CN117222624A

CN117222624A - Selective angiotensin II receptor ligands

Info

Publication number: CN117222624A
Application number: CN202280030339.9A
Authority: CN
Inventors: T·菲克斯; B·奥尔森; A·哈尔伯格; M·拉赫德
Original assignee: Vicore Pharma AB
Current assignee: Vicore Pharma AB
Priority date: 2021-03-23
Filing date: 2022-03-23
Publication date: 2023-12-12
Also published as: GB202113583D0

Abstract

The present invention provides a pharmaceutical compound of formula I,wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁶ 、X、Y、Z、Y ¹ 、Y ² 、Y ³ And Y ⁴ Having the meanings given in the specification, are useful in the treatment of autoimmune and/or fibrotic diseases, including interstitial lung diseases such as idiopathic pulmonary fibrosis and sarcoidosis.

Description

Selective angiotensin II receptor ligands

Technical Field

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

Background

Renin (protease) cleaves its only known substrate (angiotensinogen) to form angiotensin I (Ang I), which in turn acts as a substrate for Angiotensin Converting Enzyme (ACE) to form Ang II. Endogenous hormone Ang II is a linear octapeptide (Asp ¹ -Arg ² -Val ³ -Tyr ⁴ -lle ⁵ -His ⁶ -Pro ⁷ -Phe ⁸ ) And is an active ingredient of the Renin Angiotensin System (RAS). Angiotensin II type 1 (AT 1) receptors are expressed in most organs and are thought to be responsible for most of the pathological roles of Ang II.

Several studies in adult individuals appear to indicate that in the modulation of the response following stimulation of the Ang II receptor, activation of the AT2 receptor has an opposite effect to that mediated by the AT1 receptor. AT2 receptors have also been shown to be involved in apoptosis and inhibition of cell proliferation (de Gasparo M et al, pharmacol. Rev. (2000) 52, 415-472). Recently, AT2 receptor agonists have been shown to have potential utility in the treatment and/or prevention of digestive tract disorders such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see international patent application WO 99/43339). The expected pharmacological effects of AT2 receptor agonism are generally described in the paper by de gasaro M et al (supra).

The stimulatory effects of Ang II on vascular tone, cell growth, inflammation and extracellular matrix synthesis are coupled primarily to AT1 receptors in any organ, while the function of AT2 receptors appears to be more prevalent in damaged tissues and exert repair properties as well as properties against AT1 receptors. For example, the AT2 receptor has been shown to be of great importance for reducing cardiomyocyte hypertrophy and fibrosis.

Interstitial Lung Disease (ILD) is a group of lung diseases affecting the interstitium, characterized by scarring and/or thickening of tissue surrounding the alveoli and thus inhibiting the respiratory process.

ILD is different from obstructive respiratory diseases (e.g., chronic obstructive respiratory disease (COPD) and asthma) and is typically characterized by bronchoconstriction and/or bronchiolar stenosis (obstruction). ILD may be caused by lung injury that triggers an abnormal healing response, but in some cases the cause of these diseases is not clear. ILD may be triggered by chemicals (silicosis, asbestosis, certain drugs), infections (e.g., pneumonia) or other diseases (e.g., rheumatoid arthritis, systemic sclerosis, myositis or systemic lupus erythematosus).

The most common ILDs are Idiopathic Pulmonary Fibrosis (IPF) and sarcoidosis, both of which are characterized by chronic inflammation and reduced lung function.

Sarcoidosis is an unexplained disease characterized by the aggregation of inflammatory cells to form masses (granulomas), usually originating in the lungs (and skin and/or lymph nodes, but any organ may be affected). When sarcoidosis affects the lungs, symptoms include cough, wheezing, shortness of breath, and/or chest pain.

Treatment of sarcoidosis varies from patient to patient. In most cases, symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is possible, but for patients presenting with pulmonary symptoms, glucocorticoids (e.g., prednisone or prednisolone), antimetabolites and/or monoclonal anti-tumor necrosis factor antibodies are commonly employed.

IPF is an unexplained pulmonary disease that affects approximately 500 tens of thousands of people worldwide. Except in rare cases where lung transplants were performed, no curative treatment option resulted in chronic, irreversible progressive worsening of lung function and, in most cases, death within 2-5 years (median survival of 2.5 to 3.5 years). Although the overall prognosis of IPF is poor, it is difficult to predict the rate of progression in individual patients. Risk factors for IPF include age, male sex, genetic susceptibility, and smoking history. The annual incidence rate is 5-16 per 100,000 people, the prevalence rate is 13-20 per 100,000 people, and increases significantly 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 limited to the lungs and is difficult to treat with therapies directed against the immune system, which distinguishes it from systemic disease-related pulmonary fibrosis.

IPF patients often seek medical attention due to chronic and progressive effort dyspnea and cough. Pulmonary imaging examinations typically show tractional bronchodilation, she Jiange membrane thickening and subpleural alveolation. IPF is likely to be diagnosed when all three clinical manifestations exist and there is no evidence of systemic connective tissue disease or environmental exposure. Definitive diagnosis is typically made by lung biopsy and requires diagnosis by a multidisciplinary professional team (including a pulmonal, radiologist, and pathologist who are experienced in terms of interstitial lung disease).

IPF exhibits different phenotypes with different prognosis, defined as mild, moderate and severe. Mild cases follow a steady or slow progression path, and patients sometimes take years to seek medical advice. Accelerated IPF has a much faster rate of progression, a shorter lifetime, affecting a specific subset of patients, typically male smokers. Acute exacerbation IPF is defined as rapid exacerbation of the disease and the prognosis of patients in this sub-population is very poor with high mortality in the short term. The cause of IPF is not clear, but it appears to be a condition that may be caused by interactions of environmental and genetic factors, causing fibroblasts to drive constant tissue remodeling rather than normal repair; the pathogenesis is driven mainly by fibrosis and not inflammation. There is growing evidence that the disease is triggered by alveolar epithelial microdamage and apoptosis, activating adjacent epithelial cells and attracting stem or progenitor cells that produce factors responsible for expanding the fibroblast and myofibroblast populations in a tumor-like manner. The fibroblast foci secrete excess extracellular matrix that destroys the lung parenchyma and ultimately leads to loss of lung function.

The average annual decline rate of lung function (lung capacity) is in the range of 0.13 liters to 0.21 liters. Symptoms appear 1 to 2 years prior to diagnosis, and radiological signs may appear prior to symptoms (Ley B et al, am. J. Respir. Crit. Care med. (2011) 183, 431-440).

Many therapeutic approaches have been tested in preclinical models and clinical trials, such as anti-inflammatory, immunomodulating, cytotoxic, general anti-fibrotic, antioxidants, anticoagulants, anti-chemokines, anti-angiogenic drugs, as well as RAS blockers, endothelin antagonists and sildenafil, all of which have been shown to provide substantially limited or no benefit (Rafii R et al, j.thorac. Dis. (2013) 5, 48-73).

Current treatment of IPF includes oxygen supplementation. The drugs used include pirfenidone or nidazole, but have only met with success in slowing disease progression. Further, both drugs often cause (mainly the gastrointestinal tract) side effects.

There are drawbacks associated with all ILD (and IPF) drug therapies described above, and there is a real clinical need for safer and/or more effective therapies.

Restoring alveolar epithelium as a therapeutic effect of IPF is highly desirable, and stem cell therapies have also been tested. Some preclinical studies have shown the potential to repair lung injury and fibrosis using pluripotent stem cells that differentiate into lung epithelial and endothelial cells.

Currently, lung transplantation is the only intervention that can substantially improve the survival of IPF patients. Complications such as infection and graft rejection, however, are not uncommon.

Development of new IPF treatment strategies is thus important. Thus, the fundamental challenge in the future is to develop appropriate therapeutic methods to reverse or arrest the progression of the disease.

U.S. patent application 2004/0167176 describes the preparation of tricyclic heterocycles useful as Ang II receptor agonists.

Selective AT2 receptor agonists with reduced CYP 450 inhibition are described in the following documents: mahallingam et al, biorg. Med. Chem. (2010) 18,457-4590.

Transesterification methods for the synthesis of AT2 receptor ligands with improved stability in human liver microsomes are described in the following documents: wannberg et al, biorg. Med. Chem. Lett. (2018) 28,519-522.

In particular, international patent application WO 2002/096883 describes the preparation of imidazolyl, triazolyl and tetrazolyl thiophene sulfonamides and derivatives as AT2 receptor agonists. The compound described in this document (as example 1) is the compound C21 (N-butoxycarbonyl-3- (4-imidazol-1-ylmethyl-phenyl) -5-isobutylthiophene-2-sulfonamide). C21 was selected from a group of about 20 related analogs as a selective AT2 receptor agonist for clinical development. It is currently being developed clinically for the treatment of AT2 receptor related disorders (including IPF) (see, for example, international patent application WO 2016/139475).

C21 has also been shown to have potential use in the treatment of inter alia stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cancer therapy-related cardiotoxicity, peripheral neuropathy and systemic sclerosis (see for example international patent applications WO 2004/046141, WO 2016/092329, WO 2016/107879, WO 2016/139475, WO 2017/221012, WO 2019/008393 and US patent application US 2012/035232).

During development C21 has been found to have the following disadvantages: it is a potent inhibitor of several cytochrome P450 enzymes (CYPs), especially CYP 2C9 and CYP 3A4, potentially affecting the metabolism of other drugs; but also rapidly hydrolyzes to inactive sulfonamide metabolites. Thus, it is a fundamental challenge to develop potent and selective AT2 agonists that are metabolically stable and/or exhibit less inhibition of CYP enzymes.

Surprisingly, we have found that certain chemically modified compounds, as defined below, are not only selective AT2 receptor agonists, but are also more potent than C21, have significantly improved stability to metabolic hydrolysis and/or exhibit less inhibition of CYP enzymes.

Detailed Description

In a first aspect of the invention, there is provided a compound of formula I,

Wherein:

R ¹ represent C _1-4 Alkyl optionally substituted by one OR more fluorine atoms and/OR via OR ⁷ Substitution;

R ² and R is ³ Each independently represents H or C _1-6 Alkyl optionally substituted with one or more halogen atoms;

Y ¹ 、Y ² 、Y ³ and Y ⁴ Independently represents-CH-or-CF-;

z represents-O-, -N (R) ⁵ ) -or a direct bond;

R ⁴ represent C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, the alkyl portion of each of which is optionally substituted and/or capped with one or more substituents selected from-OH and halogen, or

R ⁴ Represents aryl, C _1-6 Alkylaryl, C _1-3 Alkenyl aryl, heteroaryl, C _1-6 Alkyl heteroaryl, or C _1-3 Alkenyl heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of: halogen, -CF ₃ 、-CF ₃ O、C _1-6 Alkyl and C _1-6 An alkoxy group;

R ⁵ represents H or C _1-6 Alkyl optionally substituted with one or more halogen atoms;

x represents ch= CH, CH, N, NH, O or S;

y represents ch= CH, CH, N, NH, O or S,

the conditions are as follows:

(a) X and Y are not the same and are not the same,

(b) When X represents ch=ch, then Y represents only CH,

(c) When Y represents ch=ch, then X represents only CH, and

(d) When Y represents O or S, then X does not represent CH or ch=ch;

R ⁶ represent C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl groups, each of which is optionally substituted with oneOr a plurality of halogen atoms; and is also provided with

R ⁷ Represents H or C _1-3 Alkyl optionally substituted with one or more fluorine atoms,

or a pharmaceutically acceptable salt thereof, which are collectively referred to hereinafter as "compounds of the present invention".

Compounds of the invention which may be mentioned include those as defined above and/or hereinbefore, but in which Z represents-N (R ⁵ )-。

For the purposes of explaining the present specification, the following definitions will apply, and terms used in the singular form will also include the plural and vice versa, as appropriate.

Compounds were named according to the IUPAC nomenclature generated by procedure Chemdoodle 8.1.0.

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

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.

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reacting the free acid or base form of the compounds of the invention with one or more equivalents of the appropriate acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (e.g., in vacuo, by freeze drying or by filtration). Salts may also be prepared using techniques known to those skilled in the art, such as by exchanging a counterion of the compounds of the invention in salt form with another counterion (e.g., using a suitable ion exchange resin).

Specific acid addition salts which may be mentioned include: carboxylates such as formate, acetate, trifluoroacetate, benzoate, oxalate, fumarate, maleate, and the like; sulfonates such as methanesulfonate, ethanesulfonate, toluenesulfonate, and the like; halide salts such as hydrochloride, hydrobromide, and the like; sulfates and phosphates, such as sulfates or phosphates, and the like.

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

The compounds of the present invention may exist as solids and thus the scope of the present invention includes all amorphous, crystalline and partially crystalline forms thereof, and may also exist as oils. Where the compound of formula I is present in crystalline and partially crystalline forms, such forms may include solvates, which are included within the scope of the invention.

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

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

The compounds of the present invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention (particularly those having sufficient stability to permit isolation thereof).

