis, systemic sclerosis, myositis, or systemic lupus erythematosus).

[0007] The most common 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 collections of inflammatory cells that form lumps (granulomas), often starting in the lungs (as well as the skin and / or lymph nodes; any organ can be affected). When sarcoidosis affects the lungs, symptoms include coughing, wheezing, shortness of breath, and / or chest pain.

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

[0010] IPF is a lung disease of unknown cause that affects approximately 5 million people worldwide. There are no treatment options, except for lung transplantation, which is rare. This results in chronic, irreversible, and progressive decline in lung function, with most patients dying within 2–5 years (median survival: 2.5–3.5 years). While the overall prognosis for IPF is poor, predicting the rate of progression in individual patients is difficult. Risk factors for IPF include age, male sex, genetic predisposition, and smoking history. The annual incidence rate is 5–16 per 100,000, with a prevalence of 13–20 cases per 100,000, increasing dramatically with age (King Jr TE et al., Lancet (2011); 378, 1949–1961; Noble PW et al., J. Clin. Invest. (2012); 122, 2756–2762). IPF is confined to the lungs and is refractory to treatments that target the immune system, distinguishing it from pulmonary fibrosis associated with systemic diseases.

[0011] Patients with IPF typically seek medical assistance because of chronic and progressive exertional dyspnea and cough. Lung imaging classically reveals traction bronchiectasis, thickened interlobar septa, and subpleural honeycombing. When all three findings are present and there is no evidence of systemic connective tissue disease or environmental exposure, a diagnosis of IPF is highly likely. A definitive diagnosis is usually made by lung biopsy, which requires the expertise of a multidisciplinary team including a pulmonologist, radiologist, and pathologist with experience in interstitial lung disease.

[0012] IPF exhibits a variety of phenotypes with variable prognosis, defined as mild, moderate, and severe. Mild cases follow a stable or slowly progressive course, and patients may take several years to seek medical advice. Accelerated IPF is associated with shorter survival and progresses much more rapidly, affecting a subgroup of patients, usually male smokers. Acute exacerbations of IPF are defined as a rapid worsening of the disease, and patients in this subpopulation show very poor outcomes in the short term, with high mortality rates. The cause of IPF is unknown, but it appears to be a disease that likely results from an interplay of environmental and genetic factors leading to relentless tissue remodeling by fibroblasts rather than normal repair, resulting in a pathogenesis that is primarily fibrotic rather than inflammatory. Increasing evidence suggests that the disease is initiated by microdamage and apoptosis of alveolar epithelial cells, which activate neighboring epithelial cells and attract stem or progenitor cells that produce factors responsible for the expansion of fibroblast and myofibroblast populations in a tumor-like manner. Fibroblastic foci secrete excessive amounts of extracellular matrix, which destroys the lung parenchyma and ultimately leads to loss of lung function.

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

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

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

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

[0017] Because restoring the alveolar epithelium is a highly desirable therapeutic outcome for IPF, stem cell therapy is also being tested. Several preclinical studies have shown promise in the use of pluripotent stem cells, which can differentiate into lung epithelial and endothelial cells, thereby repairing lung injury and fibrosis.

[0018] Currently, lung transplantation is the only intervention that significantly improves survival in patients with IPF, although complications such as infection and graft rejection are not uncommon.

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

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

[0021] Selective AT2 receptor agonists with reduced CYP450 inhibition are described in Mahalingam et al., Bioorg. Med. Chem. (2010); 18, 4570-4590.

[0022] A transesterification method for the synthesis of AT2 receptor ligands with improved stability in human liver microsomes is described in Wannberg et al., Bioorg. Med. Chem. Lett. (2018); 28, 519-522.

[0023] In particular, International Patent Application No. 2002 / 096883 describes the preparation of imidazolyl, triazolyl, and tetrazolylthiophene sulfonamides and derivatives as Ang II receptor agonists. Among the compounds described therein (as Example 1) is compound C21 (N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide). C21 was selected for clinical development from a group of approximately 20 related analogs as a selective AT2 receptor agonist. It is currently in clinical development for the treatment of AT2 receptor-related diseases, including IPF (see, for example, International Patent Application No. 2016 / 139475).

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

[0025] During its development, C21 was found to have the disadvantages of being a potent inhibitor of several cytochrome P450 enzymes (CYPs), particularly CYP 2C9 and CYP 3A4, potentially affecting the metabolism of other drugs, and being rapidly hydrolyzed to inactive sulfonamide metabolites. Therefore, developing potent and selective AT2 agonists that are metabolically stable and / or exhibit minimal inhibition of CYP enzymes is a fundamental challenge.

[0026] Surprisingly, we have discovered that certain chemically modified compounds described below are not only selective AT2 receptor agonists, but also are more potent, have significantly improved stability against metabolic hydrolysis, and / or exhibit less inhibition of CYP enzymes compared to C21.

[0027] Description of the invention In a first aspect of the invention, there is provided a compound of formula I, [ka] During the ceremony, R 1 is C optionally substituted with one or more halogen atoms 1-6 represents alkyl, R 2 and R 3 are independently H, or C optionally substituted by one or more halogen atoms. 1-6 represents alkyl, Y 1 , Y 2 , Y 3 , and Y 4 independently represent -CH-, -CF-, or -N-; R 4 is C 1-7 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 alkyl, each of which is optionally substituted with one or more halogen atoms, or R 4 is aryl, C 1-6 Alkylaryl, C 1-3Alkenylaryl, heteroaryl, C 1-6 alkylheteroaryl, or C 1-3 alkenylheteroaryl, each of which is halogen, CF3, CF3O, C 1-6 Alkyl, and C 1-6 optionally substituted by one or more substituents selected from alkoxy; R 5 is H or C optionally substituted with one or more halogen atoms 1-6 represents alkyl, R 6 is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 alkyl, each of which is optionally substituted with one or more halogen atoms; or a pharmaceutically acceptable salt thereof, These compounds and salts are hereinafter collectively referred to as "compounds of the present invention."

[0028] Compounds of the invention that may be mentioned include those containing R 4 C 1-7 When representing an alkyl group, the alkyl is C 1-6 Included are alkyl groups.

[0029] For the purposes of interpreting this specification, the following definitions will apply and wherever appropriate, terms used in the singular will also include the plural and vice versa.

[0030] Compounds are named according to the IUPAC nomenclature system, generated by the program Chemdoodle 8.1.0.

[0031] For the avoidance of doubt, those skilled in the art will understand that reference herein to a compound of a particular aspect of the invention (e.g., any aspect of the invention referring to a compound of formula I as defined above) includes reference to all embodiments and particular features thereof, and that the embodiments and particular features may be combined to form further embodiments.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the common meaning as understood by one of ordinary skill in the art to which this invention belongs.

[0033] 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 in any solvent or medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (for example, by vacuum, lyophilization or filtration).Salts 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 the form of a salt with another counterion, for example, by using a suitable ion exchange resin.

[0034] Particular acid addition salts that may be mentioned include carboxylates such as formates, acetates, trifluoroacetates, benzoates, oxalates, fumarates, maleates, etc.; sulfonates such as methanesulfonates, ethanesulfonates, toluenesulfonates, etc.; halide salts such as hydrochlorides, hydrobromides, etc.; sulfates and phosphates such as sulfates or phosphates, etc.

[0035] Particular base addition salts which may be mentioned include salts formed with alkali metals (such as Li, Na and K salts), alkaline earth metals (such as Mg and Ca salts), or other metals (such as Al and Zn salts), amine bases (ammonia, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, etc. More particularly, base addition salts which may be mentioned include Mg salts, Ca salts, and most particularly K salts and Na salts.

[0036] The compounds of the present invention may exist as solids, and therefore the scope of the present invention includes all amorphous, crystalline, and partially crystalline forms thereof, and may exist as oils. When the compounds of the present invention exist in crystalline and partially crystalline form, such forms may include solvates that are included within the scope of the present invention.

[0037] The compounds of the present invention may also be present in solution (i.e., in a solution in a suitable solvent). For example, the compounds of the present invention may be present in aqueous solution, in which case the compounds of the present invention may be present in the form of their hydrates.

[0038] The compounds of the present invention may contain double bonds and therefore, unless specified otherwise, may exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. Unless specified otherwise, all such isomers and mixtures thereof are included within the scope of the present invention.

[0039] Compounds of the invention may also exhibit tautomerism: all tautomeric forms and mixtures thereof are included within the scope of the invention, particularly those with sufficient stability to allow their isolation.

[0040] The compounds of the present invention may also contain one or more asymmetric carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism (i.e., exist in enantiomeric or diastereomeric forms). Diastereomers may be separated using conventional techniques, for example, chromatography or fractional crystallization. The various stereoisomers (i.e., enantiomers) may be isolated by separating a racemic or other mixture of the compounds using conventional techniques, for example, fractional crystallization or HPLC. Alternatively, the desired enantiomer or diastereomer may be obtained from the appropriate optically active starting material under conditions that will not cause racemization or epimerization (i.e., "chiral pool" methods), by reaction of the appropriate starting material with a "chiral auxiliary" that can be subsequently removed at an appropriate stage, by derivatization (i.e., resolution, including kinetic resolution, e.g., treatment with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography), or by reaction with a suitable chiral reagent or chiral catalyst; all of these methods and processes can be carried out under all conditions known to those skilled in the art. Unless otherwise specified, all stereoisomers and mixtures thereof are included within the scope of the present invention.

[0041] As used herein, the term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

[0042] Unless otherwise specified, C as defined herein 1-7 Alkyl groups, (e.g., C 1-6 Alkyl group or C 1-3 alkyl groups), and C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylaryl, C 1-6The alkyl portion of the alkylheteroaryl group (6 is the upper limit of the range in all cases) may be straight-chained or, when there is a sufficient number (i.e., a minimum of 2 or 3, where appropriate) of carbon atoms, may be branched and / or cyclic (thus C 3-7 When there is a sufficient number (i.e., a minimum of four) of carbon atoms, such groups may also be part cyclic (hence, C 4-7 (Forming a partial cycloalkyl group). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclopentyl, and cyclohexyl. Similarly, partial cyclic alkyl groups (which may also be called "partial cycloalkyl" groups) that may be mentioned include cyclopropylmethyl. When a sufficient number of carbon atoms are present, such groups may be polycyclic (e.g., bicyclic or tricyclic) or spirocyclic.

[0043] C 3-6 Alkyl groups and C 3-6 Alkoxy groups can be unsaturated and thus can incorporate double or triple bonds.

[0044] Particular alkyl groups that may be mentioned include straight-chain (i.e., not branched and / or cyclic) alkyl groups. For example, C 1-6 Alkyl groups, and C 1-6 The alkyl portion of the alkoxy group includes, but is not limited to, n-butyl, sec-butyl, isobutyl, tert-butyl; propyl, such as n-propyl, 2-methylpropyl, or isopropyl; ethyl; and methyl.

[0045] For the avoidance of any doubt, C 1-6 Alkyl groups and C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylaryl, C 1-6 The point of attachment to the alkyl moiety of an alkylheteroaryl group is through the alkyl portion of such group.

[0046] For the avoidance of doubt, alkoxy groups are attached to the remainder of the molecule through the oxygen atom of the group, and alkoxyalkyl groups are attached to the remainder of the molecule through the alkyl portion of the group.

[0047] Unless otherwise specified, alkoxy refers to an O-alkyl group, where the term "alkyl" has the meaning given above.

[0048] As used herein, references to heteroatoms may take their ordinary meaning as understood by those of ordinary skill in the art. Particular heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen, and sulfur (e.g., oxygen, nitrogen, and sulfur, such as oxygen and nitrogen).

[0049] As used herein, reference to "heteroaryl" (sometimes also referred to as heteroaromatic) may refer to a heteroaromatic group containing one or more heteroatoms (such as one or more heteroatoms selected from oxygen, nitrogen, and / or sulfur). Such heteroaryl groups may contain one, two, or three rings, at least one of which is aromatic (the aromatic ring may or may not contain one or more heteroatoms). Substituents on heteroaryl / heteroaromatic groups, where appropriate, may be located on any suitable atom in the heteroatom-containing ring system (e.g., on a suitable N atom).

[0050] The point of attachment of a heteroaryl / heteroaromatic group may be via any atom in the ring system, including (where appropriate) a heteroatom. Bicyclic heteroaryl / heteroaromatic groups may contain a benzene ring fused to one or more additional aromatic or non-aromatic heterocycles, in which case the point of attachment of a polycyclic heteroaryl / heteroaromatic group may be via the benzene ring or any of the rings comprising the heteroaryl / heteroaromatic or heterocycle.

[0051] For the avoidance of doubt, those skilled in the art will understand that the heteroaryl groups which may form part of the compounds of the present invention are chemically obtainable as known to those skilled in the art. A variety of heteroaryl groups will be known to those skilled in the art, such as pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolylthiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, and purinyl.

