Novel compounds for the treatment of diseases associated with angiotensin ii

Abstract

The present invention provides novel pharmaceutical compounds of formula I, wherein R 1 , R 2 , R 3 , R 4 , R 5 , n and Z are as defined herein, which are useful in the treatment of autoimmune and / or fibrotic diseases, including interstitial lung diseases such as idiopathic pulmonary fibrosis and sarcoidosis.

Description

Technical Field

[0001] This invention relates to novel compounds that are pharmaceutically useful, specifically compounds as angiotensin II (Ang II) agonists, more specifically agonists of the Ang II type 2 receptor (hereinafter referred to as the AT2 receptor), and especially agonists that selectively bind to this receptor. The invention also relates to the use of such compounds as pharmaceuticals, pharmaceutical compositions containing such compounds, and synthetic routes for their preparation. Background Technology

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

[0003] Several studies in adult individuals appear to demonstrate that AT2 receptor activation has an opposite effect to those mediated by AT1 receptors in the regulation of the response following Ang II receptor stimulation. AT2 receptors have also been shown to be involved in apoptosis and inhibition of cell proliferation (de Gasparo M et al., Pharmacol. Rev. (2000); 52, 415-472). Recently, AT2 receptor agonists have been shown to have potential utility in the treatment and / or prevention of gastrointestinal disorders such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see International Patent Application WO 99 / 43339). The expected pharmacological effects of AT2 receptor agonism are generally described in de Gasparo M et al. (ibid.).

[0004] The stimulatory effects of Ang II on vascular tone, cell growth, inflammation, and extracellular matrix synthesis are primarily associated with AT1 receptors in any organ, while the function of AT2 receptors appears to be more prevalent in damaged tissues and exhibits reparative and opposite properties to AT1. For example, AT2 receptors have been shown to be important for reducing myocyte hypertrophy and fibrosis.

[0005] Interstitial lung disease (ILD) is a type of lung disease that affects the interstitium, characterized by scarring and / or thickening of the tissue surrounding the alveoli, which in turn inhibits the respiratory process.

[0006] ILD differs from obstructive airway diseases (such as chronic obstructive airway disease (COPD) and asthma) that are typically characterized by narrowing (obstruction) of the bronchi and / or bronchioles. ILD can be caused by lung damage that triggers an abnormal healing response, but in some cases, these diseases have no known cause. ILD can be triggered by chemicals (silicosis, asbestosis, certain medications), infections (such as pneumonia), or other conditions (such as rheumatoid arthritis, systemic sclerosis, myositis, or systemic lupus erythematosus).

[0007] The most common ILDs are idiopathic pulmonary fibrosis (IPF) and sarcoidosis, both of which are characterized by chronic inflammation and decreased lung function.

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

[0009] Treatment for sarcoidosis is patient-specific. In most cases, symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) is possible, but for those presenting with pulmonary symptoms, glucocorticoids (such as prednisone or prednisolone), antimetabolites, and / or monoclonal anti-tumor necrosis factor antibodies are often used.

[0010] Interstitial lung disease (IPF) is a lung disease of unknown cause that affects approximately 5 million people worldwide. There is no curative treatment option except in rare cases requiring lung transplantation, leading to chronic, irreversible, and progressive deterioration of lung function and, in most cases, death within 2–5 years (median survival 2.5–3.5 years). While the overall prognosis for IPF is poor, the rate of progression in individual patients is difficult to predict. Risk factors for IPF include age, male sex, genetic predisposition, and smoking history. The annual incidence is 5–16 per 100,000 individuals, and the prevalence is 13–20 cases per 100,000 individuals, 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 resistant to therapies targeting the immune system, distinguishing it from pulmonary fibrosis, which is associated with systemic diseases.

[0011] Patients with interstitial lung disease (IPF) typically seek medical attention due to chronic and progressive exercise-induced dyspnea and cough. Lung imaging typically shows traction bronchiectasis, thickened interlobular septa, and subpleural honeycomb features. IPF is highly probable when all three features are present and there is no evidence of systemic connective tissue disease or environmental exposure. Confirmation is usually made via lung biopsy and requires a multidisciplinary team of specialists, including pulmonologists, radiologists, and pathologists experienced in interstitial lung disease.

[0012] Interstitial lung disease (IPF) exhibits different phenotypes with varying prognoses, defined as mild, moderate, and severe. Mild cases follow a stable or slow progression, and patients sometimes require years to seek treatment. Accelerated IPF has a more rapid progression and shorter survival, affecting a subgroup of patients, typically male smokers. Acute exacerbations of IPF are defined as rapid deterioration of the disease, and patients in this subgroup have very poor outcomes, with high mortality rates in the short term. The cause of IPF is unknown, but it appears to be a condition likely caused by the interaction of environmental and genetic factors, leading to fibroblast-driven, continuous tissue remodeling rather than normal repair; the pathogenesis is primarily driven by fibrosis rather than inflammation. Growing evidence suggests that the disease is triggered by micro-damage and apoptosis of alveolar epithelial cells, activating adjacent epithelial cells and attracting stem cells or progenitor cells that produce factors responsible for the tumor-like expansion of fibroblast and myofibroblast populations. Fibroblastic lesions secrete excessive extracellular matrix, which damages the lung parenchyma and ultimately leads to loss of lung function.

[0013] The average annual rate of decline in lung function (vital capacity) is in the range of 0.13–0.21 liters. Symptoms appear 1–2 years earlier than diagnosis, and radiographic signs may appear earlier than symptoms (Ley B et al., Am. J. Respir. Crit. Care Med. (2011) 183, 431–440).

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

[0015] Current treatment for IPF includes oxygen supplementation. Medications used include pirfenidone or nintedanib, but these have had limited success in slowing disease progression. Furthermore, both medications commonly cause side effects (primarily gastrointestinal).

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

[0017] Restoring alveolar epithelium is a highly effective treatment for IPF, and stem cell therapy has been tested in this area. Several preclinical studies have shown promise in the use of pluripotent stem cells, which can differentiate into lung epithelial cells and endothelial cells, thereby repairing lung injury and fibrosis.

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

[0019] Therefore, developing new treatment strategies for IPF is crucial. Thus, the fundamental challenge ahead is to develop appropriate treatments that can reverse or halt disease progression.

[0020] US Patent Application US 2004 / 0167176 describes the preparation of a tricyclic heterocycle that can be used as an Ang II receptor agonist.

[0021] Selective AT2 receptor agonists with reduced CYP 450 inhibition are described in Mahalingam et al., Bioorg. Med. Chem. (2010) 18, 4570-4590.

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

[0023] Specifically, International Patent Application WO 2002 / 096883 describes the preparation of imidazole, triazole, and tetraazole thiophene sulfonamides and their derivatives as AT2 receptor agonists. The compound described in that document (as in Example 1) is compound C21 (N-butoxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide). C21 was selected from a group of approximately 20 related analogs as selective AT2 receptor agonists for clinical development. It is currently in clinical development for the treatment of AT2 receptor-related conditions, including IPF (see, for example, International Patent Application WO 2016 / 139475).

[0024] C21 has also been shown to have potential use in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer treatment-related cardiotoxicity, peripheral neuropathy, and systemic sclerosis (see, for example, international patent applications WO 2004 / 046141, WO 2016 / 092329, WO 2016 / 107879, WO 2016 / 139475, WO 2017 / 221012, WO2019 / 008393 and US patent application US 2012 / 035232).

[0025] During development, C21 has been found to have the following drawbacks: it is a potent inhibitor of several cytochrome P450 enzymes (CYP), particularly CYP 2C9 and CYP 3A4, potentially affecting the metabolism of other drugs, and it is also rapidly hydrolyzed into inactive sulfonamide metabolites. Therefore, developing metabolically stable and / or potent and selective AT2 agonists that exhibit less inhibition of CYP enzymes is a fundamental challenge.

[0026] We were surprised to find that, compared to C21, certain chemically modified compounds, as defined below, are not only selective AT2 receptor agonists, but also more effective, exhibit significantly improved stability against metabolic hydrolysis, and / or show less inhibition of CYP enzymes. Detailed Implementation

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

[0028]

[0029] in:

[0030] n represents 1 to 4;

[0031] Z represents -O- or direct bond;

[0032] R 1 C represents a carbon atom that is optionally substituted with one or more halogen atoms. 1-6 alkyl;

[0033] R 2 and R 3 Each independently represents H or C optionally substituted with one or more halogen atoms. 1-6 alkyl;

[0034] R 4 Indicate C 1-8 Alkyl groups, optionally surrounded by one or more halogen atoms and / or OR 6 Group substitution and / or end capping; or

[0035] R 4Indicates aryl, C 1-6 alkylaryl, C 1-3 alkenylaryl, heteroaryl, C 1-6 alkyl heteroaryl or

[0036] C 1-3 Alkenyl heteroaryl groups, wherein each is optionally surrounded by one or more elements selected from halogens, CF3, CF3O, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0037] R 5 Indicate C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy-C 1-6 Alkyl groups, wherein each of them is optionally substituted with one or more halogen atoms;

[0038] R 6 Indicates H, -C(O)R 7 or C- 1-6 Alkyl, aryl, C 1-6 alkylaryl, C 1-3 alkenylaryl, heteroaryl, C 1-6 alkyl heteroaryl or C 1-3 Alkenyl heteroaryl, each of the last seven groups is optionally surrounded by one or more groups selected from halogens, CF3, CF3O, C 1-6 Alkyl and C 1-6 Alkyl substituents; and

[0039] R 7 Indicates C- 1-6 alkyl

[0040] Or its pharmaceutically acceptable salt.

[0041] The compounds and salts mentioned herein are collectively referred to as "the compounds of the present invention".

[0042] The compounds of the present invention that may be mentioned include those as defined above and / or below, but wherein, when R 4 Indicates that it is optionally separated by one or more halogen atoms and / or OR 6 Group substitution and / or C-terminus 1-8 When alkyl, it indicates that the C-axis is so optionally substituted and / or capped. 2-8 alkyl.

[0043] For the purpose of interpreting this specification, the following definitions will apply, and whenever appropriate, terms used in the singular will also include the plural form, and vice versa.

[0044] The compounds were named according to the IUPAC nomenclature generated by the program Chemdoodle 8.1.0.

[0045] For the avoidance of doubt, those skilled in the art will understand that any reference herein to compounds of a particular aspect of the invention (such as any aspect of the invention relating to compounds of Formula I as defined above) will include reference to all embodiments and specific features thereof, which may be combined to form further embodiments and features of the invention.

[0046] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those commonly understood by one of ordinary skill in the art to which this invention pertains.

[0047] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example by reacting the compound of the invention in its free acid or free base form with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., under vacuum, by freeze-drying, or by filtration). Salts can also be prepared using techniques known to those skilled in the art, such as by exchanging the counter ion of the compound of the invention in its salt form with another counter ion, for example using a suitable ion exchange resin.

[0048] Specific acid addition salts that may be mentioned include carboxylates such as formate, acetate, trifluoroacetate, benzoate, oxalate, fumarate, maleate, etc.; sulfonates such as methanesulfonate, ethanesulfonate, toluenesulfonate, etc.; halide salts such as hydrochloride, hydrobromide, etc.; and sulfates and phosphates such as sulfates or phosphates, etc.

[0049] Specific alkali addition salts that 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) and amine bases (such as ammonia, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, and tromethamine). More specifically, alkali addition salts that may be mentioned include Mg salts, Ca salts, and most specifically, K and Na salts.

[0050] The compounds of this invention can exist as solids, and therefore the scope of this invention includes all their amorphous, crystalline, and partially crystalline forms, and they can also exist as oils. When the compounds of Formula I exist in crystalline and partially crystalline forms, such forms may include solvates, which are included within the scope of this invention.

[0051] The compounds of the present invention can also be present in solution (i.e., in a solution in a suitable solvent). For example, the compounds of formula I can be present in an aqueous solution, in which case the compounds of the present invention can exist in hydrate form.

[0052] The compounds of this invention may contain double bonds and, unless otherwise specified, may exist as E (antgegen) and Z (zusammen) geometric isomers with respect to each individual double bond. All such isomers, and mixtures thereof, are included within the scope of this invention unless otherwise specified.

[0053] The compounds of this invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of this invention (specifically those that have sufficient stability to allow their separation).

[0054] The compounds of the present invention may also contain one or more asymmetric carbon atoms, and thus may exhibit optical and / or diastereomeric properties (i.e., exist in enantiomer or diastereomeric form). Diastereomers can be separated using conventional techniques, such as chromatography or fractional crystallization. Various stereoisomers (i.e., enantiomers) can be separated by using conventional techniques (e.g., fractional crystallization or HPLC) to separate racemic or other mixtures of the compound. Alternatively, the desired enantiomer or diastereomeric isomer can be obtained from a suitable starting material by reacting a suitable optically active starting material with a chiral auxiliary under conditions that do not induce racemization or epimerization (i.e., the “chiral pool” method), said “chiral auxiliary” being subsequently removed at a suitable stage by derivatization (i.e., resolution, including dynamic resolution; for example, reaction with a pure chiral acid followed by separation of the diastereomeric derivative by conventional methods such as chromatography) or by reaction with a suitable chiral reagent or chiral catalyst, all of which can be carried out under conditions known to those skilled in the art. Unless otherwise specified, all stereoisomers and mixtures thereof are included within the scope of this invention.

[0055] As used herein, the term "halogen" as used herein includes fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Similarly, the term "halogen" if used herein and as used herein includes fluorine, chlorine, bromine, and iodine.

[0056] Unless otherwise specified, C as defined in this document 1-6 alkyl groups (e.g., C) 1-3 alkyl groups), C 2-8 alkyl groups and C 1-6 The alkyl moiety of alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 alkylaryl, C 1-3 alkenylaryl, C 1-6 alkyl heteroaryl and C 1-3The alkenyl heteroaryl group can be straight-chain, or, when a sufficient number of carbon atoms are present (i.e., at least two or three, where appropriate), branched and / or cyclic (e.g., forming C...). 3-6 Or C 3-8 Cycloalkyl groups). Such groups can also be partially cyclic (e.g., forming C16 groups) when a sufficient number (i.e., at least four) of carbon atoms are present. 4-6 Or C 4-8 Partially cycloalkyl groups). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Similarly, partially cycloalkyl groups that may be mentioned (which may also be referred to as “partially cycloalkyl” groups) include cyclopropylmethyl or cyclohexylmethyl. Such groups may also be polycyclic (e.g., bicyclic or tricyclic) and / or spirocyclic when a sufficient number of carbon atoms are present.

