Selective Angiotensin II Compounds

Abstract

Pharmaceutical compounds of formula I are provided: [Formula 1] TIFF2026502510000014.tif62166 formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y 1 , Y 2 , Y 3 , X and Z have the meanings described herein, and the compounds are useful in the treatment of autoimmune and / or fibrotic diseases, including interstitial lung diseases, such as idiopathic pulmonary fibrosis and sarcoidosis.

Description

[Technical Field]

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

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

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

[0004] The stimulatory effects of Ang II on vascular tone, cell proliferation, inflammation, and extracellular matrix synthesis are primarily mediated by AT1 receptors in any organ, whereas AT2 receptor function appears to be more prevalent in injured tissues, exerting reparative and opposing properties to those of the AT1 receptor. For example, AT2 receptors have been shown to be important for myocyte 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 surrounding the alveoli, thereby impeding the respiratory process.

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

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

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

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

[0012] IPF exhibits distinct phenotypes with distinct prognoses, defined as mild, moderate, and severe. Mild cases follow a stable or slowly progressive course, and patients may take years to seek medical advice. Accelerated IPF exhibits more rapid progression, shortened survival, and affects a subgroup of patients, usually male smokers. Acute exacerbations of IPF are defined as a rapid worsening of the disease, and patients in this subpopulation have a very poor outcome with a high mortality rate in the short term. The cause of IPF is unknown, but it appears to be a disorder likely resulting from an interplay of environmental and genetic factors that leads to unrelenting tissue remodeling by fibroblasts rather than normal repair, resulting in a pathogenesis that is primarily fibrotic rather than inflammatory. Growing evidence suggests that the disease is initiated through microdamage and apoptosis of alveolar epithelial cells, 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. The fibroblastic nests secrete excessive amounts of extracellular matrix that destroys the lung parenchyma and ultimately leads to loss of lung function.

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

[0014] Many treatment 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, all of which have been shown to provide essentially limited or no benefit (Rafii R et al., J. Thorac. Dis. (2013); 5, 48-73).

[0015] Current treatments for IPF include supplemental oxygen. Medications used include pirfenidone or nintedanib, but these drugs have limited effectiveness 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 drug treatments for ILD (and IPF), and there is a compelling clinical need for safer and / or more effective treatments.

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

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

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

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

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

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

[0023] Specifically, WO 2002 / 096883 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 disorders, including IPF (see, for example, WO 2016 / 139475).

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

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

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

[0027] In a first aspect of the invention, there is provided a compound of formula I, [ka] During the ceremony, R 1 is H, a halogen atom, -CN, or C 1~7 Alkyl or C 1~7 represents alkoxy, C 1~7 Alkyl or C 1~7 Any alkoxy may optionally contain one or more halogen atoms, hydroxyl, C 1~7 Alkyl, CF 3、 OR 7 is replaced by R 2 and R 3 are independently H, a halogen atom, -CN, or C 1~7 Alkyl or C 1~7 represents alkoxy, C 1~7 Alkyl or C 1~7 Any alkoxy may optionally contain one or more halogen atoms, hydroxyl, C 1~7 Alkyl, CF3 or OR 7a is replaced by R4 is C 1~6 Alkyl, C 1~6 Alkoxy or C 1~6 Alkoxy-C 1~6 alkyl, each of which alkyl moieties is optionally substituted and / or terminated by one or more halogen atoms, —CN groups or —OH groups; or R 4 is aryl, C 1~6 Alkylaryl, C 1~3 Alkenylaryl, heteroaryl, C 1~6 alkylheteroaryl, or C 1~3 alkenylheteroaryl, each of which optionally contains one or more halogens, CF, CFO—, —CN, C 1~6 Alkyl and C 1~6 substituted with alkoxy, R 5 is H, halogen atom, hydroxyl, -CN, -NR 9a R 10a , C 1~7 Alkyl, C 1~7 Alkoxy or C 1~6 Alkoxy-C 1~6 represents alkyl, C 1~7 Alkyl, C 1~7 Alkoxy or C 1~6 Alkoxy-C 1~6 Each alkyl may optionally be one or more halogen atoms, hydroxyl, —CN, —NR 9b R 10b , C 1~7 Alkyl, or C 1~7 substituted by alkoxy, R 6 , R 7 and R 7a are independently H or C optionally substituted with one or more halogen atoms. 1~6 represents alkyl, Y 1 -CR 8 -, -N-, -NH-, O, or S; Y 2 -CR 8 -, -CR 8=CH-, -CH=CR 8 -, -CR 8 =CR 8 -, -N-, -NH-, O, or S, and Y 3 Ga-CR 8 - and R 8 is H, halogen atom, hydroxyl, -CN, -NR 9c R 10c or any of which optionally represents one or more halogen atoms, hydroxyl, —CN, —NR 9d R 10d , C 1~7 Alkyl, or C 1~7 Alkoxy-substituted C 1~7 Alkyl or C 1~7 represents alkoxy, however, (a)Y 1 and Y 2 is not the same as (b)Y 1 , Y 2 , and Y 3 In R, there exists 8 at least one of the groups does not represent H or fluorine, X and Z are independently CH=CH, CR 11 , N, NH, O, or S; however, (a) X and Z are not the same, (b) When X represents CH=CH, Z is CR 11 may represent only (c) When Z represents CH=CH, X is CR 11 may represent only R 11 is H, halogen atom, hydroxyl, -CN, -NR 9e R 10e or any of which optionally represents one or more halogen atoms, hydroxyl, amino, —CN, —NR 9f R 10f , C 1~7 Alkyl, or C 1~7 C substituted by alkoxy 1~7 Alkyl or C 1~7represents alkoxy, R 9a , R 10a , R 9b , R 10b , R 9c , R 10c , R 9d , R 10d , R 9e , R 10e , R 9f , and R 10f are each independently H or C substituted with one or more halogen atoms. 1~6 Alkyl, or a pharmaceutically acceptable salt thereof, These compounds and salts are hereinafter collectively referred to as "compounds of the invention."

[0028] Compounds of the invention that may be mentioned include those defined above, but R 1 is H, optionally one or more halogen atoms, CF or OR 7 C replaced by 1~6 represents alkyl, R 2 and R 3 are independently H or C optionally substituted with one or more halogen atoms. 1~6 represents alkyl, R 4 is C 1~6 Alkyl, C 1~6 Alkoxy or C 1~6 Alkoxy-C 1~6 alkyl, each of which alkyl moieties is optionally substituted and / or terminated by one or more halogen atoms, —CN groups or —OH groups; or R 4 is aryl, C 1~6 Alkylaryl, C 1~3 Alkenylaryl, heteroaryl, C 1~6 alkylheteroaryl, or C 1~3 alkenylheteroaryl, each of which optionally contains one or more halogens, CF, CFO—, —CN, C 1~6 Alkyl and C 1~6substituted with alkoxy, R 5 is C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy-C 1~6 alkyl, each of which is optionally substituted with one or more halogen atoms; R 6 and R 7 are independently H or C optionally substituted with one or more halogen atoms. 1~6 represents alkyl, and / or R 8 represents H, a halogen atom, or C, each of which is optionally substituted with one or more halogen atoms; 1~3 Alkyl or C 1~3 represents alkoxy.

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

[0030] Compounds are named according to the IUPAC nomenclature generated by the program ChemDraw Ultra 12.0.

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

[0032] 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.

[0033] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting the free acid or free base form of the compound of the present invention with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removing the solvent or medium using standard techniques (for example, in vacuo, by lyophilization, or by filtration). Salts can also be prepared using techniques known to those skilled in the art, for example, by exchanging the counterion of the compound of the present invention in the form of a salt with another counterion using a suitable ion exchange resin.

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

[0035] Specific 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 (such as ammonia, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, etc.) More specifically, base addition salts that may be mentioned include Mg salts, Ca salts, and most specifically K salts and Na salts.

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

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

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

[0039] The compounds of the invention may also exhibit tautomerism, and all tautomers and mixtures thereof (especially those with sufficient stability to allow their isolation) are included within the scope of the invention.

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

[0041] As used herein, the term "halogen," as used herein, includes fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Similarly, the term "halo," as used herein, includes fluoro, chloro, bromo, and iodo.

[0042] Unless otherwise specified, C 1~6 Alkyl groups (e.g., C 1~4 C such as alkyl groups 1~7 Alkyl group, C 2~4 C such as alkyl group 2~7 Alkyl groups, and C 1~6 Alkoxy group, C 1~6 Alkoxy-C 1~6 Alkyl group, C 1~6 Alkylaryl group, C 1~3 Alkenylaryl group, C 1~6 Alkylheteroaryl groups and C 1~3 C such as alkenyl heteroaryl groups 1~7 The alkyl portion of the alkoxy may be straight chain, or, when there is a sufficient number (i.e., a minimum of 2 or 3, as appropriate) of carbon atoms, branched and / or cyclic (e.g., C 3~7 , e.g. C 3~6 When there is a sufficient number (i.e., a minimum of four) of carbon atoms, such groups may also be part cyclic (e.g., C 4~6 C such as partial cycloalkyl groups 4~7 (Forming the formula:). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Similarly, partially 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 also be polycyclic (e.g., bicyclic or tricyclic) and / or spirocyclic.

[0043] Alkyl and alkoxy groups, when there is a sufficient number (ie, a minimum of three) of carbon atoms, may be unsaturated and thus incorporate double or triple bonds.

[0044] Particular alkyl groups that may be mentioned include straight-chain (i.e., not branched and / or cyclic) alkyl groups. For example, C 1~6 C such as alkyl group 1~7 Alkyl groups, and C 1~6 C such as alkoxy group 1~7 The alkyl portion of the alkoxy group includes, but is not limited to, propyl, ethyl, and methyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, n-propyl, 2-methylpropyl, or isopropyl.

[0045] For the avoidance of doubt, C 1~6 Alkyl groups and C 1~6 Alkoxy-C 1~6 Alkyl, C 1~6 Alkylaryl, C 1~3 Alkenylaryl, C 1~6 Alkylheteroaryl and C 1~3 C, such as the alkyl portion of an alkenyl heteroaryl group 1~7 The point of attachment of an alkyl group is through the alkyl portion of such group.