[0052] For the avoidance of doubt, oxides (eg N-oxides) of heteroaryl / heteroaromatic groups are also included within the scope of the present invention.

[0053] As mentioned above, heteroaryl includes polycyclic (e.g., bicyclic) groups in which one ring is aromatic (the other may or may not be aromatic). Thus, other heteroaryl groups that may be mentioned include benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazole, 3,4-dihydrobenzo[1,4]oxazinyl, dihydrobenzothiophenyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, thiochromanyl, and the like.

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

[0055] As used herein, the term aryl refers to a C 6-14 (For example, C 6-10) may refer to aromatic groups. Such groups may be monocyclic or bicyclic, and when bicyclic, may be wholly or partially aromatic. 6-10 Aryl groups include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like (eg, phenyl, naphthyl, and the like).

[0056] Those skilled in the art will recognize that the aryl groups that may form part of the compounds of the present invention are chemically available, as known to those skilled in the art.

[0057] For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any suitable carbon atom of the ring system.

[0058] The present invention also encompasses isotopically labeled compounds of the present invention, which are identical to those listed herein, except that one or more atoms are replaced with atoms having atomic masses or mass numbers different from those usually found in nature (or the most abundant ones found in nature).All isotopes of any particular atom or element identified herein are considered to be within the scope of the compounds of the present invention.Therefore, the compounds of the present invention also include deuterated compounds, i.e., compounds of the present invention in which one or more hydrogen atoms are replaced with the hydrogen isotope deuterium.

[0059] In the case where the identity of two or more substituents in the compounds of the present invention may be the same, the actual identity of each substituent is in no way interdependent. For example, in the case where two or more halo groups are present, the groups may be the same or different (e.g., two chloro groups, or a fluoro group and a chloro group). Similarly, when two or more alkyl groups are present, the groups in question may be the same or different in terms of the number of carbon atoms and / or whether they are linear, branched, unsaturated, or otherwise.

[0060] Furthermore, when a substituent is itself specified as being optionally substituted with one or more substituents (e.g., phenyl optionally substituted with one or more groups independently selected from halo), these substituents may be located on the same or different atoms, where possible. Such optional substituents may be present in any suitable number thereof (e.g., the relevant group may be substituted with one or more such substituents, for example, with one such substituent).

[0061] Where a group is referred to herein as being optionally substituted, it is specifically intended that such optionally substituted group may not be present (i.e., the reference to such optionally substituted group may be omitted), in which case the optionally substituted group may be referred to as unsubstituted.

[0062] Unless otherwise specified, substituents (whether optional or not) may be located at any point on the group to which they may be attached. In this regard, alkyl and alkoxy groups (for example) which may be substituted by one or more substituents may also be terminated by such a substituent (i.e., meaning located at the end of the alkyl or alkoxy chain, for example).

[0063] For the avoidance of doubt, in cases where the identities of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are in no way interdependent. For example, R 2 and R 3 Both are C 1-6 In the situation where the C in question is an alkyl 1-6 The alkyl groups may be the same or different.

[0064] Those skilled in the art will appreciate that the compounds of the present invention that are the subject of this invention include those that are available, i.e., that can be prepared in a stable form, i.e., compounds of the present invention include compounds that are sufficiently robust to survive isolation, e.g., isolation to a useful degree of purity from a reaction mixture.

[0065] Preferred compounds of the present invention include: R 1 is a C optionally substituted with up to three halogen atoms (e.g., CH2CHClCH2CH2F or CH2CF3). 1-4 represents an alkyl group (methyl, ethyl, propyl (e.g., n-propyl) or butyl (e.g., n-butyl)); R 2 and R 3 are independently H or C optionally substituted with up to three halogen atoms (e.g., CH2CHClCH2CH2F or CH2CF3). 1-4 represents an alkyl group (methyl, ethyl, propyl (e.g., n-propyl) or butyl (e.g., n-butyl)); R 4 is a C optionally substituted with up to three halogen atoms 1-4 alkyl groups (methyl, ethyl, propyl (e.g., n-propyl) or butyl (e.g., n-butyl)); C optionally substituted or more preferably terminated with up to three halogen atoms; 1-3 Alkoxy-C 1-3 alkyl groups; aryl (e.g., phenyl, fluorophenyl, or trifluorophenyl) optionally substituted with one or more halogen atoms; C 1-3 alkylaryl; or C 1-3 represents alkylheteroaryl, R 5 is H or C 1-4 represents an alkyl group (such as methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., n-butyl)); R 6 is C 1-4 represents an alkyl group, optionally substituted or more preferably terminated with up to three fluorine atoms; Y 1 represents -CH-, -CF-, or -N-; Y 2 represents -N-, or more preferably -CH-, -CF-, Y 3 represents -CH-, Y 4represents -CH- or -N-.

[0066] More preferred compounds of the present invention include the following: R 1 is a C optionally substituted with up to three fluorine atoms (e.g., -CHCF or -CHCHCHF) 1-3 represents an alkyl group (methyl, ethyl, propyl (e.g., n-propyl)); R 2 and R 3 independently represent methyl or ethyl, or more preferably H; R 4 is optionally substituted or more preferably terminated with up to three fluorine atoms 1-4 an alkyl group (e.g., methyl, ethyl, propyl (e.g., n-propyl) or butyl (e.g., n-butyl)); or a C optionally substituted or, more preferably, terminated with up to three fluorine atoms; 1-2 Alkoxy-C 1-3 Alkyl group; Phenyl; C 1-2 Alkylaryl (e.g., C 1-2 alkylphenyl); or C 1-2 Alkylheteroaryl (e.g., C 1-2 alkylthiophenyl), R 6 represents butyl, more preferably isobutyl, optionally substituted or more preferably terminated with up to three fluorine atoms.

[0067] Particularly preferred compounds of the present invention include the following: R 1 represents ethyl, or more preferably methyl, R 2 represents methyl, or more preferably H, R 3 represents H, R 4is an ethyl, propyl (e.g., n-propyl) or butyl (e.g., n-butyl) group optionally substituted or more preferably terminated with up to three fluorine atoms; a methoxyethyl group optionally substituted or more preferably terminated with up to three fluorine atoms; 1-2 Alkoxy-C 1-2 alkyl group; phenyl; benzyl; thiophen-2-ylmethyl; or pyridin-2-ylmethyl; R 5 represents H, R 6 represents butyl, more preferably isobutyl, Y 1 represents -CF- or, more preferably, -CH-; Y 2 , Y 3 , and Y 4 All of these represent -CH-.

[0068] Thus, particularly preferred compounds of the invention that may be mentioned are: 1-benzyl-3-(5-isobutyl-3-{p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)urea, p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea, p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, 1-butyl-3-(5-isobutyl-3-{p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)urea, p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)-1-(4,4,4-trifluorobutyl)urea, 1-benzyl-3-(3-{p-[(2-ethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)urea, p-[(2-ethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(2-methoxyethyl)urea, p-[(2,4-dimethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, and pharmaceutically acceptable salts thereof.

[0069] Furthermore, particularly preferred compounds of the invention that may be mentioned are: 3-(3-{p-[(2-ethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea, 1-benzyl-3-(3-{p-[(2,4-dimethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)urea, 3-(3-{p-[(2,4-dimethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea, 1-benzyl-3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, 1-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-3-[(1-methyl-1H-imidazol-2-yl)methyl]urea, 1-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-3-[2-(1H-imidazol-4-yl)ethyl]urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-methyl-1-[(2-pyridyl)methyl]urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(4,4,4-trifluorobutyl)urea, 3-(5-isobutyl-3-{5-[(2-methyl-1H-imidazol-1-yl)methyl]-2-pyridyl}-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, 3-(5-isobutyl-3-{2-[(2-methyl-1H-imidazol-1-yl)methyl]-5-pyrimidinyl}-2-thienylsulfonyl)-1-(2-methoxyethyl)urea, 3-(5-isobutyl-3-{2-[(2-methyl-1H-imidazol-1-yl)methyl]-5-pyrimidinyl}-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, 3-(5-isobutyl-3-{2-[(2-methyl-1H-imidazol-1-yl)methyl]-5-pyrimidinyl}-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea, 1-[(3,5-difluorophenyl)methyl]-3-(5-isobutyl-3-{5-[(2-methyl-1H-imidazol-1-yl)methyl]-2-pyridyl}-2-thienylsulfonyl)urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(2-methoxyethyl)urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[1-(2-pyridyl)ethyl]urea, 3-(3-{2-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, 3-(3-{2-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(2,2,2-trifluoroethyl)urea, 1-(3-fluoropropyl)-3-(5-isobutyl-3-{p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)urea, 1-(3,3-difluoropropyl)-3-(5-isobutyl-3-{p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)urea, 1-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(3,3,3-trifluoropropyl)urea, 1-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(2-methoxyethyl)urea, 3-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-1-[(4-fluorophenyl)methyl]urea, 1-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-propylurea, 1-[(3,4-difluorophenyl)methyl]-3-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]urea, 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-[(thiophen-2-yl)methyl]urea, 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-propylurea, 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(3,3,3-trifluoropropyl)urea, 1-[(4-chloropyridin-2-yl)methyl]-3-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]urea, 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(2-methylpropyl)urea, 1-[(4,4-difluorocyclohexyl)methyl]-3-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]urea, 1-{[3-(3-fluoro-4-{[2-(propan-2-yl)-1H-imidazol-1-yl]methyl}phenyl)-5-(2-methylpropyl)thiophen-2-yl]sulfonyl}-3-(3,3,3-trifluoropropyl)urea, 1-{[3-(3-fluoro-4-{[2-(propan-2-yl)-1H-imidazol-1-yl]methyl}phenyl)-5-(2-methylpropyl)thiophen-2-yl]sulfonyl}-3-(4,4,4-trifluorobutyl)urea, 1-{[3-(3-fluoro-4-{[2-(propan-2-yl)-1H-imidazol-1-yl]methyl}phenyl)-5-(2-methylpropyl)thiophen-2-yl]sulfonyl}-3-propylurea, 1-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-3-propoxyurea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2,2,2-trifluoroethyl)-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, and 3-(3-{3,5-difluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, and pharmaceutically acceptable salts thereof.

[0070] IUPAC names were generated from the program Chemdoodle 8.1.0.

[0071] More preferred compounds of the present invention include those of the Examples set forth below.

[0072] Compounds of formula I may be prepared according to techniques well known to those skilled in the art, for example as described below.

[0073] According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula I, the process comprising: (i) a compound of formula II [ka] (In the formula, R1 , R 2 , R 3 , R 6 , Y 1 , Y 2 , Y 3 , and Y 4 is defined hereinabove, and L is C 1-6 alkyl) and a compound of formula III or a salt thereof NHR 4 R 5 III (In the formula, R 4 and R 5 is defined hereinabove) in the presence of a suitable solvent such as, for example, toluene, acetonitrile or dioxane and / or a suitable base such as triethylamine or 4-dimethylaminopyridine at about room temperature or above (e.g., up to 90-110°C). (ii)R 5 represents H, the compound of formula IV [ka] (In the formula, R 1 , R 2 , R 3 , R 6 , Y 1 , Y 2 , Y 3 and Y 4 is defined hereinabove) and a compound of formula V R 4 -N=C=OV (In the formula, R 4 is defined herein above), for example, at about room temperature or above (e.g., up to 60-70° C.), optionally in the presence of a suitable base (e.g., pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or a mixture thereof) and a suitable solvent (e.g., pyridine, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide).

[0074] A compound of formula II may be prepared by reaction of a compound of formula IV with a compound of formula VI as defined hereinabove. [ka] In the formula, X 1 represents a suitable leaving group such as halo (e.g., chloro or bromo), and M is, for example, -OC in the presence of a suitable base (e.g., sodium bicarbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or a mixture thereof) and a suitable solvent (e.g., pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, or toluene) at below, ambient, or above room temperature (e.g., 0°C, or up to 60-70°C). 1-6 Represents alkyl.

