Imidazolylthiophene sulfonyl carbamates for use in the treatment of angiotensin II-related disorders

Abstract

RA1 for use in the treatment of diseases or conditions in which activation of the AT2 receptor is desired or required, but inhibition of CYP is undesirable. 1 , R 2 , R 3 , R 4 , R 5 and Z is as defined herein. Such compounds are particularly useful in the treatment of autoimmune and / or fibrotic diseases, including interstitial lung diseases, such as idiopathic pulmonary fibrosis and sarcoidosis. [Formula 1] JPEG2023518474000016.jpg87170

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical use of certain compounds in medicine, and to novel pharmaceutically active compounds.In particular, the present invention relates to compounds for use in the treatment of diseases or conditions where the activation of angiotensin II (Ang II) is desired or required, more particularly, the treatment of diseases or conditions where the activation of Ang II type 2 (AT2) receptor is desired or required, but the inhibition of cytochrome P450 enzymes (CYP) is not desired.In particular, it relates to the use of such compounds in the treatment of interstitial lung disease. [Background technology]

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

[0003] Some studies in adults seem to show that AT2 receptor activation has the opposite effect to that mediated by AT1 receptor in regulating responses after Ang II receptor stimulation. AT2 receptors have also been shown to be involved in the inhibition of apoptosis and cell proliferation (Non-Patent Document 1). More recently, AT2 receptor agonists have been shown to be potentially useful in the treatment and / or prevention of gastrointestinal disorders such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see Patent Document 1). The expected pharmacological effects of AT2 receptor agonism are generally described in Non-Patent Document 1.

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

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

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

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

[0008] Sarcoidosis is a disease of unknown cause characterized by collections of inflammatory cells that form lumps (granulomas), often starting in the lungs (as well as the skin and / or lymph nodes; any organ can be affected). When sarcoidosis affects the lungs, symptoms include coughing, wheezing, shortness of breath, and / or chest pain.

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

[0010] IPF is a lung disease of unknown cause affecting approximately 5 million people worldwide. In rare cases, there are no treatment options except for lung transplantation. This results in a chronic, irreversible, progressive decline in lung function, and in most cases, death occurs within 2 to 5 years (median survival: 2.5 to 3.5 years). While the overall prognosis for IPF is poor, predicting the rate of progression in individual patients is difficult. Risk factors for IPF include age, male sex, genetic predisposition, and smoking history. The annual incidence rate is 5 to 16 per 100,000 people, with a prevalence of 13 to 20 cases per 100,000, increasing dramatically with age (Non-Patent Document 2). IPF is confined to the lungs and is refractory to immune-targeted treatments, distinguishing it from pulmonary fibrosis associated with systemic disease.

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

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

[0013] The average annual rate of decline in lung function (vital capacity) is in the range of 0.13 to 0.21 liters. Symptoms precede diagnosis by 1 to 2 years, and radiographic signs may precede symptoms (Non-Patent Document 3).

[0014] Many therapeutic approaches have been tested in preclinical models and clinical trials, including anti-inflammatory, immunomodulatory, cytotoxic, general antifibrotic, antioxidant, anticoagulant, antichemokine, antiangiogenic drugs as well as RAS blockers, endothelin antagonists, and sildenafil, and have essentially been shown to provide limited or no benefit (Non-Patent Document 4).

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

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

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

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

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

[0020] US Pat. No. 5,629,999 describes the preparation of tricyclic heterocycles useful as Ang II receptor agonists.

[0021] Selective AT2 receptor agonists with reduced CYP450 inhibition are described in Non-Patent Document 5.

[0022] A transesterification method for the synthesis of AT2 receptor ligands with improved stability in human liver microsomes is described in Non-Patent Document 6.

[0023] In particular, Patent Document 3 describes the preparation of imidazolyl, triazolyl, and tetrazolylthiophene sulfonamides and derivatives as AT2 receptor agonists. Among the compounds described therein (as Example 1) is compound C21 (N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide). C21 was selected for clinical development from a group of approximately 20 related analogs as a selective AT2 receptor agonist. It is currently in clinical development for the treatment of AT2 receptor-related diseases, including IPF (see, for example, Patent Document 4).

[0024] C21 has also been indicated for potential use in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cardiotoxicity associated with cancer therapy, peripheral neuropathy, and systemic sclerosis, among others (see, e.g., Patent Documents 5-11). [Prior art documents] [Patent documents]

[0025] [Patent Document 1] WO99 / 43339 [Patent Document 2] U.S. Patent Application No. 2004 / 0167176 [Patent Document 3] WO2002 / 096883 [Patent Document 4] International Patent Application No. 2016 / 139475 [Patent Document 5] WO2004 / 046141 [Patent Document 6] WO2016 / 092329 [Patent Document 7] WO2016 / 107879 [Patent Document 8] WO2016 / 139475 [Patent Document 9] WO2017 / 221012 issue [Patent Document 10] WO2019 / 008393 [Patent Document 11] U.S. Patent Application No. 2012 / 035232 [Non-patent literature]

[0026] [Non-Patent Document 1] de Gasparo M et al.,Pharmacol.Rev.(2000);52,415-472 [Non-patent document 2] King Jr TE et al.,Lancet(2011);378,1949-1961;Noble PW et al.,J.Clin.Invest.(2012);122,2756-2762 [Non-patent document 3] Ley B et al.,Am.J.Respir.Crit.Care Med.(2011);183,431-440 [Non-patent document 4] Rafii R et al.,J.Thorac.Dis.(2013);5,48-73 [Non-patent document 5] Mahalingam et al.,Bioorg.Med.Chem.(2010);18,4570-4590 [Non-patent document 6] Wannberg et al.,Bioorg.Med.Chem.Lett.(2018);28,519-522 Summary of the Invention [Problem to be solved by the invention]

[0027] During development, C21 was found to have the disadvantages of being a potent inhibitor of several cytochrome P450 enzymes (CYPs), particularly CYP 2C9 and CYP 3A4, potentially affecting the metabolism of other drugs, and being rapidly hydrolyzed to inactive sulfonamide metabolites.

[0028] Therefore, developing potent and selective AT2 agonists that are metabolically stable and / or exhibit less inhibition of CYP enzymes is a fundamental challenge. [Means for solving the problem]

[0029] Surprisingly, it has been discovered that certain chemically modified compounds described below are not only selective AT2 receptor agonists, but also are more potent, have significantly improved stability against metabolic hydrolysis, and / or exhibit less inhibition of CYP enzymes compared to C21.

[0030] Description of the invention We have surprisingly discovered that certain AT2 receptor agonists are useful in conditions where activation of the AT2 receptor is desired or required, but inhibition of CYPs is not desired, such as interstitial lung disease.

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

[0032] In a first aspect of the invention there is provided a compound of formula I for use in the treatment of a disease or condition in which activation of the AT2 receptor is desired or required, but inhibition of one or more CYP enzymes is undesirable, [ka] During the ceremony, Z represents -O- or a direct bond; R 1 optionally substituted by one or more halogen atoms, 1-3 represents alkyl, R 2 and R 3 are each independently H or C optionally substituted by one or more halogen atoms; 1-3 represents alkyl, R 4 But C1-6 Alkyl or C 1-6 alkoxy, each of which is optionally substituted with one or more halogen atoms; or R 4 But aryl, C 1-6 Alkylaryl, heteroaryl, or C 1-6 alkylheteroaryl, each of which is selected from halogen, -CF3, -OCF3, C 1-6 Alkyl, and C 1-6 optionally substituted by one or more substituents selected from alkoxy; R 5 But C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 Alkoxy-C 1-6 alkyl, each of which is optionally substituted with one or more halogen atoms; or a pharmaceutically acceptable salt thereof is provided.