[0057] When there are a sufficient number (i.e. at least three) of carbon atoms, alkyl and alkoxy groups can be unsaturated, and therefore contain double or triple bonds.

[0058] Specific alkyl groups that may be mentioned include straight-chain (i.e., unbranched and / or cyclic) alkyl groups. For example, C 1-6 alkyl groups, C 1-8 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.

[0059] To avoid any doubt, C 1-6 alkyl groups, C 1-8 alkyl groups and C 1-6 Alkoxy-C 1-6 alkyl moiety, C 1-6 alkylaryl, C 1-3 alkenylaryl, C 1-6 alkyl heteroaryl and C 1-3 The connection point of the alkenyl heteroaryl group is achieved via the alkyl portion of such group.

[0060] To avoid any doubt, the alkoxy group is connected to the rest of the molecule via the oxygen atom in the group, and the alkoxyalkyl group is connected to the rest of the molecule via the alkyl portion of the group.

[0061] Unless otherwise specified, alkoxy refers to an O-alkyl group, where the term "alkyl" has the meaning given above.

[0062] As used herein, references to heteroatoms will be taken in the ordinary sense as understood by those skilled in the art. Specific heteroatoms that may be mentioned include phosphorus, selenium, silicon, boron, oxygen, nitrogen, and sulfur (e.g., oxygen, nitrogen, and sulfur, such as oxygen and nitrogen).

[0063] As may be used herein, references to a “heteroaryl” (also referred to as a heteroaromatic) ring or group can 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 an aromatic ring (which may or may not contain one or more heteroatoms). Where appropriate, substituents on the heteroaryl / heteroaromatic group may be located on any suitable atom in the ring system, including heteroatoms (e.g., on a suitable N atom).

[0064] The connection point of a heteroaryl / heteroaromatic group can be achieved via any atom in the ring system, including (where appropriate) heteroatoms. A bicyclic heteroaryl / heteroaromatic group may contain a benzene ring fused to one or more other aromatic or non-aromatic heterocycles; in this case, the connection point of a polycyclic heteroaryl / heteroaromatic group can be achieved via any ring, including a benzene ring or a heteroaryl / heteroaromatic or heterocyclic ring.

[0065] For the avoidance of doubt, those skilled in the art will understand that the heteroaryl groups that can form part of the compounds of the present invention are those that can be obtained chemically, as is known to those skilled in the art. Various heteroaryl groups are well known to those skilled in the art, such as pyridyl, pyrroloyl, furanyl, phenylthioyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienozothiazolyl, triazinyl, pyrimidinyl, furanylpyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolylpyrimidinyl, indolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiaphenyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzotriazolyl, and purineyl.

[0066] To avoid any doubt, oxides of heteroaryl / heteroaryl groups are also included within the scope of this invention (e.g., N-oxides).

[0067] As mentioned above, heteroaryl groups include polycyclic (e.g., bicyclic) groups, one of which is aromatic (and the other may or may not be aromatic). Therefore, other heteroaryl groups that may be mentioned include groups such as benzo[1,3]dioxacyclopentenyl, benzo[1,4]dioxacyclohexenyl, dihydrobenzo[d]isothiazolyl, 3,4-dihydrobenzo[1,4]oxazinyl, dihydrobenzothiopheneyl, dihydroindolyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, thiobenzodihydropyranyl, etc.

[0068] As may be used herein, the term "aryl" can refer to C 6-14 (e.g., C)6-10 Aromatic groups. These groups can be monocyclic or bicyclic, and when bicyclic, they can be wholly or partially aromatic. (C may be mentioned.) 6-10 Aryl groups include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, etc. (e.g., phenyl, naphthyl, etc.).

[0069] Aromatic groups can be described as cyclic groups containing a suitable number of double bonds to allow for aromaticity.

[0070] Those skilled in the art will understand that the aryl groups that can form part of the compounds of the present invention are those that can be obtained chemically, as is known to those skilled in the art.

[0071] To avoid any doubt, the connection point of the substituent on the aryl group can be achieved via any suitable carbon atom in the ring system.

[0072] This invention also covers isotopically labeled compounds of the invention, which are identical to those described herein except that one or more atoms are replaced by atoms with atomic weights or mass numbers different from those normally found in nature (or the most abundant atomic weights or mass numbers found in nature). All isotopes of any particular atom or element specified herein are covered within the scope of the compounds of the invention. Therefore, the compounds of the invention also include deuterated compounds, i.e., compounds of the invention in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

[0073] In compounds of the present invention, where two or more substituents may be identical, the actual identities of the respective substituents are not related to each other in any way. For example, in the presence of two or more halogen groups, those groups may be the same or different (e.g., two chlorine groups or one fluorine and one chlorine group). Similarly, in the presence of two or more alkyl groups, the groups in question may be the same or different in terms of their number of carbon atoms and / or whether they are straight-chain, branched, unsaturated, or otherwise.

[0074] Furthermore, when the specified substituent is optionally substituted by one or more substituents (e.g., a butyl group optionally substituted by one or more groups independently selected from halogens), these substituents may, where possible, be located on the same or different atoms. Such optional substituents may be present in any suitable number (e.g., the relevant group may be substituted by one or more such substituents, such as a single such substituent).

[0075] When a group is referred to herein as optionally substituted, it is specifically expected that such optionally substituted groups may be absent (i.e., the reference to such optionally substituted groups can be removed), in which case the optionally substituted group may be referred to as unsubstituted.

[0076] Unless otherwise specified, substituents (optionally or not) may be located at any point on the groups to which they can be connected. In this regard, alkyl and alkoxy groups (e.g.) that can be replaced by one or more substituents may also be end-capped by such substituents (we mean at the end of, for example, alkyl or alkoxy chains).

[0077] To avoid ambiguity, in compounds of formula I where two or more substituents may have the same identity, the actual identities of the corresponding substituents are not related to each other in any way. For example, in R 2 and R 3 All are C 1-6 In the case of alkyl groups, the C discussed 1-6 The alkyl groups can be the same or different.

[0078] Those skilled in the art will understand that the compounds of the present invention, which are the subject of this invention, include those that are available, i.e., those that can be prepared in a stable form. That is, the compounds of the present invention include those that are robust enough to withstand, for example, separation from the reaction mixture to a useful purity.

[0079] Preferred compounds of the present invention include those compounds, wherein:

[0080] n represents 1 or 2;

[0081] Z represents a direct bond, or more preferably -O-;

[0082] R 1 C represents a carbon atom that is optionally substituted with at most three halogen atoms. 1-4 Alkyl groups (such as methyl, ethyl, propyl (e.g., n-propyl) or butyl (e.g., n-butyl)) (e.g., CH2CHClCH2CH2F or CH2CF3);

[0083] R 2 and R 3 Independently representing H or C optionally substituted with up to three halogen atoms. 1-4 Alkyl groups (such as methyl, ethyl, propyl (e.g., n-propyl) or butyl (e.g., n-butyl)) (e.g., CH2CHClCH2CH2F or CH2CF3);

[0084] R 4 C represents 1-8 (or C) 2-8 alkyl groups (such as methyl or specifically ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., tert-butyl, isobutyl, or n-butyl), cyclohexylmethyl, cyclohexylethyl, cyclopentylmethyl, cyclobutylmethyl, cyclobutylethyl, aryl, or C 1-6 Alkyl aryl groups, wherein each is optionally surrounded by up to three halogen atoms (such as F) and / or OR.6 Group substitution or end capping;

[0085] R 5 C represents 1-4 Alkyl groups (such as methyl, ethyl, propyl (e.g., n-propyl) or butyl (e.g., isobutyl));

[0086] R 6 Indicates H, -C(O)R 7 C- 1-4 Alkyl (such as methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., n-butyl)), aryl (such as phenyl), or C 1-6 alkylaryl, the last three groups optionally being replaced by one or more elements selected from halogens, CF3, CF3O, C 1-6 Alkyl and C 1-6 Alkyl substituents; and

[0087] R 7 C represents 1-4 Alkyl groups (such as methyl, ethyl, propyl (e.g., n-propyl) or butyl (e.g., n-butyl)).

[0088] More preferably, the compounds of the present invention include those compounds, wherein:

[0089] n represents 1;

[0090] R 1 Indicates methyl, ethyl, or isopropyl;

[0091] R 2 and R 3 Independently represents H or methyl;

[0092] R 4 The nouns represent methyl, ethyl, cyclohexylmethyl, cyclopentylmethyl, n-propyl, n-butyl, or isobutyl, wherein each is optionally marked with up to three F groups and / or one or more OR groups. 6 Group substitution or capping; or more preferably, C substituted with one or more F groups. 1-6 Alkyl aryl (e.g., benzyl);

[0093] R 5 This indicates methyl, ethyl, n-propyl, n-butyl, or isobutyl;

[0094] R 6 Represents H, methyl, ethyl, n-propyl, n-butyl, optionally substituted by up to three fluorine atoms or more preferably capped; -C(O)R 7 ; or phenyl; and

[0095] R 7 It indicates methyl, ethyl, or n-propyl.

[0096] The particularly preferred compounds of the present invention include those compounds, wherein:

[0097] When n is 1, the F atom is in a meta position or preferably an ortho position relative to the methylene group that is also connected to the main imidazole ring in the compound of formula I;

[0098] R 2 and R 3 Both represent H;

[0099] R 4 This indicates that it is optionally occupied by up to three F groups or by OR. 6 An ethyl or n-butyl group capped with a functional group, or a benzyl group optionally substituted with one or more F groups;

[0100] R 5 Indicates isobutyl;

[0101] R 6 It represents H, methyl, or phenyl.

[0102] Therefore, particularly preferred compounds of the present invention that may be mentioned include:

[0103] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate,

[0104] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-phenoxyethyl ester

[0105] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate,

[0106] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-methoxyethyl ester,

[0107] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-hydroxyethyl ester,

[0108] (3-(3-fluoro-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 3,3,3-trifluoropropyl ester

[0109] (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 4-fluorobenzyl ester,

[0110] (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate,

[0111] (3-(3-fluoro-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate,

[0112] (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-hydroxyethyl ester,

[0113] (3-(3,5-difluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl ester,

[0114] 2-((((3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamoyl)oxy)ethyl neopentanoate,

[0115] Methyl (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate,

[0116] Methyl (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0117] N-((3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)neopentamide,

[0118] (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxy-2-methylpropyl ester,

[0119] (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-hydroxyethyl ester,

[0120] Methyl (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate,

[0121] N-((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)benzamide,

[0122] N-((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)pyridineamide,

[0123] (3-(3-fluoro-4-((2-isopropylimidazol-1-yl)methyl)phenyl)-5-isobutyl-2-thienyl)sulfonylcarbamate-2-hydroxyethyl ester,

[0124] N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]carbamate

[0125] N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]benzamide

[0126] N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]pyridine-2-carboxamide

[0127] N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-pyridyl)propionamide.

[0128] Other compounds of the present invention that may be mentioned include:

[0129] (1-Hydroxycyclopentyl)methyl-(3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)-phenyl)-5-isobutylthiophen-2-yl)sulfonyl carbamate,

[0130] (1-Hydroxycyclohexyl)methyl-(3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)-phenyl)-5-isobutylthiophen-2-yl)sulfonyl carbamate,

[0131] 2-((((3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamoyl)oxy)ethylpropionate,

[0132] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxybutyl ester,

[0133] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)-phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-hydroxy-2-methylpropyl ester,

[0134] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-ethoxyethyl ester,

[0135] (1-Hydroxycyclohexyl)methyl-(3-(3-fluoro-4-((2-ethyl-1H-imidazol-1-yl)methyl)-phenyl)-5-isobutylthiophen-2-yl)sulfonyl carbamate,

[0136] (3-(2-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate butyl ester.

[0137] Particularly preferred compounds of the present invention that may be mentioned include:

[0138] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate,

[0139] Methyl (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate

[0140] (3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate methyl ester.

[0141] The IUPAC name was generated by the program Chemdoodle 8.1.0.

[0142] More preferred compounds of the present invention include those described in the examples below.

[0143] Compounds of Formula I can be prepared using techniques well known to those skilled in the art, such as those described below.

[0144] According to another aspect of the present invention, a method for preparing a compound of formula I is provided, the method comprising:

[0145] (i) Reacting the compound of formula II with the compound of formula III,

[0146]

[0147] Where R 1 R 2 R 3 R 5 And n is as defined above,

[0148]

[0149] Where R 4 Z is as defined above, and X represents a suitable leaving group, such as a halogen (e.g., chlorine or bromine), reacting, for example, at about room temperature or higher (e.g., up to 60°C-70°C), in the presence of a suitable base (e.g., pyrrolidinepyridine, pyridine, triethylamine, tributylamine, trimethylamine, N-ethyldiisopropylamine, 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).

[0150] (ii) For a compound of formula I in which Z is a bond, react a compound of formula II as defined above with a compound of formula IIIa.

[0151] R 4 C(O)OH IIIa

[0152] Where R 4 As defined above, for example, by standard EDCI coupling conditions, such as in the presence of a carboxyl activator (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide).

[0153] (iii) For compounds of formula I where Z represents -O-, such that R 4 Compounds of formula I with a lower alkyl group (e.g., methyl or ethyl) or an optionally substituted aryl group (e.g., phenyl group) react with alcohols of formula IV.

[0154] R 4’ OH IV

[0155] Where R 4’ R represents the group other than the substituted group. 4 Group. The reaction can be carried out in the absence of a solvent and at the aforementioned room temperature (e.g., at the reflux temperature of the alcohol used).

[0156] Compounds of formula II can be prepared by reacting compounds of formula V with compounds of formula VI.

[0157]

[0158] Where R 5 As defined above, or its N-protected derivatives,

[0159]

[0160] Where X 2 Represents a suitable leaving group, such as a trimethylsulfonate or a halogen, such as iodine or bromine, and R 1 R 2 R 3 The reaction, as defined above, is carried out, for example, in the presence of a suitable coupling catalytic system (e.g., a palladium catalyst, such as Pd(PPh3)4 or Pd(OAc)2 / ligand (where the ligand can be, for example, PPh3, P(o-Tol)3 or 1,1'-bis(diphenylphosphine)ferrocene)) and a suitable base (e.g., sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or diisopropylamine) and a suitable solvent system (e.g., toluene, ethanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane or mixtures thereof). The reaction can be carried out above room temperature (e.g., at the reflux temperature of the solvent system used). If the protected form of the compound of formula V is used, deprotection of the SO2NH- group can be carried out under standard conditions after the reaction, as described below.

[0161] The compounds of formula II can alternatively be prepared by reacting the compound of formula VII with the compound of formula VIII.