[0075] Compounds of formula IV can be prepared by reaction of a compound of formula VII. [ka] In the formula, R 6 is as defined hereinabove or an N-protected derivative thereof, and X 2 represents a suitable cross-coupling group with a compound of formula VIII, [ka] X 3 represents a suitable cross-coupling group. The above coupling reaction is preferably a Suzuki reaction and can therefore be carried out under standard Suzuki conditions, which can be carried out by 2 and X 3 where one of R represents any of the suitable Suzuki cross-coupling groups (or "partners"), i.e., boronic acid (-B(OH)2) and halo groups such as iodo or bromo, and the other represents any other group.1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 and Y 4 is defined herein above. Standard Suzuki conditions can be applied to this reaction, including, for example, the presence of a suitable coupling catalyst system (e.g., a palladium catalyst, [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), dichloropalladium(II) complex with [1,1'-bis(diphenylphosphino)ferrocene]-dichloromethane, Pd(PPh3)4 or Pd(OAc)2 / ligand (the ligand can be, for example, PPh3, P(o-Tol)3, or 1,1'-bis(diphenylphosphino)ferrocene)) and a suitable base (e.g., sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or di-iso-propylamine), as well as a suitable solvent system (e.g., toluene, ethanol, n-butanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane or mixtures thereof). This reaction can be carried out at room temperature or above (e.g., at the reflux temperature of the solvent system used). If a protected version of the compound of formula VII is used, this reaction can be followed by deprotection of the SO2NH- group under standard conditions, for example, as described below. After the reaction of the compound of formula VII with the compound of formula VII, the intermediate thus formed can also be reacted with a suitable acid to form an acid addition salt, or more preferably, an N-protected version thereof. Suitable acid addition salts include fumarates, trifluoroacetates, and oxalates.

[0076] Alternatively, compounds of formula IV can be prepared by reaction of a compound of formula IX. [ka] In the formula, R 1 , R 2 , and R 3is defined hereinabove together with the compound of formula X, [ka] R 6 , X 1 , Y 1 , Y 2 , Y 3 and Y 4 is, for example, at about room temperature or below, in the presence of a suitable base (e.g., pyridine) and a suitable organic solvent (e.g., toluene), as defined herein above or (X 1 may in particular represent bromo), or an N-protected derivative thereof. If a protected version of the compound of formula X is used, this reaction may be followed by deprotection of the SO2NH- group under standard conditions, for example as described below. Furthermore, compounds of formula IV can be prepared in this way, for example according to or analogously to the processes described, inter alia, in British Patent Application No. 2281298.

[0077] Compounds of formula VIII may be prepared by standard techniques, for example by reaction of a compound of formula IX with a compound of formula XI as defined hereinabove. [ka] In the formula, X 1 , X 3 , Y 1 , Y 2 , Y 3 and Y 4 is defined hereinabove, for example under conditions similar to those described hereinabove for the preparation of compounds of formula IV.

[0078] Compounds of formula X are known in the art. For example, they can be prepared according to or analogously to the processes described in, inter alia, U.S. Pat. No. 5,312,820, British Patent Application No. 2281298, and / or International Patent Application No. 02 / 096883.

[0079] Compounds of formula VII are known in the art, for example, they can be prepared according to or analogously to the processes described, inter alia, in International Patent Application No. 02 / 096883.

[0080] Compounds of formula III, V, VI, VIII, IX and XI are either commercially available, known in the literature or can be obtained from available starting materials using appropriate reagents and reaction conditions according to standard techniques, either by analogy with the processes described herein or by conventional synthetic procedures.

[0081] It will be appreciated by those skilled in the art that in the processes described above and below the functional groups of intermediate compounds may need to be protected by protecting groups.

[0082] Functional groups that are desirable to protect include sulfonamide, amide, amino, and aldehyde. Suitable protecting groups for sulfonamide, amide, and amino include tert-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), or tert-butyl. Suitable protecting groups for aldehyde include alcohols such as methanol or ethanol, and diols (thus forming cyclic acetals) such as 1,3-propanediol or preferably 1,2-ethanediol. Protection and deprotection of functional groups can be carried out before or after the reaction in the above-mentioned scheme.

[0083] Protecting groups can be applied and removed according to techniques well known to those skilled in the art and as described below. For example, protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need and type of protecting groups, as well as the sequence for achieving synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Hutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference.

[0084] Medical and Pharmaceutical Applications As described herein, the compounds of the present invention, and thus compositions and kits containing same, are useful because they have pharmacological activity and / or are metabolized in the body after oral or parenteral administration to form compounds that have pharmacological activity.

[0085] Thus, according to a further aspect of the present invention there is provided a compound of the present invention, as defined hereinbefore, for use as a pharmaceutical (or for use in medicine).

[0086] In particular, the compounds of the present invention are agonists of the Ang II receptor and are therefore expected to be useful in conditions where endogenous production of Ang II is insufficient and / or where increased effects of Ang II are desired or required.

[0087] More specifically, the compounds of the present invention are agonists of the AT2 receptor and in particular are selective agonists of its sub-receptors (vs. the AT1 receptor), as can be demonstrated, for example, in the tests described below.

[0088] AT2 receptor agonists include those that fully activate AT2 receptors and those that partially activate AT2 receptors.Therefore, the compounds of the present invention can selectively bind to AT2 receptors and exhibit agonist activity at AT2 receptors.A compound that "selectively binds" to AT2 receptors includes those that have an affinity ratio (AT2:AT1) of at least 100:1, preferably at least 1000:1, of related compounds at a given concentration.

[0089] The compounds of the present invention are expected to be further useful in conditions where AT2 receptors are expressed and their stimulation is desirable or required.

[0090] In this regard, the compounds of the present invention are indicated for the treatment of conditions characterized by vasoconstriction, fibrosis, increased cell proliferation and / or differentiation, increased cardiac contractility, increased cardiovascular hypertrophy, and / or increased fluid and electrolyte retention, as well as skin and musculoskeletal disorders.

[0091] 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, for example, an antithrombotic effect) and / or may reduce vasoconstriction and / or bronchoconstriction in a therapeutic manner.

[0092] The compounds of the present invention are further indicated in the treatment of stress-related diseases and / or in improving microcirculatory and / or mucosal protective mechanisms.

[0093] Accordingly, the compounds of the invention are expected to be useful in the treatment of diseases that can be characterized as above, such as those affecting the gastrointestinal tract, cardiovascular system, respiratory tract, kidney, eye, female reproductive (ovulatory) system and central nervous system (CNS).

[0094] Gastrointestinal disorders that may be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastroesophageal reflux, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), liver disorders (such as hepatitis), gallbladder disease, multiple organ failure (MOF), and sepsis. Other gastrointestinal disorders that may be mentioned include xerostomia, gastritis, gastroparesis, hyperacidity, biliary tract disease, coeliac disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, colitis, anorexia, vomiting, nausea, dyspepsia, and Sjogren's syndrome.

[0095] Disorders of the airways that may be mentioned include inflammatory diseases such as asthma, obstructive pulmonary diseases (such as chronic obstructive pulmonary disease), non-infectious pneumonia, pulmonary hypertension, and adult respiratory distress syndrome.

[0096] Kidney diseases that may be mentioned include renal failure, nephritis, and renal hypertension.

[0097] Eye diseases that may be mentioned include diabetic retinopathy, retinopathy of prematurity, and retinal microvascularization.

[0098] Diseases of the female reproductive system that may be mentioned include ovulatory dysfunction.

[0099] 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, post-balloon dilation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina, cardiac arrhythmias, intermittent clouding, preeclampsia, myocardial infarction, reinfarction, ischemic lesions, erectile dysfunction and neointimal proliferation.

[0100] Diseases of the CNS that may be mentioned include cognitive dysfunction, dysfunction of food intake (hunger / satiety) and thirst, stroke, cerebral hemorrhage, cerebral embolism and infarction, multiple sclerosis (MS), Alzheimer's disease and Parkinson's disease.

[0101] The compounds of the invention may also be useful in regulating growth metabolism and proliferation, for example in the treatment of aging, hypertrophic diseases, benign prostatic hyperplasia, autoimmune diseases (e.g., arthritis such as rheumatoid arthritis, or systemic lupus erythematosus), psoriasis, obesity, nerve cell regeneration, ulcer healing, inhibition of adipose tissue hyperplasia, stem cell differentiation and proliferation, fibrotic diseases, cancer (e.g., of or in the gastrointestinal tract (including the esophagus or stomach)), prostate, breast, liver, kidney, as well as lymphoma, lung cancer, ovarian cancer, pancreatic cancer, hematological malignancies, etc.), inhibition of apoptosis, tumors (in general) and hypertrophy, diabetes, neuropathies and organ rejection.

[0102] The compounds of the present invention are also useful in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer therapy-related cardiotoxicity, peripheral neuropathy, and especially systemic sclerosis.

[0103] The compounds of the invention are particularly indicated for the treatment and / or prevention of ILDs such as sarcoidosis or fibrosis, more particularly pulmonary fibrosis, in particular IPF, as well as conditions which may induce ILDs, such as systemic sclerosis, rheumatoid arthritis, myositis or systemic lupus erythematosus, or conditions associated with ILDs, such as pulmonary hypertension and / or pulmonary arterial hypertension.

[0104] The compounds of the present invention are particularly useful in the treatment of pulmonary fibrosis, especially IPF.

[0105] According to a further aspect of the present invention there is provided a method for the treatment of pulmonary fibrosis, particularly IPF, which method comprises the administration to a person suffering from such a condition of a therapeutically effective amount of a compound of the present invention.

[0106] In the treatment of pulmonary fibrosis, including IPF, the compounds of the present invention can have anti-fibrotic effects, including reducing fibrosis and preventing further deposition of extracellular matrix.The compounds of the present invention can reduce lung scarring / wound healing and have anti-apoptotic effects, thereby preventing the apoptosis of alveolar endothelial cells, which is the initiating factor in the development of pulmonary fibrosis.The compounds of the present invention can also have anti-proliferative effects, thus reducing the cancerous proliferation of fibroblasts and myofibroblasts in pulmonary fibrosis.The compounds of the present invention can also improve vascular remodeling in pulmonary fibrosis, thereby alleviating secondary pulmonary hypertension.Finally, the compounds of the present invention can exhibit anti-inflammatory and anti-cytokine effects.

[0107] Furthermore, the compounds of the present invention may also be useful in treating or preventing fibrotic conditions in one or more internal organs characterized by excessive accumulation of fibrous connective tissue, and / or treating or preventing fibrosis and the morbidity and mortality that may be associated therewith. Such fibrosis may be associated with acute inflammatory conditions such as acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), multi-organ inflammation, and injury and / or failure that may be caused by internal or external trauma (e.g., injury) or infection.

[0108] Therefore, such symptoms may result from sepsis or septic shock caused by viral, bacterial, or fungal infections. Furthermore, acute lung injury, ARDS, and especially SARS, which can be caused by viruses such as coronaviruses, including novel SARS coronavirus 2 (SARS-CoV-2), can cause internal tissue damage and / or dysfunction of related internal (e.g., mucosal) tissues, such as the respiratory epithelium. Such tissue damage can then lead to severe fibrosis. For example, SARS disease, caused by the novel coronavirus SARS-CoV-2 (coronavirus disease 2019, or COVID-19), is known to often result in fibrosis.

[0109] The compounds of the present invention are particularly useful in the treatment of diseases or conditions where activation of the AT2 receptor is desired or required, but where inhibition of one or more CYP enzymes is undesirable.

[0110] In an alternative embodiment of the 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 or conditions in which activation of the AT2 receptor is desired or required, but inhibition of CYP enzymes is not desired.

[0111] By "diseases or conditions in which activation of the AT2 receptor is desired or required, but inhibition of a CYP is not desired," we include diseases or conditions known to be treatable by activation of the AT2 receptor, as described below, although existing treatments for such conditions may involve the administration of other therapeutic agents that are metabolized by CYPs. Thus, such diseases or conditions may include beneficial and / or desirable conditions in which inhibition of at least one CYP enzyme is not required, or conditions in which such inhibition would be harmful or detrimental to the patient.

[0112] The specific disease or condition that the activation of AT2 receptor is desired or required, but the inhibition of CYP enzyme is not desired is interstitial lung disease (for example, pulmonary fibrosis, IPF, systemic sclerosis and sarcoidosis), autoimmune disease (for example, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis and inflammatory bowel disease), chronic kidney disease (for example, diabetic nephropathy), pulmonary hypertension, pulmonary arterial hypertension and / or infarction (for example, myocardial infarction and stroke).Therefore, the compound of the present invention is particularly useful for treating interstitial lung disease such as IPF; autoimmune disease such as rheumatoid arthritis; chronic kidney disease such as diabetic nephropathy; pulmonary hypertension including pulmonary arterial hypertension; and / or infarction such as myocardial infarction.

[0113] According to a further aspect of the present invention, there is provided a method for treating diseases or conditions in which activation of the AT2 receptor is desired or required, but inhibition of CYP enzymes is not desired (such as pulmonary fibrosis, particularly IPF), which method comprises administering to a person suffering from the relevant condition a therapeutically effective amount of a compound of the invention.

[0114] The compounds of the invention are indicated for both the therapeutic, symptomatic and / or diagnostic treatment, and for the prophylactic treatment (thereby including the reduction and / or prevention and / or arrest of the worsening of symptoms) of any of the above conditions.