[0033] By "diseases or conditions in which activation of the AT2 receptor is desired or required, but inhibition of CYPs is not desired," we include diseases or conditions known to be treatable by activation of the AT2 receptor, as described below, although existing treatments for such conditions may involve the administration of other therapeutic agents that are metabolized by CYPs. Thus, such diseases or conditions may include advantageous and / or desirable conditions in which inhibition of at least one CYP enzyme is not required, or conditions in which such inhibition is or would be harmful to the patient.

[0034] The foregoing compounds (including pharmaceutically acceptable salts) disclosed herein for use in the treatment of diseases or conditions in which activation of the AT2 receptor is desired or required, but inhibition of CYP is not desired, are hereinafter jointly referred to as the "compounds of the invention."

[0035] According to an alternative embodiment of the first aspect of the present invention there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease or condition in which activation of the AT2 receptor is desired or required, but inhibition of CYPs is not desired.

[0036] In a further alternative embodiment of the first aspect of the invention, there is provided a method of treating a disease or condition in which activation of the AT2 receptor is desired or required, but inhibition of CYPs is not desired, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0037] For the avoidance of doubt, those skilled in the art will understand that reference herein to a compound of a particular aspect of the invention (e.g., any aspect of the invention referring to a compound of formula I as defined above) includes reference to all embodiments and particular features thereof, and that the embodiments and particular features may be combined to form further embodiments.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the common meaning as understood by one of ordinary skill in the art to which this invention belongs.

[0039] As described herein, the compounds of the present invention are useful because they have pharmacological activity and / or are metabolized in the body after oral or parenteral administration to form compounds with pharmacological activity.In particular, the compounds of the present invention are AT2 receptor agonists.Therefore, the compounds of the present invention are expected to be useful in conditions where increasing the activity of AT2 receptor is desired or required.

[0040] More specifically, the compounds of the present invention are agonists of the AT2 receptor and in particular are selective agonists of its sub-receptors (vs. the AT1 receptor), as can be demonstrated, for example, in the tests described below.

[0041] AT2 receptor agonists include those that fully activate AT2 receptors and those that partially activate AT2 receptors.Therefore, the compounds of the present invention can selectively bind to AT2 receptors and exhibit agonist activity at AT2 receptors.By a compound that "selectively binds" to AT2 receptors, we mean that the affinity ratio (AT2:AT1) of the relevant compound at a given concentration is at least 50:1, for example, at least 100:1, preferably at least 1000:1.

[0042] The compounds of the invention are further expected to be useful in conditions where AT2 receptors are expressed and their stimulation is desired or required.

[0043] In this regard, the compounds of the present invention are indicated for the treatment of conditions characterized by vasoconstriction, fibrosis, increased cell proliferation and / or differentiation, increased cardiac contractility, increased cardiovascular hypertrophy, and / or increased fluid and electrolyte retention, as well as skin and musculoskeletal disorders.

[0044] The specific disease or condition that the activation of AT2 receptor is desired or required, but the inhibition of CYP is not desired is interstitial lung disease (for example, pulmonary fibrosis, IPF, systemic sclerosis and sarcoidosis), autoimmune disease (for example, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis and inflammatory bowel disease), chronic kidney disease (for example, diabetic nephropathy), pulmonary hypertension, pulmonary arterial hypertension, and / or infarction (for example, myocardial infarction and stroke).Therefore, the compound of the present invention is particularly useful for treating interstitial lung disease such as IPF; autoimmune disease such as rheumatoid arthritis; chronic kidney disease such as diabetic nephropathy; pulmonary hypertension including pulmonary arterial hypertension; and / or infarction such as myocardial infarction.

[0045] The compounds of the invention are particularly indicated for the treatment and / or prevention of ILDs such as sarcoidosis or fibrosis, more particularly pulmonary fibrosis, in particular IPF, as well as conditions which may induce ILDs, such as systemic sclerosis, rheumatoid arthritis, myositis or systemic lupus erythematosus, or conditions associated with ILDs, such as pulmonary hypertension and / or pulmonary arterial hypertension.

[0046] The compounds of the present invention are particularly useful in the treatment of pulmonary fibrosis, especially IPF.

[0047] According to a further aspect of the present invention there is provided a method for the treatment of pulmonary fibrosis, in particular IPF, which method comprises the administration to a human suffering from such a condition of a therapeutically effective amount of a compound of the present invention.

[0048] In the treatment of pulmonary fibrosis, including IPF, the compounds of the present invention may have anti-fibrotic effects, including reducing fibrosis and preventing further deposition of extracellular matrix.The compounds of the present invention may reduce lung scarring / wound healing and have anti-apoptotic effects, thereby preventing the apoptosis of alveolar endothelial cells, which is the initiating factor in the development of pulmonary fibrosis.The compounds of the present invention may also have anti-proliferative effects, thus reducing the cancerous proliferation of fibroblasts and myofibroblasts in pulmonary fibrosis.The compounds of the present invention may also improve vascular remodeling in pulmonary fibrosis, thereby alleviating secondary pulmonary hypertension.Finally, the compounds of the present invention may exhibit anti-inflammatory, anti-growth factor (e.g., transforming growth factor beta), and / or anti-cytokine effects.

[0049] In addition, the compounds of the present invention may also be useful in treating or preventing any fibrotic condition in one or more internal organs characterized by excessive accumulation of fibrous connective tissue, and / or treating or preventing fibrosis or the morbidity or mortality that may be associated with it. Such fibrosis may be associated with acute inflammatory conditions such as acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), multi-organ inflammation, and injury and / or failure that may be caused by internal or external trauma (e.g., injury) or infection.

[0050] Thus, such conditions may result from sepsis or septic shock caused by viral, bacterial, or fungal infections (e.g., viral respiratory tract infections). Furthermore, acute lung injury, ARDS, and, in particular, SARS, can be caused by viruses, such as coronaviruses, resulting in internal tissue damage and dysfunction of relevant internal (e.g., mucosal) tissues, such as the respiratory epithelium, resulting in virus-induced pneumonia, reduced lung function, respiratory dysfunction, dyspnea, and / or respiratory failure, including novel SARS coronavirus 2 (SARS-CoV-2). Such tissue damage can also lead to severe fibrosis. For example, SARS disease, caused by the novel coronavirus SARS-CoV-2 (coronavirus disease 2019 or COVID-19), is known to often result in fibrosis.

[0051] According to a further aspect of the present invention, there is provided a method for treating diseases or conditions in which activation of the AT2 receptor is desired or required, but inhibition of CYPs is not desired (such as pulmonary fibrosis, particularly IPF), which method comprises administering to a human suffering from the relevant condition a therapeutically effective amount of a compound of the invention.

[0052] The compounds of the invention are indicated for both the therapeutic, symptomatic and / or diagnostic treatment, as well as the prophylactic treatment (thereby including prevention and / or arrest of the reduction and / or worsening of the condition) of any of the above conditions.

[0053] The compounds of the present invention are usually administered orally, intravenously, subcutaneously, buccally, rectally, cutaneously, intranasally, intratracheally, intrabronchially, by other parenteral routes, or via inhalation or pulmonary routes, or any combination thereof, in a pharmaceutically acceptable dosage form, in a solution, in a suspension, in an emulsion (including nanosuspension), or in a liposomal formulation. Additional administration methods include, but are not limited to, intraarterial, intramuscular, intraperitoneal, intraportal, intradermal, epidural, intrathecal administration, or any combination thereof.