The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism (i.e. exist in enantiomeric or diastereoisomeric forms). Diastereoisomers may be separated using conventional techniques (e.g., chromatography or fractional crystallization). The various stereoisomers (i.e., enantiomers) may be separated by separation of a racemic mixture or other mixture of the compounds using conventional (e.g., fractional crystallization or HPLC) techniques. Alternatively, the desired enantiomer or diastereomer may be obtained from the appropriate optically active starting material under conditions that do not cause racemization or epimerization (i.e., the "chiral pool" method), by reacting the appropriate starting material with a "chiral auxiliary" (which may then be derivatized at an appropriate stage (i.e., resolved, including dynamic resolution; e.g., reacted with an isospecific acid, followed by separation of the diastereomeric derivative by conventional means such as chromatography), or by reaction with an appropriate chiral reagent or chiral catalyst, all of which may be carried out under conditions known to the skilled artisan. All stereoisomers and mixtures thereof are included within the scope of the invention unless otherwise indicated.

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

Unless otherwise indicated, C as defined herein _1-6 Alkyl groups (e.g., C _1-4 Alkyl group), and C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, C _1-6 Alkylaryl, C _1-3 Alkenyl aryl, C _1-6 Alkyl heteroaryl and C _1-3 The alkyl portion of the alkenylheteroaryl group may be linear, or branched, and/or cyclic when a sufficient number (i.e., at least two or three, as appropriate) of carbon atoms are present (e.g., to form C) _3-6 Cycloalkyl groups). Such groups may also be partially cyclic (e.g., forming C) when a sufficient number (i.e., at least four) of carbon atoms are present _4-6 Part of the cycloalkyl groups). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, mention may be made ofThe partial cyclic alkyl groups of (which may also be referred to as "partial cycloalkyl" groups) include cyclopropylmethyl. Such groups may also be polycyclic (e.g., bicyclic or tricyclic) and/or spirocyclic when a sufficient number of carbon atoms are present.

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

Particular alkyl groups that may be mentioned include straight-chain (i.e., unbranched and/or cyclic) alkyl groups. For example, C _1-6 Alkyl, C _1-6 The alkyl portion of the alkoxy group includes, but is not limited to, n-butyl, sec-butyl, isobutyl, tert-butyl; propyl, such as n-propyl, 2-methylpropyl or isopropyl; an ethyl group; and methyl.

For the avoidance of any doubt, C _1-6 Alkyl group, and C _1-6 alkoxy-C _1-6 Alkyl, C _1-6 Alkylaryl, C _1-3 Alkenyl aryl, C _1-6 Alkyl heteroaryl and C _1-3 The point of attachment of the alkyl portion of the alkenylheteroaryl group is via the alkyl portion of such group.

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

Unless otherwise indicated, alkoxy refers to O-alkyl, wherein the term "alkyl" has the meaning given above.

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

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

The point of attachment of the heteroaryl/heteroaromatic group may be via any atom in the ring system, including heteroatoms where appropriate. The bicyclic heteroaryl/heteroaromatic group may comprise a benzene ring fused to one or more further aromatic or non-aromatic heterocycles, in which case the point of attachment of the polycyclic heteroaryl/heteroaromatic group may be via any ring including a benzene ring or heteroaryl/heteroaromatic or heterocyclyl ring.

For the avoidance of doubt, the skilled person will understand that heteroaryl groups which may form part of the compounds of the invention are those which can be obtained by chemical means as known to those skilled in the art. Various heteroaryl groups are well known to those skilled in the art, such as pyridyl, pyrrolyl, furyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothioyl, triazinyl, pyrimidinyl, furopyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, and purinyl.

For the avoidance of doubt, oxides of heteroaryl/heteroaromatic groups are also included within the scope of the invention (e.g. N-oxides).

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

As may be used herein, the term "aryl" may refer to C _6-14 (e.g., C _6-10 ) An aromatic group. Such groups may be monocyclic or bicyclic, and when bicyclic, may be fully or partially aromatic. Mention may be made of C _6-10 Aryl groups include phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, indanyl, and the like (e.g., phenyl, naphthyl, and the like).

Aromatic groups can be depicted as cyclic groups containing a suitable number of double bonds therein to allow for aromaticity.

The skilled artisan will appreciate that aryl groups that may form part of the compounds of the present invention are those that can be obtained by chemical methods as known to those skilled in the art.

For the avoidance of doubt, the point of attachment of the substituent to the aryl group may be via any suitable carbon atom of the ring system.

The present invention also includes isotopically-labeled compounds of the present invention which are identical to those recited herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element specified herein are contemplated within the scope of compounds of the invention and their uses. Thus, the compounds of the present invention also include deuterated compounds, i.e., compounds of the present invention in which one or more hydrogen atoms are replaced with the hydrogen isotope deuterium.

In the case where the nature of two or more substituents in a compound of the invention may be the same, the actual nature of the respective substituents does not depend on each other in any way. For example, where two or more halo groups are present, those groups may be the same or different (e.g., two chloro groups, or one fluoro group and one chloro group). Similarly, in the case where 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.

Further, when a specified substituent is itself 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 amount thereof (e.g., the relevant group may be substituted with one or more such substituents, such as one such substituent).

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

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

For the avoidance of doubt, where the identity of two or more substituents in a compound of formula I may be the same, the actual identity of the respective substituents does not depend on each other in any way. For example, where R ² And R is ³ Are all C _1-6 In the case of alkyl groups, C in question _1-6 The alkyl groups may be the same or different.

The skilled person will recognize that the compounds of the invention which are the subject of the present invention include those which are obtainable, i.e. which can be prepared in stable form. That is, the compounds of the present invention include those that are stable enough to withstand separation (e.g., separation from a reaction mixture) to give useful purity.

Preferred compounds of the invention include those wherein:

R ¹ represents methyl, ethyl, propyl (e.g., isopropyl), or butyl (e.g., n-butyl or tert-butyl), optionally substituted with up to three halogen atoms (e.g., CH) ₂ CHClCH ₂ CH ₂ F or CH ₂ CF ₃ )；

R ² And R is ³ Independently represent H or C _1-4 An alkyl group such as methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., n-butyl), optionally substituted with up to three halogen atoms (e.g., CH) ₂ CHClCH ₂ CH ₂ F or CH ₂ CF ₃ ) Substitution;

z represents O, or in particular-N (R ⁵ )-；

R ⁴ Represent C _1-4 An alkyl group such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., tert-butyl, isobutyl or n-butyl), each of which is optionally substituted and/or capped with up to three halogen (e.g., fluorine) atoms or-OH groups; a phenyl group; c (C) _1-3 Alkylaryl (e.g., benzyl); or C _1-4 Alkyl heteroaryl (e.g., 2-methylpyridinyl, 2-methylthiophene, or 2-methylfuran), each of which is optionally substituted or capped with up to three halogen (e.g., fluorine) atoms;

R ⁵ represents H or C _1-4 An alkyl group (such as methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., isobutyl));

one of X or Y represents ch=ch, O, S or N, and the other represents CH, O, S or N (provided that the structural limitation is applied as defined above);

R ⁶ represent C _1-4 Alkyl (such as methyl, ethyl, propyl (e.g., n-propyl), or butyl (e.g., n-butyl)); or C _1-4 Alkoxy C _1-4 Alkyl groups, each of which is optionally substituted with one or more fluorine atoms;

R ⁷ represents H, methyl, ethyl, or propyl (e.g., n-propyl).

More preferred compounds of the invention include those wherein Z represents O or more particularly-N (R ⁵ ) Those of:

R ¹ represents methyl, ethyl, isopropyl, or tert-butyl;

R ² and R is ³ Independently represents H or methyl;

R ⁴ represents methyl, ethyl, n-propyl, n-butyl, or isobutyl, each of which is optionally substituted and/or capped with one or more fluorine atoms or-OH groups; a benzyl group; 2-methylpyridinyl, 2-methylthiophene or 2-methylfuran;

R ⁵ Represents H, methyl, ethyl, n-propyl, n-butyl, or isobutyl;

R ⁶ represents n-propyl, n-butyl, or isobutyl, optionally substituted with up to three fluorine atoms or more preferably terminated with up to three fluorine atoms;

one of X or Y represents ch=ch and the other represents CH, or one of X or Y represents O or S and the other represents N.

Particularly preferred compounds of the invention include those wherein:

R ² and R is ³ All represent H;

Y ¹ represents-CH-or-CF-;

Y ² 、Y ³ and Y ⁴ All represent-CH-;

when Z represents-N (R) ⁵ ) -when R ⁵ Represents H;

R ⁶ represents an isobutyl group;

x represents CH and Y represents ch=ch, or X represents N and Y represents S;

R ⁷ represents H or methyl.

Further particularly preferred compounds of the invention include those wherein when Z represents a direct bond:

R ² and R is ³ All represent H;

Y ¹ represents-CH-or-CF-;

Y ² 、Y ³ and Y ⁴ All represent-CH-.

More preferred compounds of the invention include those wherein:

x represents CH, and Y represents ch=ch;

R ¹ representation armorA group, ethyl, isopropyl, or tert-butyl;

R ² and R is ³ All represent H;

Y ¹ represents-CH-or-CF-;

Y ² 、Y ³ and Y ⁴ All represent-CH-;

z represents-O-;

R ⁴ represents methyl, ethyl, or n-butyl, each of which is optionally substituted and/or capped with an-OH group;

R ⁶ Represents an isobutyl group.

Thus, particularly preferred compounds of the invention that may be mentioned include:

4- (4- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) phenyl) -2-isobutyl-N- ((thiophen-2-ylmethyl) carbamoyl) thiazole-5-sulfonamide,

4'- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -5-isobutyl-N- ((pyridin-2-ylmethyl) carbamoyl) - [1,1' -biphenyl ] -2-sulfonamide,

4'- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -5-isobutyl-N- ((thiophen-2-ylmethyl) carbamoyl) - [1,1' -biphenyl ] -2-sulfonamide,

3- (3 '-fluoro-5-isobutyl-4' - { [2- (tert-butyl) -1H-imidazol-1-yl ] methyl } -2-biphenylsulfonyl) -1- [ (2-pyridinyl) methyl ] urea,

((4 ' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl ] -2-yl) sulfonyl) carbamic acid ethyl ester,

(3 ' -fluoro-5-isobutyl-4 ' - ((2-isopropyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl ] -2-yl) sulfonyl) carbamic acid butyl ester,

((3 ' -fluoro-5-isobutyl-4 ' - ((2-isopropyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl ] -2-yl) sulfonyl) carbamic acid ethyl ester,

((3 ' -fluoro-5-isobutyl-4 ' - ((2-isopropyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl ] -2-yl) sulfonyl) carbamic acid methyl ester,

(3 ' -fluoro-5-isobutyl-4 ' - ((2-methyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl ] -2-yl) sulfonyl) carbamic acid butyl ester,

((4 ' - ((2-ethyl-1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl ] -2-yl) sulfonyl) carbamic acid butyl ester,

((3 ' -fluoro-5-isobutyl-4 ' - ((2-methyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl ] -2-yl) sulfonyl) carbamic acid ethyl ester,

methyl (3 ' -fluoro-5-isobutyl-4 ' - ((2-methyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl ] -2-yl) sulfonyl) carbamate,

((4 ' - ((2-ethyl-1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl ] -2-yl) sulfonyl) carbamic acid ethyl ester,

((4 ' - ((2-ethyl-1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl ] -2-yl) sulfonyl) carbamic acid methyl ester,

(4 '- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -5-isobutyl- [1,1' -biphenyl ] -2-yl) sulfonylcarbamic acid 2-hydroxyethyl ester,

(4 ' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl ] -2-yl) sulfonylcarbamic acid 2-hydroxyethyl ester, or

Methyl (5-isobutyl-4 '- ((2-methyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl ] -2-yl) sulfonyl carbamate.

Further provided are compounds of the invention that are not:

(4 ' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl ] -2-yl) sulfonyl) carbamic acid butyl ester; or (b)

((4 ' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl ] -2-yl) sulfonyl) carbamic acid methyl ester,

or a pharmaceutically acceptable salt of either compound.

Further provided are compounds of the invention wherein, in the compounds of formula I, when:

R ¹ represents tert-butyl or 2-hydroxypropan-2-yl;

R ² and R is ³ All represent H;

Y ¹ represents-CF-;

Y ² 、Y ³ and Y ⁴ All represent-CH-;

z represents-O-;

x represents CH;

y represents ch=ch; and is also provided with

R ⁶ When isopropyl is indicated, then

(a)R ⁴ Does not represent methyl; or alternatively

(b)R ⁴ Not representing C _1-2 An alkyl group; or alternatively

(c)R ⁴ N-butyl is not represented.

Further provided are compounds of the invention wherein, in the compounds of formula I, when R ¹ 、R ² 、R ³ 、Y ¹ 、Y ² 、Y ³ 、Y ⁴ Z, X and Y are as defined above and R ⁶ When isopropyl or isobutyl is indicated, then

(a)R ⁴ Does not represent methyl; or alternatively

(b)R ⁴ Not representing C _1-2 An alkyl group; or alternatively

(c)R ⁴ N-butyl is not represented.

Further provided are compounds of the invention wherein, in the compounds of formula I, when R ¹ 、R ² 、R ³ 、Y ¹ 、Y ² 、Y ³ 、Y ⁴ Z, X and Y are as defined above and R ⁶ When n-propyl, isopropyl or isobutyl is indicated, then

(a)R ⁴ Does not represent methyl; or alternatively

(b)R ⁴ Not representing C _1-2 An alkyl group; or alternatively

(c)R ⁴ N-butyl is not represented.