[0115] The compounds of the present invention are usually administered orally, intravenously, subcutaneously, buccally, rectally, cutaneously, intranasally, intratracheally, intrabronchially, by other parenteral routes, or via inhalation or pulmonary routes, or any combination thereof, in a pharmaceutically acceptable dosage form, in a solution, in a suspension, in an emulsion (including nanosuspension), or in a liposomal formulation. Additional administration methods include, but are not limited to, intraarterial, intramuscular, intraperitoneal, intraportal, intradermal, epidural, intrathecal administration, or any combination thereof.

[0116] In some embodiments, the compounds of the present invention can be administered singly (e.g., separately), and / or sequentially, and / or simultaneously in parallel (e.g., concurrently) using different routes of administration, but are preferably administered in known pharmaceutical formulations (including tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions, or emulsions for parenteral or intramuscular administration, or by inhalation, etc.). Administration by inhalation is preferably carried out using a nebulizer, for example, to deliver the compounds of the present invention to small lung tissue, including the alveoli and bronchioles, preferably without causing irritation or coughing in the treated subject.

[0117] Preferably, administration of a therapeutically effective amount of a compound of the invention is carried out by a combination of routes of administration, including via inhalation and orally, either separately (e.g., about 2 hours or more apart from each other), sequentially (e.g., within about 2 hours of each other), or simultaneously (e.g., concurrently), to achieve an effective dosage.

[0118] In some embodiments, methods are provided for treating diseases or conditions in which activation of the AT2 receptor is desirable or required (and such diseases or conditions in which inhibition of CYP enzymes is undesirable), including pulmonary fibrosis, particularly IPF, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention via a combination of routes of administration, either separately, sequentially, or simultaneously, preferably via inhalation and orally, to achieve a therapeutically effective amount or dosage.

[0119] Such combinations of routes of administration, preferably via inhalation and orally, can be presented as separate formulations of the compounds of the invention optimized for each route of administration.

[0120] Such formulations may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0121] Thus, according to a further aspect of the present invention there is provided a pharmaceutical formulation comprising a compound of the invention as defined above in admixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier.

[0122] The compounds of the present invention can be administered in combination with other AT2 agonists known in the art, such as C21, as well as in combination with AT1 receptor antagonists known in the art and / or in combination with inhibitors of angiotensin-converting enzyme (ACE). Non-limiting, but illustrative examples of AT1 receptor antagonists that can be used in accordance with the embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, pratosartan, lipiasartan, saprisartan, tasosartan, telmisartan, valsartan, and / or combinations thereof. Non-limiting, but illustrative examples of ACE inhibitors that may be used in accordance with embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, ceronapril, delepril, mouvertipril, and / or combinations thereof.

[0123] Other active ingredients that may be administered in combination with the compounds of the invention include cromoglycate disodium; endothelin receptor antagonists such as bosentan, ambrisentan, sitaxsentan, macitentan; PDE5 inhibitors such as sildenafil and tadalafil; prostacyclin (epoprostenol) and its analogs such as iloprost and treprostinil; other biologics including interferon gamma-1b, etanercept, infliximab, and adalimumab; and methotrexate. Additional active ingredients in development that may be co-administered with the compounds of the invention include pamrevlumab (anti-CTGF, Fibrogen), GLPG1690 (autotaxin inhibitor, Galapagos), TD139 (galectin-3 inhibitor, Galecto), PRM-151 (recombinant pentraxin-2, Promedior), BBT-877 (autotaxin inhibitor, Boehringer / Bridge), CC-90001 (JNK inhibitor, Celgene), PBI-4050 (dual GPR40 agonist / GPR84 antagonist, Prometic), BMS-986020 (lysophosphatidic acid receptor antagonist, BMS), RVT-1601 (mast cell stabilizer, Respirant), SMO4646 (wnt-signal inhibitor, United Therapeutics), KD25 (Rho-associated kinase inhibitor, Kadmon). Holdings), BG00011 (integrin antagonist, Biogen), PLN-74809 (integrin antagonist, Pilant Therapeutics), saracatinib (src kinase inhibitor, AstraZeneca), PAT-1251 (lysyl oxidase inhibitor 2, PharmaKeta), ABM-125 (IL-25MAB, Abeome), and TA5-115 (multikinase inhibitor, Otsuka).

[0124] In a further aspect of the invention, the compounds of the invention find particular utility when combined with other therapeutic agents in combination therapies to treat a variety of conditions, including those mentioned above. Because the compounds of the invention exhibit minimal CYP enzyme inhibition, such combinations are particularly advantageous when the other therapeutic agent used for use in the relevant condition is itself metabolized by a CYP enzyme.

[0125] Therefore, when the condition to be treated is interstitial lung disease, such as IPF, systemic sclerosis, or fibrotic diseases known in the art, the compounds of the present invention are preferably administered in combination with established therapies for such treatment, including but not limited to galectin-3 inhibitors, lysophosphatidic acid receptor 1 (LPA1) antagonists, autotaxin (ATX) inhibitors, recombinant human pentraxin-2 protein, or pirfenidone and / or nintedanib.Preferably, the combination of the compounds of the present invention is in combination with pirfenidone or its pharmaceutically acceptable salt, which is known to be metabolized by CYP enzymes, such as CYP1A.

[0126] Additionally, when the condition being treated is a chronic kidney-related disease, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatment, such as irbesartan and / or torsemide, which are metabolized by CYP enzymes such as CYP2C9.

[0127] When the condition being treated is pulmonary hypertension, the compounds of the invention are preferably administered in combination with one or more drugs also used in such treatment, such as selexipag and / or sildenafil, which are compounds known to be metabolized by CYP enzymes, such as CYP3A4.

[0128] When the condition to be treated or prevented is myocardial infarction and / or stroke-related disease, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatment, such as propranolol, warfarin, clopidogrel, atorvastatin, cilostazol, lidocaine and / or simvastatin, or pharmaceutically acceptable salts thereof, which are compounds known to be metabolized by CYP enzymes such as CYP1A, CYP2CP and / or CYP3A4.

[0129] When the condition being treated is an autoimmune disease such as rheumatoid arthritis, multiple sclerosis or psoriasis, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatments, including, but not limited to, steroidal anti-inflammatory drugs (NSAIDs) such as loxene, celecoxib, meloxicam or its analogues (e.g., piroxicam) or indomethacin, which are compounds known to be metabolized by CYP enzymes such as CYP1A, CYP2CP, CYP2C19 and / or CYP3A4; or drugs such as tizanidine, cyclophosphamide, cyclosporine, deflazacort and / or hydrocortisone, riluzole, or pharmaceutically acceptable salts thereof.

[0130] Therefore, the compounds of the present invention are particularly useful in treating diseases or conditions where AT2 receptor activation is desired or required, but CYP enzyme inhibition is not desired, and therefore can be administered in combination with one or more other therapeutic agents mentioned hereinabove, including pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, pirfenidone, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil and / or simvastatin, which are metabolized via CYP enzyme pathways and are useful, to treat diseases including those mentioned hereinabove. Most preferably, the compounds of the present invention are administered in combination with pirfenidone to treat interstitial lung diseases such as IPF.

[0131] When the compounds of the present invention are "combined" with other therapeutic agents as referred to in the specification above, the active ingredients may be administered together in the same formulation or separately (simultaneously or sequentially) in different formulations.

[0132] Such combination products provide for the administration of a compound of the invention in combination with another therapeutic agent, and therefore may be presented as separate formulations (at least one of which contains a compound of the invention and at least one of which contains the other therapeutic agent) or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation containing a compound of the invention and the other therapeutic agent).

[0133] therefore, (1) A pharmaceutical formulation comprising a compound of the present invention; a therapeutic agent selected from those listed above (e.g., one known to be metabolized by a CYP enzyme); and a pharmaceutically acceptable excipient (e.g., an adjuvant, diluent, or carrier), hereinafter referred to as a "combination formulation"; (2) Components: (A) a pharmaceutical formulation comprising a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier; and (B) a kit of parts comprising a pharmaceutical formulation comprising a therapeutic agent selected from those described above (e.g., known to be metabolized by a CYP enzyme) in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier; Components (A) and (B) are each provided in a form suitable for administration in combination with the other.

[0134] In a further aspect of the present invention, there is provided a process for the preparation of a combination preparation as defined herein above, which process comprises bringing into association a compound of the present invention, another anti-inflammatory agent, a therapeutic agent, with at least one (e.g., pharmaceutically acceptable) excipient.

[0135] In a further aspect of the present invention, there is provided a process for preparing a kit-of-parts as defined herein above, comprising associating components (A) and (B). As used herein, reference to associating means making the two components suitable for administration together.

[0136] Thus, by "associating" two components with each other, with respect to the process for the preparation of a kit-of-parts as defined herein above, we mean that the two components of the kit-of-parts: (i) may be provided as separate formulations (i.e., independently of each other) and then combined for use in conjunction with each other in combination therapy; or (ii) may be packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

[0137] therefore, (I) one of components (A) and (B) as defined herein, (II) A kit of parts is further provided, comprising the two components together with instructions for using the component in combination with the other of the two components.

[0138] Depending on the patient being treated and the route of administration, the compounds of the present invention may be administered in various dosages. While dosages will vary from patient to patient, a suitable daily dose will range from about 0.1 to about 1000 mg per patient (e.g., 0.1, 0.5, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 mg, etc., or any range or value therein), administered in single or multiple doses. A more preferred daily dose is in the range of about 0.1 to about 250 mg per patient (e.g., 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 44.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 mg, etc., or any range or value therein). A particularly preferred daily dose ranges from about 0.3 to about 100 mg per patient.

[0139] Individual doses of the compounds of the invention can range from about 0.1 to about 100 mg (e.g., 0.3, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg, etc., or any range or value therein).

[0140] In any event, a physician or person skilled in the art will be able to determine the actual dosage that will be most suitable for an individual patient, which will likely vary depending on the route of administration, the type and severity of the condition being treated, and the species, age, weight, sex, renal function, hepatic function, and response of the particular patient being treated. The dosages set forth above are exemplary of the average case, and there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

[0141] The advantage of using the compounds of the present invention separately and / or sequentially and / or simultaneously in parallel, preferably via a combination of administration routes, is to create a tailored treatment for the patient in need of treatment that may prevent and / or reduce side effects, and also to tailor the correct dosage level of a therapeutically effective amount of the compounds of the present invention.

[0142] The kits of parts described herein may contain two or more formulations containing suitable amounts / doses of a compound of the invention and / or two or more formulations containing suitable amounts / doses of another therapeutic agent to provide for repeated administration. When two or more formulations (containing any of the active compounds) are present, such formulations may be the same or different with respect to the dosage, chemical composition, and / or physical form of any of the compounds.

[0143] With respect to the kits of parts described herein, by "administration in combination with," we include sequential, separate, and / or simultaneous administration of each formulation containing a compound of the invention and another therapeutic agent over the course of treatment of the relevant condition.

[0144] Thus, with respect to a combination product according to the invention, the term "administration in combination with" includes administration of the two components of the combination product (a compound of the invention and another therapeutic agent) either together or sufficiently closely in time (optionally repeatedly) so as to allow a greater beneficial effect to the patient over the course of treatment of the relevant conditions than would occur if, over the same course of treatment, either a formulation comprising the compound of the invention or a formulation comprising the other agent were administered alone (optionally repeatedly) without the other component. Determining whether a combination provides a greater beneficial effect with respect to the treatment of a particular condition, and over the course of treatment, will depend on the condition being treated or prevented, but can be routinely accomplished by one of ordinary skill in the art.

[0145] Furthermore, in the context of the kit-of-parts according to the invention, the term "in combination with" includes that one or the other of the two formulations may be administered before, after, and / or simultaneously (optionally repeatedly) with the administration of the other component. When used in this context, the terms "co-administered" and "administered simultaneously with" include administration of individual doses of the relevant compound of the invention and the other anti-inflammatory agent within 48 hours (e.g., 24 hours) of each other.

[0146] The pharmaceutical compositions / formulations, combination products, and kits described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0147] Thus, in a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition / formulation as defined herein above, which process comprises combining a compound of the present invention as defined herein above with one or more pharmaceutically acceptable excipients (e.g. adjuvants, diluents and / or carriers).

[0148] In a further aspect of the present invention, there is provided a process for the preparation of a combination product or kit-of-parts as defined herein above, which process comprises combining a compound of the present invention as defined herein above with other therapeutic agents useful in the treatment of the relevant disease or disorder, and at least one pharmaceutically acceptable excipient.

[0149] Subjects suitable for treatment with the formulations of the present invention include, but are not limited to, mammalian subjects, particularly human subjects.

[0150] When used herein in reference to a particular value (such as an amount), the term "about" (or similar terms such as "approximately") is understood to indicate that such value may vary by up to 10% (particularly up to 5%, e.g., up to 1%) of the defined value. In each case, it is contemplated that such terms may be replaced with the notation "±10%" or the like (or by indicating a variation of a particular amount calculated based on the relevant value). It is also contemplated that in each case, such terms may be omitted.