[0054] In some embodiments, the compounds of the present invention can be administered singly (e.g., separately), and / or sequentially, and / or simultaneously in parallel (e.g., concurrently) using different routes of administration, but are preferably administered in known pharmaceutical formulations (including tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions, or emulsions for parenteral or intramuscular administration, or by inhalation, etc.). Administration by inhalation is preferably carried out using a nebulizer, for example, to deliver the compounds of the present invention to small lung tissue, including the alveoli and bronchioles, preferably without causing irritation or coughing in the treated subject.

[0055] Preferably, administration of a therapeutically effective amount of a compound of the invention is carried out by a combination of routes of administration, including via inhalation and orally, either separately (e.g., about 2 hours or more apart from each other), sequentially (e.g., within about 2 hours of each other), or simultaneously (e.g., concurrently), to achieve an effective dosage.

[0056] In some embodiments, methods are provided for treating diseases or conditions in which activation of the AT2 receptor is desired or required (and such diseases or conditions in which inhibition of CYPs is undesirable), including pulmonary fibrosis, and particularly IPF, comprising administering to a patient in need of such therapy a therapeutically effective amount of a compound of the invention, either separately, sequentially, or simultaneously, through a combination of routes of administration, preferably via inhalation and orally, to achieve an effective amount or dosage.

[0057] Such combinations of routes of administration, preferably via inhalation and orally, can be presented as separate formulations of the compounds of the invention optimized for each route of administration.

[0058] Such formulations may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0059] Depending on the patient being treated and the route of administration, the compounds of the present invention can be administered in a variety of dosages. While dosages will vary from patient to patient, a suitable daily dosage will be in the range of about 0.1 to about 1000 mg per patient (e.g., 0.1, 0.5, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 mg, etc., or any range or value therein), administered in single or multiple doses. More preferred daily doses are in the range of about 0.1 to about 250 mg per patient (e.g., 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 44.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 mg, etc., or any range or value therein). A particularly preferred daily dose ranges from about 0.3 to about 100 mg per patient.

[0060] Individual doses of the compounds of the invention can range from about 0.1 to about 100 mg (e.g., 0.3, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg, etc., or any range or value therein).

[0061] In any event, a physician or person skilled in the art will be able to determine the actual dosage that will be most suitable for an individual patient, which will likely vary depending on the route of administration, the type and severity of the condition being treated, and the species, age, weight, sex, renal function, hepatic function, and response of the particular patient being treated. The dosages set forth above are exemplary of the average case, and there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

[0062] The advantage of using the compounds of the present invention separately and / or sequentially and / or simultaneously in parallel, preferably via a combination of administration routes, is to create a tailored treatment for the patient in need of treatment that may prevent and / or reduce side effects, and also to tailor the correct dosage level of a therapeutically effective amount of the compounds of the present invention.

[0063] Subjects suitable for treatment with the formulations of the present invention include, but are not limited to, mammalian subjects, particularly human subjects.

[0064] The compounds of the present invention find particular utility when combined with other therapeutic agents in combination therapies to treat a variety of conditions, including those mentioned above. Because the compounds of the present invention exhibit minimal CYP enzyme inhibition, such combinations are particularly advantageous when the other therapeutic agent used for use in the relevant condition is itself metabolized by a CYP enzyme.

[0065] Therefore, when the condition to be treated is interstitial lung disease, such as IPF, systemic sclerosis, or fibrotic diseases known in the art, the compounds of the present invention are preferably administered in combination with established therapies for such treatment, including but not limited to galectin-3 inhibitors, lysophosphatidic acid receptor 1 (LPA1) antagonists, autotaxin (ATX) inhibitors, recombinant human pentraxin-2 protein, or pirfenidone and / or nintedanib.Preferably, the combination of the compounds of the present invention is in combination with pirfenidone or its pharmaceutically acceptable salt, which is known to be metabolized by CYP enzymes, such as CYP1A.

[0066] Additionally, when the condition being treated is a chronic kidney-related disease, the compounds of the invention are preferably administered in combination with one or more other drugs also used in such treatment, such as irbesartan and / or torsemide, which are metabolized by CYP enzymes such as CYP2C9.

[0067] When the condition being treated is pulmonary hypertension, the compounds of the invention are preferably administered in combination with one or more drugs also used in such treatment, such as selexipag and / or sildenafil, which are compounds known to be metabolized by CYP enzymes, such as CYP3A4.

[0068] When the condition to be treated or prevented is a myocardial infarction and / or stroke-related disease, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatments, such as propranolol, warfarin, clopidogrel, atorvastatin, cilostazol, lidocaine and / or simvastatin, or pharmaceutically acceptable salts thereof, which are compounds known to be metabolized by CYP enzymes such as CYP1A, CY2CP and / or CYP3A4.

[0069] When the condition being treated is an autoimmune disease such as rheumatoid arthritis, multiple sclerosis or psoriasis, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatments, including, but not limited to, steroidal anti-inflammatory drugs (NSAIDs) such as loxene, celecoxib, meloxicam or its analogues (e.g., piroxicam) or indomethacin, which are compounds known to be metabolized by CYP enzymes such as CYP1A, CYP2CP, CYP2C19 and / or CYP3A4; or drugs such as tizanidine, cyclophosphamide, cyclosporine, deflazacort and / or hydrocortisone, riluzole, or pharmaceutically acceptable salts thereof.

[0070] Therefore, the compounds of the present invention are particularly useful in the treatment of diseases or conditions where AT2 receptor activation is desired or required, but CYP inhibition is not desired, and therefore can be administered to treat diseases, including those mentioned hereinabove, and can be useful or can be used in combination with one or more of the other therapeutic agents metabolized through CYP enzyme pathways, including pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, pirfenidone, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil, and / or simvastatin.Most preferably, the compounds of the present invention are administered in combination with pirfenidone to treat interstitial lung diseases such as IPF.

[0071] Therapeutic agents that may be used in combination with the compounds of the invention include various standard treatments for viral infections, such as antibody therapies (e.g., LY-CoV555 / LY-CoV016 (bamlanivimab and etesevimab), LY-CoV555 (bamlanivimab, Eli Lilly), REGN-COV2 (casirivimab and imdevimab), REGN3048-3051, TZLS-501, SNG001 (Synairgen), eculizumab (Soliris; Alexion Pharmaceuticals), ravulizumab (Ultomiris; Alexion Pharmaceuticals), lenzilumab, leronlimab, tocilizumab (Actemra; Roche), sarilumab (Kevzara; Regeneron), and the like. Pharma), and Octagam (Octapharma), and antiviral drugs (e.g., oseltamivir, remdesivir, favipiravir, molnupiravir, simeprevir, daclatasvir, sofosbuvir, ribavirin, umifenovir, lopinavir, ritonavir, lopinavir / ritonavir (Kaletra; AbbVie Deutschland GmbH Co.KG), teicoplanin, baricitinib (Olumiant; Eli Lilly), ruxolitinib (Jakavi; Novartis), tofacitinib (Xeljanz; Pfizer), TMPRSS2 inhibitors, camostat, or camostat mesylate, Actemra (Roche), AT-100 (rhSP-D), MK-7110 (CD24Fc; Merck)), OYA1 (OyaGen9), BPI-002 (BeyondSpring), NP-120 (Ifenprodil; Algernon Pharmaceuticals), and galidesivir (Biocryst Pharma), anti-inflammatory drugs (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., paracetamol or opioids), antifungal agents (e.g., dextromethorphan), vaccinations (e.g., INO-4800 from Inovio Pharmaceuticals and Beijing Advaccine Biotechnology, when available), COVID-19 convalescent plasma (CCP), and / or passive antibody therapy with antibodies derived from the blood of people who have recovered from SARS-CoV or SARS-CoV-2 infection.