[0162]

[0163] Where R 1 R 2 and R 3 As defined above,

[0164]

[0165] Where R 5 And n is as defined above, and X 1 This indicates a suitable leaving group such as a halogen (e.g., chlorine or bromine, specifically bromine) or its N-protected derivative, reacted, for example, at approximately room temperature or below, in the presence of a suitable base (e.g., pyridine) and a suitable organic solvent (e.g., toluene). If the protected form of a compound of formula VIII is adopted, deprotection of the SO2NH- group can be carried out under standard conditions after this reaction, for example, as described below. Additionally, compounds of formula II can be prepared in this manner, for example, according to or similar to the method described in, particularly, British patent application GB 2281298.

[0166] Compounds of formula VI can be prepared using standard techniques, such as by reacting a compound of formula VII as defined above with a compound of formula IX.

[0167]

[0168] Where n and X 1 and X 2 As defined above, for example, under conditions similar to those described above regarding the preparation of compounds of formula II.

[0169] Compounds of formula VIII are known in the art. For example, they can be prepared according to or similar to the methods described in, in particular, U.S. Patent No. 5,312,820, UK Patent Application GB 2281298 and / or International Patent Application WO 02 / 096883.

[0170] Compounds of formula V are known in the art. For example, they can be prepared according to or similar to the methods described in, in particular, international patent application WO02 / 096883.

[0171] The compounds of formulas III, IIIa, IV, VII, and IX are commercially available, known in the literature, or can be obtained from readily available starting materials by means similar to those described herein or by conventional synthetic procedures, according to standard techniques, using appropriate reagents and reaction conditions.

[0172] Those skilled in the art will understand that, in the methods described above and below, the functional groups of the intermediate compound may need to be protected by protecting groups.

[0173] The functional groups requiring protection include sulfonamides, amides, amino groups, and aldehydes. Suitable protecting groups for sulfonamides, amides, and amino groups include tert-butoxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), or tert-butyl. Suitable protecting groups for aldehydes include alcohols, such as methanol or ethanol, and diols, such as 1,3-propanediol or preferably 1,2-ethylenediol (thus forming a cyclic acetal). Protection and deprotection of functional groups can be carried out before or after the reactions in the above schemes.

[0174] Protecting groups can be applied and removed using techniques well known to those skilled in the art, as well as those described below. For example, the protected compounds / intermediates described herein can be chemically converted into unprotected compounds using standard deprotection techniques. The type of chemistry involved will determine the need for and type of protecting groups, as well as the order in which the synthesis is completed. The use of protecting groups is fully described in “Protective Groups in Organic Synthesis,” 3rd edition, TW Greene & P. ​​GMWutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference.

[0175] Medical and pharmaceutical uses

[0176] As described herein, the compounds of the present invention, as well as compositions and kits comprising said compounds, are useful because they have pharmacological activity and / or are metabolized in vivo after oral or parenteral administration to form pharmacologically active compounds.

[0177] Therefore, according to another aspect of the invention, compounds of the invention as defined above are provided for use as pharmaceuticals (or for medical purposes).

[0178] Specifically, the compounds of the present invention are AT2 receptor agonists. Therefore, the compounds of the present invention are contemplated for use in those conditions in which endogenous production of Ang II is insufficient and / or in which increased AT2 receptor activity is desired or required.

[0179] More specifically, the compounds of the present invention are agonists of the AT2 receptor, and in particular, selective (relative to the AT1 receptor) agonists of this subreceptor, as can be demonstrated, for example, in the tests described below.

[0180] AT2 receptor agonists include those that fully and partially activate the AT2 receptor. Therefore, the compounds of the present invention selectively bind to the AT2 receptor and exhibit agonist activity against it. Compounds that are said to "selectively bind" to the AT2 receptor include those with an affinity ratio (AT2:AT1) of at least 50:1, such as at least 100:1, and preferably at least 1000:1, at a given concentration.

[0181] It is also anticipated that the compounds of the present invention can be used for those conditions in which the AT2 receptor is expressed and whose stimulation is desired or required.

[0182] In this respect, the compounds of the present invention are suitable for treating conditions characterized by vasoconstriction, fibrosis, increased cell growth and / or differentiation, increased myocardial contractility, increased cardiovascular hypertrophy and / or increased fluid and electrolyte retention, as well as skin diseases and musculoskeletal disorders.

[0183] The compounds of the present invention may also exhibit thromboxane receptor activity. In this respect, the compounds of the present invention may have an inhibitory effect on platelet activation and / or aggregation (and therefore, for example, an antithrombotic effect), and / or may therapeutically reduce vasoconstriction and / or bronchial stenosis.

[0184] The compounds of this invention are also suitable for treating stress-related diseases and / or improving microcirculation and / or mucosal protective mechanisms.

[0185] Therefore, the compounds of the present invention are intended to be used to treat conditions characterized as described above, as well as conditions of the gastrointestinal tract, cardiovascular system, respiratory tract, kidneys, eyes, female reproductive (ovulation) system, and central nervous system (CNS).

[0186] Gastrointestinal conditions that may be mentioned include esophagitis, Barrett's esophagus, gastric ulcers, duodenal ulcers, dyspepsia (including non-ulcer dyspepsia), gastroesophageal reflux, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatitis, liver disease (such as hepatitis), gallbladder disease, multiple organ failure (MOF), and sepsis. Other gastrointestinal conditions that may be mentioned include xerostomia, gastritis, gastroparesis, hyperacidity, biliary tract diseases, celiac disease, Crohn's disease, ulcerative colitis, dysentery, constipation, colic, dysphagia, vomiting, nausea, indigestion, and Sjögren's syndrome.

[0187] Respiratory conditions that may be mentioned include inflammatory conditions such as asthma, obstructive pulmonary disease (such as chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension, and adult respiratory distress syndrome.

[0188] Kidney conditions that may be mentioned include kidney failure, nephritis, and renal hypertension.

[0189] Eye conditions that may be mentioned include diabetic retinopathy, retinopathy of prematurity, and retinal microvascularization.

[0190] Women’s reproductive system disorders that may be mentioned include ovulation disorders.

[0191] Cardiovascular conditions 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 injury, post-balloon dilation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, re-infarction, ischemic injury, erectile dysfunction, and neointimal hyperplasia.

[0192] CNS conditions that may be mentioned include cognitive impairment, eating disorders (hunger / satiety) and thirst, stroke, cerebral hemorrhage, cerebral embolism and cerebral infarction, multiple sclerosis (MS), Alzheimer's disease and Parkinson's disease.

[0193] The compounds of this invention can also be used to regulate growth metabolism and proliferation, for example, to treat aging, hypertrophic diseases, benign prostatic hyperplasia, autoimmune diseases (e.g., arthritis, such as rheumatoid arthritis, or systemic lupus erythematosus), psoriasis, obesity, neuronal regeneration, ulcer healing, inhibition of adipose tissue proliferation, stem cell differentiation and proliferation, fibrotic diseases, cancer (e.g., cancers in the gastrointestinal tract (including the esophagus or stomach), prostate, breast, liver, kidney, or cancers thereof, as well as lymphoma, lung cancer, ovarian cancer, pancreatic cancer, hematologic malignancies, etc.), apoptosis, tumors (generally) and hypertrophy, diabetes, neuronal damage, and organ rejection.

[0194] The compounds of this invention can also be used to treat stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer treatment-related cardiotoxicity, peripheral neuropathy, and specifically systemic sclerosis.

[0195] The compounds of the present invention are particularly suitable for the treatment and / or prevention of ILD, such as sarcoidosis or fibrosis, more particularly pulmonary fibrosis, specifically IPF, as well as conditions that can trigger ILD, such as systemic sclerosis, rheumatoid arthritis, myositis or systemic lupus erythematosus, or conditions associated with ILD, such as pulmonary hypertension and / or pulmonary arterial hypertension.

[0196] The compounds of this invention are particularly useful for treating pulmonary fibrosis, specifically IPF.

[0197] According to another aspect of the invention, a method for treating pulmonary fibrosis, specifically IPF, is provided, the method comprising administering a therapeutically effective amount of the compound of the invention to a person suffering from the condition.

[0198] In the treatment of pulmonary fibrosis (including IPF), the compounds of the present invention can have anti-fibrotic effects, reducing fibrosis and preventing further deposition of extracellular matrix. The compounds of the present invention can reduce lung scar / wound healing and also have anti-apoptotic effects, thereby preventing apoptosis of alveolar endothelial cells, which are initiating factors in the development of pulmonary fibrosis. The compounds of the present invention can also have anti-proliferative effects, thereby reducing cancerous proliferation of fibroblasts and myofibroblasts in pulmonary fibrosis. The compounds of the present invention can also improve vascular remodeling in pulmonary fibrosis, thereby reducing secondary pulmonary hypertension. Finally, the compounds of the present invention can exhibit anti-inflammatory, anti-growth factor (e.g., transforming growth factor β), and / or anti-cytokine effects.

[0199] Furthermore, the compounds of the present invention can also be used to treat or prevent any fibrotic condition of one or more internal organs characterized by excessive accumulation of fibrous connective tissue, and / or to treat or prevent fibrosis and the morbidity and mortality that may be associated with it. Such fibrosis can be associated with acute inflammatory conditions such as acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), and multi-organ inflammation, injury, and / or failure, which can be caused by internal or external trauma (e.g., injury) or by infection.

[0200] Therefore, such illnesses can be caused by sepsis or septic shock resulting from viral, bacterial, or fungal infections (e.g., viral respiratory infections). Furthermore, acute lung injury, ARDS, and specifically SARS can be caused by viruses, such as coronaviruses, including the novel SARS coronavirus 2 (SARS-CoV-2), which can lead to damage to internal tissues and / or dysfunction of related internal tissues (e.g., mucous membranes) such as the respiratory epithelium, thus resulting in viral pneumonia, pulmonary dysfunction, respiratory distress, pain, and / or distress. This tissue damage can also cause severe fibrosis. For example, SARS caused by the novel coronavirus SARS-CoV-2 is known to lead to fibrosis in many cases.

[0201] The compounds of the present invention are particularly useful for treating diseases or conditions in which activation of the AT2 receptor is desired or required, but inhibition of one or more CYP enzymes is not desired.

[0202] In another embodiment of the invention, the use of a compound of formula I or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament for treating a disease or condition in which activation of the AT2 receptor is desired or required but inhibition of the CYP enzyme is not desired.

[0203] The term "diseases or conditions in which activation of the AT2 receptor is desired or required but inhibition of CYP is not desired" includes diseases or conditions known to be treatable by activation of the AT2 receptor, such as those mentioned below, but in which existing treatments may include the administration of other therapeutic agents metabolized by CYP. Therefore, such diseases or conditions may include those in which inhibition of at least one CYP enzyme is not desired, beneficial, and / or desired, or in which such inhibition is harmful or would be harmful to the patient.

[0204] Specific diseases or conditions for which activation of the AT2 receptor is desired or required, but inhibition of CYP enzymes is not desired, include interstitial lung diseases (e.g., pulmonary fibrosis, IPF, systemic sclerosis, and sarcoidosis), autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, and inflammatory bowel disease), chronic kidney diseases (e.g., diabetic nephropathy), pulmonary hypertension, pulmonary arterial hypertension, and / or infarction (e.g., myocardial infarction and stroke). Therefore, the compounds of the present invention are particularly useful for treating interstitial lung diseases such as IPF; autoimmune diseases such as rheumatoid arthritis; chronic kidney diseases such as diabetic nephropathy; pulmonary hypertension, including pulmonary arterial hypertension; and / or infarction, such as myocardial infarction.

[0205] According to another aspect of the invention, a method is provided for treating a disease or condition (such as pulmonary fibrosis, specifically IPF) in which activation of the AT2 receptor is desired or required but inhibition of the CYP enzyme is not desired, the method comprising administering a therapeutically effective amount of the compound of the invention to a person suffering from the relevant condition.

[0206] The compounds of the present invention are applicable to the treatment, relief and / or diagnosis of any of the above-mentioned conditions, as well as preventive treatment (including prevention and / or elimination of the deterioration and / or worsening of the condition).

[0207] The compounds of the present invention are generally administered orally, intravenously, subcutaneously, orally, rectally, through the skin, nose, trachea, bronchi, via any other parenteral route, or via inhalation or pulmonary routes, or any combination thereof, in pharmaceutically acceptable dosage forms, solutions, suspensions, emulsions (including nanosuspensions), or liposomal formulations. Other methods of administration include, but are not limited to, intra-arterial, intraperitoneal, portal venous, intradermal, epidural, intrathecal administration, or any combination thereof.

[0208] In some embodiments, the compounds of the present invention may be administered individually (e.g., separately) and / or sequentially and / or simultaneously in parallel (e.g., synchronously) using different routes of administration, but are preferably administered via known pharmaceutical formulations, including tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions, or emulsions for parenteral or intramuscular administration, or via inhalation, etc. Inhalation administration is preferably carried out using a nebulizer, thus delivering the compounds of the present invention to the small lung tissue comprising alveoli and bronchioles, preferably without causing irritation or coughing in the treated subject.

[0209] Preferably, the therapeutically effective amount of the compound of the invention is administered by a combination of administration routes, individually (e.g., spaced about 2 hours or more apart), sequentially (e.g., spaced about 2 hours apart), or simultaneously and in parallel (e.g., synchronously), including via inhalation and oral administration, thereby achieving an effective dose.

[0210] In some embodiments, a method is provided for treating a disease or condition in which activation of the AT2 receptor is desired or required (as well as in which inhibition of the CYP enzyme is not desired), said disease or condition including pulmonary fibrosis, specifically IPF, the method comprising administering a therapeutically effective amount of the compound of the invention to a patient requiring such treatment via a combination of administration routes, individually, sequentially, or simultaneously in parallel, preferably via inhalation and oral administration (in order to achieve an effective amount or dose).

[0211] This combination of administration routes, preferably via inhalation and oral administration, can exist as individual formulations of the compounds of the invention optimized for each administration route.

[0212] Such formulations can be prepared according to standards and / or recognized pharmaceutical practices.

[0213] Therefore, according to another aspect of the invention, a pharmaceutical formulation is provided comprising the compound of the invention mixed with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0214] The compounds of the present invention may be administered in combination with other AT2 agonists known in the art, such as C21, and in combination with AT1 receptor antagonists known in the art, and / or in combination with angiotensin-converting enzyme (ACE) inhibitors. Non-limiting but illustrative examples of AT1 receptor antagonists that may be used according to embodiments include azilsartan, candesartan, eprosartan, femasartan, irbesartan, losartan, mifasartan, olmesartan, pomisartan, prasartan, ripsartan, sapridesartan, tasosartan, telmisartan, valsartan, and / or combinations thereof. Non-limiting but illustrative examples of ACE inhibitors that may be used according to the implementation scheme include captopril, zolfenpril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, qundolipril, fosinopril, moxipril, cilazapril, spiropril, temopril, alapril, siropril, delapril, movipril, and / or combinations thereof.