[0046] For the avoidance of doubt, an alkoxy group is bonded to the remainder of the molecule via the oxygen atom of the group, and an alkoxyalkyl group is bonded to the remainder of the molecule via the alkyl portion of the group.

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

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

[0049] As used herein, reference to a "heteroaryl" (which may also be referred to as heteroaromatic) ring or group may refer to a heteroaromatic group containing one or more heteroatoms (e.g., 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(s) may or may not contain one or more heteroatoms). Substituents on heteroaryl / heteroaromatic groups may, where appropriate, be located on any suitable atom in the ring system, including a heteroatom (e.g., on an appropriate N atom).

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

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

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

[0053] As noted 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-dihydrobenz[1,4]oxazinyl, dihydrobenzothiophenyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, thiochromanyl, and the like groups.

[0054] 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 if bicyclic, may be wholly or partially aromatic. 6~10 Aryl groups include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like (eg, phenyl, naphthyl, and the like).

[0055] An aromatic group may be described as a cyclic group containing an appropriate number of double bonds therein to permit aromaticity.

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

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

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

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

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

[0061] Where groups are referred to herein as being optionally substituted, it is specifically contemplated that such optional substituents may not be present (i.e., reference to such optional substituents may be removed), in which case the optionally substituted group may be referred to as unsubstituted.

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

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

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

[0065] Preferred compounds of the present invention include: R 1 is H, or optionally one or more halogen atoms, CF3 or OR 7 C replaced by 1~6 When representing an alkyl group (e.g., methyl, ethyl, propyl (e.g., isopropyl, cyclopropyl) or butyl (e.g., n-butyl or tert-butyl)), R 2 and R 3 are independently H or C optionally substituted with up to three halogen atoms; 1~4 represents an alkyl group (e.g., methyl, ethyl, propyl (e.g., n-propyl) or butyl (e.g., n-butyl)) (e.g., CH2CHClCH2CH2F or CH2CF3); Y 1 Ha-CR 8 - represents Y2 -CR 8 -,-CR 8 =CH-, -CH=CR 8 -,-CR 8 =CR 8 - represents one of X and Z represents -CH=CH- and the other represents -CH-, or one of X and Z represents O or S and the other represents -CH- or N; R 4 wherein each alkyl moiety is optionally substituted and / or terminated with one or more halogen atoms, —CN or —OH groups; 1~4 alkyl groups (e.g., ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., tert-butyl, isobutyl, or n-butyl)), C 1~4 Alkoxy (e.g., methoxy, ethoxy), each optionally containing one or more halogens (such as F, Cl, or Br), CF3, -CN, C 1~6 Alkyl (e.g., methyl), and C 1~6 aryl (e.g., phenyl), heteroaryl, C substituted with alkoxy (e.g., methoxy); 1~3 Alkylaryl, or C 1~3 represents alkylheteroaryl, R 5 C 1~4 represents an alkyl group (e.g., methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., isobutyl)); R 6 and R 7 independently represent H, methyl, ethyl, or propyl (e.g., n-propyl).

[0066] More preferred compounds of the present invention include: R 1 is H, optionally halogen, CF3 or OR 7 represents methyl, ethyl, isopropyl, cyclopropyl, or tert-butyl substituted with R 2 and R 3 independently represent H or methyl; Y1 represents -CH-, Y 2 represents -CH=CH-, Y 3 Ha-CR 8 - represents X represents -CH=CH-, O, or S; Z represents -CH- or N; R 4 is a C, the alkyl portion of which is optionally substituted and / or terminated with one or more F, Cl, Br, —CN or —OH groups; 1~4 alkoxy (e.g., methoxy, ethoxy), or R 4 represents heteroaryl selected from the group of thiazole, oxazole, isoxazole, pyridine, pyridazine, triazine, pyrazine and, more preferably, pyrimidine, each optionally substituted with one or more of F, Cl, Br, CF3, —CN, Me or methoxy, R 5 represents methyl, ethyl, n-propyl, n-butyl or isobutyl; R 6 represents H or methyl, R 7 represents H, R 8 represents halogen or methyl optionally substituted with one or more halogens.

[0067] Particularly preferred compounds of the present invention include: R 1 represents methyl optionally substituted with one or more fluoro groups, or represents 2-hydroxypropan-2-yl; R 2 and R 3 Both represent H, X represents -CH=CH- or S; Z represents -CH- R 4 represents heteroaryl selected from the group of oxazole, pyridine, and more preferably pyrimidine, each of which is optionally substituted with one or more of F, Cl, Br, CF3, —CN, methyl, or methoxy; R 5 represents methyl, ethyl, n-propyl, n-butyl or isobutyl; R 6 represents H or methyl, Y 3 represents -CCl-, -C(methyl)- or -C(CF3)-.

[0068] Preferred compounds of the present invention include: R 1 represents methyl, trifluoromethyl, or 2-hydroxypropan-2-yl; Y 1 represents -CH-, Y 2 represents -CH=CH-, R 4 represents pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 5-methylpyrimidin-2-yl, 5-trifluoromethylpyrimidin-2-yl, 4,5-dimethyloxazol-2-yl, or pyridin-2-yl; R 5 represents n-butyl or isobutyl, R 6 represents H.

[0069] Further preferred compounds of the present invention include: Y 3 Ha-CR 8 - represents R 5 represents isobutyl, R 7 represents H, R 8 represents chloro, bromo, or iodo, or represents methyl optionally substituted by one or more fluoro groups.

[0070] Even more preferred compounds of the present invention include: R 1 represents methyl, Y 3 represents -CCl-, R 4 represents methoxy, R 8 represents chloro, methyl, or trifluoromethyl.

[0071] Preferred compounds of the present invention include: When X represents S and Z represents -CH-, R 1 represents methyl, trifluoromethyl, or 2-hydroxypropan-2-yl; When X represents -CH=CH- and Z represents -CH-, R 1 represents methyl.

[0072] Further preferred compounds of the present invention include: When X represents S and Z represents -CH-, R 1 represents methyl, trifluoromethyl, 2-hydroxypropan-2-yl or isopropyl, When X represents -CH=CH- and Z represents -CH-, R 1 represents methyl or isopropyl.

[0073] Thus, preferred compounds of the invention that may be mentioned are: 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyridin-2-yl)thiophene-2-sulfonamide, 5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(pyridin-2-yl)thiophene-2-sulfonamide, 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyridin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(5-fluoropyrimidin-2-yl)-5-isobutylthiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(4,5-dimethyloxazol-2-yl)-5-isobutylthiophene-2-sulfonamide, 3-(3-chloro-4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-(trifluoromethyl)pyrimidin-2-yl)thiophene-2-sulfonamide, 5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-methylpyrimidin-2-yl)thiophene-2-sulfonamide, 3'-chloro-5-isobutyl-N-(5-methoxypyrimidin-2-yl)-4'-((2-methyl-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide, 5-isobutyl-3'-methyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, 3-(3-chloro-4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-methoxythiophene-2-sulfonamide, 2-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide, 5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]-3-(trifluoromethyl)phenyl]-N-pyrimidin-2-yl-thiophene-2-sulfonamide, 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide, and Includes 3-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiophene-2-sulfonamide.

[0074] IUPAC names were generated from the program ChemDraw Ultra 12.0.

[0075] More preferred compounds of the present invention include the compounds of the Examples set forth below.

[0076] Compounds of formula I can be made according to techniques well known to those skilled in the art, for example as described below.

[0077] According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula I, said process comprising reacting a compound of formula II with a compound of formula III, or a salt thereof, [ka] In the formula, R 1 , R 2 , R3 , R 5 , R 6 , Y 1 , Y 2 , Y 3 , X, and Z are defined as above, L 1 R 4 III In the formula, R 4 is as defined above, and L 1 is a suitable leaving group (e.g., a halo group, such as chloro or bromo) in the presence of a palladium catalyst (e.g., palladium acetate), a suitable ligand (e.g., 1,1-bis(diphenylphosphino)ferrocene), a suitable solvent (e.g., toluene, acetonitrile, dimethylformamide, dioxane, water), and / or a suitable base (e.g., potassium carbonate, triethylamine, 4-dimethylaminopyridine, potassium tert-butoxide, sodium tert-butoxide, N,N'-dimethylethylenediamine, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, di-isopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or mixtures thereof) in the presence of lithium chloride at about or above room temperature (e.g., up to 80-140°C).

[0078] Alternatively, compounds of formula I may be prepared according to a process comprising reacting a compound of formula II, as defined hereinbefore, with a compound of formula III, as defined hereinbefore, in the presence of a suitable solvent (e.g., toluene, acetonitrile, dimethylformamide, dioxane, dichloromethane, e.g., toluene, acetonitrile, dimethylformamide, dioxane) and / or a suitable base (e.g., potassium carbonate, triethylamine, 4-dimethylaminopyridine, pyridine, diisopropylethylamine, e.g., potassium carbonate, triethylamine, 4-dimethylaminopyridine), for example at about room temperature or above (e.g., up to 90-140°C), optionally in the presence of copper(I) iodide and / or a suitable base (e.g., N,N'-dimethylethylenediamine, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, di-isopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or mixtures thereof), under microwave irradiation.

[0079] Compounds of formula II may be prepared by reaction of a compound of formula IV: [ka] In the formula, X, Z, R 5 , and R 6 is as previously defined or an N-protected derivative thereof, and L 2 represents a suitable cross-coupling group with a compound of formula V, [ka] In the formula, R 1 , R 2 , R 3 , Y 1 , Y 2 , and Y 3 is as defined herein before, and L 3 represents a suitable cross-coupling group.