[0072] Further therapeutic agents that may be mentioned include antifibrotic drugs (e.g., nintedanib, especially pirfenidone), vitamins (e.g., vitamins B, C, and D), and mucolytic drugs such as acetylcysteine ​​and ambroxol.

[0073] Other therapeutic agents that may be used in accordance with the present invention in combination with the compounds of the present invention, or pharmaceutically acceptable salts thereof, include corticosteroids, which include both naturally occurring and synthetic corticosteroids.

[0074] Naturally occurring corticosteroids that may be mentioned are cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, progesterone, as well as naturally occurring precursors and intermediates in corticosteroid biosynthesis, and other derivatives of naturally occurring corticosteroids, such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, 18-hydroxy-11 -deoxycorticosterone, 18-hydroxycorticosterone, 21-deoxycortisone, 11β-hydroxypregnenolone, 11β,17α,21-trihydroxypregnenolone, 17α,21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 21-hydroxypregnenolone, 11-ketoprogesterone, 11β-hydroxyprogesterone, 17α-hydroxyprogesterone, and 18-hydroxyprogesterone.

[0075] Synthetic corticosteroids that may be mentioned are those of the hydrocortisone type (group A), such as cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, tixocortol and tixocortol pivalate, prednisolone, methylprednisolone, prednisone, chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolone, fluprednisolone, loteprednol acetaminophen, prednicarbate, and triamcinolone, acetonides and related substances (group B), such as amcinonide, budesonide, desonide, fluocinolone cetonide, fluocinonide, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formocortal, fludroxycortide, flunisolide, and fluocinolone acetonide, (beta)methasone type (group C), such as beclomethasone, betamethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, fluocortolone, Halometasone, mometasone and mometasone furoate, alclometasone and alclometasone dipropionate, clobetasol and clobetasol propionate, clobetasone and clobetasone butyrate, clocortolone, desoximetasone, diflorasone, difluocortolone, fluchloron, flumethasone, fluocortin, fluprednidene and fluprednidene acetate, fluticasone, fluticasone furoate and fluticasone propionate, meprednisone, paramethasone, prednylidene, rimexolone, and urobetasol, progesterone-type drugs such as flugestone, fluorometholone, medrysone, and prebedilone acetate, and progesterone derivatives (progestins), such as chlormadinone acetate, cyproterone acetate, medrogestone, medroxyprogesterone acetate, megestrol acetate, and segesterone acetate, and other corticosteroids, such as cortivazol and 6-methyl-11β,17β-dihydroxy-17α-(1-propynyl)androsta-1,4,Contains 6-trien-3-one.

[0076] Preferred corticosteroids include cortisone, prednisone, prednisolone, methylprednisolone, and, especially, dexamethasone.

[0077] Additionally, therapeutic agents that may be used in combination with the compounds of the present invention, or pharmaceutically acceptable salts thereof, include H2 receptor blockers, anticoagulants, antiplatelet agents, as well as statins, antibacterial agents, and antiallergic / antiasthmatic agents.

[0078] H2 receptor blockers that may be mentioned include famotidine. Anticoagulants that may be mentioned include heparin and low-molecular-weight heparins (e.g., bemiparin, nadroparin, reviparin, enoxaparin, parnaparin, certoparin, dalteparin, tinzaparin), direct-acting oral anticoagulants (e.g., dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betrixaban, darexaban, otamixaban, retaxaban, elibaxaban, hirudin, lepirudin, and bivalirudin), coumarin-type vitamin K antagonists (e.g., coumarin, acenocoumarol, phenprocoumon, atromentin, and phenindione), and synthetic pentasaccharide inhibitors of factor Xa (e.g., fondaparinux, idraparinux, and idrabiotaparinux). Antiplatelet drugs that may be mentioned include irreversible cyclooxygenase inhibitors (e.g., aspirin and triflusal), adenosine diphosphate receptor inhibitors (e.g., cangrelor, clopidogrel, prasugrel, ticagrelor, and ticlopidine), phosphodiesterase inhibitors (e.g., cilostazol), protease-activated receptor-1 antagonists (e.g., vorapaxar), glycoprotein IIB / IIIA inhibitors (e.g., abciximab, eptifibatide, and tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), and thromboxane inhibitors (e.g., terutroban, ramatroban, seratrodast, and picotamide). Statins that may be mentioned include atorvastatin, simvastatin, and rosuvastatin. Antibacterial agents that may be mentioned include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam, and teicoplanin. Antiallergic / antiasthmatic drugs that may be mentioned include chlorphenamine, levocetirizine, and montelukast.

[0079] Thus, a subject may also (and / or already) be receiving any one or more of the other therapeutic agents listed above, and by this we mean receiving prescribed doses of one or more of those other therapeutic agents before, in addition to, and / or after treatment with a compound of the invention or a pharmaceutically acceptable salt thereof.

[0080] When the compounds of the present invention are "combined" with other therapeutic agents as described above, the active ingredients may be administered together in the same formulation or separately (simultaneously or sequentially) in different formulations.

[0081] Such combination products provide for the administration of a compound of the invention in combination with another therapeutic agent, and therefore may be presented as separate formulations (at least one of which contains a compound of the invention and at least one of which contains the other therapeutic agent) or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation containing a compound of the invention and the other therapeutic agent).

[0082] Therefore, (1) a pharmaceutical formulation comprising a compound of the present invention, a therapeutic agent known to be metabolized by a CYP enzyme, such as any of those mentioned hereinabove, and a pharmaceutically acceptable excipient (e.g., an adjuvant, diluent, or carrier), hereinafter referred to as a "combined preparation"; (2) A kit of parts comprising the following components: (A) a pharmaceutical formulation comprising a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier; and (B) A pharmaceutical formulation comprising a therapeutic agent known to be metabolized by a CYP enzyme, such as any of those mentioned hereinabove, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier. There is further provided a kit-of-parts in which components (A) and (B) are each provided in a form suitable for administration in combination with the other.

[0083] In a further aspect of the present invention, there is provided a process for the preparation of a combination preparation as defined herein above, comprising bringing into association a compound of the present invention, another anti-inflammatory agent, a therapeutic agent, with at least one (e.g., pharmaceutically acceptable) excipient.

[0084] In a further aspect of the present invention, there is provided a process for the preparation of a kit-of-parts as defined herein above, comprising associating components (A) and (B). As used herein, reference to associating means that the two components are suitable for administration in combination with each other.

[0085] Thus, with respect to the process for the preparation of a kit-of-parts as defined above, by "associating" two components with each other, the inventors mean that the two components of the kit-of-parts: (i) may be provided as separate formulations (i.e., independently of each other) which are then combined for use in conjunction with each other in combination therapy; or (ii) They may be packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

[0086] therefore, (I) one of components (A) and (B) as defined herein, (II) A kit of parts is further provided, comprising the two components together with instructions for using the component in combination with the other of the two components.

[0087] The kits of parts described herein may contain two or more formulations containing suitable amounts / doses of a compound of the invention and / or two or more formulations containing suitable amounts / doses of another therapeutic agent to provide for repeated administration. When two or more formulations (containing any of the active compounds) are present, such formulations may be the same or different with respect to the dosage, chemical composition, and / or physical form of any of the compounds.