[0151] The compounds of the present invention have the advantage that they are potent and / or stable to metabolic hydrolysis and / or do not inhibit the CYP enzymes described herein above.

[0152] The compounds described herein, whether for use in the treatment of IPF or otherwise, may have the advantage that they may be more effective, less toxic, longer acting, more potent, have fewer side effects, be more readily absorbed, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or possess other useful pharmacological, physical, or chemical properties than compounds known in the prior art. Such effects may be assessed clinically, objectively, and / or subjectively by a medical professional, a treated subject, or an observer. [Example]

[0153] The present invention is further illustrated by reference to the following examples, which are not intended to limit the scope of the invention.

[0154] In case of discrepancy between the nomenclature and any compound depicted in the figures, the latter takes precedence (unless it contradicts any experimental details that may be given or is clear from the context).

[0155] Experimental procedure The starting materials and intermediates used in the synthesis of the compounds described herein are either commercially available or can be prepared by methods described herein or known in the art.

[0156] Experiments were generally carried out under an inert atmosphere (nitrogen or argon), especially when oxygen- or moisture-sensitive reagents or intermediates were used.

[0157] Mass spectrometry data are reported from liquid chromatography-mass spectrometry (LC-MS) using electrospray ionization. Chemical shifts for NMR data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvents used.

[0158] For syntheses that refer to general procedures, reaction conditions (such as reaction length or temperature) may vary. Reactions were generally followed by thin layer chromatography or LC-MS and workup as needed. Purification may vary between experiments. In general, the solvents and solvent ratios used for eluents / gradients are determined by appropriate R f and / or retention times were selected to provide. Some products were purified using supercritical fluid chromatography, e.g., on a reverse-phase column using a solvent combination with mobile phase A: CO and mobile phase B: MeOH / H2O / NH3.

[0159] Compounds of the Invention The compounds were prepared according to the following synthetic scheme, which shows the synthesis of 1-benzyl-3-[[5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonyl]urea (Example 1). [ka]

[0160] Example 1 Benzyl-3-[[5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonyl]urea (a) N-tert-butyl-5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]phenyl]thiophene-2-sulfonamide 1-[(4-Bromophenyl)methyl]-2-methyl-imidazole (1.25 g; 5 mmol, prepared using a procedure similar to that described in the literature for 1-[(4-bromophenyl)methyl]-2-methyl-imidazole (see International Patent Application No. 2002 / 096883)), 5-isobutyl-2-(tert-butylaminosulfonyl)-3-thiopheneboronic acid (1.59 g; 5 mmol; prepared as described in International Patent Application No. 2002 / 096883), KCO (2.06 g; 15 mmol), and Pd(PPh) (144 mg; 120 μmol) were added to dioxane (100 mL) and water (10 mL). The mixture was heated to 95 °C overnight under a nitrogen atmosphere. Most of the solvent was evaporated. Water (50 mL) was added, and the product was extracted with diethyl ether (2 × 50 mL). After drying and evaporation, the isolated subtitle compound was used directly in the next step.

[0161] (b) 5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]phenyl]thiophene-2-sulfonamide The subtitle compound from (a) above (1.36 g) was dissolved in DCM (30 mL). Boron trichloride (15 mL, 1 M in DCM) was added and the solution was stirred at room temperature for 2 hours. Na2CO3 (saturated, 20 mL) was added and the product was extracted with EtOAc (40 mL). After drying and evaporation, the isolated subtitle compound was used directly in the next step.

[0162] (c) butyl N-[[5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonyl]-carbamate The subtitle compound from (b) above (1.2 g) and N-ethyldiisopropylamine (2.57 g; 20 mmol) were dissolved in DCM. Butyl chloroformate (2.04 g; 15 mmol) was added slowly at room temperature. After 1 h, water was added and the product was extracted with diethyl ether. Chromatography from DCM-MeOH (90:10) was performed. The amount of the isolated subtitle compound was 1.05 g (43% yield for three reaction steps). 1 H-NMR(CDCl3):0.85(t,3H),0.99(d,6H),1.24(m,2H),1.48(m,2H),1.94(m,1H),2.54(s,3H) ),2.69(d,2H),3.99(t,2H),5.11(s,2H),6.72(s,1H),6.81(m,2H),7.07(d,2H),7.60(d,2H) MS(M+H + ):Experiment 490.1824 Calculation 490.1834.

[0163] (d) 1-benzyl-3-[[5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonyl]-urea The subtitle compound from step (c) above (116 mg, 237 μmol) and benzylamine (76 mg; 711 μmol) were dissolved in toluene. The reaction was heated and maintained at 100° C. under a nitrogen atmosphere for 3 hours. The solvent was evaporated. The title product was purified using supercritical fluid chromatography in 51 mg (41%) yield. 1H-NMR(CDCl3):0.95(d,6H),1.87(m,1H),2.31(s,3H),2.63(d,2H),4.20(s,2H),5.04 (s,2H),6.67(s,1H),6.83(NH,1H),6.87-6.95(m,4H),7.12-7.23(m,5H),7.42(d,2H). MS(M+H + ): Experiment 523.1818 Calculation 523.1838.

[0164] Example 2 p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea The title compound was prepared as described in Example 1, using 2-aminomethylpyridine in the final step. 1 H-NMR(CDCl3):0.96(d,6H),1.91(m,1H),2.66(d,2H),2.74(s,3H),4.70(s,2H),5.37(s,2H),6.73(s,1H) ,7.21(s,1H),7.28(d,2H),7.41(s,1H),7.53(d,2H),7.76(m,1H),7.89(m,1H),8.30(m,1H),8.70(m,1H). MS(M+H + ): Experiment 524.1774 Calculation 524.1790.

[0165] Example 3 p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)-urea The title compound was prepared as described in Example 1, using 3,3,3-trifluoropropylamine in the final step. MS(M+H + ): Experiment 529.1552 Calculation 529.1555.

[0166] Example 4 1-Butyl-3-(5-isobutyl-3-{p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)-urea The title compound was prepared as described in Example 1, using 1-aminobutane in the final step. MS(M+H + ):Experiment 489.1999 Calculation 489.2078.

[0167] Example 5 p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)-1-(4,4,4-trifluorobutyl)-urea The title compound was prepared as described in Example 1 using 4,4,4-trifluorobutyl-amine in the final step. 1 H-NMR(CDCl3):0.95(d,6H),1.61(m,2H),1.86-2.02(m,3H),2.56(s,3H),2.65 (d,2H),3.11(m,2H),6.70(s,2H),7.05(b,1H),7.11-7.13(b,3H),7.50(d,2H). MS(M+H + ): Experiment 543.1727 Calculation 543.1711.

[0168] Example 6 1-benzyl-3-(3-{p-[(2-ethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-urea The title compound was prepared as described in Example 1, except that 1-[(4-bromophenyl)methyl]-2-ethyl-imidazole was used in the first step (prepared using a procedure similar to that described in the literature for 1-[(4-bromophenyl)methyl]-2-methyl-imidazole (see, for example, International Patent Application No. 2002 / 096883)). MS(M+H + ): Experiment 537.1996 Calculation 537.1994.

[0169] Example 7 p-[(2-ethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(2-methoxy-ethyl)urea The title compound was prepared as described in Example 1 using 1-[(4-bromophenyl)-methyl]-2-ethyl-imidazole in the first step and 2-methoxyethylamine in the last step. 1 H-NMR(CDCl3):0.96(d,6H),1.38(t,3H),1.91(m,1H),1.67(d,2H),3.06(q,2H),3.25-3.30 (b,2H),3.28(s,3H),3.36(t,2H),5.25(s,2H),6.71(s,1H),7.15-7.30(b,4H),7.54(d,2H). MS(M+H + ): Experiment 505.1973 Calculation 505.1943.

[0170] Example 8 p-[(2,4-dimethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea The title compound was prepared as described in Example 1 using 1-[(4-bromophenyl)-methyl]-2,4-dimethyl-imidazole in the first step (prepared using a procedure similar to that in the literature for 1-[(4-bromophenyl)methyl]-2-methyl-imidazole (see, for example, WO 2002 / 096883)) and 2-methoxyethylamine in the last step. 1 H-NMR(CDCl3):0.93(d,6H),1.86(m,1H),2.09-2.21(b,2H),2.15(s,3H),2.42(s,3H),2. 61(d,2H),3.20(m,2H),5.08(s,2H),6.65(s,1H),6.79(s,1H),7.03(d,2H),7.48(d,2H). MS(M+H + ):Experiment 543.1707 Calculation 543.1711.

[0171] Example 9 3-(3-{p-[(2-ethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea The title compound was prepared as described in Example 1 using 1-[(4-bromophenyl)methyl]-2-ethyl-imidazole in the first step and 2-aminomethylpyridine in the last step. The amount of title compound isolated was 45 mg (21%). 1 H-NMR(CDCl3):0.93(q,6H).1.18(t,3H),1.87(m,1H),2.62(d,2H),2,69(q,2H),4.35(d,2H),5,07( s,2H),6.67(s,1H),6.95(m,4H),7.10(m,1H),7.16(d,1H),7.49(d,2H),7.55(td,1H),8.40(d,1H). MS(M+H + ): Experiment 538.2

[0172] Example 10 1-benzyl-3-(3-{p-[(2,4-dimethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)urea The title compound was prepared as described in Example 1 using 1-[(4-bromophenyl)-methyl]-2,4-dimethyl-imidazole in the first step. The amount of title compound isolated was 34 mg (26%). 1 H-NMR(CDCl3):0.95(d,6H),1.87(m,1H),2.09(s,3H),2.29(s,3H),2.62(d,2H),4.21(d,2 H),4.95(s,2H),6.62(s,1H),6.67(s,1H),6.94(d,2H),7.10-7.25(m,5H),7.45(d,2H).). MS(M+H + ): Experiment 537.3

[0173] Example 11 3-(3-{p-[(2,4-dimethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea The title compound was prepared as described in Example 1 using 1-[(4-bromophenyl)-methyl]-2,4-dimethyl-imidazole in the first step and 2-aminomethylpyridine in the last step. The amount of title compound isolated was 12 mg (7%). 1 H-NMR(CDCl3):0.94(d,6H),1.87(m,1H),2.10(s,3H),2.31(s,3H),2.61(d,2H),4.36(d,2H) ,4.97(s,2H),6.63(s,1H),6.68(s,1H),6.99(d,2H),7.11(m,2H),7.53(m,3H),8.42(d,1H). MS(M+H + ): Experiment 538.2

[0174] Example 12 1-benzyl-3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)urea The title compound was prepared as described in Example 1 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step (prepared using a procedure similar to that described in the literature for 1-[(4-bromophenyl)methyl]-2-methyl-imidazole (see, for example, WO 2002 / 096883)). The amount of title compound isolated was 20 mg (24%). 1 H-NMR(CDCl3):0.98(d,6H),1.90(m,1H),2.66(d,2H),4.30(d,2H),5.05(s,2H),6.71(s, 1H),6.77(s,1H),6.86(s,1H),6.91(t,1H),7,13(m,2H),7.22-7.28(m,4H),7.32(d,1H). MS(M+H + ): Experiment 541.2

[0175] Example 13 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea The title compound was prepared as described in Example 1 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and 2-aminomethylpyridine in the last step. The amount of title compound isolated was 24 mg (31%). 1 H-NMR(CDCl3):0.94(d,6H),1.88(m,1H),2.43(s,3H),2.63(d,2H),4.41(d,2H),5.05(s,2H),6.67 (s,1H),6.87-6.95(m,3H),7.10(m,1H),7.16(d,1H),7.28-7.38(m,2H),7.56(t,1H),8.42(d,1H). MS(M+H + ): Experiment 542.2

[0176] Example 14 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea The title compound was prepared as described in Example 1 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and 3,3,3-trifluoropropylamine in the last step. The amount of title compound isolated was 15 mg (21%). 1 H-NMR(CDCl3):0.98(d,6H),1.92(m,1H),2.49(m,2H),2.67(d,2H),3.34(m,2H),5.10 (s,2H),6.71(s,1H),6.85(s,1H),6.93(s,1H),7.01(m,1H),7.30(m,1H),7.38(d,1H). MS(M+H +): Experiment 547.2

[0177] Example 15 1-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-3-[(1-methyl-1H-imidazol-2-yl)methyl]urea The title compound was prepared as described in Example 1 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and (1-methyl-1H-imidazol-2-yl)methylamine in the last step. The amount of title compound isolated was 69 mg (50%). MS(M+H + ): Experiment 545.2