Further provided are compounds of the invention wherein, in the compounds of formula I, when R ² 、R ³ 、Y ¹ 、Y ² 、Y ³ 、Y ⁴ Z, X and Y are as defined above and:

R ¹ represents C optionally substituted by one or more fluorine atoms _2-4 Alkyl substituted and/OR via OR ⁷ Substitution; and is also provided with

R ⁶ When isopropyl or isobutyl; then

(a)R ⁴ Does not represent methyl; or alternatively

(b)R ⁴ Not representing C _1-2 An alkyl group; or alternatively

(c)R ⁴ N-butyl is not represented.

R ⁶ When n-propyl, isopropyl, or isobutyl; then

(a)R ⁴ Does not represent methyl; or alternatively

(b)R ⁴ Not representing C _1-2 An alkyl group; or alternatively

(c)R ⁴ N-butyl is not represented.

IUPAC names are generated by program Chemdoodle 8.1.0.

More preferred compounds of the present invention include those of the examples described below.

The compounds of formula I may be prepared according to techniques well known to those skilled in the art, for example as described below.

According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula I wherein Z represents-N (R ⁵ ) -the method comprising:

(i) The compound of the formula II is allowed to react,

wherein R is ¹ 、R ² 、R ³ 、R ⁶ 、Y ¹ 、Y ² 、Y ³ 、Y ⁴ X and Y are as previously describedDefined, and L represents C _1-6 An alkyl or aryl group (e.g., phenyl), and a compound of formula III, or a salt thereof,

NHR ⁴ R ⁵ III

wherein R is ⁴ And R is ⁵ As defined hereinbefore, for example at about room temperature or higher (e.g. up to 90 ℃ to 110 ℃) in the presence of a suitable solvent such as toluene, acetonitrile or dioxane and/or a suitable base such as triethylamine or 4-dimethylaminopyridine or potassium carbonate.

(ii) Wherein R is ⁵ In the case of compounds of formula I which represent H, compounds of formula IV,

wherein R is ¹ 、R ² 、R ³ 、R ⁶ 、Y ¹ 、Y ² 、Y ³ 、Y ⁴ X and Y are as defined above, with a compound of formula V,

R ⁴ -N＝C＝O V

wherein R is ⁴ As defined hereinbefore, for example at about room temperature or higher (e.g. up to 60 ℃ to 70 ℃), optionally at cuprous (I) chloride and/or at a suitable base (e.g. pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1, 8-diazabicyclo [ 5.4.0)]Undec-7-ene, or mixtures thereof) and a suitable solvent (e.g., pyridine, methylene chloride, ethyl acetate, tetrahydrofuran, dimethylformamide).

(iii) In which Z represents-N (R) ⁵ ) -and R ⁵ In the case of compounds of formula I, which represent H, or in which Z represents a direct bond, compounds of formula IV as defined hereinbefore are reacted with compounds of formula VI,

wherein R is ⁴ As defined hereinbefore and X ¹ Is a suitable leaving group (e.g., halo (e.g., chloro or bromo), -O-C _1-6 Alkyl or-O-C _1-6 Aryl (e.g., -OPh), e.g., under microwave irradiation at above room temperature in a suitable base (e.g., sodium bicarbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, N-ethyldiisopropylamine, dimethylaminopyridine, diisopropylamine, 1, 8-diazabicyclo [ 5.4.0)]Undec-7-ene, or mixtures thereof) and a suitable solvent (e.g., acetonitrile, pyridine, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, or toluene). Alternatively, wherein X ¹ Representing a hydroxyl group, the reaction may be carried out under standard EDCI coupling conditions, for example in the presence of a carboxyl activator (e.g. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide). In the case of compounds of formula I wherein Z represents-O-, reacting a compound of formula II as described hereinbefore with a compound of formula VII,

R ⁴ OH VII

wherein R is ⁴ As defined above. The reaction may be carried out in the absence of solvent at temperatures above room temperature (e.g., at the reflux temperature of the alcohol used).

The compounds of formula II may be prepared by reacting a compound of formula IV as defined hereinbefore with a compound of formula VIII,

wherein X is ^1a And X ^1b Each represents X as defined above ¹ And may be the same or different, for example, at below, about or above room temperature (e.g., 0 ℃, or up to 50 ℃ to 70 ℃) in the presence of a suitable base (as defined above) and a suitable solvent (e.g., pyridine, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, acetonitrile, or toluene).

The compound of formula IV may be prepared by reacting a compound of formula IX,

wherein R is ⁶ X and Y are as defined hereinbefore, or an N-protected derivative thereof, and X ² Represents suitable cross-coupling groups with compounds of the formula X,

wherein R is ¹ 、R ² 、R ³ 、Y ¹ 、Y ² 、Y ³ And Y ⁴ As defined above, and X ³ Representing suitable cross-coupling groups, are reacted. The above coupling reaction is preferably a Suzuki reaction, and can therefore be carried out under standard Suzuki conditions, meaning X ² And X ³ One of them represents a suitable Suzuki cross-coupling group (or "partner") namely boric acid (-B (OH) ₂ ) Or one of a borate (e.g., MIDA derivative or pinacol ester) and a halogen group (such as iodine or bromine), and the other represents the other group. Standard Suzuki conditions can be applied to the reaction, which includes, for example, the presence of a suitable coupling catalyst system (e.g., a palladium catalyst such as [1,1' -bis (diphenylphosphino) ferrocene ]Palladium (II) dichloride, [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride dichloromethane complex, pd (PPh) ₃ ) ₄ Or Pd (OAc) ₂ Ligand (wherein the ligand may be, for example, PPh) ₃ 、P(o-Tol) ₃ Or 1,1' -bis (diphenylphosphino) ferrocene)) and a suitable base (e.g., sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, or diisopropylamine), and a suitable solvent system (e.g., toluene, ethanol, dimethoxymethane, dimethylformamide, ethylene glycol dimethyl ether, water, dioxane, or mixtures thereof). The reaction may be carried out at a temperature above room temperature (e.g., at the reflux temperature of the solvent system used). The reaction may be carried out at above room temperature under microwave irradiation. If a protected form of the compound of formula IX is employed, the reaction may be followed by subsequent reaction with SO under standard conditions (e.g., as described below) ₂ Deprotection of the NH-group. The reaction of the compound of formula IX with the compound of formula X may also be followed by reacting the intermediate thus formed with a suitable acid to form an acid addition salt, or more preferably an N-protected form thereof. Suitable acid addition salts include fumarate, trifluoroacetate and oxalate.

Alternatively, the compound of formula IV may be prepared by reacting a compound of formula XI,

Wherein R is ¹ 、R ² And R is ³ As defined above, with a compound of formula XII,

wherein R is ⁶ 、X ¹ 、Y ¹ 、Y ² 、Y ³ 、Y ⁴ X and Y are as defined above (X ¹ In particular bromine) or an N-protected derivative thereof, for example at about room temperature or below in the presence of a suitable base (e.g. pyridine) and a suitable organic solvent (e.g. toluene). If a protected form of the compound of formula XI is employed, the reaction may be followed by subsequent reaction with SO under standard conditions (e.g., as described below) ₂ Deprotection of the NH-group. In addition, the compounds of formula IV may be prepared in this way, for example according to or analogous to the processes described in particular in british patent application GB 2281298.

The compounds of formula X may be prepared by standard techniques, for example by reacting a compound of formula IX as hereinbefore described with a compound of formula XIII,

wherein X is ¹ 、X ³ 、Y ¹ 、Y ² 、Y ³ And Y ⁴ As defined hereinbefore, e.g. in relation to formula IV as described hereinbeforeThe preparation of the compounds is carried out under conditions analogous to those described.

Compounds of formula XII are known in the art. For example, they may be prepared according to or analogously to the processes described in, inter alia, U.S. patent No. 5,312,820, uk patent application GB 2281298 and/or international patent application WO 02/096883.

Compounds of formula IX are known in the art. For example, they can be prepared according to or analogously to the processes described in particular in International patent application WO 02/096883.

Compounds of formulas III, V, VI, VII, VIII, XI and XIII are commercially available, known in the literature, or may be obtained by methods similar to those described herein, or prepared by conventional synthetic procedures from readily available starting materials according to standard techniques using appropriate reagents and reaction conditions.

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

Functional groups that are desired to be protected include sulfonamide groups, amido groups, amino groups, and aldehydes. Suitable protecting groups for sulfonamide, amido, and amino groups include t-butoxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), or t-butyl. Suitable protecting groups for aldehydes include alcohols such as methanol or ethanol, and diols such as 1, 3-propanediol, or preferably 1, 2-ethanediol (thus forming cyclic acetals). Protection and deprotection of functional groups may be performed either before or after the reaction in the schemes described above.

The protecting groups may be applied or removed according to techniques well known to those skilled in the art or as described below. For example, the protected compounds/intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The chemical type involved will determine the need and type of protecting groups and the order in which the synthesis is completed. The use of protecting groups is described fully in the following documents: "Protective Groups in Organic Synthesis", 3 rd edition, T.W.Greene & P.G.M.Wutz, wiley-Interscience (1999), the contents of which are incorporated herein by reference.

Medical and pharmaceutical use

As described herein, the compounds of the present invention, and thus compositions and kits comprising these compounds, are useful because they possess pharmacological activity and/or are metabolized in vivo following oral or parenteral administration to form compounds that possess pharmacological activity.

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 (or in) a medicament.

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

More particularly, the compounds of the invention are agonists of the AT2 receptor, and in particular selective (relative to the AT1 receptor) agonists of this sub-receptor, as demonstrated by the assays described below.

AT2 receptor agonists include agonists that fully activate AT2 receptors and agonists that partially activate AT2 receptors. Thus, the compounds of the invention can selectively bind to AT2 receptors and exhibit agonist activity AT2 receptors. A compound that "selectively binds" to an AT2 receptor includes a ratio of affinities (AT 2: AT 1) for the relevant compound AT a given concentration of AT least 50:1, such as AT least 100:1, preferably AT least 1000:1.

It is further contemplated that the compounds of the invention may be useful in those conditions in which AT2 receptors are expressed and their stimulation is desired or required.

In this regard, the compounds of the invention are useful in the treatment of conditions characterized by increased vascular contraction, fibrosis, cell growth and/or differentiation, increased myocardial contractility, increased cardiovascular hypertrophy and/or fluid and electrolyte retention, as well as skin and musculoskeletal disorders.

The compounds of the 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 (and thus, e.g., an antithrombotic effect), and/or may therapeutically reduce vasoconstriction and/or bronchoconstriction.

The compounds of the invention are further useful for treating stress-related disorders, and/or improving microcirculation and/or mucosal protection mechanisms.

Thus, the compounds of the invention are expected to be useful for the treatment of conditions which may be characterized as indicated above and are such as conditions of the gastrointestinal tract, cardiovascular system, respiratory tract, kidneys, eyes, female reproductive (ovulation) system and Central Nervous System (CNS).

Gastrointestinal disorders that may be mentioned include esophagitis, barrett's esophagus, gastric ulcers, duodenal ulcers, dyspepsia (including non-ulcerative dyspepsia), gastroesophageal reflux, irritable Bowel Syndrome (IBS), inflammatory Bowel Disease (IBD), pancreatitis, liver disorders such as hepatitis, gallbladder disease, multiple Organ Failure (MOF), and sepsis. Other gastrointestinal disorders that may be mentioned include xerostomia, gastritis, gastroparesis, hyperacidity, biliary tract disorders, celiac disease, crohn's disease, ulcerative colitis, diarrhea, constipation, colic, dysphagia, vomiting, nausea, dyspepsia and Sjogren syndrome.

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

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

Eye disorders that may be mentioned include diabetic retinopathy, retinopathy of prematurity and retinal microvasculature.

Female reproductive system disorders that may be mentioned include ovulation dysfunction.

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

CNS disorders that may be mentioned include cognitive dysfunction, food intake (hunger/satiety) and thirst dysfunction, stroke, cerebral hemorrhage, cerebral embolism and cerebral infarction, multiple Sclerosis (MS), alzheimer's disease and parkinson's disease.

The compounds of the invention are also useful for modulating growth metabolism and proliferation, for example for the treatment of aging, hypertrophic disorders, prostatic hyperplasia, autoimmune diseases (e.g., arthritis such as rheumatoid arthritis or systemic lupus erythematosus), psoriasis, obesity, neuronal regeneration, ulcer healing, adipose tissue proliferation inhibition, stem cell differentiation and proliferation, fibrotic diseases, cancers (e.g., cancers in the gastrointestinal tract (including the esophagus or stomach), prostate, breast, liver, kidneys or themselves, as well as lymphomas, lung cancers, ovarian cancers, pancreatic cancers, hematological malignancies, etc.), apoptosis, tumors (general) and hypertrophy, diabetes, neuronal disorders and organ rejection.

The compounds of the invention are also useful in the treatment of stroke, spinal cord injury, sickle cell disease, muscular dystrophy, cardiac toxicity associated with cancer treatment, peripheral neuropathy, and, in particular, systemic sclerosis.