[0088] With respect to the kit of parts described herein, by "administration in combination with," we include sequential, separate, and / or simultaneous administration of each formulation containing a compound of the invention and another therapeutic agent over the course of treatment of the relevant condition.

[0089] Thus, with respect to a combination product according to the invention, the term "administration in combination with" includes administration of the two components of the combination product (a compound of the invention and another therapeutic agent) either together or sufficiently closely in time (optionally repeatedly) so as to allow a greater beneficial effect to the patient over the course of treatment of the relevant condition than would occur if, over the same course of treatment, either a formulation comprising the compound of the invention or a formulation comprising the other agent were administered alone (optionally repeatedly) without the other component. Determining whether a combination provides a greater beneficial effect with respect to the treatment of a particular condition, and over the course of treatment, will depend on the condition being treated or prevented, but can be routinely accomplished by one of ordinary skill in the art.

[0090] Furthermore, in the context of a kit-of-parts according to the invention, the term "in combination with" includes that one or the other of the two formulations may be administered before, after, and / or simultaneously (optionally repeatedly) with the administration of the other component. When used in this context, the terms "co-administered" and "administered simultaneously with" include administration of individual doses of the relevant compound of the invention and the other anti-inflammatory agent within 48 hours (e.g., 24 hours) of each other.

[0091] The pharmaceutical compositions / formulations, combination products and kits described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0092] Thus, in a further aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition / formulation as defined herein above, which process comprises combining a particular compound of the present invention as defined herein above with one or more pharmaceutically acceptable excipients (e.g., adjuvants, diluents, and / or carriers).

[0093] In a further aspect of the present invention, there is provided a process for the preparation of a combination product or kit-of-parts as defined herein above, which process comprises combining a compound of the present invention as defined herein above with other therapeutic agents useful in the treatment of the relevant disease or disorder, and at least one pharmaceutically acceptable excipient.

[0094] Certain compounds of the present invention may be novel and / or not previously used in human medicine. Thus, in a further aspect of the present invention, there is provided a compound of the present invention (i.e., of formula I) as defined hereinabove, or a pharmaceutically acceptable salt thereof, except that Z represents -O- and R 1 represents methyl, and R 2 and R 3 Both represent H, and R 4 When represents n-butyl, R 5 does not represent isobutyl.

[0095] Preferred compounds of the present invention include: Z represents -O-; R 1 is C optionally substituted with up to three halogen atoms 1-3 represents an alkyl group (such as methyl, ethyl, or propyl (e.g., n-propyl), preferably methyl or ethyl) (e.g., CHF or CHCF), R 2 and R 3 are independently H or C optionally substituted with up to three halogen atoms (e.g., CHF or CHCF). 1-3represents an alkyl group (such as methyl, ethyl, or propyl (e.g., n-propyl)); R 4 is C optionally substituted with up to three halogen atoms 1-4 an alkyl group (such as methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., n-butyl)), optionally substituted with, or more preferably terminated by, up to three halogen atoms; 1-6 alkoxy groups, aryl (e.g., phenyl, fluorophenyl, or trifluorophenyl) optionally substituted with one or more halogen atoms, C 1-3 Alkylaryl, or C 1-3 represents alkylheteroaryl, R 5 is optionally substituted or more preferably terminated by up to three fluorine atoms, C 1-4 represents an alkyl group.

[0096] More preferred compounds of the present invention include the following: Z represents -O-; R 1 represents methyl or ethyl (e.g., CHF or CHCF), optionally substituted with up to three fluorine atoms; R 2 and R 3 independently represent methyl or ethyl, or more preferably H; R 4 is optionally substituted or more preferably terminated by up to three fluorine atoms, C 1-4 Alkyl groups (such as methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., n-butyl)), phenyl, C 1-2 Alkylaryl, or C 1-2 represents alkylheteroaryl, R 5 represents butyl, more preferably isobutyl, optionally substituted or more preferably terminated with up to three fluorine atoms.

[0097] Particularly preferred compounds of the present invention include the following: Z represents -O-; R 1 represents ethyl, or more preferably methyl, R 2 represents methyl, or more preferably H, R 3 represents H, R 4 represents an ethyl, propyl (e.g., n-propyl), or butyl (e.g., n-butyl) group, phenyl, benzyl, or pyridin-2-ylmethyl, optionally substituted or more preferably terminated with up to three fluorine atoms; R 5 represents butyl, more preferably isobutyl.

[0098] Thus, particular preferred compounds of the invention that may be mentioned are: butyl(5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl-carbamate, butyl(3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl-carbamate, Includes ethyl (5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl-carbamate.

[0099] Particular novel compounds of the present invention that may be mentioned are: butyl(3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl-carbamate, Includes ethyl (5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl-carbamate.

[0100] Compounds are named according to the IUPAC nomenclature generated by the program ChemDraw Ultra 12.0.

[0101] More preferred compounds of the present invention include those of the Examples set forth below.

[0102] For the purposes of interpreting this specification, the following definitions will apply and wherever appropriate, terms used in the singular will also include the plural and vice versa.

[0103] Pharmaceutically acceptable salts include acid addition salts and base addition salts.Such salts can be formed by conventional means, for example, by reacting the free acid or free base form of the compound of the present invention with one or more equivalents of a suitable acid or base in any solvent or medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (for example, by vacuum, lyophilization or filtration).Salts can also be prepared using techniques known to those skilled in the art, such as by exchanging the counterion of the compound of the present invention in the form of a salt with another counterion, for example, using a suitable ion exchange resin.

[0104] Particular acid addition salts that may be mentioned include carboxylates such as formates, acetates, benzoates, oxalates, fumarates, maleates, etc.; sulfonates such as methanesulfonates, ethanesulfonates, toluenesulfonates, etc.; halide salts such as hydrochlorides, hydrobromides, etc.; sulfates and phosphates such as sulfates or phosphates, etc.

[0105] Particular base 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), amine bases (ammonia, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, etc.) More particularly, base addition salts that may be mentioned include Mg salts, Ca salts, and most particularly K salts and Na salts.

[0106] The compounds of the present invention may exist as solids, and therefore the scope of the present invention includes all amorphous, crystalline, and partially crystalline forms thereof, and may exist as oils. When compounds of formula I exist in crystalline and partially crystalline form, such forms may include solvates that are included within the scope of the present invention.

[0107] The compounds of the present invention may also be present in solution (i.e., in a suitable solvent). For example, the compounds of formula I may be present in aqueous solution, in which case the compounds of the present invention may be present in the form of their hydrates.

[0108] The compounds of the present invention may contain double bonds and therefore, unless specified otherwise, may exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. Unless specified otherwise, all such isomers and mixtures thereof are included within the scope of the present invention.

[0109] Compounds of the invention may also exhibit tautomerism: all tautomeric forms and mixtures thereof are included within the scope of the invention, particularly those with sufficient stability to allow their isolation.

[0110] The compounds of the present invention may also contain one or more asymmetric carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism (i.e., exist in enantiomeric or diastereomeric forms). Diastereomers may be separated using conventional techniques, such as chromatography or fractional crystallization. The various stereoisomers (i.e., enantiomers) may be isolated by separating a racemic or other mixture of the compounds using conventional techniques, such as fractional crystallization or HPLC. Alternatively, the desired enantiomer or diastereomer may be obtained from appropriate optically active starting materials under conditions that do not cause racemization or epimerization (i.e., "chiral pool" methods), by reaction of the appropriate starting materials with a "chiral auxiliary" that can be subsequently removed at a suitable stage, by derivatization (i.e., resolution, including kinetic resolution, e.g., treatment with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography), or by reaction with an appropriate chiral reagent or chiral catalyst; all of these methods and processes may be carried out under conditions known to those skilled in the art. Unless otherwise specified, all stereoisomers and mixtures thereof are included within the scope of the present invention.