[0178] Example 16 1-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-3-[2-(1H-imidazol-4-yl)ethyl]urea The title compound was prepared as described in Example 1 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and histamine in the last step. The amount of title compound isolated was 52 mg (47%). MS(M+H + ): Experiment 545.2

[0179] Example 17 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-methyl-1-[(2-pyridyl)methyl]urea The title compound was prepared as described in Example 1 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and N-methyl-N-(2-pyridylmethyl)amine in the last step. The amount of title compound isolated was 17 mg (16%). 1 H-NMR(CDCl3):0.96(d,6H),1.89(m,1H),2.45(s,3H),2.64(d,2H),2.91(s,3H),4.38(s,2H),5.10 (s,2H),6.65(s,1H),6.65-6.75(b,2H),7.00-7.25(b,3H),7.43(m,2H),7.60(m,1H),8.41(m,1H). MS(M+H + ): Experiment 556.2

[0180] Example 18 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(4,4,4-trifluorobutyl)urea The title compound was prepared as described in Example 1 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and 4,4,4-trifluorobutylamine in the last step. The amount of title compound isolated was 8 mg (12%). 1 H-NMR(CDCl3):0.96(d,6H),1.64(m,2H),1.82-2.02(m,3H),2.51(s,3H),2.65(d,2H),3.15(m, 2H),5.10(s,2H),6.70(s,1H),6.88(s,1H),6.96(s,1H),7.01(t,1H),7.28(d,1H),7.38(d,1H). MS(M+H + ): Experiment 561.2

[0181] Example 19 3-(5-isobutyl-3-{5-[(2-methyl-1H-imidazol-1-yl)methyl]-2-pyridyl}-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea The title compound was prepared as described in Example 1 using 2-bromo-5-[(2-methylimidazol-1-yl)methyl]pyridine in the first step (prepared using a procedure similar to that described in the literature for 1-[(4-bromophenyl)methyl]-2-methyl-imidazole (see, for example, International Patent Application No. 2002 / 096883)) and 3,3,3-trifluoropropylamine in the last step. The amount of title compound isolated was 11 mg (15%). MS(M+H + ): Experiment 530.2

[0182] Example 20 3-(5-Isobutyl-3-{2-[(2-methyl-1H-imidazol-1-yl)methyl]-5-pyrimidinyl}-2-thienylsulfonyl)-1-(2-methoxyethyl)urea The title compound was prepared as described in Example 1 using 5-bromo-2-[(2-methylimidazol-1-yl)methyl]pyrimidine in the first step (prepared using a procedure similar to that described in the literature for 1-[(4-bromophenyl)methyl]-2-methyl-imidazole (see, for example, International Patent Application No. 2002 / 096883)) and 2-methoxymethylamine in the last step. The amount of title compound isolated was 15 mg (17%). 1 H-NMR(CDCl3):0.97(d,6H),1.90(m,1H),2.51(s,3H),2.67(d,2H),3.29(m,5H) ,3.37(t,2H),5.37(s,2H),6.69(s,1H),7.06(s,1H),7.13(s,1H),8.90(s,2H). MS(M+H + ): Experiment 493.2

[0183] Example 21 3-(5-isobutyl-3-{2-[(2-methyl-1H-imidazol-1-yl)methyl]-5-pyrimidinyl}-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea The title compound was prepared as described in Example 1 using 5-bromo-2-[(2-methylimidazol-1-yl)methyl]pyrimidine in the first step and 3,3,3-trifluoropropylamine in the last step. The amount of title compound isolated was 43 mg (46%). MS(M+H + ): Experiment 531.2

[0184] Example 22 3-(5-Isobutyl-3-{2-[(2-methyl-1H-imidazol-1-yl)methyl]-5-pyrimidinyl}-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea The title compound was prepared as described in Example 1 using 5-bromo-2-[(2-methylimidazol-1-yl)methyl]pyrimidine in the first step and 2-aminomethylpyrimidine in the last step. The amount of title compound isolated was 61 mg (32%). 1 H-NMR(CD3OD):0.98(d,6H),1.91(m,1H),2.39(s,3H),2.69(d,2H),4.30(s,2H),5.37 (s,2H),6.84(m,2H),7.08(s,1H),7.23(m,2H),7.71(m,1H),8.39(m,1H),9.02(s,2H). MS(M+H + ): Experiment 526.2

[0185] Example 23 1-[(3,5-difluorophenyl)methyl]-3-(5-isobutyl-3-{5-[(2-methyl-1H-imidazol-1-yl)methyl]-2-pyridyl}-2-thienylsulfonyl)urea The title compound was prepared as described in Example 1 using 5-bromo-2-[(2-methylimidazol-1-yl)methyl]pyrimidine in the first step and 3,5-difluorobenzylamine in the last step. The amount of title compound isolated was 26 mg (42%). 1H-NMR(CDCl3):1.02(d,6H),1.97(m,1H),2.39(s,3H),2.74(d,2H),4.46(s,2H),5.16(s,2H),6.70 (t,1H),6.79(d,2H),6.89(s,1H),7.03(s,1H),7.10(s,1H),7.40(m,1H),7.61(m,1H),8.61(m,1H). MS(M+H + ): Experiment 560.2

[0186] Example 24 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(2-methoxyethyl)urea The title compound was prepared as described in Example 1 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and 2-methoxyethylamine in the last step. The amount of title compound isolated was 2 mg (3%). 1 H-NMR(CDCl3):1.00(d,6H),1.94(m,1H),2.48(s,3H),2.69(d,2H),3.31(m,5H),3.38(t,2H) ,5.12(s,2H),6.72(s,1H),6.88(s,1H),6.93(s,1H),6.98(t,1H),7.33(d,1H),7.37(d,1H). MS(M+H + ): Experiment 509.2

[0187] Example 25 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[1-(2-pyridyl)ethyl]urea The title compound was prepared as described in Example 1 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and 1-pyridin-2-yl-ethylamine in the last step. The amount of title compound isolated was 6 mg (9%). 1 H-NMR(CDCl3):0.97(d,6H),1.40(d,3H),1.90(m,1H),2.43(s,3H),2.66(d,2H),4.94(m,1H),5.06(s,2H),6.71(s, 1H),6.81(s,1H),6.87(s,1H),6.92(t,1H),7.13-7.19(m,2H),7.31(d,1H),7.36(d,1H),7.60(t,1H),8.50(d,1H). MS(M+H + ): Experiment 556.2

[0188] Example 26 3-(3-{2-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea The title compound was prepared as described in Example 1 using 1-[(4-bromo-3-fluorophenyl)methyl]-2-methyl-imidazole in the first step (prepared using a procedure similar to that described in the literature for 1-[(4-bromophenyl)methyl]-2-methyl-imidazole (see, for example, International Patent Application No. 2002 / 096883)) and 3,3,3-trifluoropropylamine in the last step. The amount of title compound isolated was 7 mg (6%). 1 H-NMR(CDCl3):1.01(d,6H),1.96(m,1H),2.31(m,2H),2.63(s,3H),2.73(d,2H),3.41 (q,2H),5.25(s,2H),6.75(s,1H),6.95(m,2H),7.13(d,1H),7.26(d,1H),7.49(t,1H). MS(M+H + ): Experiment 547

[0189] Example 27 3-(3-{2-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(2,2,2-trifluoroethyl)urea The title compound was prepared as described in Example 1 using 1-[(4-bromo-3-fluorophenyl)methyl]-2-methyl-imidazole in the first step and 2,2,2-trifluoroethylamine in the last step. The amount of title compound isolated was 7 mg (5%). 1 H-NMR(CDCl3):1.01(d,6H),1.96(m,1H),2.62(s,3H),2.73(d,2H),3.80(m,2H),5 .25(s,2H),6.75(s,1H),6.92-6.97(m,2H),7.14(d,1H),7.26(d,1H),7.48(t,1H). MS(M+H + ): Experiment 533

[0190] Example 28 1-(3-fluoropropyl)-3-(5-isobutyl-3-{p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)urea The title compound was prepared as described in Example 1, using 3-fluoropropylamine hydrochloride in the final step. The amount of title compound isolated was 55 mg (26%). 1 H-NMR(CDCl3):1.01(d,6H),1.84(dp,2H),1.96(m,1H),2.67(s,3H),2.72(d,2H),3.25(q,2H) ,4.41(dt,2H),5.25(s,2H),6.77(s,1H),7.11(d,1H),7.21(d,2H),7.26(d,1H),7.57(d,2H). MS(M+H + ): Experiment 493

[0191] Example 29 1-(3,3-Difluoropropyl)-3-(5-isobutyl-3-{p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)urea The title compound was prepared as described in Example 1, using 3,3-difluoropropylamine hydrochloride in the final step. 1 H-NMR(CDCl3):1.01(d,6H),1.91-2.03(m,3H),2.56(s,3H),2.72(d,2H),3.28(q,2H),5. 20(s,2H),5.77(tt,2H),6.77(s,1H),7.06(s,1H),7.08(s,1H),7.17(d,2H),7.55(d,2H).

[0192] Example 30 1-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(3,3,3-trifluoropropyl)urea trifluoroacetic acid (a) N-tert-butyl-3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophene-2-sulfonamide 5-Isobutyl-2-(tert-butylaminosulfonyl)-3-thiopheneboronic acid (803 mg; 2.5 mmol), 1-[(4-bromo-2-fluorophenyl)methyl]-2-ethyl-imidazole (712 mg; 2.5 mmol; prepared using a procedure similar to that described in the literature for 1-[(4-bromophenyl)methyl]-2-methyl-imidazole (see, for example, International Patent Application No. 2002 / 096883), K2CO3 (1.04 g; 7.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (184 mg; 0.25 mmol) were added to dioxane (10 mL) and water (3 mL). The mixture was thoroughly degassed (by bubbling argon through the stirred suspension), vigorously stirred, and heated at 80 °C for 2 h. After cooling to room temperature, water was added and the crude product was extracted with EtOAc. After drying and evaporation, the crude product was purified on silica gel (Autoflash, Biotage Sfar Silica, 60 μm, 25 g). The mobile phases were DCM and DCM / MeOH / NH3 (28%) = 100 / 10 / 1. The gradient of the latter mobile phase was 5-60%. The amount of the isolated subtitle compound was 760 mg (63%). 1 H-NMR(400MHz,DMSO-d6)δ 7.45(m,2H),7.36(d,J=7.9Hz,1H),7.09(s,1H),7.03(t,J=8.1Hz,1H),6.97(s,1H),6.80(s,1H),5.23(s,2H),2.68(d,J= 7.0Hz,2H),2.60(q,J=7.5Hz,2H),1.87(dt,J=13.0,6.6Hz,1H),1.16(t,J=7.1Hz,3H),0.96(s,9H),0.92(d,J=6.6Hz,6H).

[0193] (b) 3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophene-2-sulfonamide The sub-compound (a) (760 mg; 1.6 mmol), triethylsilane (1.5 mL), and TFA (10 mL) were added to DCM (10 mL) and stirred overnight at 43 °C. The mixture was evaporated to give a brown oil. NaHCO3 (saturated, 25 mL) was added, and the crude product was extracted with EtOAc (250 mL). After drying and evaporation, the crude product was purified on silica gel (Autoflash, Biotage Sfar Silica, 60 μm, 25 g). The mobile phase was DCM and DCM / MeOH / NH3 (28%) = 100 / 10 / 1. The gradient of the latter mobile phase was 5-50%. The amount of the isolated sub-title compound was 420 mg (62%). 1 H-NMR(400MHz,DMSO-d6)δ 7.66(s,2H),7.49(d,J=11.4Hz,1H),7.38(d,J=8.0Hz,1H),7.10(s,1H),7.00(t,J=8.0Hz,1H),6.96(s,1H),6.81(s,1H),5.2 3(s,2H),2.68(d,J=7.0Hz,2H),2.62(q,J=7.5Hz,2H),1.87(dt,J=13.6,6.7Hz,1H),1.19-1.15(m,3H),0.93(d,J=6.6Hz,6H).

[0194] (c) Ethyl N-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]carbamate The subtitle compound from (b) above (0.46 g; 1.1 mmol), ethyl chloroformate (0.12 g; 1.1 mmol), and triethylamine (0.22 g; 2.2 mmol) were mixed in 40 ml of DCM at 0° C. and stirred for 1 h. Water was added and the solvent was removed under reduced pressure. The amount of the subtitle compound isolated was 0.69 g (100%). HPLC purity (220 nm): 95%. 1 H-NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 12.1 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.08-7.02 (m, 2H), 6.84 (s, 1H), 5.29 (s, 2H), 3.71 (q, J = 7.1 Hz, 2H), 2.75 (q, J = 7.5 Hz, 2H), 2.61 (d, J = 7.0 Hz, 2H), 1.84 (dp, J = 13.5, 6.7 Hz, 1H), 1.19 (t, J = 7.3 Hz, 3H, overlap with triethylamine), 0.99 (t, J = 7.1 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H). Contains approximately 2 equivalents of triethylamine. MS(M+H + ):Experiment 494 Calculation 494.