[0080] The coupling reaction can be a palladium-catalyzed CH activation, which is2 and L 3 where one of the groups represents one of the suitable cross-coupling groups, i.e., H, and the other represents the other group (e.g., a halo group, such as iodo or bromo). Standard C-H activation conditions can be applied in this reaction, for example, using a suitable coupling catalyst system (e.g., palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane, Pd(PPh3)4 or Pd(OAc)2 / ligand (wherein the ligand is, for example, PPh3, P(o-Tol) 3、 or 1,1'-bis(diphenylphosphino)ferrocene) and a suitable base (e.g., sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, or diisopropylamine), and a suitable solvent system (e.g., toluene, ethanol, n-butanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane, or mixtures thereof). The reaction may be carried out at room temperature or above (e.g., at the reflux temperature of the solvent system used). The reaction can be carried out under microwave irradiation at temperatures above room temperature.

[0081] The above coupling reaction may also be a Suzuki reaction and may be carried out under standard Suzuki conditions. 2 and L 3 represents a suitable Suzuki cross-coupling group (or "partner"), i.e., either a boronic acid (-B(OH)2) or a MIDA boronate (e.g., 5-methyl-3,7-dioxo-2,8-dioxa-5-azonia-1-boranuidabicyclo[3.3.0]octan-1-yl), and a halo group, such as iodo or bromo; L 2 and L 3and the other represents the other group. Standard Suzuki conditions can be applied to this reaction, which include, for example, the presence of a suitable coupling catalyst system (e.g., a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), a complex of [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) with dichloromethane, Pd(PPh3)4, or Pd(OAc)2 / ligand (wherein the ligand can be, for example, PPh3, P(o-Tol)3, or 1,1'-bis(diphenylphosphino)ferrocene)) and a suitable base (e.g., sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, or diisopropylamine), and a suitable solvent system (e.g., toluene, ethanol, n-butanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane, or mixtures thereof). The reaction may be carried out above room temperature (for example, at the reflux temperature of the solvent system used). The reaction can be carried out under microwave irradiation above room temperature.

[0082] If a protected version of the compound of formula IV is used, this reaction may be followed by deprotection of the SO2NH group under standard conditions, for example, as described below. The reaction of the compound of formula IV with the compound of formula V may also be followed by reaction of the intermediate so formed with a suitable acid to form an acid addition salt, or more preferably, an N-protected version thereof. Suitable acid addition salts include fumarates, trifluoroacetates, and oxalates.

[0083] Compounds of formula II may be prepared, for example, by reaction of compounds of formula VI with compounds of formula VII in the presence of a suitable base (e.g., pyridine) and a suitable organic solvent (e.g., toluene) at about or below room temperature; [ka] In the formula, R 1 , R 2 and R 3is as defined herein before, [ka] In the formula, R 5 , R 6 , Y 1 , Y 2 , Y 3 , X, and Z are as previously defined herein; L 4 represents a suitable leaving group (e.g., especially bromo) or an N-protected derivative thereof. If a protected version of the compound of formula VII is used, this reaction may be followed by deprotection of the SO2NH group under standard conditions, for example as described below. Furthermore, compounds of formula II may be prepared in this way, for example, according to or analogously to the processes described, inter alia, in British Patent Application No. 2281298.

[0084] Compounds of formula V may be prepared by standard techniques, for example by reaction of a compound of formula VI, as defined hereinbefore, with a compound of formula VIII, in the presence of a suitable base (e.g. sodium hydride, potassium carbonate, potassium hydroxide, for example sodium hydride or potassium carbonate) and a suitable solvent (e.g. dimethylformamide, acetonitrile, dimethylsulfoxide, for example dimethylformamide or acetonitrile), at room temperature, at room temperature (e.g. at 0°C) or above room temperature (e.g. at the reflux temperature of the solvent system used), for example at room temperature or at room temperature, [ka] In the formula, L 3 , L 4 , Y 1 , Y 2 , and Y 3 is as defined earlier in this specification.

[0085] Compounds of formula VII are known in the art. For example, they can be prepared according to or analogously to the processes described in, inter alia, U.S. Patent No. 5,312,820, British Patent Application No. 2281298, and / or WO 02 / 096883.

[0086] 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.

[0087] Compounds of formula III, VI and VIII are either commercially available, known in the literature, or may 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.

[0088] 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.

[0089] 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 such as 1,3-propanediol, or preferably 1,2-ethanediol (thus forming a cyclic acetal). Protection and deprotection of functional groups can be carried out before or after the reaction in the schemes mentioned above.

[0090] Protecting groups can be applied and removed according to techniques well known to those skilled in the art and described below. For example, protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemical reaction involved will dictate the need and type of protecting groups, as well as the sequence for achieving the synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P. ​​G.M. Wutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference.

[0091] Medical and Pharmaceutical Use As described herein, the compounds of the present invention, and therefore the compositions and kits comprising them, are useful because they have pharmaceutical activity and / or are metabolized in the body after oral or parenteral administration to form compounds that have pharmaceutical activity.

[0092] Thus, according to a further aspect of the present invention there is provided a compound of the present invention as defined hereinbefore for use as a pharmaceutical (or for use in medical applications).

[0093] Specifically, the compounds of the present invention are agonists of the AT2 receptor and are therefore expected to be useful in conditions where there is a deficiency in endogenous production of Ang II and / or where increased activity of the AT2 receptor is desirable or required.

[0094] More particularly, the compounds of the invention are agonists of the AT2 receptor and in particular selective agonists of its sub-receptors (vs. the AT1 receptor), as can be demonstrated, for example, in the tests described below.

[0095] AT2 receptor agonists include those that fully activate AT2 receptors and those that partially activate AT2 receptors. Therefore, the compounds of the present invention can selectively bind to AT2 receptors and exhibit agonist activity at AT2 receptors. A compound that "selectively binds" to AT2 receptors includes those in which 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.

[0096] Compounds of the invention are further expected to be useful in conditions where AT2 receptors are expressed and their stimulation is desirable or required.

[0097] In this regard, the compounds of the invention are indicated for the treatment of conditions characterized by vasoconstriction, fibrosis, increased cell proliferation and / or differentiation, increased myocardial contractility, increased cardiovascular hypertrophy, and / or increased fluid and electrolyte retention, as well as skin and musculoskeletal disorders.

[0098] The compounds of the present invention may also exhibit thromboxane receptor activity. In this regard, the compounds of the present invention may have an inhibitory effect on platelet activation and / or aggregation (thus, for example, an antithrombotic effect) and / or may reduce vasoconstriction and / or bronchoconstriction in a therapeutic manner.

[0099] The compounds of the invention are further indicated for the treatment of stress-related disorders and / or for improving microcirculatory and / or mucosal protective mechanisms.

[0100] Thus, the compounds of the invention may be characterized as set forth above and are expected to be useful in the treatment of disorders of, for example, the gastrointestinal tract, cardiovascular system, respiratory tract, kidney, eye, female reproductive (ovulatory) system, and central nervous system (CNS).

[0101] Gastrointestinal disorders that may be mentioned include esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastroesophageal reflux, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatitis, liver disorders (such as hepatitis), gallbladder disease, multiple organ failure (MOF), and sepsis. Other gastrointestinal disorders that may be mentioned include xerostomia, gastritis, gastroparesis, hyperacidity, biliary disorders, celiac disease, Crohn's disease, ulcerative colitis, diarrhea, constipation, colic, dysphagia, vomiting, nausea, dyspepsia, and Sjogren's syndrome.

[0102] Disorders of the airways that may be mentioned include asthma, obstructive pulmonary diseases (such as chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension, and inflammatory disorders such as adult respiratory distress syndrome.

[0103] Renal disorders that may be mentioned include renal failure, nephritis, and renal hypertension.

[0104] Ocular disorders that may be mentioned include diabetic retinopathy, retinopathy of prematurity, and retinal microangiogenesis.

[0105] Disorders of the female reproductive system that may be mentioned include ovulatory dysfunction.

[0106] Cardiovascular disorders that may be mentioned include hypertension, cardiac hypertrophy, heart failure (including heart failure with preserved ejection fraction), atherosclerosis, arterial thrombosis, venous thrombosis, endothelial dysfunction, endothelial lesions, post-balloon dilation stenosis, angiogenesis, diabetic complications, microvascular dysfunction, angina pectoris, cardiac arrhythmias, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic lesions, erectile dysfunction, and neointimal proliferation.

[0107] Disorders of the CNS that may be mentioned include cognitive dysfunction, dysfunction of food intake (hunger / satiety) and thirst, stroke, cerebral hemorrhage, cerebral embolism and infarction, multiple sclerosis (MS), Alzheimer's disease, and Parkinson's disease.

[0108] The compounds of the invention may also be useful in regulating growth metabolism and proliferation, for example, in the treatment of aging, hypertrophic diseases, benign prostatic hyperplasia, autoimmune disorders (e.g., arthritis such as rheumatoid arthritis, or systemic lupus erythematosus), psoriasis, obesity, nerve cell regeneration, ulcer healing, inhibition of adipose tissue hyperplasia, stem cell differentiation and proliferation, fibrotic disorders, cancer (e.g., in or among the gastrointestinal tract (including the esophagus or stomach), prostate, breast, liver, kidney, as well as lymphoma, lung cancer, ovarian cancer, pancreatic cancer, hematological malignancies, etc.), apoptosis, tumors (generally), and hypertrophy, diabetes, neuropathies, and organ rejection.

[0109] The compounds of the present invention are also useful in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer treatment-related cardiotoxicity, peripheral neuropathy, and, specifically, systemic sclerosis.

[0110] The compounds of the invention have particular application in the treatment and / or prevention of ILDs such as sarcoidosis or fibrosis, more particularly pulmonary fibrosis and especially IPF, as well as conditions which may induce ILDs, such as systemic sclerosis, rheumatoid arthritis, myositis or systemic lupus erythematosus, or conditions otherwise associated with ILDs, such as pulmonary hypertension and / or pulmonary arterial hypertension.

[0111] The compounds of the present invention are particularly useful in the treatment of pulmonary fibrosis, particularly IPF.