[0111] As used herein, the term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

[0112] Unless otherwise specified, C 1-6 Alkyl groups (e.g., C 1-3 alkyl groups), and C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylaryl, C 1-6 The alkyl portion of the alkylheteroaryl group (6 is the upper limit of the range in all cases) may be straight-chained or, when there is a sufficient number (i.e., a minimum of 2 or 3, where appropriate) of carbon atoms, may be branched and / or cyclic (thus C 3-6When there is a sufficient number (i.e., a minimum of four) of carbon atoms, such groups may also be part cyclic (hence, C 4-6 (forming a partial cycloalkyl group). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclopentyl, and cyclohexyl. Similarly, partial cyclic alkyl groups (which may also be called "partial cycloalkyl" groups) that may be mentioned include cyclopropylmethyl. When a sufficient number of carbon atoms are present, such groups may be polycyclic (e.g., bicyclic or tricyclic) and / or spirocyclic.

[0113] C 3-6 Alkyl groups and C 3-6 Alkoxy groups can be unsaturated and thus can incorporate double or triple bonds.

[0114] Particular alkyl groups that may be mentioned include straight-chain (i.e., not branched and / or cyclic) alkyl groups. For example, C 1-6 Alkyl groups, and C 1-6 The alkyl portion of the alkoxy group includes, but is not limited to, n-butyl, sec-butyl, isobutyl, tert-butyl; propyl, such as n-propyl, 2-methylpropyl, or isopropyl; ethyl; and methyl.

[0115] For the avoidance of any doubt, C 1-6 Alkyl groups and C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylaryl, C 1-6 The point of attachment to the alkyl moiety of an alkylheteroaryl group is through the alkyl portion of such group.

[0116] For the avoidance of doubt, alkoxy groups are attached to the remainder of the molecule through the oxygen atom of the group, and alkoxyalkyl groups are attached to the remainder of the molecule through the alkyl portion of the group.

[0117] Unless otherwise specified, alkoxy refers to an O-alkyl group, where the term "alkyl" has the meaning given above.

[0118] As used herein, references to heteroatoms may take their ordinary meaning as understood by those of ordinary skill in the art. Particular heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen, and sulfur (e.g., oxygen, nitrogen, and sulfur, such as oxygen and nitrogen).

[0119] As used herein, reference to "heteroaryl" (sometimes also referred to as heteroaromatic) may refer to a heteroaromatic group containing one or more heteroatoms (such as one or more heteroatoms selected from oxygen, nitrogen, and / or sulfur). Such heteroaryl groups may contain one, two, or three rings, at least one of which is aromatic (the aromatic ring may or may not contain one or more heteroatoms). Substituents on heteroaryl / heteroaromatic groups, where appropriate, may be located on any suitable atom in the heteroatom-containing ring system (e.g., on a suitable N atom).

[0120] The point of attachment of a heteroaryl / heteroaromatic group may be via any atom in the ring system, including (where appropriate) a heteroatom. Bicyclic heteroaryl / heteroaromatic groups may contain a benzene ring fused to one or more additional aromatic or non-aromatic heterocycles, in which case the point of attachment of a polycyclic heteroaryl / heteroaromatic group may be via the benzene ring or any of the rings comprising the heteroaryl / heteroaromatic or heterocycle.

[0121] For the avoidance of doubt, those skilled in the art will understand that the heteroaryl groups which may form part of the compounds of the present invention are chemically obtainable as known to those skilled in the art. A variety of heteroaryl groups will be known to those skilled in the art, such as pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolylthiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, and purinyl.

[0122] For the avoidance of doubt, oxides (eg N-oxides) of heteroaryl / heteroaromatic groups are also included within the scope of the present invention.

[0123] As mentioned above, heteroaryl includes polycyclic (e.g., bicyclic) groups in which one ring is aromatic (the other may or may not be aromatic). Thus, other heteroaryl groups that may be mentioned include benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazole, 3,4-dihydrobenzo[1,4]oxazinyl, dihydrobenzothiophenyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, thiochromanyl, and the like.

[0124] As used herein, the term aryl refers to a C 6-14 (For example, C 6-10 ) may refer to aromatic groups. Such groups may be monocyclic or bicyclic, and when bicyclic, may be wholly or partially aromatic. 6-10Aryl groups include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like (eg, phenyl, naphthyl, and the like).

[0125] An aromatic group can be represented as a cyclic group containing a suitable number of double bonds therein to permit aromaticity.

[0126] Those skilled in the art will recognize that the aryl groups that may form part of the compounds of the present invention are chemically available, as known to those skilled in the art.

[0127] For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any suitable carbon atom of the ring system.

[0128] The present invention also encompasses isotopically labeled compounds of the present invention that are identical to those listed herein, except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from that normally found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element specified herein are contemplated within the scope of the compounds of the present invention. Thus, the compounds of the present invention also include deuterated compounds, i.e., compounds of the present invention in which one or more hydrogen atoms have been replaced with the hydrogen isotope deuterium.

[0129] In the case where the identity of two or more substituents in the compounds of the present invention may be the same, the actual identity of each substituent is in no way interdependent. For example, in the case where two or more halo groups are present, the groups may be the same or different (e.g., two chloro groups, or a fluoro group and a chloro group). Similarly, when two or more alkyl groups are present, the groups in question may be the same or different in terms of the number of carbon atoms and / or whether they are linear, branched, unsaturated, or otherwise.

[0130] Furthermore, when a substituent is itself specified as being optionally substituted with one or more substituents (e.g., phenyl optionally substituted with one or more groups independently selected from halo), these substituents may be located on the same or different atoms, where possible. Such optional substituents may be present in any suitable number thereof (e.g., the relevant group may be substituted with one or more such substituents, e.g., one such substituent).

[0131] Where a group is referred to herein as being optionally substituted, it is specifically intended that such optionally substituted group may not be present (i.e., the reference to such optionally substituted group may be omitted), in which case the optionally substituted group may be referred to as unsubstituted.

[0132] Unless otherwise specified, substituents (whether optional or not) may be located at any point on the group to which they may be attached. In this regard, alkyl and alkoxy groups (for example) which may be substituted by one or more substituents may also be terminated by such a substituent (i.e., meaning located at the end of the alkyl or alkoxy chain, for example).

[0133] For the avoidance of doubt, in cases where the identities of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are in no way interdependent. For example, R 2 and R 3 Both are C 1-3 In the situation where the C in question is an alkyl 1-3 The alkyl groups may be the same or different.

[0134] Those skilled in the art will appreciate that the compounds of the present invention that are the subject of this invention include those that are available, i.e., that can be prepared in a stable form, i.e., compounds of the present invention include compounds that are sufficiently robust to survive isolation, e.g., isolation to a useful degree of purity from a reaction mixture.

[0135] Compounds of formula I may be prepared according to techniques well known to those skilled in the art, for example as described below.

[0136] According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula I, the process comprising: (i) a compound of formula II [ka] (In the formula, R 1 , R 2 , R 3 , and R 5 is as defined hereinabove), a compound of formula III [ka] (In the formula, R 4 and Z are as defined herein above, and X represents a suitable leaving group, for example, halo (e.g., chloro or bromo), for example, at about room temperature or above (e.g., up to 60-70° C.), in the presence of a suitable base (e.g., pyrrolidinopyridine, 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).