[0195] (d) 1-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(3,3,3-trifluoropropyl)urea trifluoroacetic acid The subtitle compound from step (c) above (47 mg; 75 μmol), triethylamine (15 mg; 150 μmol), and 3,3,3-trifluoropropylamine hydrochloride (12 mg; 82 μmol) were added to dioxane (1 ml) and stirred at 90° C. overnight. The mixture was diluted with water and acetonitrile, acidified with TFA, and purified by reverse-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, gradient over 12 min, 25 ml / min). The amount of the title compound isolated was 41 mg (81%). HPLC purity (220 nm): >95%. 1 H-NMR(400MHz,DMSO-d6)δ 7.69-7.63(m,2H),7.47(d,J=11.3Hz,1H),7.40-7.36(m,2H),6.95(s,1 H),6.56(t,J=5.7Hz,1H),5.52(s,2H),3.19(q,J=6.6Hz,2H),3.01(q,J= 7.5Hz,2H),2.72(d,J=7.0Hz,2H),2.32(tq,J=11.5,6.8,5.7Hz,2H),1.88(dp,J=13.5,6.7Hz,1H),1.24(t,J=7.5Hz,3H),0.93(d,J=6.6Hz,6H). MS(M+H + ):Experiment 561 Calculation 561.

[0196] Example 31 1-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(2-methoxyethyl)urea trifluoroacetic acid The title compound was prepared as described in Example 30, using 2-methoxyethylamine in the final step. The amount of title compound isolated was 34 mg (71%). HPLC purity (220 nm): >95%. 1H-NMR(400MHz,DMSO-d6)δ 7.68-7.64(m,2H),7.48(d,J=11.2Hz,1H),7.41-7.37(m,2H),6.95(s,1 H),6.34(t,J=5.1Hz,1H),5.52(s,2H),3.25(t,J=5.5Hz,2H),3.21(s,3H ),3.09(q,J=5.4Hz,2H),3.01(q,J=7.5Hz,2H),2.72(d,J=7.0Hz,2H),1.89(dp,J=13.5,6.6Hz,1H),1.24(t,J=7.5Hz,3H),0.93(d,J=6.6Hz,6H). MS(M+H + ):Experiment 523 Calculation 523.

[0197] Example 32 3-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-1-[(4-fluorophenyl)methyl]urea trifluoroacetic acid The title compound was prepared as described in Example 30, using 4-fluorobenzylamine in the final step. The amount of title compound isolated was 36 mg (70%). HPLC purity (220 nm): >95%. 1 H-NMR(400MHz,DMSO-d6)δ 7.66-7.60(m,2H),7.48(d,J=11.2Hz,1H),7.42-7.36(m,2H),7.17-7.07(m,4H),6.96(s,1H),6.85(t,J=5.8Hz,1H),5.51(s,2H),4.12( d,J=5.9Hz,2H),2.98(q,J=7.5Hz,2H),2.71(d,J=7.0Hz,2H),1.87(dp,J=13.3,6.5Hz,1H),1.21(t,J=7.5Hz,3H),0.93(d,J=6.6Hz,6H). MS(M+H + ):Experiment 573 Calculation 573.

[0198] Example 33 1-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-propylurea trifluoroacetic acid The title compound was prepared as described in Example 30, using propylamine in the final step. The amount of title compound isolated was 33 mg (71%). HPLC purity (220 nm): >95%. 1 H-NMR(400MHz,DMSO-d6)δ 7.66-7.63(m,2H),7.47(d,J=11.3Hz,1H),7.41-7.36(m,2H),6.95(s,1H),6.31(t,J=5.5Hz,1H),5.51(s,2H),3.00(q,J=7.5Hz,2H),2. 88(q,J=6.6Hz,2H),2.72(d,J=7.0Hz,2H),1.88(dp,J=13.4,6.7Hz,1H),1.33-1.21(m,5H),0.93(d,J=6.6Hz,6H),0.73(t,J=7.4Hz,3H). MS(M+H + ):Experiment 507 Calculation 507.

[0199] Example 34 1-[(3,4-difluorophenyl)methyl]-3-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]urea trifluoroacetic acid The title compound was prepared as described in Example 30 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and 3,4-difluorobenzylamine in the last step. The amount of title compound isolated was 27 mg (39%). HPLC purity (220 nm): >95%. 1H-NMR(400MHz,DMSO-d6)δ 7.62-7.60(m,2H),7.46(d,J=11.1Hz,1H),7.43-7.30(m,3H),7.17-7.09(m,1H),7.00(t,J=6.0Hz,1H),6.98-6.93(m,2H), 5.48(s,2H),4.12(d,J=5.9Hz,2H),2.71(d,J=7.0Hz,2H),2.60(s,3H),1.87(dp,J=13.4,6.7Hz,1H),0.92(d,J=6.6Hz,6H). MS(M+H + ):Experiment 577 Calculation 577.

[0200] Example 35 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-[(thiophen-2-yl)methyl]urea trifluoroacetic acid The title compound was prepared as described in Example 30 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and 2-aminomethylthiophene in the last step. The amount of title compound isolated was 40 mg (60%). HPLC purity (220 nm): >95%. 1 H-NMR(400MHz,DMSO-d6)δ 10.98(s,1H),7.63-7.60(m,2H),7.45(d,J=11.1Hz,1H),7.40-7.33(m,3H),6.95(s,1H),6.94-6.84(m,3H),5.48(s ,2H),4.30(d,J=5.8Hz,2H),2.72(d,J=7.0Hz,2H),2.60(s,3H),1.88(dp,J=13.4,6.5Hz,1H),0.94(d,J=6.6Hz,6H). MS(M+H + ):Experiment 547 Calculation 547.

[0201] Example 36 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-propylurea trifluoroacetic acid The title compound was prepared as described in Example 30 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and propylamine in the last step. The amount of title compound isolated was 33 mg (54%). HPLC purity (220 nm): >95%. 1 H-NMR(400MHz,DMSO-d6)δ 10.72(s,1H),7.65-7.61(m,2H),7.49-7.35(m,3H),6.95(s,1H),6.31(t,J=5.4Hz,1H),5.49(s,2H),2.87(q,J=6.6Hz,2H),2.72 (d,J=7.0Hz,2H),2.63(s,3H),1.88(dp,J=13.4,6.7Hz,1H),1.28(h,J=7.2Hz,2H),0.93(d,J=6.6Hz,6H),0.72(t,J=7.4Hz,3H). MS(M+H + ):Experiment 493 Calculation 493.

[0202] Example 37 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(3,3,3-trifluoropropyl)urea trifluoroacetic acid The title compound was prepared as described in Example 30 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and 3,3,3-trifluoropropylamine hydrochloride in the last step. The amount of title compound isolated was 22 mg (67%). HPLC purity (220 nm): >95%. 1H-NMR(400MHz,DMSO-d6)δ 7.65-7.60(m,2H),7.49-7.36(m,3H),6.95(s,1H),6.44(t,J=6.0Hz,1H),5.49(s,2H),3.20(q,J=6.5Hz,2H),2.72( d,J=7.0Hz,2H),2.62(s,3H),2.32(tq,J=11.9,7.1,5.9Hz,2H),1.88(dt,J=13.4,6.9Hz,1H),0.93(d,J=6.6Hz,6H). MS(M+H + ):Experiment 547 Calculation 547.

[0203] Example 38 1-[(4-chloropyridin-2-yl)methyl]-3-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]urea trifluoroacetic acid The title compound was prepared as described in Example 30 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and 4-chloro-2-pyridinemethanamine in the last step. The amount of title compound isolated was 34 mg (66%). HPLC purity (220 nm): >95%. 1 H-NMR(400MHz,DMSO-d6)δ 8.47(d,J=5.4Hz,1H),7.64-7.60(m,2H),7.49(d,J=11.1Hz,1H),7.45-7.36(m,3H),7.26-7.25(m,1H),7.03(t,J=5.5Hz,1H),6.96 (s,1H),5.48(s,2H),4.28(d,J=5.6Hz,2H),2.71(d,J=7.0Hz,2H),2.61(s,3H),1.87(dp,J=13.5,6.8Hz,1H),0.92(d,J=6.6Hz,6H). MS(M+H + ):Experiment 576 Calculation 576.

[0204] Example 39 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(2-methylpropyl)urea trifluoroacetic acid The title compound was prepared as described in Example 30 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and isobutylamine in the last step. The amount of title compound isolated was 30 mg (64%). HPLC purity (220 nm): >95%. 1 H-NMR(400MHz,DMSO-d6)δ 7.66-7.61(m,2H),7.49-7.36(m,3H),6.96(s,1H),6.29(t,J=5.5Hz,1H),5.49(s,2H),2.77-2.70(m,4H),2.63( s,3H),1.88(dp,J=13.4,6.7Hz,1H),1.53(dp,J=13.5,6.8Hz,1H),0.93(d,J=6.6Hz,6H),0.71(d,J=6.7Hz,6H). MS(M+H + ):Experiment 507 Calculation 507.

[0205] Example 40 1-[(4,4-Difluorocyclohexyl)methyl]-3-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]urea trifluoroacetic acid The title compound was prepared as described in Example 30 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-imidazole in the first step and (4,4-difluorocyclohexyl)methanamine in the last step. The amount of title compound isolated was 44 mg (84%). HPLC purity (220 nm): >95%. 1H-NMR(400MHz,DMSO-d6)δ 7.63(d,J=1.6Hz,2H),7.47(d,J=11.1Hz,1H),7.45-7.36(m,2H),6.96(s,1H),6.46(t,J=5.5Hz,1H),5.48(s,2H),2.85 (t,J=6.3Hz,2H),2.72(d,J=7.0Hz,2H),2.63(s,3H),1.99-1.37(m,8H),1.03(q,J=10.4Hz,2H),0.93(d,J=6.6Hz,6H). MS(M+H + ):Experiment 583 Calculation 583.

[0206] Example 41 1-{[3-(3-fluoro-4-{[2-(propan-2-yl)-1H-imidazol-1-yl]methyl}phenyl)-5-(2-methylpropyl)thiophen-2-yl]sulfonyl}-3-(3,3,3-trifluoropropyl)urea trifluoroacetic acid The title compound was prepared as described in Example 30 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-(propan-2-yl)-imidazole in the first step (prepared using a procedure similar to that described in the literature for 1-[(4-bromophenyl)methyl]-2-methyl-imidazole (see, for example, WO 2002 / 096883)) and 3,3,3-trifluoropropylamine hydrochloride in the last step. The amount of title compound isolated was 28 mg (54%). HPLC purity (220 nm): >95%. 1H-NMR(400MHz,DMSO-d6)δ 7.71(d,J=1.9Hz,1H),7.64(d,J=1.8Hz,1H),7.48(d,J=11.6Hz,1H),7.42-7.34( m,2H),6.96(s,1H),6.54(t,J=5.8Hz,1H),5.57(s,2H),3.55(dt,J=13.8,6.9Hz, 1H),3.20(q,J=6.6Hz,2H),2.72(d,J=7.0Hz,2H),2.34(ddt,J=17.9,11.4,5.7Hz ,2H),1.88(dp,J=13.4,6.6Hz,1H),1.26(d,J=6.9Hz,6H),0.93(d,J=6.6Hz,6H). MS(M+H + ):Experiment 575 Calculation 575.

[0207] Example 42 1-{[3-(3-fluoro-4-{[2-(propan-2-yl)-1H-imidazol-1-yl]methyl}phenyl)-5-(2-methylpropyl)thiophen-2-yl]sulfonyl}-3-(4,4,4-trifluorobutyl)urea trifluoroacetic acid The title compound was prepared as described in Example 30 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-(propan-2-yl)-imidazole in the first step and 3,3,3-trifluorobutylamine hydrochloride in the last step. The amount of title compound isolated was 32 mg (61%). HPLC purity (220 nm): >95%. 1H-NMR(400MHz,DMSO-d6)δ 7.71(d,J=1.9Hz,1H),7.64(d,J=1.8Hz,1H),7.48(d,J=11.6Hz,1H),7.41-7.34(m ,2H),6.96(s,1H),6.52(t,J=5.6Hz,1H),5.57(s,2H),3.55(dt,J=13.9,6.9Hz,1H ),3.01(q,J=6.5Hz,2H),2.71(d,J=7.0Hz,2H),2.19-2.04(m,2H),1.88(dp,J=13. 6,6.7Hz,1H),1.51(p,J=7.2Hz,2H),1.26(d,J=6.9Hz,6H),0.93(d,J=6.6Hz,6H). MS(M+H + ):Experiment 589 Calculation 589.