[0112] The term "IPF" will be understood to include not only prototypical IPF, the well-known progressive fibrosing ILD characterized by accelerated respiratory failure, frequent disease exacerbations, and earlier death, but also "progressive fibrosing ILD" (PF-ILD), a condition in which some individuals develop a progressive phenotype similar to IPF (see, e.g., Flaherty et al., N. Engl. J. Med., 381, 1718 (2019) and Wells, Lancet, 9, 437 (2021)). The PF-ILD phenotype is often due to diseases (such as connective tissue diseases like rheumatoid arthritis, scleroderma, dermatomyositis / polymyositis, associated ILD (CTD-ILD), fibrotic hypersensitivity pneumonitis (fHP), asbestosis, and pneumoconiosis like silicosis), sarcoidosis, idiopathic nonspecific interstitial pneumonia (NSIP), and unclassifiable ILD. Regardless of the disease trigger, PF-ILD has similar risk factors, progresses through similar mechanisms as prototypical IPF, such as self-sustaining dysregulated cellular repair, fibroblast proliferation, and alveolar dysfunction, and together can be targeted in a similar manner. To avoid unnecessary overlap, the conditions IPF and PF-ILD will hereinafter be referred to together as "IPF."

[0113] According to a further aspect of the invention there is provided a method of treating pulmonary fibrosis, in particular IPF, which method comprises administering to a person suffering from such a condition a therapeutically effective amount of a compound of the invention.

[0114] 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 apoptosis of alveolar endothelial cells, which is an initiating factor in the development of pulmonary fibrosis. The compounds of the present invention may also have anti-proliferative effects, thereby 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 reducing secondary pulmonary hypertension. Finally, the compounds of the present invention may exhibit anti-inflammatory, anti-growth factor (e.g., transforming growth factor beta) and / or anti-cytokine effects.

[0115] In addition, the compounds of the present invention may also be useful in treating or preventing any fibrotic condition of one or more internal organs characterized by excessive accumulation of fibrous connective tissue, and / or in treating or preventing fibrosis and the morbidity and mortality that may be associated therewith. Such fibrosis may be associated with acute inflammatory conditions such as acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), multi-organ inflammation, damage and / or failure that may be caused by internal or external trauma (e.g., injury), or by infectious disease.

[0116] Thus, such conditions can result from sepsis or septic shock caused by viral, bacterial, or fungal infections (e.g., viral respiratory tract infections). Furthermore, acute lung injury (ARDS), particularly SARS, can be caused by viruses such as coronaviruses, including novel SARS coronavirus 2 (SARS-CoV-2), resulting in internal tissue damage and dysfunction of relevant internal (e.g., mucosal) tissues, such as the respiratory epithelium, leading to virus-induced pneumonia, pulmonary dysfunction, respiratory dysfunction, distress, and / or failure. Such tissue damage can also result in severe fibrosis. For example, SARS disease (coronavirus disease 2019, or COVID-19), caused by the novel coronavirus SARS-CoV-2, is known to often result in fibrosis.

[0117] The compounds of the present invention are particularly useful in the treatment of diseases or conditions in which activation of the AT2 receptor is desirable or required, but inhibition of one or more CYP enzymes is undesirable.

[0118] In an alternative embodiment of the invention, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of diseases or conditions in which activation of the AT2 receptor is desirable or required, but inhibition of CYP enzymes is undesirable.

[0119] "Diseases or conditions in which activation of the AT2 receptor is desirable or required, but inhibition of CYPs is undesirable" includes diseases or conditions, such as those mentioned below, that are known to be treatable by activation of the AT2 receptor, but includes the fact that existing treatments for such conditions may include the administration of other therapeutic agents that are metabolized by CYPs. Thus, such diseases or conditions may include conditions in which inhibition of at least one CYP enzyme is not required, advantageous, and / or undesirable, or conditions in which such inhibition is or may be harmful to the patient.

[0120] Specific diseases or conditions in which activation of the AT2 receptor is desirable or required, but inhibition of CYP enzymes is undesirable, include interstitial lung disease (such as pulmonary fibrosis, IPF, systemic sclerosis, and sarcoidosis), autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, and inflammatory bowel disease), chronic kidney disease (such as diabetic nephropathy), pulmonary hypertension, pulmonary arterial hypertension, and / or infarction (such as myocardial infarction and stroke). Thus, the compounds of the present invention are particularly useful for treating interstitial lung disease such as IPF, autoimmune diseases such as rheumatoid arthritis, chronic kidney disease such as diabetic nephropathy, pulmonary hypertension, including pulmonary arterial hypertension, and / or infarction, such as myocardial infarction.

[0121] According to a further aspect of the invention, there is provided a method of treating a disease or condition in which activation of the AT2 receptor is desirable or required but inhibition of CYP enzymes is undesirable (such as pulmonary fibrosis, particularly IPF), which method comprises administering a therapeutically effective amount of a compound of the invention to a person suffering from the relevant condition.

[0122] The compounds of the invention are indicated in both the therapeutic, palliative, and / or diagnostic treatment, as well as the prophylactic treatment (including preventing and / or arresting the deterioration and / or worsening of the condition) of any of the above conditions.

[0123] The compounds of the present invention are typically administered orally, intravenously, subcutaneously, bucally, 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, suspension, emulsion (including nanosuspension), or in a liposomal formulation. Additional methods of administration include, but are not limited to, intraarterial, intramuscular, intraperitoneal, intraportal, intradermal, epidural, intrathecal administration, or any combination thereof.

[0124] 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., simultaneously) using different routes of administration, but are preferably administered via known pharmaceutical formulations, including tablets, capsules, or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions, or emulsions for parenteral or intramuscular administration, or by inhalation, etc. Administration via inhalation is preferably carried out by using a nebulizer, thus delivering the compounds of the present invention to small lung tissues, including the alveoli and bronchioles, preferably without causing irritation or coughing in the treated subject.

[0125] Preferably, administration of a therapeutically effective amount of a compound of the present invention is carried out by any combination of routes of administration, either separately (e.g., at least about 2 hours apart), sequentially (e.g., within about 2 hours of each other), or simultaneously in parallel (e.g., simultaneously), including via inhalation and orally, to achieve an effective dosage.

[0126] In some embodiments, methods are provided for treating diseases or conditions in which activation of the AT2 receptor is desirable or required (and such diseases or conditions in which inhibition of CYP enzymes is undesirable), including pulmonary fibrosis, particularly IPF, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention via a combination of routes of administration, either separately, sequentially, or simultaneously, preferably via inhalation and orally, to achieve an effective dosage.

[0127] Such combinations of routes of administration, preferably via inhalation and orally, may be presented as separate formulations of the compounds of the invention optimized for each route of administration.

[0128] Such formulations may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0129] Thus, according to a further aspect of the present invention there is provided a pharmaceutical formulation comprising a compound of the present invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0130] The compounds of the present invention may be administered in combination with other AT2 agonists known in the art, such as C21, as well as in combination with AT1 receptor antagonists known in the art, and / or in combination with inhibitors of angiotensin-converting enzyme (ACE). Non-limiting, but illustrative examples of AT1 receptor antagonists that can be used in accordance with embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, pratosartan, ripiasartan, saprisartan, tasosartan, telmisartan, valsartan, and / or combinations thereof. Non-limiting, but illustrative examples of ACE inhibitors that may be used in accordance with embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, alacepril, ceronapril, delepril, moveltipril, and / or combinations thereof.

[0131] Other active ingredients that may be administered in combination with the compounds of the invention include cromoglycate disodium; endothelin receptor antagonists such as bosentan, ambrisentan, sitaxsentan, and macitentan; PDE5 inhibitors such as sildenafil and tadalafil; prostacyclin (epoprostenol) and its analogs such as iloprost and treprostinil; other biologics including interferon gamma-1b, etanercept, infliximab, and adalimumab; and methotrexate. Additional active ingredients in development that may be co-administered with the compounds of the invention include pamrevlumab (anti-CTGF, Fibrogen); GLPG1690 (autotaxin inhibitor, Galapagos), TD139 (galectin-3 inhibitor, Galecto), PRM-151 (recombinant pentraxin-2, Promedior), BBT-877 (autotaxin inhibitor, Boehringer / Bridge), CC-90001 (JNK inhibitor, Celgene), PBI-4050 (dual GPR40 agonist / GPR84 antagonist, Prometic), BMS-986020 (lysophosphatidic acid receptor antagonist, BMS), RVT-1601 (mast cell stabilizer, Respirant), SMO4646 (wnt-signal inhibitor, United Therapeutics), KD25 (Rho-associated kinase inhibitor, Kadmon). Holdings), BG00011 (integrin antagonist, Biogen), PLN-74809 (integrin antagonist, Pilant Therapeutics), saracatinib (src kinase inhibitor, AstraZeneca), PAT-1251 (lysyl oxidase inhibitor 2, PharmaKeta), ABM-125 (IL-25MAB, Abeome), and TA5-115 (multikinase inhibitor, Otsuka).

[0132] In a further aspect of the present invention, the compounds of the present invention find particular utility when combined with other therapeutic agents in combination therapy for treating various conditions, including those previously mentioned herein. 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.

[0133] Therefore, when the condition to be treated is an interstitial lung disease, such as IPF, systemic sclerosis, or a fibrotic disease known in the art, the compound of the present invention is preferably administered in combination with established therapies for such treatment, including but not limited to galectin-3 inhibitors, lysophosphatidic acid receptor 1 (LPA1) antagonists, autotaxin (ATX) inhibitors, recombinant human pentraxin-2 protein, or pirfenidone and / or nintedanib.Preferably, the combination of the compound of the present invention is with pirfenidone or a pharmaceutically acceptable salt thereof, and the compound is known to be metabolized by CYP enzymes, such as CYP1A.

[0134] Furthermore, when the condition being treated is a chronic kidney-related disease, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatments, such as irbesartan and / or torsemide, which compounds are known to be metabolized by CYP enzymes, such as CYP2C9.

[0135] When the condition being treated is pulmonary hypertension, the compounds of the invention are preferably administered in combination with one or more other drugs also used in such treatment, such as selexipag and / or sildenafil, which compounds are known to be metabolized by CYP enzymes, such as CYP3A4.

[0136] When the condition to be treated or prevented is myocardial infarction and / or stroke-related disease, the compounds of the present invention are preferably administered in combination with one or more other drugs also used in such treatments, such as propranolol, warfarin, clopidogrel, atorvastatin, cilostazol, lidocaine and / or simvastatin, or pharmaceutically acceptable salts thereof, which compounds are known to be metabolized by CYP enzymes such as CYP1A, CYP2CP, and / or CYP3A4.