[0215] Other active ingredients that can be used in combination with the compounds of the present invention include disodium cromoglycate; endothelin receptor antagonists, such as bosentan, ambesentan, sitassentan, and macitentan; PDE5 inhibitors, such as sildenafil and tadalafil; cyclic prostaglandins (eprostol) and their analogues, such as iloprost and treprostol; other biologics, including interferon-γ-1b, etanercept, infliximab, and adalimumab; and methotrexate. Other active ingredients under development that can be co-administered with the compounds of this invention include piracetamab (anti-CTGF, Fibrogen); GLPG1690 (autocrine motor factor inhibitor, Galapagos); TD139 (galactoglobulin-3 inhibitor, Galecto); PRM-151 (recombinant pentamericin-2, Promedior); BBT-877 (autocrine motor factor inhibitor, Boehringer / Bridge); CC-90001 (JNK inhibitor, Celgene); PBI-4050 (dual GPR40 agonist / GPR84 antagonist, Prometic); BMS-986020 (lysophosphatidylcholine receptor antagonist, BMS); RVT-1601 (mast cell stabilizer, Respivant); SMO4646 (Wnt signaling inhibitor, United Therapeutics); and KD25 (Rho-associated kinase inhibitor, Kadmon). Holdings, BG00011 (integrin antagonist, Biogen), PLN-74809 (integrin antagonist, Pilant Therapeutics), Saracatinib (src kinase inhibitor, AstraZeneca), PAT-1251 (lysyl oxidase inhibitor 2, PharmAkea), ABM-125 (IL-25MAB, Abeome), and TA5-115 (multi-kinase inhibitor, Otsuka).

[0216] In another aspect of the invention, the compounds of the invention have been found to be particularly useful in combination with other therapeutic agents for combination therapy 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 other therapeutic agents used for the relevant conditions are themselves metabolized by CYP enzymes.

[0217] Therefore, when the condition to be treated is interstitial lung disease, such as IPF, systemic sclerosis, or fibrotic disease known in the art, the compounds of the present invention are preferably administered in combination with galactolectin-3 inhibitors, lysophosphatidylcholine receptor 1 (LPA1) antagonists, autocrine motor factor (ATX) inhibitors, recombinant human pentamin-2 protein, or established therapies for such treatment (including, but not limited to, pirfenidone and / or nintedanib). Preferably, the compounds of the present invention are combined with pirfenidone or a pharmaceutically acceptable salt thereof, said compounds being known to be metabolized by CYP enzymes such as CYP1A.

[0218] Furthermore, when the condition to be treated is chronic kidney-related disease, the compounds of the present invention are preferably administered in combination with one or more other drugs also used for such treatment, such as irbesartan and / or torasemide, said compounds being known to be metabolized by CYP enzymes such as CYP2C9.

[0219] When the condition to be treated is pulmonary hypertension, the compounds of the present invention are preferably administered in combination with one or more other drugs also used for such treatment, such as celecoxib and / or sildenafil, said compounds being known to be metabolized by CYP enzymes such as CYP3A4.

[0220] 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 for such treatment, such as propranolol, warfarin, clopidogrel, atorvastatin, cilostazol, lidocaine and / or simvastatin or pharmaceutically acceptable salts thereof, said compounds being known to be metabolized by CYP enzymes such as CYP1A, CYP2CP and / or CYP3A4.

[0221] When the condition to be treated is an autoimmune disease such as rheumatoid arthritis, multiple sclerosis, or psoriasis, the compounds of the present invention are preferably administered in combination with one or more other drugs also used for such treatment, including but not limited to nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen, celecoxib, meloxicam or analogues thereof (e.g., piroxicam) or indomethacin; or drugs such as tizanidine, cyclophosphamide, cyclosporine, difflux and / or hydrocortisone, riluzole or pharmaceutically acceptable salts thereof, the compounds being known to be metabolized by CYP enzymes such as CYP1A, CYP2CP, CYP2C19 and / or CYP3A4.

[0222] Therefore, the compounds of the present invention are particularly useful for treating diseases or conditions in which activation of AT2 is desired or required but inhibition of CYP enzymes is not desired. They can thus be administered in combination with one or more other therapeutic agents mentioned above to treat diseases including those mentioned above, which are metabolized via the CYP enzyme pathway and are useful or potentially useful, including pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxiconazole, torasemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, difflux, hydrocortisone, lidocaine, celecoxib, sildenafil, and / or simvastatin. Most preferably, the compounds of the present invention are administered in combination with pirfenidone to treat interstitial lung diseases, such as IPF.

[0223] Therapeutic agents that can be used in combination with the compounds of the present invention include standard treatments for a variety of applications of viral infection, including antibody therapies (e.g., LY-CoV555 / LY-CoV016 (barnivir and etexilvir), LY-CoV555 (barnivir, Eli Lilly), REGN-COV2 (cascirelimab and edemumab), REGN3048-3051, TZLS-501, SNG001 (Synairgen), eculizumab (Soliris; Alexion Pharmaceuticals), levomiris (Ultomiris; Alexion Pharmaceuticals), lenzrumab, leuromab, tocilizumab (Actemra; Roche), salimumab (Kevzara; Regeneron)). Pharma) and Octagam (Octapharma)), antiviral drugs (such as oseltamivir, remdesivir, favipiravir, monopicvir, simespirivir, daclatasvir, sofosbuvir, ribavirin, umifenovir, lopinavir, ritonavir, lopinavir / ritonavir (Kaletra; AbbVie DeutschlandGmbH Co.KG), teicoplanin, baricitinib (Olumiant; Eli Lilly), Ruxotinib (Jakavi; Novartis), Tofacitinib (Xeljanz; Pfizer), TMPRSS2 inhibitors camomostat or camomostat mesylate, Actemra (Roche), AT-100 (rhSP-D), MK-7110 (CD24Fc; Merck), OYA1 (OyaGen9), BPI-002 (BeyondSpring), NP-120 (Algernon) Pharmaceuticals) and galaczidox (BiocrystPharma), anti-inflammatory agents (e.g., NSAIDs, such as ibuprofen, ketorolac, naproxen, etc.), chloroquine, hydroxychloroquine, interferons (e.g., interferon beta (interferon beta-1a), tocilizumab (Actemra), lenalidomide, pomalidomide, and thalidomide), analgesics (e.g., acetaminophen or opioids), antitussives (e.g., dextromethorphan), vaccines (e.g., INO-4800 from Inovio Pharmaceuticals and Beijing Advaccine Biotechnology, if available), COVID-19 convalescent plasma (CCP), and / or passive antibody therapy using antibodies from the blood of people who have recovered from SARS-CoV or SARS-CoV-2 infection.

[0224] Other therapeutic agents that may be mentioned include antifibrotic agents (such as nintedanib, specifically dipyfenidone), vitamins (such as vitamins B, C, and D), and mucolytics such as acetylcysteine ​​and ambroxol.

[0225] Other therapeutic agents that can be used in combination with the compounds of the present invention or their pharmaceutically acceptable salts include corticosteroids. Corticosteroids include naturally occurring corticosteroids and synthetic corticosteroids.

[0226] Naturally occurring corticosteroids that may be mentioned include cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, progesterone, and naturally occurring precursors and intermediates in the biosynthesis of corticosteroids, as well as other naturally occurring derivatives of corticosteroids, such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, 18-hydroxy-11-deoxycorticosterone, 18-hydroxycorticosterone, 21-deoxycortisone, 11β-hydroxypregnenolone, 11β,17α,21-trihydroxypregnenolone, 17α,21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 21-hydroxypregnenolone, 11-oxoprogesterone, 11β-hydroxyprogesterone, 17α-hydroxyprogesterone, and 18-hydroxyprogesterone.

[0227] Synthetic corticosteroids that may be mentioned include those of the hydrocortisone type (Group A), such as cortisone acetate, hydrocortisone acetate propionate, hydrocortisone acetate, hydrocortisone propionate and butyl propionate, hydrocortisone butyrate, hydrocortisone valerate, tecortisone and tecortisone neovalerate, prednisolone, methylprednisolone, prednisone, chlorprednisolone, chlorprednisolone alcohol, difluoroprednisolone, fludrocortisone, fluocinolone, flusperidone, etc.

[0228] Fluprednisolone, clotiprednisolone, prednicarbamate, and triamcinolone; dexamethasone and related substances (Group B), such as ancinonide, budesonide, desonide, fluocinolone acetonide, fluocinolone acetate, halcinonide, triamcinolone acetonide, cyclosporine, deficotinide, formococcal, flunisolone, flunisolone acetate, and fluocinolone acetonide; (β) betamethasone-type substances (Group C), such as beclomethasone, betamethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, fluocinolone, halometasone, mometasone and mometasone furoate, aclomethasone and aclomethasone dipropionate, clobetasol and clobetasol propionate, clobetasol and clobetasol butyrate, clocotropin, deshydroxymethasone, diflural ... Fluphenazine, fluclofenoxate, flumethasone, fluocinolone, fluprednisolone and fluprednisolone acetate, fluticasone, fluticasone furoate and fluticasone propionate, methylprednisolone, peramisone, prednisolone, limexolone and ubetasol; progesterone-type steroids, such as fluprogesterone, flumethasone, medroxyprogesterone acetate and prebediolone acetate, and progesterone derivatives (progesterone), such as chlormedrone acetate, cyproterone acetate, meroprogesterone acetate, megestrol acetate and selenium acetate; and other corticosteroids, such as quadiva and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androst-1,4,6-trien-3-one.

[0229] Preferred corticosteroids include cortisone, prednisone, prednisolone, methylprednisolone, and especially dexamethasone.

[0230] In addition, therapeutic agents that can be used in combination with the compounds of the present invention or their pharmaceutically acceptable salts include H2 receptor blockers, anticoagulants, antiplatelet drugs, as well as statins, antimicrobial agents, and anti-allergy / antiasthmatic drugs.

[0231] H2 receptor antagonists that may be mentioned include famotidine. Anticoagulants that may be mentioned include heparin and low molecular weight heparin (e.g., bemiparin, natroparin, reveparin, enoxaparin, parheparin, sertoparin, dalteparin, tinzaparin); direct-acting oral anticoagulants (e.g., dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betriciban, daraxaban, omexaban, litaxaban, iribasilban, hirudin, lepirudin, and bivalirudin); coumarin vitamin K antagonists (e.g., coumarins, acenaphthol, phenylpropargyl, atromanin, and phenylindanedione) and factor Xa synthesis pentasaccharide inhibitors (e.g., fondaparinux sodium, edolipaparin, and biotinylated edrolepane). Antiplatelet drugs that may be mentioned include irreversible cyclooxygenase inhibitors (e.g., aspirin and trifluralin); adenosine diphosphate receptor inhibitors (e.g., cangreloxol, clopidogrel, prasugrel, ticagrelor, and ticlopidine); phosphodiesterase inhibitors (e.g., cilostazol); protease-activated receptor-1 antagonists (e.g., vorapasal); glycoprotein IIB / IIIA inhibitors (e.g., abciximab, efofibatide, and tirofiban); adenosine reuptake inhibitors (e.g., dipyridamole); and thromboxane inhibitors (e.g., terbutaline, ramatroban, cetrastase, and piscotamide). Statins that may be mentioned include atorvastatin, simvastatin, and rosuvastatin. Antimicrobial agents that may be mentioned include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam, and teicoplanin. Antihistamines / asthma medications that may be mentioned include chlorpheniramine, levocetirizine, and montelukast.

[0232] Therefore, the subject may also (and / or may have) received one or more of the other therapeutic agents described above, which means receiving a prescription dose of one or more of those other therapeutic agents before, during and / or after treatment with the compound of the present invention or its pharmaceutically acceptable salt.

[0233] When the compounds of the present invention are "combined" with other therapeutic agents mentioned above, the active ingredients may be administered together in the same formulation or separately (simultaneously or sequentially) in different formulations.

[0234] Such combination products provide for the combined administration of the compounds of the present invention with other therapeutic agents, and can therefore exist as individual formulations, wherein at least one of these formulations contains the compounds of the present invention and at least one of these formulations contains other therapeutic agents, or can exist as combination formulations (i.e., formulations) (i.e., as a single formulation containing the compounds of the present invention and other therapeutic agents).

[0235] Therefore, the following is also provided:

[0236] (1) A pharmaceutical formulation comprising the compounds of the present invention; a therapeutic agent selected from those described above (e.g., a therapeutic agent known to be metabolized by a CYP enzyme); and a pharmaceutically acceptable excipient (e.g., an adjuvant, diluent, or carrier), the formulation being referred to below as a “combination formulation”; and

[0237] (2) A kit containing the following components:

[0238] (A) A pharmaceutical formulation comprising the compound of the present invention mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier; and

[0239] (B) A pharmaceutical preparation comprising a therapeutic agent selected from those described above, mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. (e.g., a therapeutic agent known to be metabolized by CYP enzymes.)

[0240] Components (A) and (B) are each provided in a form suitable for application in combination with the other.

[0241] In another aspect of the invention, a method for preparing a combination formulation as defined above is provided, the method comprising combining the compound of the invention, other therapeutic agents, and at least one (e.g., pharmaceutically acceptable) excipient.

[0242] In another aspect of the invention, a method for preparing a kit as defined above is provided, the method comprising combining components (A) and (B) together. As used herein, reference to combination will mean making the two components suitable for administration in combination with each other.

[0243] Therefore, regarding the preparation method of the kit as defined above, the term "combining" the two components with each other can include the two components of the kit:

[0244] (i) provided as separate formulations (i.e., independently of each other), and then put together for use in combination therapy; or

[0245] (ii) Packaged and presented together as individual components in a “combination package” for use in combination therapy.

[0246] Therefore, a kit is also provided, comprising:

[0247] (I) one of components (A) and (B) as defined herein; and

[0248] (II) Instructions for use of this component in combination with the other of the two components.

[0249] Depending on the patient being treated and the route of administration, the compounds of the present invention can be administered in different doses. Although the dose will vary from patient to patient, a suitable daily dose is in the range of about 0.1 mg to about 1000 mg per patient (e.g., 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, etc., or any range or value thereof), administered in single or multiple doses. A more preferred daily dose is in the range of approximately 0.1 mg to approximately 250 mg per patient (e.g., 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 3...). 5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, etc., or any range or value thereof. Particularly preferred daily doses are in the range of about 0.3 mg to about 100 mg per patient.