The compounds of the invention are particularly useful for the treatment and/or prophylaxis of ILD such as sarcoidosis or fibrosis, more particularly pulmonary fibrosis (and in particular IPF), and conditions that may trigger ILD such as systemic sclerosis, rheumatoid arthritis, myositis or systemic lupus erythematosus or conditions otherwise associated with ILD such as pulmonary arterial hypertension and/or arterial pulmonary arterial hypertension.

The compounds of the invention are particularly useful for the treatment of pulmonary fibrosis, in particular IPF.

According to a further aspect of the invention there is provided a method of treating pulmonary fibrosis (and in particular IPF), the method comprising administering to a person suffering from such a condition a therapeutically effective amount of a compound of the invention.

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

Furthermore, the compounds of the invention may also be used for the treatment or prevention of any fibrotic condition of one or more internal organs characterized by excessive accumulation of fibrous connective tissue, and/or for the treatment or prevention of fibrogenesis and 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), and multi-organ inflammation, injury, and/or failure, which may be caused by internal or external trauma (e.g., injury) or infection.

Thus, such conditions may be caused by sepsis or septic shock caused by viral, bacterial or fungal infection (e.g., viral respiratory tract infection). Furthermore, acute lung injury, ARDS (particularly SARS) may be caused by viruses such as coronaviruses, including the novel SARS coronavirus 2 (SARS-CoV-2), which may cause internal tissue injury and/or related internal (e.g., mucosal) tissue dysfunction such as airway epithelium, resulting in virus-induced pneumonia, impaired lung function, respiratory dysfunction, distress and/or failure. Such tissue damage may also lead to severe fibrosis. For example, SARS disease (coronavirus disease 2019 or COVID-19) caused by the novel coronavirus SARS-CoV-2 is known to cause fibrosis in many cases.

The compounds of the invention are particularly useful in the treatment of diseases or conditions in which activation of the AT2 receptor is desired or required but inhibition of one or more CYP enzymes is not desired.

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 and conditions in which activation of the AT2 receptor is desired or required but in which inhibition of CYP enzymes is not desired.

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

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

According to a further aspect of the present invention there is provided a method of treating a particular disease or condition in which activation of the AT2 receptor is desired or required but in which inhibition of CYP enzymes is not desired, such as pulmonary fibrosis, in particular IPF, the method comprising administering to a person suffering from the relevant condition a therapeutically effective amount of a compound of the present invention.

The compounds of the invention are useful in the therapeutic, palliative and/or diagnostic treatment of any of the following conditions, as well as in the prophylactic treatment (including prevention and/or elimination of exacerbation and/or exacerbation of the condition) of the condition.

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

In some embodiments, the compounds of the invention may be administered separately (e.g., separately), and/or sequentially, and/or at the same time in parallel (e.g., simultaneously) using different routes of administration, but preferably by known pharmaceutical formulations (including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions or emulsions for parenteral or intramuscular administration, or the like, or via inhalation.

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

In some embodiments, there is provided a method of treating a disease or condition in which activation of AT2 receptors is desired or required (and such diseases or conditions in which inhibition of CYP enzymes is not desired), including pulmonary fibrosis and in particular IPF, comprising administering to a patient in need of such therapy a therapeutically effective amount of a compound of the invention, separately, sequentially or AT the same time in parallel (preferably via inhalation and oral administration), by a combination of routes of administration, so as to achieve an effective amount or dose.

Such a combination of routes of administration, preferably via inhalation and oral administration, may be presented as separate formulations of the compounds of the invention optimized for each route of administration.

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

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.

The compounds of the invention may be administered in combination with other AT2 agonists known in the art, such as C21, and in combination with AT1 receptor antagonists known in the art, and/or in combination with inhibitors of Angiotensin Converting Enzyme (ACE). Illustrative, but non-limiting examples of AT1 receptor antagonists that can be used according to the embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, mi Fasha, olmesartan, telmisartan, prasterartan, li Piya, sha Pusha, tasosartan, telmisartan, valsartan, and/or combinations thereof. Illustrative, but non-limiting examples of ACE inhibitors that may be used according to the embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, idapril, trandolapril, fosinopril, moexipril, cilazapril, spiropril, temopril, alapril, cilazapril, dillapril, mevalpril, and/or combinations thereof.

Other active ingredients that may be administered in combination with the compounds of the present invention include disodium cromoglycate; endothelin receptor antagonists such as bosentan, ambrisentan, sitaxsentan and macitentan; PDE5 inhibitors such as sildenafil and tadalafil: prostacyclin (epoprostenol) and analogs thereof, such as iloprost and treprostinil; other biological agents including interferon gamma-1 b, etanercept, infliximab, and adalimumab; and methotrexate. Further active ingredients under development that may be co-administered with the compounds of the present invention include Pan Ruilu mab (anti-CTGF, fibrogen); GLPG1690 (autotaxin inhibitor, galapagos), TD139 (galectin-3 inhibitor, galecto), PRM-151 (recombinant pentamin-2, promedia), BBT-877 (autotaxin inhibitor, boehringer/Bridge), CC-90001 (JNK inhibitor, celgene), PBI-4050 (dual GPR40 agonist/GPR 84 antagonist, prometc.), BMS-986020 (lysophosphatidic acid receptor antagonist, BMS), RVT-1601 (mast cell stabilizer, respitant), SMO4646 (wnt signal inhibitor, united Therapeutics), KD25 (Rho-related kinase inhibitor, kadmon holdins), BG00011 (integrin antagonist, biogen), PLN-74809 (integrin antagonist, pilant Therapeutics), celebrinib (Saracanib; src kinase inhibitor, asterazeneca), PAT-1251 (lysyl oxidase, A-25), phamomum-115 (Abame), and ABone-25 (Abame-A).

In a further aspect of the invention, the compounds of the invention are particularly useful when combined with other therapeutic agents in combination therapy to treat a variety of conditions, including those previously mentioned. Since the compounds of the present invention exhibit minimal CYP enzyme inhibition, such combinations are particularly advantageous when other therapeutic agents for the relevant disorder are themselves metabolized by the CYP enzyme.

Thus, when the condition to be treated is a interstitial lung disease known in the art, such as IPF, systemic sclerosis or fibrosis, the compounds of the invention are preferably administered in combination with a galectin-3 inhibitor, a lysophosphatidic acid receptor 1 (LPA 1) antagonist, an Autotaxin (ATX) inhibitor, a recombinant human pentamin-2 protein or established therapies for such treatment, including but not limited to pirfenidone and/or nidanib. Preferably, the combination of compounds of the invention is with pirfenidone or a pharmaceutically acceptable salt thereof (which is known to be metabolized by CYP enzymes such as CYP 1A).

Further, where the condition to be treated is a chronic kidney-related disease, the compounds of the invention are preferably administered in combination with one or more other drugs (such as irbesartan and/or torasemide, which are known to be metabolized by CYP enzymes such as CYP2C 9) that are also used in such treatment.

When the condition to be treated is pulmonary arterial hypertension, the compounds of the invention are preferably administered in combination with one or more other drugs (such as celecoxib and/or sildenafil) also used in such treatment, which compounds are known to be metabolized by CYP enzymes such as CYP3 A4.

When the condition to be treated or prevented is myocardial infarction and/or stroke related disease, the compounds of the invention are preferably administered in combination with one or more other drugs (such as propranolol, warfarin, clopidogrel, atorvastatin, cilostazol, lidocaine and/or simvastatin, or pharmaceutically acceptable salts thereof), which are also useful in such treatment, these compounds are known to be metabolized by CYP enzymes such as CYP1A, CYP2CP and/or CYP3 A4.

When the condition to be treated is an autoimmune disease such as rheumatoid arthritis, multiple sclerosis or psoriasis, the compounds of the invention are preferably administered in combination with one or more other drugs (including but not limited to non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen, celecoxib, meloxicam or analogues thereof (e.g. piroxicam) or indomethacin, or drugs such as tizanidine, cyclophosphamide, cyclosporine, dif-cortisone and/or hydrocortisone, riluzole, or pharmaceutically acceptable salts thereof, known to be metabolized by CYP enzymes such as CYP1A, CYP CP, CYP2C19 and/or CYP3 A4).

Thus, the compounds of the invention are particularly useful for treating diseases or conditions in which activation of the AT2 receptor is desired or required but inhibition of the CYP enzyme is not desired, and thus may be administered in combination with one or more of the other therapeutic agents mentioned previously which are metabolized by the CYP enzyme pathway, useful or useful, including pirfenidone, naproxen, propranolol, riluzole, tizanidine, warfarin, celecoxib, clopidogrel, irbesartan, meloxicam, piroxicam, torasemide, indomethacin, atorvastatin, cilostazol, cyclosporin, difenocort, hydrocortisone, lidocaine, celecoxib, sildenafil and/or simvastatin. Most preferably, the compounds of the invention are administered in combination with pirfenidone to treat interstitial lung diseases (such as IPF).

Therapeutic agents that may be used in combination with the compounds of the present invention include standard therapies for various applications of viral infection including antibody therapy (e.g., LY-CoV555/LY-CoV016 (Bamlanivism b) and etallic Wei Shankang (etesevisab)), LY-CoV555 (Eli Lilly), REGN-COV2 (Caslizumab) (caslizumab) and illilimumab (imdemab)), REGN3048-3051, TZLS-501, SNG001 (Syntain), solkulizumab (Soliris; alexion Pharmaceuticals), lei Fuli bead monoclonal antibody (Ultemitis; alexion Pharmaceuticals), lezileumab (lenzilumab), leuzumab (tociclesonidab) (Rogowab), sha Lilu monoclonal antibody (Salimab) (Kegama), resiidan and Uigreep (Castimab), uvalnemab (Uygen), uvalnemorgasel) and Uvalnemab (Uvalnemab), uvalnemab (Phvalnemab), uvalacir (Phvalnemab) and Uvalnemab (Phami), uvalnemab (Phamitraz) 24-and Uvalnemab (Phamitraz), phalafil-100, phalafil (Phamitraz) and the antiviral drugs (Phalafil) alone, phalafil-2, phalafil-P2, primab and Uvalirox (Phalafil) and (Phalafil) alone, phalafil-P2, phalafila-et-P-West, phalamic acid, and the inhibitors OYA1 (OyaGen 9), BPI-002 (BeyondSpring), NP-120 (Ifenprodil; algernon Pharmaceuticals) and Li Dexi (Biocryst Pharma), anti-inflammatory agents (e.g., NSAIDs such as ibuprofen, ketorolac, naproxen, etc.), chloroquine, hydroxychloroquine, interferons (e.g., interferon beta-1 a), tolizumab (Actemra), lenalidomide, pomalidomide and thalidomide), analgesics (e.g., paracetamol or opioids), antitussive agents (e.g., dextromethorphan), vaccinations (e.g., INO-4800, provided by Inovio Pharmaceuticals and Beijing Ai Diwei euphoric Biotechnology Co., if available), COVID-19 convalescence plasma (SARS), and/or passive antibody therapy using antibodies in the blood of a SARS-CoV or CoV-2 infected convalescence patient.

Further therapeutic agents that may be mentioned include anti-fibrotic drugs (e.g. nidanib, and in particular pirfenidone), vitamins (e.g. vitamin B, vitamin C and vitamin D) and mucolytics (such as acetylcysteine and ambroxol).

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

Naturally occurring corticosteroids that may be mentioned include: cortisol (hydrocortisone), aldosterone, corticosterone, cortisone, pregnenolone, progesterone; and naturally occurring precursors and intermediates in corticosteroid biosynthesis; and other derivatives of naturally occurring corticosteroids such as 11-deoxycortisol, 21-deoxycortisol, 11-dehydrocortisone, 11-deoxycorticosterone, 18-hydroxy-11-deoxycorticosterone, 18-hydroxycortion, 21-deoxycortisone, 11 beta-hydroxy pregnenolone, 11 beta, 17 alpha, 21-tri-hydroxy pregnenolone, 17 alpha, 21-dihydroxypregnenolone, 17 alpha-hydroxy pregnenolone, 21-hydroxy pregnenolone, 11-ketoprogesterone, 11 beta-hydroxy progesterone, 17 alpha-hydroxy progesterone, and 18-hydroxy progesterone.

Synthetic corticosteroids that may be mentioned include those of the hydrocortisone type (group a) such as hydrocortisone acetate, hydrocortisone pyruvate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, hydrocortisone and tibetasone pivalate, prednisolone, methylprednisolone, prednisone, prednisolone, difluprednate, fludrocortisone, fluocinolone, fluprednisolone, loteprednol, prednisone and triamcinolone; acetonide and related substances (group B) such as ambroxide, budesonide, fluocinonide, halcinonide, triamcinolone acetonide, ciclesonide, deflazacort, formosant, fluocinonide, flunisolide and fluocinonide; those of the (beta) betamethasone type (group C), such as beclomethasone, betamethasone dipropionate and betamethasone valerate, dexamethasone, flucortisone, halometasone, mometasone and mometasone furoate, aclitasone and aclitasone dipropionate, clobetasol and clobetasol propionate, clobetasol and clobetasol butyrate, clocortolone, desirtolone, diflorasone, diflucolone, fluclodrone, flucortisone, fluprednisone and fluprednisone acetate, fluticasone furoate and fluticasone propionate, methylprednisolone, palatethasone, prednisone, rimexolone and ubebetasol; those of progesterone type such as fluoroprogesterone, fluorometholone, megestrol and pregnanediol acetate, and progesterone derivatives (progestins) such as chlordygesterone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate and medroxyprogesterone acetate; other corticosteroids such as cocoa-varroa-and 6-methyl-11 beta, 17 beta-dihydroxy-17 alpha- (1-propynyl) androsta-1, 4, 6-trien-3-one.