[0137] 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 agents also used in such treatments, including, but not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen, celecoxib, meloxicam or its analogs (such as piroxicam) or indomethacin; or agents such as tizanidine, cyclophosphamide, cyclosporine, deflazacort, and / or hydrocortisone, riluzole, or pharmaceutically acceptable salts thereof, which compounds are known to be metabolized by CYP enzymes, such as CYP1A, CYP2CP, CYP2C19, and / or CYP3A4.

[0138] Therefore, the compounds of the present invention are particularly useful for treating diseases or conditions in which AT2 receptor activation is desirable or required, but CYP enzyme inhibition is undesirable, and therefore can be administered in combination with one or more of the other therapeutic agents mentioned hereinbefore, including pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam, torsemide, cyclophosphamide, indomethacin, atorvastatin, cilostazol, cyclosporine, deflazacort, hydrocortisone, lidocaine, selexipag, sildenafil, and / or simvastatin, which are metabolized via the CYP pathway and are useful or may be useful, to treat diseases including those mentioned hereinbefore. Most preferably, the compounds of the present invention are administered in combination with pirfenidone to treat interstitial lung diseases such as IPF.

[0139] Therapeutic agents that may be used in combination with the compounds of the invention include variously applied standard therapies 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 others. Pharma), and Octagam (Octapharma), antiviral drugs (e.g., oseltamivir, remdesivir, favilavir, molnupiravir, simeprevir, daclatasvir, sofosbuvir, ribavirin, umifenovir, lopinavir, ritonavir, lopinavir / ritonavir (Kaletra; AbbVie Deutschland GmbH Co.KG), teicoplanin, baricitinib (Olumient; Eli Lilly), ruxolitinib (Jakavi; Novartis), tofacitinib (Xeljanz; Pfizer), the TMPRSS2 inhibitor camostat or camostat mesylate, Actemra (Roche), AT-100 (rhSP-D), MK-7110 (CD24Fc; Merck)), OYA1 (OyaGen9), BPI-002 (BeyondSpring), NP-120 (Ifenprodil; Algernon Pharmaceuticals), and 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), cough suppressants (e.g., dextromethorphan), vaccinations (e.g., INO-4800 by Inovio Pharmaceuticals and Beijing Advaccine Biotechnology, when available), COVID-19 convalescent plasma (CCP), and / or passive antibody therapy with antibodies from the blood of people who have recovered from infection with SARS-CoV or SARS-CoV-2.

[0140] Further mentioned therapeutic agents include antifibrotic agents (e.g., nintedanib, especially pirfenidone), vitamins (e.g., vitamins B, C, D), and mucolytic agents such as acetylcysteine ​​and ambroxol.

[0141] Other therapeutic agents that can be used in combination with the compounds of the invention, or pharmaceutically acceptable salts thereof, include corticosteroids, including both natural and synthetic corticosteroids.

[0142] Naturally occurring corticosteroids that may be mentioned include cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, progesterone, and naturally occurring precursors and intermediates in corticosteroid biosynthesis, as well as other derivatives of naturally occurring corticosteroids, such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocorticosterone, 11-deoxycorticosterone, 18-hydroxycortisol, 11-hydroxycortisone ... 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.

[0143] Among the 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, prednicarbate and 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 types (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, flucloron, flumethasone, fluocortin, fluprednidene and fluprednidene acetate, fluticasone, fluticasone furoate and fluticasone propionate, meprednisone, paramethasone, prednylidene, rimex solon 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-1,4,6-trien-3-one.

[0144] Preferred corticosteroids include cortisone, prednisone, prednisolone, methylprednisolone, and especially dexamethasone.

[0145] Further, 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.

[0146] 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, phenindione) and synthetic pentasaccharide inhibitors of factor Xa (e.g., fondaparinux, idraparinux, idrabiotaparinux). Antiplatelet drugs that may be mentioned include irreversible cyclooxygenase inhibitors (e.g., aspirin, triflusal), adenosine diphosphate receptor inhibitors (e.g., cangrelor, clopidogrel, prasugrel, ticagrelor, ticlopidine), phosphodiesterase inhibitors (e.g., cilostazol), protease-activated receptor 1 antagonists (e.g., vorapaxal), glycoprotein IIB / IIIA inhibitors (e.g., abciximab, eptifibatide, tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), thromboxane inhibitors (e.g., terutroban, ramatroban, seratrodast, picotamide). Statins that may be mentioned include atorvastatin, simvastatin, and rosuvastatin. Antibacterial agents that may be mentioned include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam, and teicoplanin. Antiallergic / antiasthmatic drugs that may be mentioned include chlorpheniramine, levocetirizine, and montelukast.

[0147] Thus, the subject may also be receiving (and / or may already be receiving) any one or more of the aforementioned other therapeutic agents, meaning that they are receiving prescribed doses of one or more of these other therapeutic agents prior to, in addition to, and / or after treatment with a compound of the invention or a pharmaceutically acceptable salt thereof.

[0148] When the compounds of the present invention are "combined" with other therapeutic agents as mentioned hereinabove, the active ingredients may be administered together in the same formulation or separately (simultaneously or sequentially) in different formulations.

[0149] Such combination products provide for the administration of a compound of the invention in conjunction with another therapeutic agent and therefore may be presented as separate formulations, at least one of which contains a compound of the invention and at least one of which contains the other therapeutic agent, or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation containing a compound of the invention and the other therapeutic agent).

[0150] therefore, (1) A pharmaceutical formulation comprising a compound of the present invention, a therapeutic agent selected from those listed above (e.g., one known to be metabolized by a CYP enzyme), and a pharmaceutically acceptable excipient (e.g., an adjuvant, diluent, or carrier), hereinafter referred to as a "combination preparation"; (2) 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 selected from those described above (e.g., known to be metabolized by a CYP enzyme) in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier; Components (A) and (B) are each provided in a form suitable for administration in conjunction with the other; Kit of parts and is further provided.

[0151] In a further aspect of the present invention, there is provided a process for the preparation of a combination preparation as defined hereinbefore, which process comprises bringing into association a compound of the present invention, another therapeutic agent, and at least one (e.g., pharmaceutically acceptable) excipient.

[0152] In a further aspect of the present invention, there is provided a process for the preparation of the kit-of-parts defined herein before, the process comprising combining components (A) and (B). As used herein, reference to associating shall mean that the two components are suitable for administration in conjunction with one another.

[0153] Thus, with respect to the process for the preparation of a kit-of-parts as defined hereinabove by "associating" two components with one another, the two components of the kit-of-parts are (i) may be provided as separate formulations (i.e., independently of each other) and then combined for use in conjunction with each other in combination therapy; or (ii) may be packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy;

[0154] therefore, (I) one of components (A) and (B) as defined herein, (II) A kit-of-parts is further provided that includes the component together with instructions for use in conjunction with the other of the two components.

[0155] Depending on the patient being treated and the route of administration, the compounds of the present invention may be administered in varying doses. While the dose will vary from patient to patient, a suitable daily dose is 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, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 mg, etc., or any range or value therein). Particularly preferred daily doses range from about 0.3 to about 100 mg per patient.

[0156] 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).

[0157] 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 with the condition being treated, as well as the age, weight, sex, 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.

[0158] The advantage of using the compounds of the present invention separately and / or sequentially and / or simultaneously in parallel via a combination of administration routes is to produce a tailored treatment for the patient in need of treatment, potentially preventing and / or reducing side effects, and also to tailor the correct dosage level of the therapeutically effective amount of the compounds of the present invention.

[0159] The kit-of-parts described herein may include 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 other therapeutic agents to provide for repeated administration. When two or more formulations (containing any active compound) are present, such formulations may be identical or different with respect to dosage, chemical composition(s), and / or physical form(s) of any compound.

[0160] "Administered in conjunction with" in reference to a kit of parts described herein includes sequential, separate and / or simultaneous administration of each formulation containing a compound of the invention and another therapeutic agent over the course of treatment of the relevant condition.

[0161] Thus, with respect to a combination product according to the invention, the term "administered in conjunction with" includes administering the two components of the combination product (a compound of the invention and another therapeutic agent) together, or sufficiently closely in time (optionally repeatedly) to allow for a greater beneficial effect to the patient over the course of treatment of the relevant condition than when either the formulation comprising the compound of the invention or the formulation comprising the other agent is administered alone (optionally repeatedly) over the same course of treatment in the absence of the other component. The determination of whether a combination provides a greater beneficial effect with respect to the treatment of a particular condition, and over that course of treatment, depends on the condition being treated or prevented, but can be routinely accomplished by one of ordinary skill in the art.

[0162] Furthermore, in the context of a kit-of-parts according to the invention, the term "in conjunction with" includes that one or the other of the two formulations may be administered (optionally repeatedly) before, after, and / or simultaneously with the administration of the other component. 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.

[0163] The pharmaceutical compositions / formulations, combination products and kits described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0164] Thus, in a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition / formulation as defined hereinbefore, which process comprises bringing into association certain compounds of the present invention as defined hereinbefore with one or more pharmaceutically acceptable excipients (e.g., adjuvants, diluents, and / or carriers).

[0165] 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 hereinbefore, the process comprising associating certain compounds of the invention as defined hereinbefore with other therapeutic agents useful in the treatment of the relevant disease or disorder, and at least one pharmaceutically acceptable excipient.

[0166] Suitable subjects to be treated with the formulations of the present invention include, but are not limited to, mammalian subjects, particularly human subjects.

[0167] When used herein in connection with a particular value (e.g., 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 by expressions such as "±10%" (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.

[0168] The compounds of the present invention have the advantage that they are more potent and / or stable to metabolic hydrolysis and / or do not inhibit the CYP enzymes mentioned hereinbefore.

[0169] The compounds of the invention, whether for use in the treatment of IPF or not, may have the advantage that they may be more effective, less toxic, longer acting, more potent, have fewer side effects, be more easily 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]

[0170] The present invention will be further illustrated by reference to the following examples, which are not intended to limit the scope of the invention.