[0137] The compound of formula II may be a compound of formula IV [ka] (In the formula, R 5 is as defined hereinbefore or an N-protected derivative thereof, [ka] (In the formula, X 2 represents a suitable leaving group such as trimethylsulfonate or halo, e.g., iodo or bromo, and R 1 , R 2 , and R 3 is as defined hereinabove) in the presence of a suitable coupling catalyst system (e.g., a palladium catalyst, such as Pd(PPh3)4 or Pd(OAc)2 / ligand (the ligand can be, for example, PPh3, P(o-Tol)3, or 1,1'-bis(diphenylphosphino)ferrocene)) and a suitable base (e.g., sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, or di-iso-propylamine), and a suitable solvent system (e.g., toluene, ethanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane, or a mixture thereof). The reaction can be carried out at room temperature or above (e.g., at the reflux temperature of the solvent system used). When a protected version of the compound of formula IV is used, the reaction can be followed by deprotection of the SO2NH- group under standard conditions, for example, as described below.

[0138] Alternatively, the compound of formula II may be a compound of formula VI [ka] (In the formula, R 1 , R 2 , and R 3 is as defined hereinabove), a compound of formula VII [ka] (In the formula, R 5 is as defined hereinabove, and X 1can be prepared by reaction with a suitable leaving group such as halo (e.g., chloro or bromo, especially bromo), or an N-protected derivative thereof, for example, at about room temperature or below in the presence of a suitable base (e.g., pyridine) and a suitable organic solvent (e.g., toluene). If a protected version of a compound of formula VII is used, this reaction can be followed by deprotection of the SO2NH- group under standard conditions, for example, as described below. Additionally, compounds of formula II can be prepared in this way, for example, according to or analogously to the processes described, inter alia, in UK patent application GB 2281298.

[0139] Compounds of formula V can be prepared by standard techniques, for example by reacting compounds of formula VI with compounds of formula VIII as defined hereinabove. [ka] (In the formula, X 1 and X 2 is as defined hereinabove) under conditions similar to those described hereinabove for the preparation of compounds of formula II.

[0140] Compounds of formula VII are known in the art. For example, they can be prepared according to or analogously to the processes described, inter alia, in U.S. Pat. No. 5,312,820, British Patent Application No. 2281298, and / or International Patent Application No. 02 / 096883.

[0141] Compounds of formula IV are known in the art, for example they can be prepared according to or analogously to the processes described, inter alia, in WO 02 / 096883.

[0142] Otherwise, compounds of Formulas II-IV, VI, VII, and VIII are commercially available, known in the literature, or can be obtained from readily available starting materials using appropriate reagents and reaction conditions according to standard techniques, either by analogy with the processes described herein or by conventional synthetic procedures.

[0143] It will be appreciated by those skilled in the art that in the processes described above and below the functional groups of intermediate compounds may need to be protected by protecting groups.

[0144] Functional groups that are desirable to protect include sulfonamide, amide, amino, and aldehyde. Suitable protecting groups for sulfonamide, amide, and amino include tert-butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), or tert-butyl. Suitable protecting groups for aldehyde include alcohols such as methanol or ethanol, and diols (thus forming cyclic acetals) such as 1,3-propanediol or preferably 1,2-ethanediol. Protection and deprotection of functional groups can be carried out before or after the reaction in the above-described scheme.

[0145] Protecting groups can be applied and removed according to techniques well known to those skilled in the art and as described below. For example, protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need and type of protecting groups, as well as the sequence for achieving synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Hutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference.

[0146] When used herein in reference to a particular value (such as an amount), the term "about" (or similar terms such as "approximately") is understood to indicate that such value may vary by up to 10% (particularly up to 5%, e.g., up to 1%) of the defined value. In each case, it is contemplated that such terms may be replaced with the notation "±10%" or the like (or by indicating a variation of a particular amount calculated based on the relevant value). It is also contemplated that in each case, such terms may be omitted.

[0147] The compounds of the present invention have the advantage that they are potent and / or stable to metabolic hydrolysis and / or do not inhibit the CYP enzymes described herein above.

[0148] The compounds described herein, whether for use in the treatment of IPF or otherwise, may have the advantage that they may be more effective, less toxic, longer acting, more potent, have fewer side effects, be more readily absorbed, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or possess other useful pharmacological, physical, or chemical properties than compounds known in the prior art. Such effects may be assessed clinically, objectively, and / or subjectively by a medical professional, a treated subject, or an observer. [Example]

[0149] The present invention is further illustrated by reference to the following examples, which are not intended to limit the scope of the invention.

[0150] In case of discrepancy between the nomenclature and any compound depicted in the figures, the latter takes precedence (unless it contradicts any experimental details that may be given or is clear from the context).

[0151] Experimental procedure The starting materials and intermediates used in the synthesis of the compounds described herein are either commercially available or can be prepared by methods described herein or known in the art.

[0152] Experiments were generally carried out under an inert atmosphere (nitrogen or argon), especially when oxygen- or moisture-sensitive reagents or intermediates were used.

[0153] Mass spectrometry data are reported from liquid chromatography-mass spectrometry (LC-MS) using electrospray ionization. Chemical shifts for NMR data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvents used.

[0154] For syntheses that refer to general procedures, reaction conditions (such as reaction length or temperature) may vary. Reactions were generally followed by thin layer chromatography or LC-MS and workup as needed. Purification may vary between experiments. In general, the solvents and solvent ratios used for eluents / gradients are determined by appropriate R f and / or retention times were selected to provide. Some products were purified using supercritical fluid chromatography, e.g., on a reverse-phase column using a solvent combination with mobile phase A: CO and mobile phase B: MeOH / H2O / NH3.

[0155] Example 1 Butyl (5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate (a) N-tert-butyl-5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]phenyl]thiophene-2-sulfonamide 1-[(4-Bromophenyl)methyl]-2-methyl-imidazole (1.25 g, 5 mmol, prepared using a procedure similar to that described in the literature for 1-[(4-bromophenyl)methyl]-2-methyl-imidazole (see, for example, International Patent Application No. 2002 / 096883)), 5-isobutyl-2-(tert-butylaminosulfonyl)-3-thiopheneboronic acid (1.59 g, 5 mmol, prepared as described in International Patent Application No. 2002 / 096883), KCO (2.06 g, 15 mmol), and Pd(PPh) (144 mg, 120 μmol) were added to dioxane (100 mL) and water (10 mL). The mixture was heated to 95 °C overnight under a nitrogen atmosphere. Most of the solvent was evaporated. Water (50 mL) was added, and the product was extracted with diethyl ether (2 × 50 mL). After drying and evaporation, the isolated subtitle compound was used directly in the next step.

[0156] (b) 5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]phenyl]thiophene-2-sulfonamide The subtitle compound from step (a) above (1.36 g) was dissolved in dichloromethane (30 mL). Boron trichloride (15 mL, 1 M in dichloromethane) was added and the solution was stirred at room temperature for 2 hours. Na2CO3 (saturated, 20 mL) was added and the product was extracted with ethyl acetate (40 mL). After drying and evaporation, the isolated subtitle compound was used directly in the next step.