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

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, and statins, antimicrobial agents, and antiallergic/antiasthmatic agents.

H2 receptor blockers that may be mentioned include famotidine. Anticoagulants that may be mentioned include heparin and low molecular weight heparin (e.g., bemiparin, nadroparin, revascularization heparin, enoxaparin, paparin, cetophenarin, dalteparin, tinzaparin); direct acting oral anticoagulants (e.g., dabigatran, argatroban, rivaroxaban, apixaban, edoxaban, betrofloxaban, dar Lei Shaban, oxaxaban, letababan, ai Ruiba xaban (ebaxaban), hirudin, lepirudin, and bivalirudin); coumarin type vitamin K antagonists (e.g., coumarin, acebrodole, coumarins, atomoxetine, and phenylindendione), synthetic pentasaccharide inhibitors of factor Xa (e.g., fondaparinux, idoxaparin (idraparinux), and biotinylated idoxaparin (idrabotoapinux)). Antiplatelet agents that may be mentioned include irreversible cyclooxygenase inhibitors (e.g., aspirin and triflusal); adenosine diphosphate receptor inhibitors (e.g., cangrelor, clopidogrel, prasugrel, ticagrelor, and ticlopidine); phosphodiesterase inhibitors (e.g., cilostazol); protease-activated receptor 1 antagonists (e.g., verapamil); glycoprotein IIB/IIIA inhibitors (e.g., acipimab, eptifibatide, and tirofiban); adenosine reuptake inhibitors (e.g., dipyridamole); and thromboxane inhibitors (e.g., ter Lu Quban, ramatroban, sertraline and picoamide). Statins that may be mentioned include atorvastatin, simvastatin and rosuvastatin. Antimicrobial agents that may be mentioned include azithromycin, ceftriaxone, cefuroxime, doxycycline, fluconazole, piperacillin, tazobactam and teicoplanin. Antiallergic/antiasthmatic drugs that may be mentioned include chlorphenamine, levocetirizine and montelukast.

Thus, the subject may also (and/or may have already) received one or more of any of the other therapeutic agents described above, meaning that one or more of those other therapeutic agents is received at a prescribed dose prior to, in addition to, and/or after treatment with the compound of the invention or a pharmaceutically acceptable salt thereof.

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

Such combination products provide for the co-administration of the compounds of the invention with other therapeutic agents and thus may be presented as separate formulations, wherein at least one of those formulations comprises a compound of the invention and at least one comprises the other therapeutic agent; or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation comprising the compound of the invention and the other therapeutic agent).

Thus, there is further provided:

(1) A pharmaceutical formulation comprising: the compounds of the invention; therapeutic agents selected from those described above (e.g., therapeutic agents known to be metabolized by CYP enzymes); and a pharmaceutically acceptable excipient (e.g., adjuvant, diluent, or carrier), which formulation is hereinafter referred to as a "combined preparation"; and

(2) A kit of parts comprising the following components:

(A) A pharmaceutical formulation comprising a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and

(B) Pharmaceutical formulations comprising a therapeutic agent selected from those described above (e.g., a therapeutic agent known to be metabolized by CYP enzymes), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier,

wherein components (a) and (B) are each provided in a form suitable for administration in combination with another.

In a further aspect of the invention there is provided a process for preparing a combined preparation as defined hereinbefore, which process comprises bringing together a compound of the invention, an additional therapeutic agent and at least one (e.g. pharmaceutically acceptable) excipient.

In a further aspect of the invention there is provided a method for preparing a kit of parts as defined hereinbefore, the method comprising bringing together components (a) and (B). As used herein, reference to a combination will mean that the two components are adapted to be administered in combination with each other.

Thus, with respect to a method for preparing a kit of parts as defined hereinbefore, two components are "bound to each other", including the two components of the kit of parts, can:

(i) Provided as separate formulations (i.e., independent of each other) which are then brought together for use in combination with each other in combination therapy; or alternatively

(ii) The individual components as a "combination pack" are packaged and presented together for use in combination with one another in combination therapy.

Accordingly, there is further provided a kit of parts comprising:

(I) One of components (a) and (B) as defined herein; there are also

(II) instructions for use of one of the two components in combination with the other component.

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

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

In any event, the physician or technician will be able to determine the actual dosage that best suits the individual patient, which may vary with the condition being treated, as well as the age, weight, sex and response of the particular patient being treated. The doses mentioned above are examples of average cases; of course, there may be separate situations where higher or lower dosage ranges are required, and this is within the scope of the invention.

The use of the compounds of the present invention via separate and/or sequential and/or parallel combination routes of administration at the same time has the benefit of producing tailored treatments for patients in need of such treatment, with the possibility of preventing and/or reducing side effects, and also adjusting the correct dosage level of a therapeutically effective amount of the compounds of the present invention.

The kit of parts described herein may comprise more than one formulation comprising the appropriate amount/dose of a compound of the invention, and/or more than one formulation comprising the appropriate amount/dose of another therapeutic agent, in order to provide for repeated administration. If more than one formulation (comprising any active compound) is present, such formulations may be the same or may differ in the dosage, chemical composition and/or physical form of any compound.

With respect to the kit of parts described herein, "co-administration" includes sequential, separate and/or simultaneous administration of the respective formulations comprising the compounds of the invention and the other therapeutic agent during the course of treatment of the relevant disorder.

Thus, with respect to a combination product according to the invention, the term "co-administration" includes administration (optionally repeated) of the two components of the combination product (the compound of the invention and the other therapeutic agent) together, or sufficiently close in time, to enable a beneficial effect to be produced on a patient during treatment of the relevant condition, which effect is greater than when a formulation comprising the compound of the invention or a formulation comprising the other agent is administered alone (optionally repeated) in the absence of the other component during the same treatment. Determining whether a combination provides a greater benefit with respect to or during treatment of a particular disorder will depend on the disorder to be treated or prevented, but may be routinely accomplished by the skilled artisan.

Further, in the context of a kit of parts according to the invention, the term "in combination" includes that one or the other of the two formulations may be administered (optionally repeated) before, after and/or at the same time as the other components are administered. The terms "concurrently administered" and "administered at the same time" as used in this context include administration of individual doses of the related compounds of the invention and other anti-inflammatory agents within 48 hours (e.g., 24 hours) of each other.

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

Thus, in a further aspect of the 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 invention as defined hereinbefore with one or more pharmaceutically acceptable excipients (e.g. adjuvants, diluents and/or carriers).

In a further aspect of the invention there is provided a method for preparing a combination product or kit of parts as defined hereinbefore, which method comprises combining certain compounds of the invention as defined hereinbefore with other therapeutic agents useful in the treatment of the relevant disease or condition and at least one pharmaceutically acceptable excipient.

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

When used herein with respect to a particular value (such as an amount), the term "about" (or similar terms such as "about") will be understood to indicate that such value may vary by up to 10% (in particular, up to 5%, such as up to 1%) based on the defined value. It is contemplated that such terms may be replaced in each case with the symbol "±10%" or the like (or by indicating the variance of a specific amount calculated based on the correlation value). It is also contemplated that such terms may be deleted in each case.

The compounds of the invention have the following advantages: they are more potent than the aforementioned CYP enzymes, and/or are stable to metabolic hydrolysis, and/or do not inhibit the aforementioned CYP enzymes.

The compounds of the invention may also have the following advantages: whether used for the treatment of IPF or other uses, they may be more potent, less toxic, have longer duration of action, be more potent, produce fewer side effects, be more readily absorbed, and/or have better pharmacokinetic characteristics (e.g., higher oral bioavailability and/or lower clearance), and/or have other useful pharmacological, physical or chemical properties than compounds known in the art. Such effects may be assessed clinically, objectively, and/or subjectively by a healthcare professional, a treatment subject, or an observer.

Examples

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

If there is a difference between the name and any compound graphically depicted, the latter is to be taken into account (unless contradicted by any experimental details that may be given, or unless clearly apparent from the context).

Experimental procedure

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

The experiments are generally carried out under an inert atmosphere (nitrogen or argon), in particular in the case of using reagents or intermediates sensitive to oxygen or moisture. Unless otherwise indicated, experiments were performed in oven-dried glassware using standard techniques for treating air and moisture sensitive materials.

All solvents and chemicals purchased were used without further purification. The microwave heating reaction was performed in a gasket-sealed Biotage vial, producing a 2450MHz controlled irradiation with a power of 0W to 400W using a Biotage single mode microwave reactor equipped with an in-line infrared sensor. The reaction was monitored by Thin Layer Chromatography (TLC), performed on Merck silica gel 60F-254 plates, and visualized using UV light (λ=254 nm). Automated Flash Column Chromatography (FCC) was performed on a Biotage Isolera Dalton instrument using a commercial silica gel column. Manual FCC was performed using a commercial silica gel column. Analytical HP LC/ESI-MS was performed using UV detection (214, 254 and 280 nm) and electrospray ionization (ESI) MS, on a C18 column (50 x 3.0mm,2.6 μm particle size,pore size) was used as a gradient of mobile phase (flow rate 1.5 mL/min) using acetonitrile in 0.05% HCOOH. High resolution molecular mass (HRMS) was measured on a mass spectrometer equipped with ESI source and 7-T hybrid linear ion trap (LTQ). Nuclear Magnetic Resonance (NMR) spectra were recorded on Bruker Avance III HD or Bruker Avance Neo instruments. Recording at 400MHz, 101MHz, 126MHz and 376MHz, respectively ¹ H、 ¹³ C and C ¹⁹ F NMR spectrum. Chemical shift (delta) is reported in ppm via residual solvent signal with reference to trimethylsilane ¹ H：CDCl ₃ -d, meOD-d4 at 7.26 ppm: 3.31ppm pentad, acetone d6:2.09ppm, DMSO-d6, at 2.50ppm, heptad, ¹³ C：CDCl ₃ :77.16ppm, triplet; meOD-d4:49.00ppm, seven modes; acetone-d 6:29.84ppm, seven modes; DMSO-d6:39.52 seven states). Recording proton decoupling ¹³ C NMR ¹⁹ F NMR spectrum. The data are reported as follows: chemical shift delta/ppm, integral (only ¹ H) Multiple (s=singlet, d=doublet, t=triplet, q=quadruple, br. =broad, m=multiplet, or a combination thereof; unless otherwise indicated ¹³ The C signal is unimodal), the coupling constant J is assigned in hertz (Hz). Use under appropriate conditions ¹ H COSY, HSQC and HMBC to promote structural distribution. All final compounds were > 95% pure as determined by HPLC (UV, 254 nm) and NMR.

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

The reaction conditions (such as reaction length or temperature) may be different for the synthesis with reference to the general procedure. Generally, the reaction is followed by thin layer chromatography or LC-MS analysis and, where appropriate, by workup. Purification may vary from experiment to experiment: in general, the solvent and solvent ratio are chosen for the eluent/gradientRate to provide proper R _f And/or retention time. Some products are purified using supercritical fluid chromatography (e.g., using a column with mobile phase a (CO ₂ ) And B (MeOH/H) ₂ O/NH ₃ ) Solvent combination of (c) is purified. Some compounds are prepared by HPLC, flash column chromatography or with H ₂ The O/MeCN polar manual C18 reverse phase column was used for purification.

Examples

Example 1

4- (4- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) phenyl) -2-isobutyl-N- ((thiophen-2-ylmethyl) Carbamoyl) thiazole-5-sulfonamide

(a)4-bromo-2-isobutylthiazole

Pd (OAc) was taken up under nitrogen ₂ (0.03 mmol,0.03 eq.) and xantphos (0.05 mmol,0.05 eq.) are combined in dry THF. After stirring for 5 minutes, the solution was transferred to a separate vessel containing 2, 4-dibromothiazole (1.03 mmol,1 eq.) and alkyl zinc bromide (0.5M in THF, 1.08mmol,1.05 eq.) under nitrogen. The sealed vessel was stirred at 80 ℃ for 16 hours. After cooling to room temperature, the mixture was filtered through a pad of celite to remove insoluble solids (with CH ₂ Cl ₂ Elution). The filtrate is treated with H ₂ Dilute with O (50 mL) and use CH ₂ Cl ₂ (3X 50 mL) extraction. The combined organic extracts were washed with brine (30 mL), over MgSO ₄ Dried and concentrated in vacuo to give the crude product. The crude product was purified by FCC (0% to 10% ethyl acetate in isohexane) to give the corresponding product in 55% to 65% yield. ¹ H-NMR (400 MHz, chloroform-d) delta 7.01 (s, 1H), 2.80 (d, J=7.2 Hz, 2H), 2.12-1.97 (m, 1H), 0.92 (d, J=6.6 Hz, 6H). ¹³ C-NMR (101 MHz, chloroform-d). Delta. 171.6,124.1,115.9,42.4,29.7,22.2.