[0171] In case of discrepancy between the nomenclature and any compound depicted in the figures, the latter takes precedence (unless contradicted by any experimental details that may be provided and / or clear from the context).

[0172] 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.

[0173] Experiments were generally carried out under an inert atmosphere (nitrogen or argon), especially when oxygen- or moisture-sensitive reagents or intermediates were used. Unless otherwise stated, experiments were carried out in oven-dried glassware using standard techniques for handling air- and moisture-sensitive materials.

[0174] All purchased solvents and chemicals were used without further purification. Microwave-heated reactions were performed in septum-sealed Biotage vials equipped with a Biotage single-mode microwave reactor generating controlled irradiation at 2450 MHz with a power range of 0–400 W and equipped with a built-in online IR sensor. Reactions were monitored by thin-layer chromatography (TLC) performed on Merck Silica Gel 60 F-254 plates and visualized with UV light (λ = 254 nm). Automated flash column chromatography (FCC) was performed on a Biotage Isolera Dalton 2000 instrument using commercially available silica cartridges. Manual FCC was performed using commercially available silica cartridges. Analytical HPLC / ESI-MS was performed using UV detection (214, 254, and 280 nm) and electrospray ionization (ESI) MS on a C18 column (50 × 3.0 mm, 2.6 μm particle size, 100 Å pore size) with a gradient of acetonitrile in 0.05% aqueous HCOOH as the mobile phase at a flow rate of 1.5 mL / min. High-resolution mass spectrometry (HRMS) was determined on a mass spectrometer equipped with an ESI source and a 7-T hybrid linear ion trap (LTQ). Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance III HD or Bruker Avance Neo instrument. 1 H, 13 C, and 19 F NMR spectra were recorded at 400 MHz, 101 MHz, 126 MHz, and 376 MHz, respectively. Chemical shifts (δ) were determined by the residual solvent signal (1 H: 7.26 ppm CDCl3-d, MeOD-d4: 3.31 ppm quintet, acetone-d6: 2.09 ppm, septet; 2.50 ppm septet DMSO-d6, 13 C: CDCl3: 77.16 ppm, triplet; MeOD-d4: 49.00 ppm, septet; acetone-d6: 29.84 ppm, septet; DMSO-d6: 39.52 septet). 13 C NMR and 19 F NMR spectra were recorded with proton decoupling. Data are reported as follows: chemical shift δ / ppm, integral ( 1 H only), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br. = broad, m = multiplet or a combination thereof; 13 C signals are singlets unless otherwise stated), coupling constant J (in Hertz (Hz)), and assignment. To facilitate structure assignment, 1 H COSY, HSQC, and HMBC were used where appropriate. All final compounds were ≥95% pure as determined by HPLC (UV at 254 nm) and NMR. Mass spectrometry data from liquid chromatography-mass spectrometry (LC-MS) are reported. Chemical shifts for NMR data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvents used.

[0175] In 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 work-up where appropriate. Purification may vary between experiments. In general, solvents and the ratios of solvents used in eluents / gradients are chosen according to the appropriate R f and / or retention times were selected to provide a suitable solubility. Some products were purified using supercritical fluid chromatography, such as a reversed-phase column using a solvent combination of mobile phase A: CO and mobile phase B: MeOH / HO / NH. Some compounds were purified using preparative HPLC, flash column chromatography, or a manual C18 reversed-phase column with HO / MeCN polarity.

[0176] Example Example 1 3-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiophene-2-sulfonamide (a) 1-[(4-bromo-2-chloro-phenyl)methyl]-2-methyl-imidazole 2-Methylimidazole (1.64 g, 20 mmol) and K2CO3 (5.53 g, 40 mmol) were dissolved in acetonitrile (50 ml). After 30 minutes, 4-bromo-2-chlorobenzyl bromide (2.84 g, 10 mmol) was added. The reaction was stirred at room temperature for 3 days. The solid material was filtered. The solvent was evaporated. The remaining solid was washed with water overnight. The solid was isolated in an amount of 2.4 g, 84% yield. 1 H-NMR (CDCl3): 2.36(s,3H), 5.11(s,2H), 6.54(d,1H), 6.85(s,1H), 7.03(s,1H), 7.37(d,1H), 7.62(s,1H). MS(M+H):285.07, calculated value 284.9794.

[0177] (b) 3-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-thiophene-2-sulfonamide 1-[(4-Bromo-2-chloro-phenyl)methyl]-2-methyl-imidazole (prepared according to step (a) above; 240 mg, 840 μmol), N-tert-butyl-5-isobutyl-thiophene-2-sulfonamide (268 mg, 840 μmol), K2CO3 (348 mg, 2521 μmol), and Pd(PPh3)4 (24 mg, 21 μmol) were added to dioxane (10 ml) and water (1 ml). The reaction was heated to 90 °C overnight under a nitrogen atmosphere. Water and ethyl acetate were added. The organic layer was dried, filtered, and the solvent was evaporated. The crude material was dissolved in CHCl2 (5 ml). BCl3 was added at room temperature. After 3 hours, ethyl acetate (25 ml) and water (10 ml) were added. NH3 (aq) (3 ml) was added. The organic layer was dried, filtered, and the solvent was evaporated. Chromatography from methanol-ethyl acetate, 10-90. The product was isolated in the amount of 175 mg, 49% yield. 1 H-NMR(CDCl3):0.98(d,6H), 1.92(m,1H), 2.04(s,3H), 2.68(d,2H), 5.17 (s,2H), 6.74(m,2H), 6.88(s,1H), 7.00(s,1H), 7.47(d,1H), 7.66(s,1H). MS(M+H):423.93, calculated value 424.0920.

[0178] (c) 3-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiophene-2-sulfonamide 3-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-thiophene-2-sulfonamide (prepared according to step (b) above; 212 mg, 0.5 mmol), 2-bromopyrimidine (119 mg, 0.75 mmol), palladium(II) acetate (2.8 mg, 12.5 μmol), 1,1-bis(diphenylphosphino)ferrocene (6.9 mg, 12.5 μmol), LiCl (42 mg, 1.0 mmol), and potassium t-butoxide (185 mg, 1.65 mmol) were dissolved in dioxane (10 ml). The reaction was heated to 80 °C overnight under a nitrogen atmosphere. Water (10 ml) and CHCl (10 ml) were added. The organic layer was dried, filtered, and the solvent evaporated. 14 mg of the product was purified using HPLC and isolated as the CFCOOH salt. 1 H-NMR(CD3OD):0.98(d,6H), 1.93(m,1H), 2.38(s,3H), 2.72(d,2H), 5.28(s,2H), 6.77(s,1H) , 6.84(d,1H), 6.91(t,1H), 6.94(d,1H), 7.07(d,1H), 7.35(m,1H), 7.46(d,1H), 8.33(d,2H). MS(M+H):502.0, calculated value 502.1138.

[0179] Example 2 3-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-(2-pyridyl)thiophene-2-sulfonamide The title compound was prepared using a process similar to that described in Example 1 above, except that 3-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-5-isobutyl-thiophene-2-sulfonamide (prepared according to step (b) in Example 1 above; 212 mg, 0.5 mmol) and 2-bromopyridine (118 mg, 0.75 mmol) were used. The product was isolated as the CFCOOH salt in an amount of 18 mg. 1H-NMR(CD3OD):0.97(d,6H), 1.91(m,1H), 2.70(m,5H), 5.47(s,2H), 6.82(s,1H), 6.87(t,1H ), 7.15~7.25(m,2H), 7.41(s,1H), 7.46~7.53(m,2H), 7.63(d,1H), 7.76(t,1H), 7.84(s,1H). MS(M+H):501.0, calculated value 501.1186.

[0180] Example 3 5-Isobutyl-3-[3-methyl-4-[(2-methylimidazol-1-yl)methyl]phenyl]-N-(2-pyridyl)thiophene-2-sulfonamide (a) 1-[(4-bromo-2-methyl-phenyl)methyl]-2-methyl-imidazole The title compound was prepared using a process similar to that described in step (a) of Example 1 above, except using 4-bromo-1-methylbromido-2-methylbenzene (736 mg, 2.8 mmol) and 2-methylimidazole (458 mg, 5.6 mmol). The subtitle compound was obtained in the amount of 500 mg, 68% yield. 1 H-NMR (CDCl3): 2.30(s,3H), 2.39(s,3H), 4.99(s,2H), 6.59(d,1H), 6.76(s,1H), 7.01(s,1H), 7.32(d,1H), 7.41(s,1H). MS(M+H):265.13, calculated value 265.0340.

[0181] (b) 5-isobutyl-3-[3-methyl-4-[(2-methylimidazol-1-yl)methyl]phenyl]thiophene-2-sulfonamide The subtitled compound was prepared by a method similar to that described in step (b) of Example 1 above, except using 1-[(4-bromo-2-methyl-phenyl)methyl]-2-methyl-imidazole (330 mg, 1.24 mmol) and N-tert-butyl-5-isobutyl-thiophene-2-sulfonamide (397 mg, 1.24 mmol). The subtitled compound was obtained in the amount of 465 mg, 93% yield. 1H-NMR(CDCl3): 1.00(d,6H), 1.94(m,1H), 2.36(s,3H), 2.41(s,3H), 2.69(d,2H), 5 .10(s,2H), 6.73~6.77(m,2H), 6.80(s,1H), 7.01(s,1H), 7.39(m,1H), 7.48(s,1H). MS(M+H):404.17, calculated value 404.1466.

[0182] (c) 5-isobutyl-3-[3-methyl-4-[(2-methylimidazol-1-yl)methyl]phenyl]-N-(2-pyridyl)thiophene-2-sulfonamide The title compound was prepared by a method similar to that described in step (c) of Example 1 above, except using 5-isobutyl-3-[3-methyl-4-[(2-methylimidazol-1-yl)methyl]phenyl]thiophene-2-sulfonamide (175 mg, 0.434 mmol) and 2-bromopyridine (103 mg, 0.650 mmol). 18 mg of the title compound was obtained as the CFCOOH salt. 1 H-NMR(CD3OD):0.98(d,6H), 1.91(m 1H), 2.20(s,3H), 2.63(s,3H), 2.71(d,2H), 5.35(s,2H), 6.75(s,1H), 6.82(b,1H), 6.8 7(t,1H), 7.14(b,1H), 7.24(b,2H), 7.32(d,1H), 7.47(d,1H), 7.75(b,1H), 7.87(b,1H). MS(M+H):481.0, calculated value 481.1732.