[0250] The single dose of the compound of the present invention can be in the range of about 0.1 mg to about 100 mg (e.g. 0.3 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, etc., or any range or value thereof).

[0251] In any case, a physician or technician will be able to determine the actual dosage that will be best suited to the individual patient, which may vary depending on the condition to be treated and the age, weight, sex, and response of the specific patient. The dosages described above are examples of average cases; of course, there may be individual cases where higher or lower dosage ranges are advantageous, and this is within the scope of the invention.

[0252] The beneficial effects of using the compounds of the present invention alone and / or sequentially and / or simultaneously in combination via a route of administration are to produce a customized treatment for patients in need of treatment, with the possibility of preventing and / or reducing side effects, and also to adjust the correct dosage level of the therapeutically effective amount of the compounds of the present invention.

[0253] The kits described herein may include more than one formulation containing an appropriate amount / dosage of the compounds of the present invention, and / or more than one formulation containing an appropriate amount / dosage of other therapeutic agents to provide repeated dosing. If more than one formulation (containing any active compound) is present, such formulations may be identical or may differ in the dosage, chemical composition, and / or physical form of any compound.

[0254] Regarding the kits described herein, the term "combined administration" includes the sequential, individual, and / or simultaneous administration of a corresponding formulation comprising the compounds of the present invention and other therapeutic agents during the treatment of the relevant condition.

[0255] Therefore, with respect to combination products according to the invention, the term "combined administration" includes the administration of two components of the combination product (the compounds of the invention and other therapeutic agents) together or at sufficiently close temporal proximity (optionally repeatedly) such that the beneficial effect on the patient during the treatment of the relevant condition is greater than that of the formulation containing the compounds of the invention or the formulation containing other agents administered alone (optionally repeatedly) in the absence of other components during the same treatment. Determining whether the combination is relevant to a particular condition and provides a greater beneficial effect during the treatment of that condition will depend on the condition to be treated or prevented, but can be conventionally performed by those skilled in the art.

[0256] Furthermore, in the context of the kits according to the invention, the term "combination" includes the possibility that one or the other of two formulations may be administered before, after, and / or simultaneously with the administration of other components (optionally repeatedly). When used in this context, the terms "simultaneous administration" and "administered at the same time" include the administration of a single dose of the relevant compound of the invention and other anti-inflammatory agents within 48 hours (e.g., 24 hours) of each other.

[0257] The pharmaceutical compositions / formulations, combination products and kits described herein may be prepared in accordance with standards and / or recognized pharmaceutical practices.

[0258] Therefore, in another aspect of the invention, a method for preparing a pharmaceutical composition / formulation as defined above is provided, the method comprising combining certain compounds of the invention as defined above with one or more pharmaceutically acceptable excipients (e.g., adjuvants, diluents and / or carriers).

[0259] In other aspects of the invention, a method for preparing a combination product or kit as defined above is provided, the method comprising combining certain compounds of the invention as defined above with other therapeutic agents that can be used to treat related diseases or conditions and at least one pharmaceutically acceptable excipient.

[0260] Subjects suitable for treatment with the formulations of the present invention include, but are not limited to, mammalian subjects, specifically human subjects.

[0261] When used herein with respect to specific values ​​(such as quantities), the term “about” (or similar terms such as “approximately”) should be understood to indicate that such a value may vary by a defined value by up to 10% (specifically, up to 5%, such as up to 1%). It is anticipated that in each case, such a term may be replaced by the symbol “±10%” or similar (or by indicating a change in a specific quantity calculated based on the relevant value). It is also anticipated that in each case, such a term may be deleted.

[0262] The advantages of the compounds of the present invention are that they are more effective and / or stable to metabolic hydrolysis, and / or do not inhibit the CYP enzymes mentioned above.

[0263] The compounds of this invention also have the advantages of being more effective, less toxic, having a longer duration of action, being more potent, producing fewer side effects, being more easily absorbed, and / or having better pharmacokinetic properties (e.g., higher oral bioavailability and / or lower clearance) and / or other useful pharmacological, physical, or chemical properties than compounds known in the prior art, whether used to treat IPF or other conditions. These effects can be clinically, objectively, and / or subjectively evaluated by healthcare professionals, treatment subjects, or observers.

[0264] Example

[0265] The invention will be further described with reference to the following embodiments, which are not intended to limit the scope of the invention.

[0266] If there is a discrepancy between the name and the illustration for any compound, the latter shall prevail (unless it contradicts any experimental details that may be given or unless it is clearly apparent from the context).

[0267] Experimental Procedure

[0268] The starting materials and intermediates used to synthesize the compounds described herein are commercially available or can be prepared by the methods described herein or by methods known in the art.

[0269] Experiments are usually conducted in an inert atmosphere (nitrogen or argon), especially when using oxygen or moisture-sensitive reagents or intermediates.

[0270] Mass spectrometry data are reported by liquid chromatography-mass spectrometry (LC-MS). Chemical shifts in NMR data are expressed in parts per million (ppm, δ), with reference to residual peaks from the deuterated solvent used.

[0271] For synthesis following a general procedure, reaction conditions (such as reaction length or temperature) can be varied. Generally, thin-layer chromatography or LC-MS is performed after the reaction, with post-processing as appropriate. Purification can vary between experiments: generally, the solvent and solvent ratio used for the eluent / gradient are selected to provide appropriate R... f And / or retention time. Some products were purified using supercritical fluid chromatography, for example on a reversed-phase column using a solvent combination with mobile phase A; CO2 and B: MeOH / H2O / NH3-. Some compounds were purified using preparative HPLC, rapid column chromatography, or a manual C18 reversed-phase column with H2O / MeCN polarity.

[0272] Example

[0273] Example 1

[0274] Butyl(3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonate Acyl carbamate trifluoroacetic acid

[0275] (a) 1-[(4-bromo-2-fluorophenyl)methyl]-2-methyl-1H-imidazolium

[0276] 4-Bromo-1-(bromomethyl)-2-fluorobenzene (16.1 g, 60 mmol), 2-methyl-1H-imidazole (14.8 g, 180 mmol), and potassium carbonate (24.9 g, 180 mmol) were stirred in DMF (80 mL) for 3 hours at 50 °C. The reaction mixture was cooled to ambient temperature. Water (150 mL) was added, and the reaction mixture was extracted with diethyl ether (2 × 250 mL). The combined organic phases were washed with water (3 × 200 mL) and brine (200 mL) and dried over Na₂SO₄. Evaporation yielded an oily substance, which solidified into a white solid upon the addition of n-heptane. The isolated subtitle compound was 11.8 g (73%).

[0277] 1H-NMR (400MHz, DMSO-d6) δ7.60 (dd, J=9.8, 1.8Hz, 1H), 7.42 (dd, J=8.2, 1.7Hz, 1H) ,7.06(s,br,1H),6.96(t,J=8.2Hz,1H),6.76(s,br,1H),5.16(s,2H),2.24(s,3H).

[0278] (b) N-tert-butyl-3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutylthiophene- 2-Sulfanamide

[0279] In a screw-capped vial (40 mL), [2-(tert-butylaminosulfonyl)-5-(2-methylpropyl)thiophen-3-yl]boronic acid (2.24 g, 7.0 mmol), the subtitle compound obtained from step (a) above (1.70 g, 6.3 mmol), potassium carbonate (2.91 g, 21.0 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (513 mg, 0.70 mmol) were mixed in 1,4-dioxane (25 mL) and water (8 mL). The reaction mixture was thoroughly degassed (by bubbling Ar through a stirred suspension). The reaction mixture in the sealed vial was vigorously stirred and heated at 80 °C for 2 hours. After cooling the reaction mixture to room temperature, water and EtOAc were added, the phases were separated, and the organic phase was filtered through diatomaceous earth. The filtrate was washed with brine, dried (MgSO4), and evaporated to dryness. The mixture was then placed in silica gel (Autoflash, Biotage). The crude product was purified using a Silica (60 μm, 25 g) mobile phase. The mobile phase consisted of DCM and DCM / MeOH / NH3 (28%) = 100 / 10 / 1. The gradient of the latter mobile phase was 5%–60%. The obtained subtitle compound was 3.00 g (92%).

[0280] 1 H-NMR (400MHz, DMSO-d6) δ7.45(m,2H),7.37(d,J=8.0Hz,1H),7.09(s,1H),7.05(t,J=8.0Hz,1H),6.97(s,1H),6.77(s, 1H), 5.22 (s, 2H), 2.68 (d, J = 7.0Hz, 2H), 2.26 (s, 3H), 1.87 (dp, J = 13.6, 6.8Hz, 1H), 0.96 (s, 9H), 0.92 (d, J = 6.6Hz, 6H).

[0281] (c) 3-[3-fluoro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide

[0282] In a screw-capped vial, the subtitle compound (1.0 g, 2.1 mmol) obtained from step (b) above was dissolved in DCM (10 mL). Triethylsilane (1.5 mL) and TFA (10 mL) were added. The reaction mixture was kept at 43 °C overnight. The reaction mixture was evaporated to give a brown oil, which was partitioned between EtOAc (250 mL) and NaHCO3 (saturated aqueous solution, 25 mL). After phase separation, the organic phase was washed with brine, dried (MgSO4), and evaporated to give a brown oil (920 mg). The solution was then placed in silica gel (Autoflash, Biotage). Purification was performed on a Silica (60 μm, 25 g) mobile phase. The mobile phase consisted of DCM and DCM / MeOH / NH3 (28%) = 100 / 10 / 1. The gradient of the latter mobile phase was 5%–50%. The isolated subtitle compound was 720 mg (82%).

[0283] 1 H-NMR (400MHz, DMSO-d6) δ7.67(s,2H),7.51(s,1H),7.39(d,J=9.1Hz,1H),7.11(s,1H),7.03(t,J=8.0Hz,1H),6.96(s, 1H), 6.78 (s, 1H), 5.22 (s, 2H), 2.68 (d, J = 7.0Hz, 2H), 2.28 (s, 3H), 1.89 (dt, J = 13.3, 6.5Hz, 1H), 0.93 (d, J = 6.6Hz, 6H).

[0284] (d) Ethyl N-[(3-{3-fluoro-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-5-isobutylthiophene-2- [Sulfoyl]carbamate trifluoroacetic acid

[0285] At 0 °C, the subtitle compound (41 mg, 100 μmol), ethyl chloroformate (16 mg, 150 μmol), and triethylamine (31 mg, 300 μmol) obtained from step (c) above were mixed in 4 mL of DCM and stirred in a sealed vial for 1 hour. The solvent was removed under reduced pressure. The residue was diluted with water and acetonitrile, acidified with TFA, and purified by reversed-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, 12 min gradient, 25 mL / min). The purified fractions were collected and lyophilized. The isolated title compound was 22 mg (37%).

[0286] 1H-NMR (400MHz, DMSO-d6) δ7.64(d,J=1.9Hz,1H),7.62(d,J=2.0Hz,1H),7.49–7.34(m,3H),6.99(s,1H),5.50(s,2H),3.97(q, J=7.1Hz,2H),2.73(d,J=7.0Hz,2H),2.61(s,3H),1.89(dp,J=13.1,6.5Hz,1H),1.05(t,J=7.1Hz,3H),0.93(d,J=6.6Hz,6H). HPLC purity (220nm): >95%. LCMS(ESI + ): m / z[M+H] + Calculated value: 480, measured value: 480.

[0287] Example 2

[0288] Butyl(3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonate Acyl carbamate trifluoroacetic acid

[0289] The title compound was prepared by a method similar to that described in Example 1, except for the additional final step (e), in which ethyl (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate (36 mg, 75 μmol; see Example 1 above) and butanol (200 μL) were mixed in pure and stirred at 90 °C for 1 hour in a sealed vial.

[0290] The reaction mixture was diluted with water and acetonitrile, acidified with TFA, and purified by reversed-phase chromatography (Gemini NX-C18, 21*150 mm, water (0.1% TFA) / acetonitrile, 12 min gradient, 25 mL / min). The purified fractions were collected and lyophilized. The isolated title compound was 27 mg (58%).

[0291] 1H-NMR (400MHz, DMSO-d6) δ7.63(d,J=5.2Hz,2H),7.47–7.41(m,2H),7.36(d,J=8.9Hz,1H),7.01(s,1H),5.50(s,2H),3.95(t,J=6.5Hz,2H),2.73(d, J=7.0Hz,2H),2.61(s,3H),1.89(dp,J=13.8,6.9Hz,1H),1.40(p,J=6.6Hz , 2H), 1.17 (h, J = 7.4Hz, 2H), 0.94 (d, J = 6.6Hz, 6H), 0.81 (t, J = 7.4Hz, 3H). HPLC purity (220nm): >95%. LCMS(ESI + ): m / z[M+H] + Calculated value: 508, measured value: 508.

[0292] Example 3

[0293] 2-Methoxyethyl(3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene- 2-yl)sulfonylcarbamate trifluoroacetic acid

[0294] The title compound was prepared by a method similar to that described in Example 2, except that methoxyethanol was used in the final step. The isolated title compound was 27 mg (58%).

[0295] 1 ¹H-NMR (400MHz, DMSO-d⁶) δ 7.68–7.59 (m, 2H), 7.49–7.36 (m, 3H), 6.98 (s, 1H), 5.49 (s, 2H), 4.10–4.04 (m, 2H), 3.19 (s, 3H), 2.73 (d, J = 7.0Hz, 2H), 2.61 (s, 3H), 1.89 (dp, J = 13.1, 6.4Hz, 1H), 0.94 (d, J = 6.6Hz, 6H). A -CH₂- peak was observed in the water. HPLC purity (220nm): >95%. LCMS (ESI) + ): m / z[M+H] + Calculated value: 510, measured value: 510.

[0296] Example 4

[0297] 2-Hydroxyethyl(3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2- 2-(2-)sulfonyl carbamate trifluoroacetic acid

[0298] The title compound was prepared by a method similar to that described in Example 2, except that ethylene glycol was used in the final step. The isolated title compound was 16 mg (52%).

[0299] 1 H-NMR (400MHz, DMSO-d6) δ7.66–7.60(m,2H),7.47(d,J=11.1Hz,1H),7.44–7.35(m,2H),6.98(s,1H),5.49(s,2H),3.97(t ,J=4.9Hz,2H),3.49–3.43(m,2H),2.73(d,J=7.0Hz,2H),2.61(s,3H),1.90(dq,J=13.6,6.7Hz,1H),0.94(d,J=6.6Hz,6H). HPLC purity (220nm): >90%. LCMS(ESI + ): m / z[M+H] + Calculated value: 496, measured value: 496.