(b)4-bromo-2-isobutylthiazole-5-sulfonic acid

4-bromo-2-isobutylthiazole (1 mmol,1 eq.) was dissolved in DMF (2 mL) and after cooling to 5℃chlorosulfonic acid (5 mmol,5 eq.) was slowly added to this extent. Then, the process is carried out, The mixture was stirred at 120℃for 16h. After cooling to room temperature, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (10% MeOH in DCM) to give the sub-title product. ¹ H-NMR (400 MHz, methanol-d) ₄ )δ2.72(d,J＝7.2Hz,2H),2.00–1.93(m,1H),0.89(d,J＝6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ171.5,112.8,41.4,29.6,21.0。

(c)4-bromo-2-isobutylthiazole-5-sulfonyl chloride

4-bromo-2-isobutylthiazole-5-sulfonic acid (from step (b) above, 1mmol,1 eq.) was dissolved in 10mL DCM and PCl was slowly added ₅ (2 mmol,2 eq.) and the reaction mixture was stirred at 60 ℃ overnight. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with water (30 mL), brine (25 mL), and over anhydrous MgSO ₄ Dried, and concentrated in vacuo. The crude product was purified by FCC (0% to 25% ethyl acetate in isohexane) to give chloride intermediates in 80% to 95% yield. ¹ H-NMR (400 MHz, chloroform-d) delta 2.94 (d, j=7.1 hz, 2H), 2.30-2.14 (m, 1H), 1.06 (d, j=6.7 hz, 6H). ¹³ C-NMR (101 MHz, chloroform-d). Delta. 177.8,134.4,131.9,43.0,29.8,22.2.

(d)4-bromo-N- (tert-butyl) -2-isobutylthiazole-5-sulfonamide

4-bromo-2-isobutylthiazole-5-sulfonyl chloride (from step (c) above, 1mmol,1 eq.) was dissolved in DCM (2 mL) and tert-butylamine (1.1 mmol,1.1 eq.) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then extracted with DCM (2X 50 mL). The combined organic layers were washed with water (30 mL), brine (25 mL), and over anhydrous MgSO ₄ Dried, and concentrated in vacuo. The crude product was purified by FCC (0% to 30% ethyl acetate in isohexane) to give the corresponding sulfonamide in 90% to 95% yield. ¹ H-NMR (400 MHz, chloroform-d) delta 5.16 (s, 1H), 2.87 (d, j=7.2 hz, 2H), 2.20-2.06 (m, 1H), 1.32 (s, 9H), 1.01 (d, j=6.6 hz, 6H). ¹³ C-NMR (101 MHz, chloroform-d). Delta. 174.1,134.8,126.4,55.5,42.6,29.9,29.7,22.1.

(e)N- (tert-butyl) -4- (4- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) phenyl) -2-isobutylthiazole- 5-sulfonamides

4-bromo-N- (tert-butyl) -2-isobutylthiazole-5-sulfonamide (from step (d) above, 1mmol,1 eq.), 1- (4-bromobenzyl) -2- (tert-butyl) -1H-imidazole (1 mmol,1 eq.), K ₂ CO ₃ (4 mmol,4 eq.) and Pd (dppf) Cl ₂ (0.05 mmol,0.05 eq.) was suspended in 1, 2-dimethoxyethane (3 mL) and water (0.6 mL). The vial was sealed and the resulting reaction mixture was stirred under microwave irradiation at 120 ℃ for 60min. The mixture was cooled to ambient temperature and then extracted with chloroform (3×2 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous MgSO ₄ Dried, and concentrated. The crude product was isolated by manual FCC (0% to 10% MeOH in DCM) to give the product in 70% to 85% yield.

(f)4- (4- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) phenyl) -2-isobutylthiazole-5-sulfonamide

N- (tert-butyl) -4- (4- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) phenyl) -2-isobutyl-thiazole-5-sulfonamide (from step (e), 0.15 mmol) was stirred in trifluoroacetic acid (2.5 mL) overnight at 50 ℃. The reaction was diluted with water (10 mL) and the product was extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous MgSO ₄ Dried, and concentrated. The sulfonamide was purified through a small silica plug (0% to 5% MeOH in acetonitrile) and used in the subsequent carbamate formation reaction without further purification.

(g)4- (4- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) phenyl) -2-isobutyl-N- ((thiophen-2-ylmethylene) Group) carbamoyl) thiazole-5-sulfonamide

4- (4- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) phenyl) -2-isobutylthiazole-5-sulfonamide (from step (f) above, 60mg,0.14mmol,1 eq.) and cuprous chloride (I) (2.0 mg,0.021mmol,15 mol%) were dissolved in dry DMF at room temperature and 2- (isocyanatomethyl) thiophene (0.044 mL,0.35mmol,2.5 eq.) was added under argon atmosphere and the reaction mixture stirred for 24H. After the completion of the reaction, the reaction mixture, The crude mixture was poured into 0.1 aqueous NHCl, diluted with ethyl acetate (25 mL), and the organic and aqueous phases were separated. The aqueous phase was extracted twice with ethyl acetate (20 mL), and the combined organic phases were washed with brine (20 mL) over MgSO ₄ Dried, and the solvent evaporated in vacuo to give the crude product. The crude product was purified by preparative HPLC (20% to 90% acetonitrile in water) and obtained as a white amorphous solid (31 mg, 39% yield). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ7.68(d,J＝7.8Hz,2H),7.24–7.12(m,2H),7.07(dd,J＝5.0,1.3Hz,1H),6.99(d,J＝8.0Hz,2H),6.78–6.68(m,2H),5.46(s,2H),4.17(s,2H),2.74(d,J＝7.1Hz,2H),2.03–1.95(m,1H),1.36(s,9H),0.90(d,J＝6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ172.0,157.4,153.1,152.8,142.6,135.7,133.5,130.2,126.3,126.2,126.2,125.1,124.2,124.2,119.3,51.5,41.5,38.0,33.4,29.6,27.7,21.3。

Example 2

4' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -5-isobutyl-N- ((pyridin-2-ylmethyl) amino methyl) Acyl) - [1,1' -biphenylyl]-2-sulfonamides

The title compound is prepared by reacting 4'- (2- (tert-butyl) -1H-imidazol-1-yl) -4-isobutyl- [1,1' -biphenyl]Prepared by a similar method to that described in example 1 (steps (b) to (f)) above, except using 1-bromo-4-isobutylbenzene (1 mmol) instead), with phenyl N- (2-pyridylmethyl) carbamate (40.2 mg,0.18mmol,1.5 eq.) and DBU (0.026 mL,0.18mmol,1.5 eq.) were dissolved in 1.5mL acetonitrile and the reaction mixture was heated at MW for 1 h. After the reaction was complete (as indicated by TLC), the solvent was evaporated under reduced pressure. The residue was then dissolved in ethyl acetate and extracted with 0.1N HCl. The aqueous phase was extracted twice with ethyl acetate (20 mL), and the combined organic phases were washed with brine (20 mL) over MgSO ₄ Dried, and the solvent evaporated in vacuo to give the crude product. The crude product was first filtered through a manual C-18 reverse phase column with methanol acetonitrile polarity, then purified by preparative HPLC (20% to 90% acetonitrile in water),and the product was obtained as a white amorphous solid (crude, 35%). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.34(d,J＝4.9Hz,1H),7.96(d,J＝8.2Hz,1H),7.63(td,J＝7.7,1.7Hz,1H),7.31–7.09(m,5H),7.06–6.92(m,4H),6.89(d,J＝1.5Hz,1H),5.41(s,2H),4.19(s,2H),2.46(d,J＝7.2Hz,2H),1.85–1.75(m,1H),1.35(s,9H),0.82(d,J＝6.6Hz,6H)。

Example 3

4' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -5-isobutyl-N- ((thiophen-2-ylmethyl) aminomethyl Acyl) - [1,1' -biphenylyl]-2-sulfonamides

The title compound was prepared using a method similar to that described in example 1 above except that 1-bromo-4-isobutylbenzene (1 mmol) was used instead. The crude product was purified by preparative HPLC (20% to 90% acetonitrile in water) and the crude product was obtained as a white amorphous solid (crude, 33%). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ7.95(d,J＝8.2Hz,1H),7.22(dd,J＝8.2,1.8Hz,1H),7.19–7.09(m,3H),7.04(d,J＝1.7Hz,1H),6.96(d,J＝1.6Hz,1H),6.94–6.87(m,3H),6.82–6.74(m,2H),5.42(s,2H),4.20(s,2H),2.46(d,J＝7.2Hz,2H),1.85–1.75(m,1H),1.36(s,9H),0.83(d,J＝6.6Hz,6H)。

Example 4

((4 ' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl)]-2- Group) sulfonyl) butyl carbamate

(a)1- (4-bromo-2-fluorobenzyl) -2- (tert-butyl) -1H-imidazole

NaH (0.460 g,12.0mmol,1.5 eq.) was added to a stirred solution of 2-tert-butyl-1H-imidazole (1.02 g,8.21mmol,1 eq.) in DMF (0.27M) at 0deg.C. After 20min, 4-bromo-1- (bromomethyl) -2-fluoro-benzene (2.20 g,8.21mmol,1 eq.) was added. The resulting mixture was warmed to ambient temperature and stirred overnight, then quenched with water (15 mL). The crude product was purified by FCC (30% ethyl acetate in isohexane) to give the product as pale yellow amorphous Solid (2.56 g, 39% yield). ¹ H-NMR (400 MHz, chloroform-d) delta 7.24 (dd, j=9.5, 1.9hz, 1H), 7.21-7.16 (m, 1H), 6.93 (d, j=1.4 hz, 1H), 6.67 (d, j=1.4 hz, 1H), 6.55 (t, j=8.1 hz, 1H), 5.25 (s, 2H), 1.35 (s, 9H). ¹⁹ F-NMR (376 MHz, chloroform-d) delta-115.61 (t, J=8.7 Hz).

(b)N- (tert-butyl) -4-isobutyl-2- (6-methyl-4, 8-dioxo-1, 3,6, 2-dioxaborane-2- Radical) benzenesulfonamide

N-butyllithium (7.59 mL,19.0mmol,4.74 eq.) was added dropwise to a stirred solution of N-tert-butyl-4-isobutyl-benzenesulfonamide (1.08 g,4.00mmol,1 eq.) in THF at-78deg.C. The resulting pale yellow solution was stirred at-78℃for 30min, followed by 45min at 0 ℃. The reaction mixture was cooled to-78 ℃ and triisopropyl borate (2.71 ml,11.7mmol,2.94 eq.) was added dropwise. After 15min, the solution was warmed to 0 ℃ and stirred for a further 45min during which time the formation of a white precipitate was observed. Hydrochloric acid (25 ml,2m aqueous solution) was added and the reaction mixture was stirred for 15min. The resulting clear solution was partially evaporated, diluted with water (10 mL), and the product was taken up in CH ₂ Cl ₂ (3X 25 mL) extraction. The combined organic layers were dried over MgSO ₄ Dried, and concentrated to give a viscous yellow oil. The crude boric acid was dissolved in DMSO (2 mL) and toluene (30 mL). Methyliminodiacetic acid (0.696 g,4.73mmol,1.18 eq.) was added and the mixture refluxed for 3h. The reaction was brought to ambient temperature, diluted with ethyl acetate and washed with hydrochloric acid (3×50ml,0.1m aqueous). The organic phase was subjected to MgSO ₄ Dried, and concentrated to give the crude product as a yellow solid. The crude product was purified by FCC (10% to 100% ethyl acetate in isohexane) to give the product as a white amorphous solid (0.92 g, 54% yield). ¹ H-NMR (400 MHz, chloroform-d) delta 7.42 (d, j=3.7 hz, 1H), 6.68 (d, j=3.7 hz, 0H), 4.46 (s, 1H), 2.69 (d, j=7.1 hz, 2H), 2.07-1.76 (m, 1H), 1.28 (s, 9H), 0.95 (d, j=6.6 hz, 6H).

(c)4' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl ]]-2- Sulfonamide compounds

1- [ (4-bromo-2-fluoro-benzene)Radical) methyl radical]2-tert-butyl-imidazole (0.293 g,0.942mmol,1 eq.) and N- (tert-butyl) -4-isobutyl-2- (6-methyl-4, 8-dioxo-1, 3,6, 2-dioxaborolan-2-yl) benzenesulfonamide (0.420 g,0.989mmol,1.05 eq.), potassium carbonate (0.415 g,3.00mmol,3 eq.) and tetrakis (triphenylphosphine) palladium (0) (57.8 mg,0.50mmol,0.05 eq.) were suspended in a mixture of degassed toluene (6 mL), etOH (2 mL) and water (1 mL). The reaction mixture was stirred in a sealed microwave vial at 120 ℃ for 60min under microwave irradiation and then allowed to cool to ambient temperature. The reaction was quenched with water (10 mL), extracted with ethyl acetate (2×25 mL), and the combined organic layers were washed with brine (25 mL), over anhydrous Na ₂ SO ₄ Dried, and concentrated to give a yellow viscous oil. The crude product was dissolved in trifluoroacetic acid (12 mL) and stirred at 45 ℃. The reaction mixture was quenched with water (10 mL) and the product was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ Dried, and concentrated. The crude product was purified by FCC (on CH ₂ Cl ₂ From 0% to 10% MeOH) to afford the product as a pale yellow amorphous solid (0.250 g, 60% yield). ¹ H-NMR (400 MHz, chloroform-d) delta 7.95 (d, J=8.1 Hz, 1H), 7.37 (s, 1H), 7.28-7.19 (m, 3H), 7.13-6.97 (m, 3H), 5.50 (s, 2H), 5.32 (s, br.2H), 2.51 (d, J=7.2 Hz, 2H), 1.96-1.78 (m, 1H), 1.57 (s, 9H), 0.89 (d, J=6.6 Hz, 6H). ¹⁹ F-NMR (376 MHz, chloroform-d) delta-75.37.