[0183] Example 4 Compounds of the Invention The following compounds are made according to the experimental techniques described herein above. 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyridin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(5-fluoropyrimidin-2-yl)-5-isobutylthiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(4,5-dimethyloxazol-2-yl)-5-isobutylthiophene-2-sulfonamide, 3-(3-chloro-4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-(trifluoromethyl)pyrimidin-2-yl)thiophene-2-sulfonamide, 5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-methylpyrimidin-2-yl)thiophene-2-sulfonamide, 3'-chloro-5-isobutyl-N-(5-methoxypyrimidin-2-yl)-4'-((2-methyl-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide, 5-isobutyl-3'-methyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, 3-(3-chloro-4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, and 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-methoxythiophene-2-sulfonamide.

[0184] Example 5 (2-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide (a) 2-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-benzenesulfonamide 1-[(4-Bromo-2-chloro-phenyl)methyl]-2-methyl-imidazole (571 mg, 2 mmol), [2-(tert-butylsulfamoyl)-5-isobutyl-phenyl]boronic acid (930 mg, 3 mmol), K2CO3 (829 mg, 6 mmol), and Pd(PPh3)4 (86 mg, 75 μmol) were added to dioxane (30 ml) and water (3 ml). The reaction was heated to 90 °C overnight under a nitrogen atmosphere. Water and ethyl acetate were added. The organic layer was dried, filtered, and the solvent was evaporated. The crude material was dissolved in CF3COOH (20 ml). The reaction was heated to 45 °C overnight. The excess acid was evaporated. The crude material was dissolved between ethyl acetate and NaHCO3 (aq). The organic layer was dried, filtered, and the solvent was evaporated. Chromatography from ethyl acetate. The product was isolated in 320 mg, 38% yield. 1 H-NMR(CDCl3):0.95(d,6H), 1.93(m,1H), 2.41(s,3H), 2.58(d,2H), 5.22(s,2H), 6.74 (d,1H), 6.91(s,1H), 7.04(s,1H), 7.09(d,1H), 7.33(m,2H), 7.58(d,1H), 8.08(d,1H). MS(M+H): 417.9, calculated value 418.1356.

[0185] (b) (2-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide 2-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-benzenesulfonamide (220 mg, 526 μmol), 2-bromopyrimidine (126 mg, 790 μmol), palladium(II) acetate (12 mg, 53 μmol), 1,1-bis(diphenylphosphino)ferrocene (29 mg, 53 μmol), LiCl (45 mg, 1053 μmol), and potassium t-butoxide (195 mg, 1737 μmol) were dissolved in dioxane (15 mL). The reaction was refluxed under nitrogen for 3 hours. Ethyl acetate (10 mL) was added, and the mixture was filtered. The solvent was evaporated. The product was purified using supercritical fluid chromatography in a 3.3 mg quantity. 1 H-NMR(CD3OD):0.92(d,6H), 1.91(m,1H), 2.38(s,3H), 2.57(d,2H), 5.26(s,2H), 6.78(d,1H), 6.82(b,1H) , 6.91(s,1H), 7.00(s,1H), 7.07(s,1H), 7.17(d,1H), 7.25(s,1H), 7.35(d,1H), 8.13(d,1H), 8.28(b,2H). MS(M+H):496.1, calculated value 496.1574.

[0186] Example 6 5-Isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]-3-(trifluoromethyl)phenyl]-N-pyrimidin-2-yl-thiophene-2-sulfonamide 5-Isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]-3-(trifluoromethyl)phenyl]thio-phene-2-sulfonamide (183 mg, 400 μmol), 2-bromopyrimidine (95 mg, 600 μmol), palladium(II) acetate (9 mg, 40 μmol), 1,1-bis(diphenylphosphino)ferrocene (22 mg, 40 μmol), LiCl (34 mg, 800 μmol), and potassium t-butoxide (148 mg, 1320 μmol) were dissolved in dioxane (15 mL). The reaction was heated to reflux under a nitrogen atmosphere for 3 hours. Ethyl acetate (10 mL) was added, and the solid was filtered. The product was purified using supercritical fluid chromatography in a 3.2 mg amount. 1 H-NMR(CD3OD):0.90(d,6H), 1.83(m,1H), 2.23(s,3H), 2.60(d,2H), 5.30(s,2H), 6.50 (b,1H), 6.63~6.69(m,2H), 6.85(s,1H), 6.99(s,1H), 7.81~7.85(m,2H), 8.09(d,2H). MS(M+H):536.1, calculated value 536.1402.

[0187] Example 7 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide (a) 1-[(4-bromo-2-chloro-phenyl)methyl]-2-isopropyl-imidazole 2-Isopropylimidazole (3.30 g, 30 mmol) and K2CO3 (8.29 g, 60 mmol) were dissolved in acetonitrile (75 ml). After 15 minutes, 4-bromo-2-chloro-1-bromomethylbenzene (4.26 g, 15 mmol) was added. The reaction was stirred at room temperature for 3 days. The solid was filtered and the solvent evaporated. The crude product was washed with water. The isolated crystalline product was dried under vacuum. Amount 3.69 g, Yield 78%. 1H-NMR (CDCl3): 1.28(d,6H), 2.88(sep,1H), 5.11(s,2H), 6.46(d,1H), 6.77(s,1H), 7.05(s,1H), 7.33(d,1H), 7.59(s,1H). MS(M+H):313.1, calculated value 313.0107.

[0188] (b) 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-benzenesulfonamide 1-[(4-Bromo-2-chlorophenyl)methyl]-2-isopropylimidazole (586 mg, 1.87 mmol), [2-(tert-butylsulfamoyl)-5-isobutylphenyl]boronic acid (585 mg, 1.87 mmol), K2CO3 (774 mg, 5.60 mmol), and Pd(PPh3)4 (54 mg, 47 μmol) were added to dioxane (20 ml) and water (2 ml). The reaction was heated to 90 °C overnight under a nitrogen atmosphere. Water and diethyl ether were added. The organic layer was dried, filtered, and the solvent was evaporated. The crude material was dissolved in CF3COOH (10 ml). The solution was stirred for 3 days. The excess acid was evaporated. The crude material was dissolved between ethyl acetate and NaHCO3 (aq). The organic layer was dried, filtered, and the solvent was evaporated. Chromatography from ethyl acetate. The product was isolated in 589 mg, 71% yield. 1 H-NMR(CDCl3):0.92(d,6H), 1.30(d,6H), 1.90(sep,1H), 2.54(d,2H), 2.94(sep,1H), 5.23(s, 2H), 6.68(d,1H), 6.83(s,1H), 7.02~7.07(m,2H), 7.27~7.31(m,2H), 7.55(s,1H), 8.04(d,1H). MS(M+H):446.2, calculated value 446.1669.

[0189] (c) 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide 2-[3-Chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-benzenesulfonamide (437 mg, 980 μmol), 2-bromopyrimidine (312 mg, 1961 μmol), palladium(II) acetate (44 mg, 196 μmol), 1,1-bis(diphenylphosphino)ferrocene (109 mg, 196 μmol), LiCl (83 mg, 1961 μmol), and potassium t-butoxide (220 mg, 1961 μmol) were dissolved in dioxane (10 mL). The reaction was heated to reflux under a nitrogen atmosphere for 3 hours. Ethyl acetate (10 mL) was added, and the solid was filtered. The product was purified using supercritical fluid chromatography in an 8.5 mg amount. 1 H-NMR (CD3OD): 0.91(d,6H), 1.27(d,6H), 1.90(sep,1H), 2.56(d,2H), 3.10(sep,1H), 5.27(s,2H), 6.73( d,1H), 6.85(s,1H), 6.90~7.03(m,4H), 7.09(m,1H), 7.20(s,1H), 7.38(d,1H), 8.15(d,1H), 8.34(b,2H). MS(M+H):524.3, calculated value 524.1887.

[0190] Example 8 3-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiophene-2-sulfonamide (a) 3-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-thiophene-2-sulfonamide The title compound was prepared by a process similar to that described in Example 7 above for 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-benzenesulfonamide, except for 1-[(4-bromo-2-chloro-phenyl)methyl]-2-isopropyl-imidazole (627 mg, 2 mmol) and N-tert-butyl-5-isobutyl-thiophene-2-sulfonamide (638 mg, 2 mmol). Amount: 431 mg, Yield: 48%. 1H-NMR(CDCl3):0.98(d,6H), 1.44(d,6H), 1.91(sep,1H), 2.68(d,2H), 3.30(sep,1H), 5. 34(s,2H), 6.74(s,1H), 7.02(d,1H), 7.26(s,1H), 7.42(s,1H), 7.57(d,1H), 7.66(s,1H). MS(M+H):452.1, calculated value 452.1233.

[0191] (b) 3-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiophene-2-sulfonamide The title compound was prepared by a process similar to that described in Example 7 above for 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide, except for 3-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-thiophene-2-sulfonamide (203 mg, 449 μmol). Amount 0.5 mg.

[0192] Biological assays The biological activity of the example compounds described hereinabove was evaluated (and compared to C21) using the following biological assays.

[0193] metabolic stability Pooled human liver microsomes in PBS at a concentration of 0.5 mg / mL were incubated with or without 1 mM NADPH at 37°C for 70 minutes. Test compounds were added 10 minutes later to a final concentration of 1 μM. Samples were collected at 0, 5, 15, and 60 minutes and added to test tubes containing acetonitrile and terfenadine, used as an internal standard, to stop the reaction. After centrifugation at 10,000 × g for 5 minutes, the supernatant was diluted 1:1 with 1% formic acid. Samples were separated on a reversed-phase column and detected by a triple quadrupole MS / MS (Agilant Model 6540). The concentration of the parent compound at different time points was measured using an external standard curve with terfenadine as an internal standard, and the initial metabolic rate in the presence or absence of NADPH was calculated. [Table 1] An asterisk (*) represents the average of data from two runs.