[0300] Example 5

[0301] 3,3,3-Trifluoropropyl(3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiazolyl phen-2-yl)sulfonyl carbamate trifluoroacetic acid

[0302] The title compound was prepared by a method similar to that described in Example 2, except that ethyl (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate was used, 3,3,3-trifluoropropanol was employed in the final step, and the reaction was stirred overnight at 90°C instead of 1 hour. The isolated title compound was 21 mg (41%).

[0303] 1 H-NMR (400MHz, DMSO-d6) δ7.70–7.63(m,2H),7.47(d,J=11.1Hz,1H),7.42–7.36(m,2H),6.99(s,1H),5.52(s,2H),4.18(t,J=5.8Hz,2H), 3.01(q,J=7.5Hz,2H),2.72(d,J=7.0Hz,2H),2.60–2.52(m,2H),1.89(dp,J=13.3,6.6Hz,H),1.24(t,J=7.5Hz,3H),0.93(d,J=6.6Hz,6H). HPLC purity (220nm): >95%. LCMS(ESI + ): m / z[M+H] + Calculated value: 562, measured value: 562.

[0304] Example 6

[0305] 4-Fluorobenzyl(3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiazolyl

[0306] phen-2-yl)sulfonyl carbamate trifluoroacetic acid

[0307] The title compound was prepared by a method similar to that described in Example 2, except that ethyl (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate was used, 4-fluorobenzyl alcohol was used in the final step, and the reaction was stirred overnight at 90°C instead of 1 hour. The isolated title compound was 33 mg (64%).

[0308] 1 H-NMR (400MHz, DMSO-d6) δ7.66–7.61(m,2H),7.45(d,J=11.1Hz,1H),7.40–7.33(m,2H),7.29–7.25(m,2H),7.20–7.14(m,2H),6.97(s,1H),5.5 1(s,2H),4.99(s,2H),2.98(q,J=7.5Hz,2H),2.70(d,J=7.0Hz,2H),1.86(dp,J=13.2,6.5Hz,1H),1.22(t,J=7.5Hz,3H),0.92(d,J=6.6Hz,6H). HPLC purity (220nm): >95%. LCMS(ESI + ): m / z[M+H] + Calculated value: 574, measured value: 574.

[0309] Example 7

[0310] Ethyl(3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophene-2-

[0311] 2-(2-)sulfonyl carbamate trifluoroacetic acid

[0312] The title compound was prepared by a method similar to that described in Example 1, except that 2-ethyl-1H-imidazole was used. The isolated subtitle compound was 29 mg (64%).

[0313] 1H-NMR (400MHz, DMSO-d6) δ7.69–7.64(m,2H),7.47–7.33(m,3H),7.00(s,1H),5.53(s,2H),3.99(q,J=7.1Hz,2H),3.00(q,J=7.5 Hz, 2H), 2.73 (d, J = 7.0Hz, 2H), 1.89 (dp, J = 13.5, 6.7Hz, 1H), 1.24 (t, J = 7.5Hz, 3H), 1.06 (t, J = 7.1Hz, 3H), 0.93 (d, J = 6.6Hz, 6H). HPLC purity (220nm): >95%. LCMS(ESI + ): m / z[M+H] + Calculated value: 494, measured value: 494.

[0314] Example 8

[0315] Ethyl(3-(3-fluoro-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl) sulfonyl carbamate trifluoroacetic acid

[0316] The title compound was prepared by a method similar to that described in Example 1, except that 2-isopropyl-1H-imidazole was used. The isolated title compound was 42 mg (90%).

[0317] 1 ¹H-NMR (400MHz, DMSO-d⁶) δ 7.72 (d, J = 1.9Hz, 1H), 7.64 (d, J = 1.8Hz, 1H), 7.45 (d, J = 10.9Hz, 1H), 7.43–7.35 (m, 2H), 7.00 (s, 1H), 5.59 (s, 2H), 4.00 (q, J = 7.1Hz, 2H), 3.59–3.53 (m, 1H, overlapping with water peak), 2.73 (d, J = 7.0Hz, 2H), 1.89 (dp, J = 13.4, 6.7Hz, 1H), 1.26 (d, J = 6.9Hz, 6H), 1.07 (t, J = 7.1Hz, 3H), 0.93 (d, J = 6.6Hz, 6H). HPLC purity (220nm): >95%. LCMS (ESI) + ): m / z[M+H] + Calculated value: 508, measured value: 508.

[0318] Example 9

[0319] (3-(3-fluoro-4-((2-methylimidazol-1-yl)methyl]phenyl)-5-isobutyl-2-thienyl)sulfonylamino 2-Phenoxyethyl formate

[0320] Butyl (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-yl)sulfonylcarbamate (90 mg, 177 μmol; prepared according to Example 2 above) and 2-phenoxyethanol (245 mg, 1773 μmol) were added to dioxane (10 mL). The mixture was refluxed overnight, and then the solvent was evaporated. The crude product was dissolved in acetonitrile and purified by supercritical fluid chromatography. The isolated title compound was 10 mg (10%).

[0321] 1 H-NMR(CDCl3): 0.96(6H,d),1.90(1H,m),2.62(3H,s),2.63(2H,d),3.97(2H,t),4.26(2H,t),4.89(2H,s) ,6.54(1H,s),6.68(1H,s),6.78(2H,d),6.88(1H,s),6.94(2H,t),7.24(2H,m),7.34(1H,d),7.63(1H,d).

[0322] Example 10

[0323] (1-Hydroxycyclopentyl)methyl-(3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)-phenyl)-5-iso Butylthiophene-2-yl)sulfonyl carbamate

[0324] The title compound was prepared by a method similar to that described in Example 2, except that 1-(hydroxymethyl)cyclopentanol was used in the final step.

[0325] Example 11

[0326] (1-Hydroxycyclohexyl)methyl-(3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)-phenyl)-5-iso Butylthiophene-2-yl)sulfonyl carbamate

[0327] The title compound was prepared by a method similar to that described in Example 2, except that 1-(hydroxymethyl)cyclohexanol was used in the final step.

[0328] Example 12

[0329] 2-((((3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl Acyl)carbamoyl)oxy)ethylpropionate

[0330] The title compound was prepared by a method similar to that described in Example 2, except that 2-hydroxyethyl propionate was used in the final step.

[0331] Example 13

[0332] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl 2-Hydroxybutyl carbamate

[0333] The title compound was prepared by a method similar to that described in Example 2, except that butane-1,2-diol was used in the final step.

[0334] Example 14

[0335] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)-phenyl)-5-isobutylthiophen-2-yl)sulfonyl 2-Hydroxy-2-methylpropyl carbamate

[0336] The title compound was prepared by a method similar to that described in Example 2, except that 2-methylpropane-1,2-diol was used in the final step.

[0337] Example 15

[0338] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl 2-Ethoxyethyl carbamate

[0339] The title compound was prepared by a method similar to that described in Example 2, except that 2-ethoxyethanol was used in the final step.

[0340] Example 16

[0341] (1-Hydroxycyclohexyl)methyl-(3-(3-fluoro-4-((2-ethyl-1H-imidazol-1-yl)methyl)-phenyl)-5-iso Butylthiophene-2-yl)sulfonyl carbamate

[0342] The title compound was prepared by means similar to that described in Example 2, except that 2-ethyl-1H-imidazole was used and 1-(hydroxymethyl)cyclohexanol was used in the final step.

[0343] Example 17

[0344] (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl 2-Hydroxyethyl Acylcarbamate

[0345] (a) 1-(4-Bromo-2-fluorobenzyl)-2-(tert-butyl)-1H-imidazolium

[0346] At 0 °C, NaH (0.460 g, 12.0 mmol, 1.5 equivalents) was added to a stirred solution of 2-tert-butyl-1H-imidazolium (1.02 g, 8.21 mmol, 1 equivalent) in DMF (0.27 M). After 20 minutes, 4-bromo-1-(bromomethyl)-2-fluorobenzene (2.20 g, 8.21 mmol, 1 equivalent) was added. The resulting mixture was heated to ambient temperature and stirred overnight, then quenched with water (15 mL). The crude product was purified by FCC (30% EtOAc in isohexane solution) to give a product as a pale yellow amorphous solid (2.56 g, 39% yield).

[0347] 1¹H-NMR (400MHz, chloroform-d) δ 7.24 (dd, J = 9.5, 1.9 Hz, 1H), 7.21–7.16 (m, 1H), 6.93 (d, J = 1.4 Hz, 1H), 6.67 (d, J = 1.4 Hz, 1H), 6.55 (t, J = 8.1 Hz, 1H), 5.25 (s, 2H), 1.35 (s, 9H). 19 F-NMR (376MHz, chloroform-d) δ-115.61 (t, J=8.7Hz).

[0348] (b) N-tert-butyl-3-[4-[(2-tert-butylimidazol-1-yl)methyl]-3-fluorophenyl]-5-isobutylthiophene-2- sulfonamide

[0349] The subtitle compound obtained from step (a) above (3.1 g, 10 mmol), N-tert-butyl-5-isobutylthiophene-2-sulfonamide (3.2 g, 10 mmol), K₂CO₃ (4.1 g, 30 mmol), and Pd(PPh₃)₄ (289 mg, 250 μmol) were added to dioxane (100 mL) and water (10 mL). The reaction 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). The product was separated from the diethyl ether by chromatography. The isolated subtitle compound was 4.6 g (95%).

[0350] 1 H-NMR(CDCl3): 0.97(d,6H),1.04(s,9H),1.41(s,9H),1.91(m,1H),2.68(d,2H),5.38 (s,2H),6.72(s,1H),6.73(s,1H),6.78(t,1H),6.97(s,1H),7.32(d,1H),7.43(d,1H).

[0351] (c) 3-[4-[(2-tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutylthiophene-2-sulfonamide

[0352] The subtitle compound (3.5 g, 6.9 mmol) obtained from step (b) above was dissolved in DCM (45 mL). Boron trichloride (21 mL, 1 M DCM solution) was added, and the solution was stirred at room temperature for 3 hours. Na₂CO₃ (saturated, 20 mL) was added, and the product was extracted with diethyl ether (40 mL). Chromatographic separation was performed from DCM:MeOH (90:10). The isolated subtitle compound was 2.8 g (90%).

[0353] 1H-NMR(CDCl3): 0.98(d,6H),1.40(s,9H),1.91(m,1H),2.67(d,2H),5.37(s,2H),6.72-6.80(m,3H),6.95(s,1H),7.30(d,1H),7.39(d,1H).

[0354] (d) N-[[3-[4-[(2-tert-butylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutyl-2-thienyl]sulfonyl 2-Hydroxyethyl carbamate (acyl)

[0355] The subtitle compound (450 mg, 330 μmol) obtained from step (c) above, diphenyl carbonate (106 mg, 495 μmol), and K₂CO₃ (91 mg, 660 μmol) were dissolved in acetonitrile (15 mL), and the reaction mixture was heated overnight at 60 °C under a nitrogen atmosphere. The solid was filtered off, and the solvent was evaporated. The crude product and ethylene glycol (62 mg, 1 mmol) were dissolved in dioxane (10 mL). The reaction mixture was heated to 60 °C overnight. The solvent was evaporated, and 70 mg of the crude product was purified by HPLC and separated into CF₃COOH- salt.

[0356] 1 ¹H NMR (CD₃OD): 0.98 (d, 6H), 1.62 (s, 9H), 1.93 (m, 1H), 2.70 (d, 2H), 3.62 (t, 2H), 3.98 (t, 2H), 5.48 (s, 2H), 6.75 (s, 1H), 7.07 (s, 1H), 7.20–7.25 (b, 2H), 7.30–7.38 (b, 2H). MS (M+H): 538.0, calculated 538.2.

[0357] Example 18

[0358] (3-(3,5-difluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonate 2-Hydroxyethyl Acylcarbamate

[0359] The title compound was prepared by a method similar to that described in Example 17, except that 4-bromo-1-(bromomethyl)-3,5-fluorobenzene (1 equivalent) was used in step (a). 36 mg of the final product was isolated.

[0360] 1 ¹H-NMR (CDCl₃): 0.97 (d, 6H), 1.92 (m, 1H), 2.69 (d, 2H), 2.71 (s, 3H), 3.62 (t, 2H), 4.03 (t, 2H), 5.28 (s, 2H), 6.72 (s, 1H), 7.15 (s, 1H), 7.18 (s, 1H), 7.21 (s, 2H). MS (M+H): 466.1, calculated value 466.1.

[0361] Example 19

[0362] 2-((((3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl Acyl)carbamoyl)oxy)ethyl neopentanoate

[0363] 2-Hydroxyethyl (3-(3-fluoro-4-((2-methylimidazol-1-yl)methyl)phenyl)-5-isobutyl-2-thienyl)sulfonylcarbamate (62 mg, 125 μmol; prepared as described in Example 4) and N-ethyldiisopropylamine (32 mg, 250 μmol) were dissolved in DCM (25 mL). Neopentanoyl chloride (23 mg, 188 μmol) was added to the solution, and the reaction mixture was stirred at room temperature for 4 hours. The solvent was then evaporated, and 25 mg of the crude product was purified by HPLC.

[0364] 1 ¹H-NMR (CDCl₃): 1.00 (d, 6H), 1.17 (s, 9H), 1.95 (m, 1H), 2.72 (d, 2H), 2.84 (s, 3H), 4.21 (t, 2H), 4.31 (t, 2H), 5.25 (s, 2H), 6.74 (s, 1H), 7.10 (s, 1H), 7.20–7.45 (m, 4H). MS (M+H): 580.2, calculated value 580.2.

[0365] Example 20

[0366] (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl Methyl acylcarbamate

[0367] 3-(4-((2-tert-butylimidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophene-2-sulfonamide (116 mg, 258 μmol; prepared as described in Example 17) and N-ethyldiisopropylamine (180 μL, 1032 μmol) were dissolved in DCM (15 mL). Methyl chloroformate (60 μL, 774 μmol) was added to the solution, and the reaction mixture was stirred at room temperature for 3 hours. The solvent was then evaporated, and 53 mg of the crude product was purified by HPLC and separated as a CF3COOH salt.

[0368] 1 ¹H-NMR (CDCl₃): 0.99 (d, 6H), 1.66 (s, 9H), 1.97 (m, 1H), 2.73 (d, 2H), 3.70 (s, 3H), 5.49 (s, 2H), 6.76 (s, 1H), 6.96 (s, 1H), 7.05 (t, 1H), 7.36 (m, 2H), 7.50 (s, 1H). MS (M+H): 508.0, calculated 508.2.