(d)((4 ' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl)]- 2-yl) sulfonyl) carbamic acid butyl ester

The title compound was obtained by dissolving the sulfonamide (125 mg,0.280mmol,1 eq.) from step (c) above in CH ₂ Cl ₂ (2 mL). Triethylamine (182. Mu.L, 1.31mmol,5 eq.) was added, and then butyl chloroformate (42.9. Mu.L, 0.336mmol,1.2 eq.) was added. The reaction mixture was stirred at 0 ℃ and after 1h the reaction was quenched. The reaction was quenched with water, with CH ₂ Cl ₂ Dilute and subject the product to CH ₂ Cl ₂ (3X 5 mL) extraction. The combined organic layersWashed with brine (3 mL), over Na ₂ SO ₄ Dried, and concentrated. The crude product was purified by FCC (on CH ₂ Cl ₂ 5% MeOH) to afford the product as a white amorphous solid (58.8 mg, 39% yield). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.05(d,J＝8.2Hz,1H),7.34(dd,J＝8.2,1.8Hz,1H),7.26–7.01(m,6H),5.57(s,2H),3.86(t,J＝6.5Hz,2H),2.56(d,J＝7.2Hz,2H),2.06–1.75(m,1H),1.54(s,9H),1.49–1.35(m,2H),1.34–1.16(m,2H),0.92(d,J＝6.6Hz,6H),0.85(t,J＝7.4Hz,3H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ160.8(d, ¹ J _C-F ＝246.6Hz),156.8,154.9,147.6,144.3(d, ³ J _C-F ＝8.6Hz),140.0,138.8,133.6,130.7,129.9(d, ⁴ J _C-F ＝4.0Hz),129.7,127.0(d, ³ J _C-F ＝3.3Hz),124.1,123.0(d, ² J _C-F ＝14.6Hz),122.9,117.9(d, ² J _C-F ＝22.0Hz),66.3,47.3(d, ³ J _C-F ＝4.1Hz),45.8,34.7,32.0,31.2,29.4,22.7,20.0,14.1。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-113.55–-127.68(m)。HRMS(ESI ⁺ )：C ₂₉ H ₃₉ FN ₃ O ₄ S[M+H] ⁺ Calculated 544.2645; found values: 544.2623.

example 5

((4 ' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl)]-2- Group) sulfonyl) carbamic acid methyl ester

The title compound was synthesized by stirring the final compound (33.0 mg,60.7 μmol) obtained according to the preparation described in example 4 above in MeOH (1 mL). The crude product was concentrated and purified by FCC (on CH ₂ Cl ₂ 5% meoh) to afford the product as a white amorphous solid (17.5 mg, 58% yield). ¹ H-NMR (400 MHz, methanol-d) ₄ Chloroform-d) delta 8.05 (d, j=8.2 hz, 1H), 7.34 (dt, j=8.2, 1.7hz, 1H), 7.27-7.14 (m, 4H), 7.13-7.03 (m, 2H), 5.58 (s, 2H), 3.45 (s, 3H), 2.57 (d, j=7.1 hz, 2H), 2.06-1.77 (m, j=6.7 hz, 1H), 1.55 (s, 9H), 0.93 (d, j=3H)6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ Chloroform-d) delta 160.6 (d, ¹ J _C-F ＝246.7Hz),157.5,154.6,147.2,144.2(d, ³ J _C-F ＝8.5Hz),139.7,138.6,133.3,130.5,129.5(d, ⁴ J _C-F ＝2.3Hz),126.8(d, ³ J _C-F ＝3.3Hz),123.9,122.7,122.5(d, ² J _C-F ＝14.4Hz),117.8(d, ² J _C-F ＝22.0Hz),52.8,47.1(d, ³ J _C-F ＝4.0Hz),45.7,34.5,31.0,29.3,22.6。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ Chloroform-d) delta-116.33-132.46 (m). HRMS (ESI) ⁺ )：C ₂₆ H ₃₃ FN ₃ O ₄ S ⁺ Calculated values: [ M+H ]] ⁺ 502.2176; found values: 502.2184.

example 6

((4 ' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl)]-2- Group) sulfonyl) carbamic acid ethyl ester

The title compound was synthesized by stirring the final compound (33.0 mg, 60.7. Mu. Mol) obtained according to the preparation described in example 4 above in EtOH (1 mL). The crude product was concentrated and purified by FCC (2% to 6% MeOH in CH) ₂ Cl ₂ In (c) to give the product as a white amorphous solid (10.2 mg, 33%). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.05(d,J＝8.2Hz,1H),7.35(dd,J＝8.2,1.8Hz,1H),7.26–7.17(m,2H),7.14(dt,J＝8.4,1.5Hz,2H),7.12–7.04(m,2H),5.57(s,2H),3.90(q,J＝7.1Hz,2H),2.57(d,J＝7.2Hz,2H),2.03–1.79(m,1H),1.54(s,9H),1.08(t,J＝7.1Hz,3H),0.93(d,J＝6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ160.8(d, ¹ J _C-F ＝246.6Hz),156.9,154.9,147.6,144.4,140.0,138.8,133.6,130.8,129.9(d, ³ J _C-F ＝3.3Hz),129.7,127.1(d, ³ J _C-F ＝2.9Hz),124.1,123.1(d, ² J _C-F ＝14.5Hz),122.9,117.9(d, ² J _C-F ＝21.9Hz),62.4,47.3(d, ³ J _C-F ＝3.1Hz),45.8,34.7,31.3,29.3,22.6,14.8。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-116.55–-124.40(m)。HRMS(ESI ⁺ )：C ₂₇ H ₃₅ FN ₃ O ₄ S ⁺ Calculated values: [ M+H ]] ⁺ 516.2332; found values: 516.2327.

example 7

((3 ' -fluoro-5-isobutyl-4 ' - ((2-isopropyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl)]-2-yl) Sulfonyl) carbamic acid butyl ester

The title compound was synthesized as described for the compound of example 4 above except that 2-isopropyl-1H-imidazole was used instead in step (a). The crude product was purified by FCC (on CH ₂ Cl ₂ 2% to 4% MeOH) to afford the product as a white amorphous solid (74.7 mg, 50% yield). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.06(d,J＝8.2Hz,1H),7.32(dd,J＝8.2,1.8Hz,1H),7.30–7.14(m,5H),7.03(d,J＝1.8Hz,1H),5.40(s,2H),3.86(t,J＝6.5Hz,2H),3.58–3.38(m,1H),2.54(d,J＝7.2Hz,2H),1.99–1.81(m,1H),1.52–1.39(m,2H),1.34(d,J＝6.9Hz,6H),1.30–1.14(m,2H),0.91(d,J＝6.6Hz,6H),0.86(t,J＝7.4Hz,3H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ161.0(d, ¹ J _C-F ＝246.6Hz),157.4,153.9,147.2,144.7(d, ³ J _C-F ＝8.5Hz),139.9(d, ⁴ J _C-F ＝1.7Hz),139.2,133.6,130.7,130.4(d, ³ J _C-F ＝3.8Hz),129.6,127.1(d, ⁴ J _C-F ＝3.2Hz),123.1,122.6(d, ² J _C-F ＝14.7Hz),122.1,118.1(d, ² J _C-F ＝22.4Hz),66.1,45.7,45.4(d, ³ J _C-F ＝3.2Hz),32.0,31.2,26.6,22.7,21.4,20.0,14.1。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-119.89–-119.99(m)。HRMS(ESI ⁺ )：C ₂₈ H ₃₇ FN ₃ O ₄ S ⁺ Calculated values: [ M+H ]] ⁺ 530.2489; found values: 530.2479.

example 8

(3 '-fluoro-5-isobutyl group-4' -(2-isopropyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl]-2-yl) Sulfonyl) carbamic acid ethyl ester

The title compound was synthesized using the final compound (35.0 mg, 66.1. Mu. Mol) obtained according to the preparation described in example 7 in EtOH (1 mL). The crude product was concentrated and purified by FCC (2% to 6% MeOH in CH) ₂ Cl ₂ In (c) to give the product as a white amorphous solid (13.5 mg, 42%). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.05(d,J＝8.2Hz,1H),7.34(dd,J＝8.2,1.8Hz,1H),7.26–7.14(m,5H),7.05(d,J＝1.8Hz,1H),5.39(s,2H),3.91(q,J＝7.1Hz,2H),3.40(p,J＝6.9Hz,1H),2.57(d,J＝7.2Hz,2H),2.02–1.82(m,1H),1.34(d,J＝6.9Hz,6H),1.09(t,J＝7.1Hz,3H),0.92(d,J＝6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ161.0(d, ¹ J _C-F ＝246.5Hz),156.8,154.2,147.6,144.5(d, ³ J _C-F ＝8.6Hz),140.1,138.8,133.7,130.8,130.1(d, ³ J _C-F ＝4.1Hz),129.7,127.1(d, ⁴ J _C-F ＝3.3Hz),124.0,123.0(d, ² J _C-F ＝14.7Hz),122.1,118.0(d, ² J _C-F ＝22.3Hz),62.4,45.8,45.1(d, ³ J _C-F ＝3.8Hz),31.3,26.8,22.6,21.5,14.7。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-120.43–-120.55(m)。HRMS(ESI ⁺ )：C ₂₆ H ₃₃ FN ₃ O ₄ S ⁺ Calculated values: [ M+H ]] ⁺ 502.2176; found values: 502.2186

Example 9

((3 ' -fluoro-5-isobutyl-4 ' - ((2-isopropyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl)]-2-yl) Sulfonyl) carbamic acid methyl ester

The title compound was synthesized using the final compound (30.0 mg, 56.6. Mu. Mol) obtained according to the preparation described in example 7 with stirring in MeOH (1 mL). The crude product was concentrated and purified by FCC (4% to 6% MeOH in CH) ₂ Cl ₂ A gradient in (a)) to give the product as a white amorphous solid (15.6 mg, 55％)。 ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.05(d,J＝8.2Hz,1H),7.33(dd,J＝8.2,1.8Hz,1H),7.28(d,J＝1.9Hz,1H),7.26–7.19(m,4H),7.04(d,J＝1.8Hz,1H),5.41(s,2H),3.54–3.39(m,1H),3.45(s,3H),2.55(d,J＝7.2Hz,2H),1.97–1.81(m,1H),1.35(d,J＝6.9Hz,6H),0.92(d,J＝6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ161.1(d, ¹ J _C-F ＝246.5Hz),158.3,154.0,147.3,144.9(d, ³ J _C-F ＝8.7Hz),139.9(d, ⁴ J _C-F ＝1.7Hz),139.2,133.6,130.7,130.3(d, ³ J _C-F ＝3.9Hz),129.6,127.1(d, ⁴ J _C-F ＝3.2Hz),122.9,122.5(d, ² J _C-F ＝14.6Hz),122.3,118.1(d, ² J _C-F ＝22.3Hz),52.8,45.8,45.5(d, ³ J _C-F ＝3.7Hz),31.2,26.7,22.7,21.3。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-120.35(dd,J＝11.0,7.5Hz)。HRMS(ESI ⁺ )：C ₂₅ H ₃₁ FN ₃ O ₄ S ⁺ Calculated values: [ M+H ]] ⁺ 488.2019; found values: 488.2014.

example 10

((3 ' -fluoro-5-isobutyl-4 ' - ((2-methyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl)]-2-yl) sulphone Acyl) carbamic acid butyl ester

The title compound was synthesized as described for the compound of example 4 above except that 2-methyl-1H-imidazole was used instead in step (a). The crude product was purified by FCC (on CH ₂ Cl ₂ 2% to 4% MeOH) to afford the product as a white amorphous solid (58.2 mg, 39% yield). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.05(dd,J＝8.1,2.6Hz,1H),7.36–7.15(m,5H),7.14–7.06(m,1H),7.05–6.99(m,1H),5.31(s,2H),3.84(t,J＝6.6Hz,2H),2.58(s,3H),2.53(d,J＝7.1Hz,2H),1.95–1.78(m,1H),1.52–1.33(m,2H),1.31–1.14(m,2H),0.91(d,J＝6.5Hz,6H),0.85(t,J＝7.3Hz,3H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ161.1(d, ¹ J _C-F ＝246.4Hz),158.2,147.1,146.0,145.0,139.8,139.5,133.5,130.7,130.6,129.6,127.1,122.6,121.9(d, ² J _C-F ＝14.9Hz),121.8,,118.1(d, ² J _C-F ＝21.5Hz),66.0,45.8,45.7(d, ³ J _C-F ＝4.9Hz),32.0,31.2,22.7,20.0,14.1,11.5。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-119.86–-120.30(m)。HRMS(ESI ⁺ )：C ₂₆ H ₃₃ FN ₃ O ₄ S ⁺ Calculated values: [ M+H ]] ⁺ 502.2176; found values: 502.2157.