[0157] (c) butyl N-[[5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]phenyl]-2-thienyl]sulfonyl]-carbamate The subtitle compound from step (b) above (1.2 g) and N-ethyldiisopropylamine (2.57 g, 20 mmol) were dissolved in dichloromethane. Butyl chloroformate (2.04 g; 15 mmol) was added slowly at room temperature. After 1 h, water was added and the product was extracted with diethyl ether. The subtitle compound was isolated using column chromatography from dichloromethane-methanol (90:10). The amount of isolated subtitle compound was 1.05 g (43% yield over three reaction steps). 1 H-NMR(CDCl3):0.85(t,3H),0.99(d,6H),1.24(m,2H),1.48(m,2H),1.94(m,1H),2.54(s,3H) ),2.69(d,2H),3.99(t,2H),5.11(s,2H),6.72(s,1H),6.81(m,2H),7.07(d,2H),7.60(d,2H) MS (M+H): Exp. 490.1824 Calc. 490.1834.

[0158] Example 2 Ethyl (5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate The title compound is prepared by a process similar to that described in Example 1, except that ethyl chloroformate is used in the final step.

[0159] Example 3 Butyl (3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonylcarbamate The title compound is prepared by a process similar to that described in Example 1, except that 1-[(4-bromophenyl)methyl]-2-ethylimidazole is used in the first step.

[0160] Biological assays The biological activity of the exemplary compounds described herein above was evaluated (and compared to C21) using the following biological assays.

[0161] Binding to AT1 and AT2 receptors Compounds were evaluated for binding to human recombinant AT2 and AT1 receptors using a radiometric scintillation assay according to Eurofins protocols ITEM26 and ITEM24.

[0162] Briefly, recombinant proteins were incubated with test compounds at concentrations of 1, 10, 100, and 1000 nM for the AT2 receptor and 1 and 10 μM for the AT1 receptor at 37°C for 2-4 hours. 125 I(sar1, IIe8)-AT-II was used as a ligand for the AT1 receptor. 125 ICGP 42112A was used as a ligand for the AT2 receptor. The inhibition rate of control specific binding was calculated according to 100-(measured specific binding / control specific binding) x 100. [Table 1]

[0163] CYP inhibitors Compounds were evaluated at 10 μM for inhibition of major cytochrome P450 isoforms (CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using isoform-specific substrates incubated with human liver microsomes (Eurofins protocol ITEMG232). The following substrates were used: CYP1A phenacetin, CYP2B6 bupropion, CYP2C8 paclitaxel and amodiaquine, CYP2C9 diclofenac, CYP2C19 omeprazole, CYP2D6 dextromethorphan, and CYP3A midazolam and testosterone.

[0164] At the end of the incubation, metabolite formation was monitored by HPLC-MS / MS as peak area response. [Table 2] [Table 3]

[0165] Abbreviation The following abbreviations may be used herein: DMSO dimethyl sulfoxide NMR nuclear magnetic resonance rt room temperature THF tetrahydrofuran

Claims

1. 1. A compound of formula I for the treatment of a disease or condition in which activation of the AT2 receptor is desired or required, but inhibition of CYP is undesired, said disease or condition being selected from the group consisting of interstitial lung disease, autoimmune disease, chronic kidney disease, pulmonary hypertension, obstructive airway disease, viral respiratory tract infection and resulting pneumonia, and infarction; 【Chemistry 1】 During the ceremony, Z represents —O— or a direct bond; R １ may be substituted by one or more halogen atoms, C １－３ represents alkyl, R ２ and R ３ each independently optionally substituted by H or one or more halogen atoms, C １－３ represents alkyl, R ４ each of which may be substituted with one or more halogen atoms １－６ Alkyl or C １－６ represents alkoxy, or R ４ Each of them is a halogen, -CH ２ F, -OCF ３ , C １－６ Alkyl, and C １－６ aryl, optionally substituted by one or more substituents selected from alkoxy; １－６ alkylaryl, heteroaryl, or C １－６ represents alkylheteroaryl, R ５ each of which may be optionally substituted with one or more halogen atoms; １－６ Alkyl, C １－６ Alkoxy, or C １－６ Alkoxy-C １－６ Representing an alkyl, compound, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical product of claim 1, wherein Z represents -O-.

3. R １ The pharmaceutical product according to claim 1 or 2, wherein represents methyl or ethyl.

4. R ２ and R ３ The pharmaceutical agent of any one of claims 1 to 3, wherein independently represent H, methyl, or ethyl.

5. R ４ may be substituted or terminated by up to three fluorine atoms, C １－４ Alkyl group, phenyl, C １－３ alkylaryl, or C １－３ The pharmaceutical product according to any one of claims 1 to 4, which represents alkylheteroaryl.

6. R ５ may be substituted or terminated by up to three fluorine atoms, C １－４ The pharmaceutical product according to any one of claims 1 to 5, wherein the alkyl group is represented.

7. The compound of formula I, wherein the compound is butyl(5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl-carbamate. butyl(3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl-carbamate, or The pharmaceutical agent according to any one of claims 1 to 6, which is ethyl (5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl-carbamate.

8. In the formula I, Z represents —O—, and R １ represents methyl, R ２ and R ３ Both represent H, and R ４ represents n-butyl, R ５ The pharmaceutical product according to any one of claims 1 to 6, wherein does not represent isobutyl.

9. The compound of formula I is butyl(3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl-carbamate, or The pharmaceutical product of claim 8, which is ethyl (5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl-carbamate.

10. 10. A pharmaceutical formulation comprising a pharmaceutical agent according to claim 8 or 9 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

11. A pharmaceutical product according to any one of claims 1 to 9, a therapeutic agent known to be metabolized by a CYP enzyme selected from the group consisting of pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil, simvastatin, and a pharmaceutically acceptable salt of any of these agents; a pharmaceutically acceptable adjuvant, diluent, or carrier; 10. A pharmaceutical formulation comprising:

12. (A) a pharmaceutical formulation comprising the pharmaceutical agent of any one of claims 1 to 9 mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier; (B) a pharmaceutical formulation comprising a therapeutic agent known to be metabolized by a CYP enzyme, selected from the group consisting of pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil, simvastatin, and pharmaceutically acceptable salts of any of these agents, mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, A kit-of-parts in which components (A) and (B) are each provided in a form suitable for administration in combination with the other.

13. The medicament according to any one of claims 1 to 9, the pharmaceutical formulation according to claim 10 or 11, or the kit-of-parts according to claim 12, wherein the disease or condition is selected from the group: rheumatoid arthritis, diabetic nephropathy, pulmonary arterial hypertension, chronic obstructive airway disease, viral-induced pneumonia, and myocardial infarction.

14. The pharmaceutical product according to any one of claims 1 to 9, the pharmaceutical preparation according to claim 10 or 11, or the kit-of-parts according to claim 12, wherein the disease is an interstitial lung disease.

15. The pharmaceutical product according to any one of claims 1 to 9, the formulation according to claim 10 or 11, or the kit-of-parts according to claim 12, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

16. The pharmaceutical product according to any one of claims 1 to 9, the pharmaceutical preparation according to claim 10 or 11, or the kit-of-parts according to claim 12, wherein the interstitial lung disease is sarcoidosis.

17. 13. The pharmaceutical formulation of claim 11 or the kit-of-parts of claim 12, wherein the therapeutic agent known to be metabolized by a CYP enzyme is pirfenidone, or a pharmaceutically acceptable salt thereof.

18. 10. A method for preparing a pharmaceutical product according to claim 8 or 9, comprising: (i) a compound of formula II 【Chemistry 2】 (In the formula, R １ , R ２ , R ３ , and R ５ is as defined in claim 8), 【Transformation 3】 (In the formula, R ４ and Z is as defined in claim 8, and X represents a suitable leaving group.

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