[0369] Example 21

[0370] (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl Methyl carbamate

[0371] The title compound was prepared by a method similar to that described in Example 20, except that 3-[3-fluoro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide (246 mg, prepared as described in Example 1) was used. 67 mg of the final product was obtained.

[0372] 1 ¹H-NMR (CDCl₃): 1.00 (d, 6H), 1.97 (m, 1H), 2.73 (d, 2H), 2.84 (s, 3H), 3.71 (s, 3H), 5.29 (s, 2H), 6.74 (s, 1H), 7.09 (t, 1H), 7.26–7.40 (m, 4H). MS (M+H): 466.1, calculated value 466.1.

[0373] Example 22

[0374] N-((3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl Neopentylamide

[0375] The same steps as in Example 20 were used, except that 3-[3-fluoro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide (155 mg; prepared as described in Example 1) and neopentanoic anhydride (117 mg) were used. 36 mg of the final product was obtained.

[0376] 1 ¹H-NMR (CDCl₃): 0.88 (s, 9H), 0.90 (d, 6H), 1.87 (m, 1H), 2.44 (s, 3H), 2.64 (d, 2H), 5.12 (s, 2H), 6.66 (s, 1H), 6.92 (s, 1H), 6.97 (s, 1H), 7.25–7.31 (m, 2H). MS (M+H): 492.2, calculated value 492.2.

[0377] Example 23

[0378] (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluoro-phenyl)-5-isobutylthiophen-2-yl)sulfonyl 2-Hydroxy-2-methylpropyl acylcarbamate

[0379] The same steps as in Example 17 were used, except that 2-methyl-1,2-propanediol (90 mg, 1000 μmol) was used. 35 mg of the final product in the form of CF3COOH salt was isolated.

[0380] 1 ¹H-NMR (CDCl₃): 0.99 (d, 6H), 1.14 (s, 6H), 1.61 (s, 9H), 1.94 (m, 1H), 2.72 (d, 2H), 3.89 (s, 2H), 5.50 (s, 2H), 6.77 (s, 1H), 7.11 (m, 2H), 7.30–7.40 (b, 3H). MS (M+H): 566.0, calculated 566.2.

[0381] Example 24

[0382] (3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl 2-Hydroxyethyl carbamate

[0383] (a) N-tert-butyl-3-[4-[(2-ethylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutylthiophene-2-sulfonyl amide

[0384] The title compound was prepared by a method similar to that described in Example 17, except that 1-[(4-bromo-2-fluoro-phenyl)methyl]-2-ethyl-imidazolium (2.5 g) was used in step (b). The subtitle product was isolated in 88% yield.

[0385] 1 H-NMR(CDCl3): 0.93(d,6H),1.09(s,9H),1.32(t,3H),1.92(m,1H),2.65-2.70(m,4H),5. 13(s,2H),6.71(s,1H),6.82(s,1H),6.88(t,1H),7.03(s,1H),7.31(d,1H),7.38(d,1H).

[0386] (b) 3-[4-[(2-ethylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutylthiophene-2-sulfonamide The subtitle compound was prepared by a method similar to that described in Example 17, except that 3.7 g of the subtitle compound obtained from step (a) above was used. The subtitle compound was isolated in 77% yield.

[0387] 1 H-NMR(CDCl3): 0.98(d,6H),1.35(t,3H),1.91(m,1H),2.67(d,2H),2.83(q,2H),5.18 (s,2H),6.74(s,1H),6.96(s,1H),7.01(t,1H),7.06(s,1H),7.38(d,1H),7.46(d,1H).

[0388] (c) (3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl 2-Hydroxyethyl carbamate

[0389] The compound was prepared by a method similar to that described in Example 17, except that the subtitle (211 mg) and ethylene glycol (93 mg) obtained from step (b) above were used. 11 mg of the final product in the form of CF3COOH-salt was isolated.

[0390] 1 ¹H-NMR (CDCl₃): 0.99 (d, 6H), 1.42 (t, 3H), 1.94 (m, 1H), 2.71 (d, 2H), 3.10 (q, 2H), 3.67 (t, 2H), 4.05 (t, 2H), 5.30 (s, 2H), 6.75 (s, 1H), 7.20–7.40 (m, 5H). MS (M+H): 510.0, calculated 510.2.

[0391] Example 25

[0392] (3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl Methyl carbamate

[0393] The same steps as in Example 20 were used, except that 3-[4-[(2-ethylimidazol-1-yl)methyl]-3-fluoro-phenyl]-5-isobutylthiophene-2-sulfonamide (118 mg; prepared as described in Example 24) was used. 34 mg of the final product was obtained.

[0394] 1 H-NMR(CDCl3): 0.99(d,6H),1.41(t,3H),1.96(m,1H),2.72(d,2H),3.09(q,2H),3 .69(s,3H),5.28(s,2H),6.74(s,1H),7.13(s,1H),7.19(t,1H),7.26-7.35(m,3H).

[0395] MS(M+H): 480.0, calculated value 480.1.

[0396] Example 26

[0397] N-((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl) sulfonyl)benzamide

[0398] 3-(4-((2-tert-butylimidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophene-2-sulfonamide (135 mg, 0.3 mmol; prepared as described in Example 17), benzoic acid (46 mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol), and N,N-dimethylaminopyridine (44 mg, 0.36 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 hours. HCl (1 M, 10 mL) was added, and the reaction mixture was stirred for another 2 hours. The organic layer was washed with water (10 mL), HCl (1 M, 10 mL), and water (10 mL). The organic layer was dried, filtered, and the solvent was evaporated. The final product was purified by HPLC, and 11 mg of CF3COOH- salt was isolated.

[0399] 1 ¹H-NMR (CDCl₃): 1.00 (d, 6H), 1.56 and 1.64 (s, 9H, two peaks attributed to hindered rotation), 1.97 (m, 1H), 2.73 (d, 2H), 5.46 and 5.56 (s, 2H, hindered rotation), 6.66 (s, 1H), 6.74 (m, 2H), 7.30–7.70 (m, 9H). MS (M+H): 553.9, calculated 554.2.

[0400] Example 27

[0401] N-((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl) sulfonyl)pyridine amide

[0402] The same steps as described in Example 26 were used, except that pyridinecarboxylic acid (46 mg, 1.3 equivalents) was used. 26 mg of the product was isolated.

[0403] 1 ¹H-NMR (CDCl₃): 1.00 (d, 6H), 1.65 (s, 9H), 1.96 (m, 1H), 2.72 (d, 2H), 5.47 (s, 2H), 6.75 (s, 1H), 6.88 (s, 1H), 7.05 (t, 1H), 7.37 (m, 2H), 7.49 (s, 1H), 7.56 (m, 1H), 7.91 (t, 1H), 8.12 (d, 1H), 8.53 (d, 1H). MS (M+H): 555.0, calculated 555.2.

[0404] Example 28

[0405] (3-(2-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl Butyl carbamate

[0406] The title compound was prepared by a method similar to that described in Example 2 above, except that 1-bromo-4-(bromomethyl)-2-fluorobenzene was used.

[0407] Example 29

[0408] (3-(3-fluoro-4-((2-isopropylimidazol-1-yl)methyl)phenyl)-5-isobutyl-2-thienyl)sulfonylamino 2-Hydroxyethyl carbamate

[0409] (a) N-tert-butyl-3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutylthiophene-2- sulfonamide

[0410] The subtitle compound was prepared by a method similar to that described in step (b) of Example 17 above, except that 1-[(4-bromo-2-fluoro-phenyl)methyl]-2-isopropyl-imidazolium (2.6 g, 1 equivalent) was used. The subtitle compound was isolated in 99% yield.

[0411] 1 H-NMR(CDCl3): 0.96(d,6H),1.03(s,9H),1.29(d,6H),1.90(m,1H),2.66(d,2H),2.99(m,1H) ,5.16(s,2H),6.71(s,1H),6.82(s,1H),6.89(t,1H),7.02(s,1H),7.32(d,1H),7.40(d,1H).

[0412] (b) 3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide

[0413] The subtitle compound was prepared by a method similar to step (c) of Example 17 above, except that the subtitle compound (4.3 g) obtained from step (a) above was used. The subtitle compound was isolated in 89% yield.

[0414] 1 H-NMR(CDCl3): 0.98(d,6H),1.29(d,6H),1.91(m,1H),2.67(d,2H),3.01(m,1H),5.20 (s,2H),6.74(s,1H),6.83(s,1H),6.88(t,1H),6.99(s,1H),7.32(d,1H),7.38(d,1H).

[0415] (c) (3-(3-fluoro-4-((2-isopropylimidazol-1-yl)methyl)phenyl)-5-isobutyl-2-thienyl)sulfonyl 2-Hydroxyethyl carbamate

[0416] The subtitle compound was prepared by a method similar to step (d) of Example 17 above, except that the subtitle compound (218 mg) and ethylene glycol (93 mg) obtained from step (b) above were used in the final step. 109 mg of the final product in the form of the CF3COOH-salt was isolated.

[0417] 1 ¹H-NMR (CDCl₃): 0.98 (d, 6H), 1.42 (d, 6H), 1.93 (m, 1H), 2.70 (d, 2H), 3.41 (m, 1H), 3.63 (t, 2H), 4.01 (t, 2H), 5.32 (s, 2H), 6.74 (s, 1H), 7.17 (s, 1H), 7.20–7.40 (b, 4H). MS (M+H): 523.9, calculated 524.2.

[0418] Example 30

[0419] (3-(3-fluoro-4-((2-isopropylimidazol-1-yl)methyl)phenyl)-5-isobutyl-2-thienyl)sulfonylamino Methyl carbamate

[0420] The title compound was prepared by a method similar to that described in Example 20, except that 3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide (110 mg) and methyl chloroformate (72 mg) were used. 8 mg of the product was isolated.

[0421] 1 ¹H-NMR (CDCl₃): 1.02 (d, 6H), 1.57 (d, 6H), 1.98 (m, 1H), 2.75 (d, 2H), 3.42 (m, 1H), 3.74 (s, 3H), 5.34 (s, 2H), 6.76 (s, 1H), 7.11 (s, 1H), 7.20 (t, 1H), 7.32–7.39 (m, 2H), 7.45 (s, 1H). MS (M+H): 493.9, calculated 494.2.

[0422] Example 31

[0423] N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl [Benzoamide]

[0424] The title compound was prepared by a method similar to that described in Example 26, except that 3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide (87 mg) was used. 38 mg of the final product was isolated.

[0425] 1¹H-NMR (CDCl₃): 1.03 (d, 6H), 1.52 (d, 6H), 1.99 (m, 1H), 2.76 (d, 2H), 3.37 (m, 1H), 5.30 (s, 2H), 6.74 (s, 1H), 7.04 (t, 1H), 7.10 (s, 1H), 7.17 (d, 1H), 7.22 (d, 1H), 7.43–7.49 (m, 3H), 7.64 (t, 1H), 7.68–7.74 (m, 2H), 8.53. MS (M+H): 540.0, calculated 540.2.

[0426] Example 32

[0427] N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl [Pyridine-2-carboxamide]

[0428] The title compound was prepared by a method similar to that described in Example 26, except that 3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide (131 mg) and pyridinecarboxylic acid (46 mg) were used. 26 mg of the final product was isolated.

[0429] 1 ¹H-NMR (CDCl₃): 1.00 (d, 6H), 1.51 (d, 6H), 1.95 (m, 1H), 2.75 (d, 2H), 3.35 (m, 1H), 5.30 (s, 2H), 6.75 (s, 1H), 7.02 (s, 1H), 7.32–7.43 (m, 3H), 7.50 (s, 1H), 7.60 (m, 1H), 7.93 (m, 1H), 8.15 (d, 1H), 8.55 (dd, 1H). MS (M+H): 541.0, calculated 541.2.

[0430] Example 33

[0431] N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl-]sulfonyl 3-(2-pyridyl)propionamide

[0432] The title compound was prepared by a method similar to that described in Example 26, except that 3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutylthiophene-2-sulfonamide (131 mg; prepared as described in Example 29) and 3-(2-pyridyl)propionic acid (57 mg) were used. 20 mg of the final product was isolated.

[0433] 1¹H-NMR (CDCl₃): 0.98 (d, 6H), 1.44 (d, 6H), 1.93 (m, 1H), 2.70 (d, 2H), 2.74 (t, 2H), 3.26 (t, 2H), 3.42 (m, 1H), 5.33 (s, 2H), 6.73 (s, 1H), 7.21–7.37 (m, 5H), 7.76 (m, 2H), 8.28 (t, 1H), 8.6 (d, 1H). MS (M+H): 569.0, calculated 569.2.

[0434] Bioassay

[0435] The bioactivity of the compounds described above was evaluated using the following bioassays (and compared with C21).

[0436] metabolic stability

[0437] Collected human liver microsomes at a concentration of 0.5 mg / mL were incubated in PBS at 37°C for 70 min with or without 1 mM NADPH. After 10 min, the test compound was added to a final concentration of 1 μM. Samples were removed at 0, 5, 15, and 60 min and added to tubes containing acetonitrile to stop the reaction, with terfenadine used as an internal standard. After centrifugation at 10,000 × g for 5 min, the supernatant was diluted 1:1 with 1% formic acid. Samples were separated on a reversed-phase column and detected by a triple quadrupole MSMS (Agilant model 6540). Using terfenadine as an internal standard, the concentration of the parent compound at different time points was measured using an external standard curve, and the initial metabolic rate in the presence or absence of NADPH was calculated.

[0438]

[0439]

[0440] Binding to AT1 and AT2 receptors

[0441] According to Eurofins protocols ITEM26 and ITEM24, the binding of compounds to human recombinant AT2 and AT1 receptors was evaluated using radioscintillation assays.

[0442] In short, the recombinant protein was incubated with the test compound at concentrations of 1 nM, 10 nM, 100 nM, and 1000 nM (for the AT2 receptor) and 1 μM and 10 μM (for the AT1 receptor) at 37°C for 2–4 hours. (Using...) 125 I(sarl,IIe8)-AT-II is used as a ligand for AT1, and... 125ICGP 42112A was used as a ligand for AT2. The percentage of inhibition of control-specific binding was calculated as 100 - (measured specific binding / control specific binding) × 100.