[0208] Example 43 1-{[3-(3-fluoro-4-{[2-(propan-2-yl)-1H-imidazol-1-yl]methyl}phenyl)-5-(2-methylpropyl)thiophen-2-yl]sulfonyl}-3-propylurea trifluoroacetic acid The title compound was prepared as described in Example 30 using 1-[(4-bromo-2-fluorophenyl)methyl]-2-(propan-2-yl)-imidazole in the first step and propylamine in the last step. The amount of title compound isolated was 17 mg (36%). HPLC purity (220 nm): >95%. 1 H-NMR (400 MHz, DMSO-d6) δ 7.70(d,J=1.5Hz,1H),7.63(d,J=1.6Hz,1H),7.48(d,J=11.6Hz,1H),7.38(d, J=6.1Hz,2H),6.95(s,1H),6.28(t,J=5.1Hz,1H),5.57(s,2H),3.54(p,J=7.0H z,1H),2.88(q,J=6.7Hz,2H),2.72(d,J=7.0Hz,2H),1.88(dp,J=13.4,6.7Hz,1 H),1.28(dd,J=13.6,7.0Hz,8H),0.93(d,J=6.6Hz,6H),0.74(t,J=7.4Hz,3H). MS(M+H+ ):Experiment 521 Calculation 521.

[0209] Example 44 Further compounds The following compounds are prepared using methods similar to those disclosed in one or more of the examples above. 1-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-3-propoxyurea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2,2,2-trifluoroethyl)-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, and 3-(3-{3,5-difluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea.

[0210] Biological assays The biological activity of the exemplary compounds described herein above was evaluated using the following biological assays.

[0211] metabolic stability Pooled human liver microsomes in PBS at a concentration of 0.5 mg / ml were incubated with or without 1 mM NADPH at 37°C for 70 minutes. Test compounds were added after 10 minutes to a final concentration of 1 μM. Samples were removed at 0, 5, 15, and 60 minutes and added to test tubes containing acetonitrile to stop the reaction. Terfenadine was used as an internal standard. After centrifugation at 10,000 x g for 5 minutes, the supernatant was diluted 1:1 with 1% formic acid. Samples were separated on a reversed-phase column and detected by a triple quadrupole MS / MS (Agilant Model 6540). The concentration of the parent compound at different time points was measured using an external standard curve with terfenadine as an internal standard, and the initial metabolic rate in the presence or absence of NADPH was calculated. [Table 1]

[0212] Binding to AT1 and AT2 receptors Compounds were evaluated for binding to human recombinant AT2 and AT1 receptors using a radiometric scintillation assay according to Eurofins protocols ITEM26 and ITEM24.

[0213] Briefly, recombinant proteins were incubated with test compounds at concentrations of 1, 10, 100 and 1000 nM for the AT2 receptor, and 1 and 10 uM for the AT1 receptor at 37°C for 2-4 hours. 125 I(sar1, IIe8)-AT-II was used as a ligand for the AT1 receptor. 125 ICGP 42112A was used as a ligand for the AT2 receptor. The inhibition rate of control specific binding was calculated according to 100-(measured specific binding / control specific binding) x 100. [Table 2]

[0214] CYP inhibitors Compounds were evaluated at 10 μM for inhibition of major cytochrome P450 isoforms (CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A4&5) using isoform-specific substrates incubated with human liver microsomes (Eurofins protocol ITEMG232). The following substrates were used: CYP1A phenacetin, CYP2B6 bupropion, CYP2C8 paclitaxel and amodiaquine, CYP2C9 diclofenac, CYP2C19 omeprazole, CYP2D6 dextromethorphan, and CYP3A midazolam and testosterone.

[0215] At the end of the incubation, metabolite formation was monitored by HPLC-MS / MS as peak area response. [Table 3] [Table 4]

[0216] Abbreviation The following abbreviations may be used herein: DMSO: dimethyl sulfoxide DCM: dichloromethane EtOAc: ethyl acetate MeOH: Methanol NMR: nuclear magnetic resonance TFA: Trifluoroacetic acid

Claims

1. A compound of formula I, 【Chemistry 1】 During the ceremony, R １ is C optionally substituted with one or more halogen atoms １－６ represents alkyl, R ２ and R ３ are independently H or C optionally substituted by one or more halogen atoms. １－６ represents alkyl, Y １ , Y ２ , Y ３ , and Y ４ independently represent —CH—, —CF—, or —N—; R ４ is C １－７ Alkyl, C １－６ Alkoxy, C １－６ Alkoxy-C １－６ alkyl, each of which is optionally substituted with one or more halogen atoms; or R ４ is aryl, C １－６ Alkylaryl, C １－３ Alkenylaryl, heteroaryl, C １－６ alkylheteroaryl, or C １－３ alkenylheteroaryl, each of which is halogen, CF ３ , C.F. ３ O.C. １－６ Alkyl, and C １－６ optionally substituted by one or more substituents selected from alkoxy; R ５ is H or C optionally substituted with one or more halogen atoms １－６ represents alkyl, R ６ is C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkoxy-C １－６ alkyl, each of which is optionally substituted with one or more halogen atoms; or a pharmaceutically acceptable salt thereof.

2. R １ C optionally substituted with up to three fluorine atoms １－３ The compound of claim 1 , which represents an alkyl group.

3. R ２ and R ３ 3. The compound of claim 1 or 2, wherein independently represents H, methyl or ethyl.

4. R ４ C optionally substituted or terminated with up to three fluorine atoms １－４ alkyl group; or C optionally substituted or terminated with up to three fluorine atoms １－２ Alkoxy-C １－３ Alkyl group; Phenyl; C １－３ alkylaryl; or C １－３ 10. A compound according to any one of the preceding claims, which represents alkylheteroaryl.

5. R ５ is H or C １－４ 10. A compound according to any one of the preceding claims, which represents an alkyl group.

6. R ６ C optionally substituted or more preferably terminated with up to three fluorine atoms １－４ 10. A compound according to any one of the preceding claims, which represents an alkyl group.

7. Y １ represents —CH—, —CF—, or —N—; Y ２ represents —CH— or —CF—; Y ３ represents —CH—, and / or Y ４ A compound according to any one of the preceding claims, wherein represents -CH- or -N-.

8. Y １ represents —CH— or —CF, and / or Y ２ , Y ３ and Y ４ The compound according to claim 7, wherein all of

9. 1-benzyl-3-(5-isobutyl-3-{p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)urea, p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea, p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, 1-butyl-3-(5-isobutyl-3-{p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)urea, p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)-1-(4,4,4-trifluorobutyl)urea, 1-benzyl-3-(3-{p-[(2-ethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)urea, p-[(2-ethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(2-methoxyethyl)urea, or p-[(2,4-dimethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, 3-(3-{p-[(2-ethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea, 1-benzyl-3-(3-{p-[(2,4-dimethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)urea, 3-(3-{p-[(2,4-dimethyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea, 1-benzyl-3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, 1-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-3-[(1-methyl-1H-imidazol-2-yl)methyl]urea, 1-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-3-[2-(1H-imidazol-4-yl)ethyl]urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-methyl-1-[(2-pyridyl)methyl]urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(4,4,4-trifluorobutyl)urea, 3-(5-isobutyl-3-{5-[(2-methyl-1H-imidazol-1-yl)methyl]-2-pyridyl}-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, 3-(5-isobutyl-3-{2-[(2-methyl-1H-imidazol-1-yl)methyl]-5-pyrimidinyl}-2-thienylsulfonyl)-1-(2-methoxyethyl)urea, 3-(5-isobutyl-3-{2-[(2-methyl-1H-imidazol-1-yl)methyl]-5-pyrimidinyl}-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, 3-(5-isobutyl-3-{2-[(2-methyl-1H-imidazol-1-yl)methyl]-5-pyrimidinyl}-2-thienylsulfonyl)-1-[(2-pyridyl)methyl]urea, 1-[(3,5-difluorophenyl)methyl]-3-(5-isobutyl-3-{5-[(2-methyl-1H-imidazol-1-yl)methyl]-2-pyridyl}-2-thienylsulfonyl)urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(2-methoxyethyl)urea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-[1-(2-pyridyl)ethyl]urea, 3-(3-{2-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, 3-(3-{2-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(2,2,2-trifluoroethyl)urea, 1-(3-fluoropropyl)-3-(5-isobutyl-3-{p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)urea, 1-(3,3-difluoropropyl)-3-(5-isobutyl-3-{p-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-thienylsulfonyl)urea, 1-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(3,3,3-trifluoropropyl)urea, 1-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(2-methoxyethyl)urea, 3-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-1-[(4-fluorophenyl)methyl]urea, 1-[(3-{4-[(2-ethyl-1H-imidazol-1-yl)methyl]-3-fluorophenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-propylurea, 1-[(3,4-difluorophenyl)methyl]-3-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]urea, 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-[(thiophen-2-yl)methyl]urea, 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-propylurea, 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(3,3,3-trifluoropropyl)urea, 1-[(4-chloropyridin-2-yl)methyl]-3-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]urea, 1-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]-3-(2-methylpropyl)urea, 1-[(4,4-difluorocyclohexyl)methyl]-3-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2-methylpropyl)thiophen-2-yl)sulfonyl]urea, 1-{[3-(3-fluoro-4-{[2-(propan-2-yl)-1H-imidazol-1-yl]methyl}phenyl)-5-(2-methylpropyl)thiophen-2-yl]sulfonyl}-3-(3,3,3-trifluoropropyl)urea, 1-{[3-(3-fluoro-4-{[2-(propan-2-yl)-1H-imidazol-1-yl]methyl}phenyl)-5-(2-methylpropyl)thiophen-2-yl]sulfonyl}-3-(4,4,4-trifluorobutyl)urea, 1-{[3-(3-fluoro-4-{[2-(propan-2-yl)-1H-imidazol-1-yl]methyl}phenyl)-5-(2-methylpropyl)thiophen-2-yl]sulfonyl}-3-propylurea, 1-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-3-propoxyurea, 3-(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-(2,2,2-trifluoroethyl)-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea, and 3. A compound according to any one of the preceding claims which is 3-(3-{3,5-difluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutyl-2-thienylsulfonyl)-1-(3,3,3-trifluoropropyl)urea; or a pharmaceutically acceptable salt of any of the above compounds.

10. A compound according to any one of claims 1 to 9 for use as a pharmaceutical.

11. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 9 in admixture with a pharmaceutically or cosmetically acceptable adjuvant, diluent or carrier.

12. A compound according to any one of claims 1 to 9 for use in the treatment of autoimmune diseases, fibrotic diseases, chronic kidney disease, pulmonary hypertension, heart failure and / or myocardial infarction.

13. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of autoimmune diseases, fibrotic diseases, chronic kidney disease, pulmonary hypertension, heart failure and / or myocardial infarction.

14. A method for treating autoimmune diseases, fibrotic diseases, chronic kidney disease, pulmonary hypertension, heart failure and / or myocardial infarction, comprising administering a compound according to any one of claims 1 to 9 to a patient in need of such treatment.

15. 15. The compound for use according to claim 12, the use according to claim 13, or the method of treatment according to claim 14, wherein the disease is interstitial lung disease.

16. 16. The compound for use, use or method of treatment according to claim 15, wherein the interstitial lung disease is idiopathic pulmonary fibrosis or sarcoidosis.

17. 15. The compound for use according to claim 12, the use according to claim 13, or the method of treatment according to claim 14, wherein the autoimmune disease is rheumatoid arthritis or systemic sclerosis.

18. 15. The compound for use according to claim 12, the use according to claim 13, or the method of treatment according to claim 14, wherein the chronic kidney disease is diabetic nephropathy.

19. 15. The compound for use according to claim 12, the use according to claim 13, or the method of treatment according to claim 14, wherein the pulmonary hypertension is pulmonary arterial hypertension.

20. 15. The compound for use according to claim 12, the use according to claim 13, or the method of treatment according to claim 14, wherein the heart failure is a condition with preserved ejection fraction.

21. A process for the preparation of a compound of formula I according to any one of claims 1 to 9, comprising (i) a compound of formula II 【Chemistry 2】 (In the formula, R １ , R ２ , R ３ , R ６ , Y １ , Y ２ , Y ３ and Y ４ is optionally described in any one of claims 1 to 9, and L is C １－６ alkyl) and a compound of formula III NER ４ R ５ --- (In the formula, R ４ and R ５ is as defined in any one of claims 1 to 9), or (ii) R ５ represents H, a compound of formula IV 【Transformation 3】 (In the formula, R １ , R ２ , R ３ , R ６ , Y １ , Y ２ , Y ３ and Y ４ optionally as defined in any one of claims 1 to 9) and a compound of formula V R ４ -N=C=O V (In the formula, R ４ is as defined in any one of claims 1 to 9.

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