[0194] 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.

[0195] In short, IC 50 For measurements, recombinant proteins were incubated with test compounds at concentrations of 1, 10, 100, and 1000 nM for the AT2 receptor and 1 and 10 μM for the AT1 receptor at 37°C for 2-4 hours. Ki values ​​at the AT2 receptor were determined using a 7-point dose-response curve. 125 I(sar1,IIe8)-AT-II was used as a ligand at the AT2 receptor. 125 ICGP42112A was used. The inhibition percentage of control specific binding was calculated according to 100-(measured specific binding / control specific binding)×100. [Table 2] An asterisk (*) represents the average of data from two runs.

[0196] CYP inhibitors Compounds were evaluated at 10 μM for inhibition of major cytochrome P450 isoforms (CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A4&5) using isoform-specific substrates incubated with human liver microsomes (Eurofins protocol ITEMG232). The following substrates were used: CYP1A phenacetin, CYP2B6 bupropion, CYP2C8 paclitaxel and amodiaquine, CYP2C9 diclofenac, CYP2C19 omeprazole, CYP2D6 dextromethorphan, and CYP3A midazolam and testosterone.

[0197] At the end of the incubation, metabolite formation was monitored by HPLC-MS / MS as peak area response. [Table 3]

[0198] Abbreviation The following abbreviations may be used herein: DCM dichloromethane DMF Dimethylformamide EtOAc ethyl acetate FCC flash column chromatography MeCN acetonitrile MeOH Methanol MW microwave NMR nuclear magnetic resonance

Claims

1. A compound of formula I, 【Chemistry 1】 During the ceremony, R １ is H, a halogen atom, —CN, or C １～７ Alkyl or C １～７ represents alkoxy, C １～７ Alkyl or C １～７ Any alkoxy may optionally contain one or more halogen atoms, hydroxyl, C １～７ Alkyl, CF ３ , or OR ７ is replaced by R ２ and R ３ are independently H, a halogen atom, —CN, or C １～７ Alkyl or C １～７ represents alkoxy, C １～７ Alkyl or C １～７ Any alkoxy may optionally contain one or more halogen atoms, hydroxyl, C １～７ Alkyl, CF ３ , or OR ７ａ is replaced by R ４ is C １～６ Alkyl, C １～６ Alkoxy or C １～６ Alkoxy-C １～６ alkyl, each alkyl moiety of which is optionally substituted and / or terminated by one or more halogen atoms, —CN groups, or —OH groups; or R ４ is aryl, C １～６ Alkylaryl, C １～３ Alkenylaryl, heteroaryl, C １～６ alkylheteroaryl, or C １～３ alkenylheteroaryl, each of which optionally contains one or more halogens, CF ３ , C.F. ３ O-, -CN, C １～６ Alkyl, and C １～６ substituted with alkoxy, R ５ represents H, a halogen atom, hydroxyl, —CN, —NR ９ａ R １０ａ , C １～７ Alkyl, C １～７ Alkoxy, or C １～６ Alkoxy-C １～６ alkyl, each of which optionally contains one or more halogen atoms, hydroxyl, —CN, —NR ９ｂ R １０ｂ , C １～７ Alkyl, or C １～７ substituted by alkoxy, R ６ , R ７ and R ７ａ are independently H or C optionally substituted with one or more halogen atoms. １～６ represents alkyl, Y １ is -CR ８ -, -N-, -NH-, O, or S; Y ２ is -CR ８ -, -CR ８ =CH-, -CH=CR ８ -, -CR ８ =CR ８ -, -N-, -NH-, O, or S; Y ３ Ha-CR ８ - and R ８ represents H, a halogen atom, hydroxyl, —CN, —NR ９ｃ R １０ｃ or each optionally represents one or more halogen atoms, hydroxyl, —CN, —NR ９ｄ R １０ｄ , C １～７ Alkyl, or C １～７ C substituted with alkoxy １～７ Alkyl or C １～７ represents alkoxy, however, (a) Y １ and Y ２ is not the same as, and (b) Y １ , Y ２ and Y ３ In the ８ at least one of the groups does not represent H or fluorine, X and Z are independently CH=CH, CR １１ , N, NHmO, or S; however, (a) X and Z are not the same, (b) When X represents CH=CH, Z is CR １１ may represent only (c) When Z represents CH=CH, X is CR １１ may represent only R １１ represents H, a halogen atom, hydroxyl, —CN, —NR ９ｅ R １０ｅ or any of which optionally represents one or more halogen atoms, hydroxyl, amino, —CN, —NR ９ｆ R １０ｆ , C １～７ Alkyl, or C １～７ C substituted by alkoxy １～７ Alkyl or C １～７ represents alkoxy, R ９ａ , R １０ａ , R ９ｂ , R １０ｂ , R ９ｃ , R １０ｃ , R ９ｄ , R １０ｄ , R ９ｅ , R １０ｅ , R ９ｆ , and R １０ｆ are each independently H or C substituted with one or more halogen atoms. １－６ represents alkyl, or a pharmaceutically acceptable salt thereof. compound.

2. R １ is H, or optionally halogen, CF ３ OR ７ C substituted with １～６ represents alkyl, R ２ and R ３ are independently H or C optionally substituted with one or more halogen atoms １～６ represents alkyl, R ４ But C １～６ Alkyl, C １～６ Alkoxy or C １～６ Alkoxy-C １～６ alkyl, each alkyl moiety of which is optionally substituted and / or terminated by one or more halogen atoms, —CN groups, or —OH groups; or R ４ is aryl, C １～６ Alkylaryl, C １～３ Alkenylaryl, heteroaryl, C １～６ alkylheteroaryl, or C １～３ alkenylheteroaryl, each of which optionally contains one or more halogens, CF ３ , C.F. ３ O-, -CN, C １～６ Alkyl and C １～６ substituted with alkoxy, R ５ But C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkoxy-C １～６ alkyl, each of which is optionally substituted with one or more halogen atoms; R ６ and R ７ are independently H or C optionally substituted with one or more halogen atoms １～６ represents alkyl, and / or R ８ represents H, a halogen atom, or C, each of which is optionally substituted with one or more halogen atoms; １～３ Alkyl or C １～３ represents alkoxy, The compound of claim 1.

3. R １ is H, optionally halogen, CF ３ OR ７ 3. A compound according to claim 1, wherein R represents methyl, ethyl, isopropyl, cyclopropyl or tert-butyl substituted with R.

4. R ２ and R ３ 4. A compound according to any one of claims 1 to 3, wherein represents H or methyl.

5. R ４ optionally containing one or more halogen atoms, CF ３ 5. A compound according to any one of claims 1 to 4, wherein R represents heteroaryl substituted with -CN, Me or methoxy.

6. R ４ is C １～４ represents alkoxy, C １～４ 5. The compound of any one of claims 1 to 4, wherein the alkyl portion of the alkoxy is optionally substituted and / or terminated with one or more F, Cl, Br, -CN or -OH groups.

7. R ５ 7. The compound of any one of claims 1 to 6, wherein represents H, methyl, ethyl, n-propyl, n-butyl, or isobutyl.

8. R ６ 8. A compound according to any one of claims 1 to 7, wherein represents H or methyl.

9. Y １ represents —CH—, and Y ２ represents -CH=CH-, and / or Y ３ Ga-CR ８ 9. The compound according to claim 1, wherein R represents -.

10. R ８ 10. A compound according to any one of claims 1 to 9, wherein represents halogen or methyl optionally substituted by one or more halogens.

11. 11. A compound according to any one of claims 1 to 10, wherein X represents -CH=CH-, O or S, and / or Z represents -CH- or N.

12. 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyridin-2-yl)thiophene-2-sulfonamide, 5-isobutyl-3-(3-methyl-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(pyridin-2-yl)thiophene-2-sulfonamide, 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyridin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(5-fluoropyrimidin-2-yl)-5-isobutylthiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-N-(4,5-dimethyloxazol-2-yl)-5-isobutylthiophene-2-sulfonamide, 3-(3-chloro-4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-(trifluoromethyl)pyrimidin-2-yl)thiophene-2-sulfonamide, 5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)-3-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(5-methylpyrimidin-2-yl)thiophene-2-sulfonamide, 3'-chloro-5-isobutyl-N-(5-methoxypyrimidin-2-yl)-4'-((2-methyl-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-sulfonamide, 5-isobutyl-3'-methyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, 3-(3-chloro-4-((2-(2-hydroxypropan-2-yl)-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-(pyrimidin-2-yl)thiophene-2-sulfonamide, 3'-chloro-5-isobutyl-4'-((2-methyl-1H-imidazol-1-yl)methyl)-N-(pyrimidin-2-yl)-[1,1'-biphenyl]-2-sulfonamide, 3-(3-chloro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutyl-N-methoxythiophene-2-sulfonamide, 2-[3-chloro-4-[(2-methylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide, 5-isobutyl-3-[4-[(2-methylimidazol-1-yl)methyl]-3-(trifluoromethyl)phenyl]-N-pyrimidin-2-yl-thiophene-2-sulfonamide, 2-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-4-isobutyl-N-pyrimidin-2-yl-benzenesulfonamide, and 3-[3-chloro-4-[(2-isopropylimidazol-1-yl)methyl]phenyl]-5-isobutyl-N-pyrimidin-2-yl-thiophene-2-sulfonamide, 12. The compound of any one of claims 1 to 11, wherein

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

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

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

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

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

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

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

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

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

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

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

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

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

26. 26. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 25, said process comprising the reaction of a compound of formula II 【Chemistry 2】 In the formula, R １ , R ２ , R ３ , R ５ , R ６ , X, Z, Y １ , Y ２ and Y ３ is as defined in any one of claims 1 to 11 for compounds of formula III, . １ ( ４ ..| In the formula, R ４ is as defined in any one of claims 1, 5 or 6, and L １ represents a suitable leaving group, process.

Images