[0443] <![CDATA[AT2 IC 50 [nM]]]> <![CDATA[AT1 IC 50 [nM]]]> Example 1 2.4 >1000 Example 2 0.28 >1000 Example 3 3.5 >1000 Example 4 2.4 >1000 Example 5 5.3 >1000 Example 6 1.8 >1000 Example 7 1.8 >1000 Example 8 3.5 >1000 Example 9 3.4 >1000 Example 18 0.87 16000 Example 19 4.1 9000 Example 21 0.15 15000 Example 22 7.5 30000 Example 24 0.0976 5500 Example 25 0.109 4400 Example 27 1.8202 2300 C21 5.1 >1000

[0444] CYP inhibition

[0445] The inhibition of 10 μM compounds on major cytochrome P450 isotypes (CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A4 and 5) was evaluated using isotype-specific substrates (Eurofins protocol ITEMG232) incubated with human liver microsomes. The following substrates were used: CYP1A phenacetin, CYP2B6 bupropion, CYP2C8 paclitaxel and amodiaquine, CYP2C9 diclofenac, CYP2C19 omeprazole, CYP2D6 dextromethorphan, CYP3A midazolam, and testosterone.

[0446] At the end of the incubation, the formation of metabolites was monitored by HPLC-MS / MS using peak area response.

[0447]

[0448]

[0449]

[0450] abbreviation

[0451] The following abbreviations may be used in this article.

[0452] DCM dichloromethane

[0453] DMF (dimethylformamide)

[0454] DMSO (dimethyl sulfoxide)

[0455] EtOAc (ethyl acetate)

[0456] MeOH (methanol)

[0457] NMR (Nuclear Magnetic Resonance)

[0458] rt room temperature

[0459] TFA (trifluoroacetic acid)

Claims

1. A pharmaceutical formulation comprising a compound of formula I that can be mixed with a pharmaceutically acceptable adjuvant. in: n represents 1 to 4; Z represents -O- or a direct bond; R 1 C represents a carbon atom that is optionally substituted with one or more halogen atoms. 1-6 alkyl; R 2 and R 3 Each independently represents H or C optionally substituted with one or more halogen atoms. 1-6 alkyl; R 4 Indicate C 1-8 Alkyl groups, optionally surrounded by one or more halogen atoms and / or OR 6 Group substitution; or R 4 Indicate C 6-14 Aryl, C 1-6 Alkyl C 6-14 Aryl, C 1-3 alkenyl C 6-14 Aryl, heteroaryl, C 1-6 alkyl heteroaryl or C 1-3 Alkenyl heteroaryl groups, wherein each is optionally surrounded by one or more elements selected from halogens, CF3, CF3O, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; or R 4 This represents cyclohexylmethyl or cyclopentylmethyl, wherein each is optionally marked with up to three F groups and / or one or more OR groups. 6 Group substitution; R 5 Indicate C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy-C 1-6 Alkyl groups, wherein each of them is optionally substituted with one or more halogen atoms; R 6 Indicates H, -C(O)R 7 Or C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkyl C 6-14 Aryl, C 1-3 alkenyl C 6-14 Aryl, heteroaryl, C 1-6 alkyl heteroaryl or C 1-3 Alkenyl heteroaryl, each of the last seven groups is optionally surrounded by one or more groups selected from halogens, CF3, CF3O, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 7 Indicate C 1-6 Alkyl; and The heteroaryl group is selected from pyridinyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, triazinyl, pyrimidinyl, and pyrazinyl. Or its pharmaceutically acceptable salt.

2. The pharmaceutical preparation according to claim 1, wherein the adjuvant is a diluent.

3. The pharmaceutical formulation according to claim 1, wherein the adjuvant is a carrier.

4. The pharmaceutical preparation according to claim 1, wherein n represents 1.

5. The pharmaceutical preparation according to claim 1, wherein, When n is 1, the F atom is in the ortho position relative to the methylene group that is also connected to the imidazole ring.

6. The pharmaceutical preparation according to any one of claims 1 to 5, wherein Z represents -O-.

7. The pharmaceutical preparation according to any one of claims 1 to 5, wherein R 1 It indicates methyl, ethyl, or isopropyl.

8. The pharmaceutical preparation according to any one of claims 1 to 5, wherein R 2 and R 3 Independently represents H or methyl.

9. The pharmaceutical preparation according to any one of claims 1 to 5, wherein R 4 The nouns represent methyl, ethyl, cyclohexylmethyl, cyclopentylmethyl, n-propyl, n-butyl, or isobutyl, wherein each is optionally marked with up to three F groups and / or one or more OR groups. 6 Group substitution; or C optionally substituted with one or more F groups. 1-6 Alkyl C 6-14 Aryl.

10. The pharmaceutical formulation according to claim 7, wherein C 1-6 Alkyl C 6-14 The aryl group is benzyl.

11. The pharmaceutical preparation according to any one of claims 1 to 5, wherein R 5 It represents methyl, ethyl, n-propyl, n-butyl, or isobutyl.

12. The pharmaceutical preparation according to any one of claims 1 to 5, wherein R 6 H represents methyl, ethyl, n-propyl, and n-butyl, which are optionally substituted with up to three fluorine atoms; -C(O)R 7 ; or phenyl.

13. The pharmaceutical preparation according to any one of claims 1 to 5, wherein R 7 It indicates methyl, ethyl, or n-propyl.

14. A compound or a pharmaceutically acceptable salt thereof, said compound being: (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophene-2-yl)sulfonylcarbamate 2-phenoxyethyl ester (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-methoxyethyl ester, (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl ester, (3-(3-fluoro-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 3,3,3-trifluoropropyl ester (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 4-fluorobenzyl ester, (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(3-fluoro-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(3,5-difluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl ester, Methyl (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-((((3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamoyl)oxy)ethyl neopentanoate, N-((3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)neopentamide, Methyl (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl ester, (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxy-2-methylpropyl ester, Methyl (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl ester, N-((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)benzamide, N-((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)pyridineamide, (3-(3-fluoro-4-((2-isopropylimidazol-1-yl)methyl)phenyl)-5-isobutyl-2-thienyl)sulfonylcarbamate-2-hydroxyethyl ester, Methyl (3-(3-fluoro-4-((2-isopropylimidazol-1-yl)methyl)phenyl)-5-isobutyl-2-thienyl)sulfonylcarbamate N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]benzamide N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]pyridine-2-carboxamide N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-pyridyl)propionamide.

15. A compound or a pharmaceutically acceptable salt thereof, said compound being: (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, or (3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate methyl ester.

16. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable adjuvant in the preparation of a medicament for treating diseases selected from autoimmune diseases, fibrotic diseases, chronic kidney disease, pulmonary hypertension, heart failure, preeclampsia, interstitial lung disease, viral pneumonia, or myocardial infarction, said diseases being mediated by AT2 receptors. in: n represents 1 to 4; Z represents -O- or a direct bond; R 1 C represents a carbon atom that is optionally substituted with one or more halogen atoms. 1-6 alkyl; R 2 and R 3 Each independently represents H or C optionally substituted with one or more halogen atoms. 1-6 alkyl; R 4 Indicate C 1-8 Alkyl groups, optionally surrounded by one or more halogen atoms and / or OR 6 Group substitution; or R 4 Indicate C 6-14 Aryl, C 1-6 Alkyl C 6-14 Aryl, C 1-3 alkenyl C 6-14 Aryl, heteroaryl, C 1-6 alkyl heteroaryl or C 1-3 Alkenyl heteroaryl groups, wherein each is optionally surrounded by one or more elements selected from halogens, CF3, CF3O, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; or R 4 This represents cyclohexylmethyl or cyclopentylmethyl, wherein each is optionally marked with up to three F groups and / or one or more OR groups. 6 Group substitution; R 5 Indicate C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy-C 1-6 Alkyl groups, wherein each of them is optionally substituted with one or more halogen atoms; R 6 Indicates H, -C(O)R 7 Or C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkyl C 6-14 Aryl, C 1-3 alkenyl C 6-14 Aryl, heteroaryl, C 1-6 alkyl heteroaryl or C 1-3 Alkenyl heteroaryl, each of the last seven groups is optionally surrounded by one or more groups selected from halogens, CF3, CF3O, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 7 Indicate C 1-6 Alkyl; and The heteroaryl group is selected from pyridinyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, triazinyl, pyrimidinyl, and pyrazinyl.

17. The use according to claim 16, wherein the adjuvant is a diluent.

18. The use according to claim 16, wherein the adjuvant is a carrier.

19. The use according to claim 16, wherein n represents 1.

20. The use according to claim 16, wherein, When n is 1, the F atom is in the ortho position relative to the methylene group that is also connected to the imidazole ring.

21. The use according to any one of claims 16-20, wherein Z represents -O-.

22. The use according to any one of claims 16-20, wherein R 1 It indicates methyl, ethyl, or isopropyl.

23. The use according to any one of claims 16-20, wherein R 2 and R 3 Independently represents H or methyl.

24. The use according to any one of claims 16-20, wherein R 4 The nouns represent methyl, ethyl, cyclohexylmethyl, cyclopentylmethyl, n-propyl, n-butyl, or isobutyl, wherein each is optionally marked with up to three F groups and / or one or more OR groups. 6 Group substitution; or C optionally substituted with one or more F groups. 1-6 Alkyl C 6-14 Aryl.

25. The use according to claim 24, wherein the C 1-6 Alkyl C 6-14 The aryl group is benzyl.

26. The use according to any one of claims 16-20, wherein R 5 It represents methyl, ethyl, n-propyl, n-butyl, or isobutyl.

27. The use according to any one of claims 16-20, wherein R 6 H represents methyl, ethyl, n-propyl, and n-butyl, which are optionally substituted with up to three fluorine atoms; -C(O)R 7 ; or phenyl.

28. The use according to any one of claims 16-20, wherein R 7 It indicates methyl, ethyl, or n-propyl.

29. The use according to any one of claims 16-20, wherein the compound is: (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-phenoxyethyl ester (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-methoxyethyl ester, (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-hydroxyethyl ester, (3-(3-fluoro-4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 3,3,3-trifluoropropyl ester (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 4-fluorobenzyl ester, (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(3-fluoro-4-((2-isopropyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(3,5-difluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl ester, Methyl (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate 2-((((3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)carbamoyl)oxy)ethyl neopentanoate, N-((3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl)neopentamide, Methyl (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl ester, (3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxy-2-methylpropyl ester, Methyl (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate-2-hydroxyethyl ester, N-((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)benzamide, N-((3-(4-((2-(tert-butyl)-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonyl)pyridineamide, (3-(3-fluoro-4-((2-isopropylimidazol-1-yl)methyl)phenyl)-5-isobutyl-2-thienyl)sulfonylcarbamate-2-hydroxyethyl ester, Methyl (3-(3-fluoro-4-((2-isopropylimidazol-1-yl)methyl)phenyl)-5-isobutyl-2-thienyl)sulfonylcarbamate N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]benzamide N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]pyridine-2-carboxamide N-[[3-[3-fluoro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-2-thienyl]sulfonyl]-3-(2-pyridyl)propionamide, Or a pharmaceutically acceptable salt of any of the above compounds.

30. The use according to claim 29, wherein the compound is: (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, (3-(3-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, or Methyl (3-(4-(((2-ethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate, Or a pharmaceutically acceptable salt of any of the above compounds.

31. The use according to claim 16, wherein the disease is interstitial lung disease.

32. The use according to claim 16, wherein the interstitial lung disease is idiopathic pulmonary fibrosis or sarcoidosis.

33. The use according to claim 16, wherein the autoimmune disease is rheumatoid arthritis or systemic sclerosis.

34. The use according to claim 16, wherein the chronic kidney disease is diabetic nephropathy.

35. The use according to claim 16, wherein the pulmonary hypertension is pulmonary arterial hypertension.

36. The use according to claim 16, wherein the heart failure has a preserved ejection fraction.

37. The use according to claim 16, wherein the pneumonia caused by the virus is caused by a viral respiratory infection.

38. The use according to claim 16, wherein the fibrotic disease is pulmonary fibrosis.

39. A method for preparing a pharmaceutical formulation according to any one of claims 1-13, comprising preparing a compound of formula I as defined in any one of claims 1-13 or a pharmaceutically acceptable salt thereof, the method comprising: (i) Reacting the compound of formula II with the compound of formula III, Where R 1 R 2 R 3 and n as defined in the relevant preceding claims, Where X represents the leaving group, and Z and R 4 and R 5 As defined in the relevant foregoing claims The compound or salt is then mixed with a pharmaceutically acceptable adjuvant.

40. The method of claim 39, wherein the method comprises For a compound of formula I where Z is a bond, reacting a compound of formula II as defined above with a compound of formula IIIa, R 4 C(O)OH IIIa Where R 4 As defined in the relevant preceding claims.

41. The method of claim 39, wherein the method comprises For compounds of formula I where Z represents -O-, such that R 4 The reaction of compounds of formula I corresponding to lower alkyl groups with compounds of formula IV, R 4’ OH IV Where R 4’ Indicate C 1-8 Alkyl group, wherein the alkyl group is atomized by one or more halogen atoms and / or OR 6 Group substitution; or R 4’ Indicate C 6-14 Aryl, C 1-6 Alkyl C 6-14 Aryl, C 1-3 alkenyl C 6-14 Aryl, heteroaryl, C 1-6 alkyl heteroaryl or C 1-3 Alkenyl heteroaryl groups, wherein each is optionally surrounded by one or more elements selected from halogens, CF3, CF3O, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; or R 4’ This represents cyclohexylmethyl or cyclopentylmethyl, wherein each is optionally marked with up to three F groups and / or one or more OR groups. 6 Group substitution; or For compounds of formula I where Z represents -O-, such that R 4 The reaction of a compound of formula I with a optionally substituted aryl group and a compound of formula IV. R 4’ OH IV Where R 4’ Indicate C 1-8 Alkyl groups, optionally surrounded by one or more halogen atoms and / or OR 6 Group substitution; or R 4’ Indicates heteroaryl, C 1-6 alkyl heteroaryl or C 1-3 Alkenyl heteroaryl groups, wherein each is optionally surrounded by one or more elements selected from halogens, CF3, CF3O, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; or R 4’ This represents cyclohexylmethyl or cyclopentylmethyl, wherein each is optionally marked with up to three F groups and / or one or more OR groups. 6 Group substitution, Where R 6 Indicates H, -C(O)R 7 Or C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkyl C 6-14 Aryl, C 1-3 alkenyl C 6-14 Aryl, heteroaryl, C 1-6 alkyl heteroaryl or C 1-3 Alkenyl heteroaryl, each of the last seven groups is optionally surrounded by one or more groups selected from halogens, CF3, CF3O, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; Where R 7 Indicate C 1-6 Alkyl; and The heteroaryl group is selected from pyridinyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, triazinyl, pyrimidinyl, and pyrazinyl.

42. The method according to any one of claims 39 to 41, wherein the adjuvant is a diluent.

43. The method according to any one of claims 39 to 41, wherein the adjuvant is a carrier.

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