example 11

((4 ' - ((2-ethyl-1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl)]-2-yl) sulphone Acyl) carbamic acid butyl ester

The title compound was synthesized as described for the compound of example 4 above except that 2-ethyl-1H-imidazole was used instead in step (a). The crude product was purified by FCC (on CH ₂ Cl ₂ 2% to 4% MeOH) to afford the product as a white amorphous solid (45.8 mg, 34% yield). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.07(d,J＝8.2Hz,1H),7.35(dd,J＝8.2,1.8Hz,1H),7.30(d,J＝1.8Hz,1H),7.28–7.18(m,3H),7.17(d,J＝1.8Hz,1H),7.06(d,J＝1.8Hz,1H),5.37(s,2H),3.87(t,J＝6.5Hz,2H),2.96(q,J＝7.6Hz,2H),2.58(d,J＝7.2Hz,2H),1.99–1.85(m,1H),1.53–1.39(m,2H),1.35(t,J＝7.6Hz,3H),1.31–1.19(m,2H),0.94(d,J＝6.6Hz,6H),0.88(t,J＝7.4Hz,3H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ161.1(d, ¹ J _C-F ＝246.7Hz),157.4,150.6,147.4,144.7(d, ³ J _C-F ＝8.4Hz),140.0,139.1,133.6,130.7,130.3(d, ³ J _C-F ＝3.9Hz),129.6,127.1(d, ⁴ J _C-F ＝3.1Hz),123.1,122.5(d, ² J _C-F ＝14.7Hz),122.5,118.1(d, ² J _C-F ＝22.3Hz),66.2,45.8,45.4(d, ³ J _C-F ＝3.9Hz),32.0,31.3,22.7,20.0,20.0,14.1,11.8。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-120.28(dd,J＝10.9,7.2Hz)。HRMS(ESI ⁺ )：C ₂₇ H ₃₅ FN ₃ O ₄ S ⁺ Calculated values: [ M+H ]] ⁺ 516.2332; found values: 516.2327.

example 12

((3 ' -fluoro-5-isobutyl-4 ' - ((2-methyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl)]-2-yl) sulphone Acyl) carbamic acid ethyl ester

The title compound was synthesized using the final compound (25.0 mg, 49.8. Mu. Mol) obtained according to the preparation described in example 10 in EtOH (1 mL). The crude product was concentrated and purified by FCC (2% to 6% MeOH in CH) ₂ Cl ₂ In (c) to give the product as a white amorphous solid (9.8 mg, 42%). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.07(d,J＝8.2Hz,1H),7.36(dd,J＝8.2,1.8Hz,1H),7.33(d,J＝1.8Hz,1H),7.30–7.18(m,3H),7.15(d,J＝1.8Hz,1H),7.07(d,J＝1.8Hz,1H),5.36(s,2H),3.90(q,J＝7.1Hz,2H),2.58(d,J＝7.2Hz,5H),2.57(s,3H),2.00–1.84(m,1H),1.10(t,J＝7.1Hz,3H),0.94(d,J＝6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ161.1(d, ¹ J _C-F ＝246.4Hz),157.3,147.5,146.3,144.7,140.0,139.1,133.6,130.7,130.4(d, ³ J _C-F ＝4.0Hz),129.7,127.1,122.9,122.7,122.4(d, ² J _C-F ＝14.6Hz),118.1(d, ² J _C-F ＝22.2Hz),62.2,45.8,45.6(d, ³ J _C-F ＝3.8Hz),31.3,22.6,14.8,11.7。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-120.46(dd,J＝11.1,7.4Hz)。HRMS(ESI ⁺ )：C ₂₄ H ₂₉ FN ₃ O ₄ S ⁺ Calculated values: [ M+H ]] ⁺ 474.1863; found values: 474.1870.

example 13

((3 ' -fluoro-5-isobutyl-4 ' - ((2-methyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl)]-2-yl) sulphone Acyl) carbamic acid methyl ester

The title compound was synthesized using the final compound (15.0 mg, 29.9. Mu. Mol) obtained according to the preparation described in example 10 with stirring in MeOH (1 mL). The crude product was concentrated and purified by FCC (4% to 6% MeOH in CH) ₂ Cl ₂ In (c) to give the product as a white amorphous solid (8.2 mg, 60%). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.04(d,J＝8.2Hz,1H),7.37–7.18(m,5H),7.17(d,J＝1.9Hz,1H),7.03(d,J＝1.8Hz,1H),5.35(s,2H),3.43(s,3H),2.58(s,3H),2.55(d,J＝7.2Hz,2H),2.11–1.75(m,1H),0.92(d,J＝6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ161.2(d, ¹ J _C-F ＝246.3Hz),158.9,147.1,146.2,145.1(d, ³ J _C-F ＝8.7Hz),139.8,139.5,133.4,130.6,130.5,129.6,127.2(d, ³ J _C-F ＝3.3Hz),122.8,121.9(d, ² J _C-F ＝15.0Hz),121.9,118.1(d, ² J _C-F ＝22.3Hz),52.7,45.8,45.8(d, ³ J _C-F ＝3.1Hz),31.3,22.6,11.5。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-120.41(dd,J＝10.7,7.9Hz)。HRMS(ESI ⁺ )：C ₂₃ H ₂₇ FN ₃ O ₄ S ⁺ Calculated values: [ M+H ]] ⁺ 460.1706; found values: 460.1707.

example 14

((4 ' - ((2-ethyl-1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl)]-2-yl) sulphone Acyl) carbamic acid ethyl ester

The title compound was synthesized using the final compound (24.5 mg, 47.5. Mu. Mol) obtained according to the preparation described in example 11 in EtOH (1 mL). The crude product was concentrated and purified by FCC (2% to 6% MeOH in CH) ₂ Cl ₂ In (c) to give the product as a white amorphous solid (7.6 mg, 33%). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.05(d,J＝8.1Hz,1H),7.34(dd,J＝8.2,1.8Hz,1H),7.30(d,J＝1.8Hz,1H),7.26–7.15(m,4H),7.04(d,J＝1.8Hz,1H),5.36(s,2H),3.89(q,J＝7.1Hz,2H),2.94(q,J＝7.6Hz,2H),2.56(d,J＝7.2Hz,2H),2.00–1.83(m,J＝6.8Hz,1H),1.34(t,J＝7.6Hz,3H),1.08(t,J＝7.1Hz,3H),0.92(d,J＝6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ161.1(d, ¹ J _C-F ＝246.4Hz),157.3,150.6,147.5,144.7(d, ³ J _C-F ＝8.4Hz),140.0,139.0,133.6,130.7,130.3(d, ³ J _C-F ＝3.9Hz),129.7,127.1,123.1,122.6,122.5(d, ² J _C-F ＝14.8Hz),118.0(d, ² J _C-F ＝22.1Hz),62.3,45.8,45.4(d, ³ J _C-F ＝3.8Hz),31.3,22.6,20.0,14.8,11.8。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-120.42(dd,J＝11.0,7.0Hz)。HRMS(ESI ⁺ )：C ₂₅ H ₃₁ FN ₃ O ₄ S ⁺ Calculated values: [ M+H ]] ⁺ 488.2019; found values: 488.2004.

example 15

((4 ' - ((2-ethyl-1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl)]-2-yl) sulphone Acyl) carbamic acid methyl ester

The title compound was synthesized using the final compound (13.4 mg,26.0 μmol) obtained according to the preparation described in example 11 with stirring in MeOH (1 mL). The crude product was concentrated and purified by FCC (4% to 6% MeOH in CH) ₂ Cl ₂ In (c) to give the product as a white amorphous solid (9.5 mg, 77%). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.04(d,J＝8.2Hz,1H),7.33(dt,J＝5.2,2.6Hz,2H),7.27–7.18(m,4H),7.04(d,J＝1.8Hz,1H),5.38(s,2H),3.44(s,3H),2.96(q,J＝7.6Hz,2H),2.56(d,J＝7.2Hz,2H),2.00–1.81(m,1H),1.34(t,J＝7.6Hz,3H),0.92(d,J＝6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ161.1(d, ¹ J _C-F ＝246.3Hz),158.5,150.6,147.3,144.9,139.9,139.3,133.5,130.6,130.3(d, ³ J _C-F ＝4.0Hz),129.6,127.1,122.7,122.6,122.3(d, ² J _C-F ＝14.9Hz),118.1(d, ² J _C-F ＝22.1Hz),52.7,45.8,45.5(d, ³ J _C-F ＝3.6Hz),31.3,22.6,20.0,11.6。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-120.48(dd,J＝11.0,7.3Hz)。HRMS(ESI ⁺ )：C ₂₄ H ₂₉ FN ₃ O ₄ S ⁺ Calculated values: [ M+H ]] ⁺ 474.1863; found values: 474.1863.

example 16

(4 '- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -5-isobutyl- [1,1' -biphenyl)]-2-yl) sulphonyl 2-hydroxy ethyl carbamate

(a)1- (4-bromobenzyl) -2- (tert-butyl) -1H-imidazole

NaH (0.460 g,12.0mmol,1.5 eq.) was added to a stirred solution of 2-tert-butyl-1H-imidazole (0.993 g,8.00mmol,1 eq.) in DMF (0.27M) at 0deg.C. After 20min, 4-bromobenzyl bromide (2.00 g,8.00mmol,1 eq.) was added. The resulting mixture was warmed to ambient temperature and stirred overnight, then quenched with water (15 mL). The product was extracted with ethyl acetate (3X 25 mL). The combined organic layers were washed with brine (5X 20 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo to give the product as a pale yellow crystalline solid (2.34 g, yield>99%) purity of>95％。 ¹ H-NMR (400 MHz, chloroform-d) delta 7.48 (d, J=8.5 Hz, 2H), 7.08-6.98 (m, 1H), 6.96-6.85 (m, 2H), 6.71 (d, J=1.4 Hz, 1H), 5.27 (s, 2H), 1.42 (s, 9H).

N-butyllithium (7.59 mL,19.0mmol,4.74 eq.) was added dropwise to a stirred solution of N-tert-butyl-4-isobutyl-benzenesulfonamide (1.08 g,4.00mmol,1 eq.) in THF at-78deg.C. The resulting pale-yellow solution was stirred at-78℃for 30min, followed by 45min at 0 ℃. The reaction mixture was cooled to-78 ℃ and triisopropyl borate (2.71 ml,11.7mmol,2.94 eq.) was added dropwise. After 15min, the solution was warmed to 0 ℃ and stirred for a further 45min during which time the formation of a white precipitate was observed. Hydrochloric acid (25 ml,2m aqueous solution) was added and the reaction mixture was stirred for 15min. The resulting clear solution was partially evaporated, diluted with water (10 mL), and the product was taken up in CH ₂ Cl ₂ (3X 25 mL) extraction. The combined organic layers were dried over MgSO ₄ Dried, and concentrated to give a viscous yellow oil. The crude boric acid was dissolved in DMSO (2 mL) and toluene (30 mL). Methyliminodiacetic acid (0.696 g,4.73mmol,1.18 eq.) was added and the mixture refluxed for 3h. The reaction was brought to ambient temperature, diluted with ethyl acetate and washed with hydrochloric acid (3×50ml,0.1m aqueous). The organic phase was subjected to MgSO ₄ Dried, and concentrated to give the crude product as a yellow solid. The crude product was purified by FCC (10% to 100% ethyl acetate in isohexane) to give the product as a white amorphous solid (0.92 g, 54% yield). ¹ H-NMR (400 MHz, chloroform-d) delta 7.42 (d, j=3.7 hz, 1H), 6.68 (d, j=3.7 hz, 0H), 4.46 (s, 1H), 2.69 (d, j=7.1 hz, 2H), 2.07-1.76 (m, 1H), 1.28 (s, 9H), 0.95 (d, j=6.6 hz, 6H).

(c)4'- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -5-isobutyl- [1,1' -biphenyl]-2-sulfonamides

1- [ (4-bromophenyl) methyl group]2-tert-butyl-benzimidazole (0.293 g,1.00mmol,1 eq), N- (tert-butyl) -4-isobutyl-2- (6-methyl-4, 8-dioxo-1, 3,6, 2-dioxaborane-2-yl) benzenesulfonamide (0.4476 g,1.05mmol,1.05 eq), potassium carbonate (0.415 g,3.00mmol,3 eq.) and tetrakis (triphenylphosphine) palladium (0) (57.8 mg,0.50mmol,0.05 eq.) were suspended in a mixture of degassed toluene (6 mL), etOH (2 mL) and water (1 mL). The reaction mixture was stirred in a sealed microwave vial at 120 ℃ for 60min under microwave irradiation and then allowed to cool to ambient temperature. The reaction was quenched with water (10 mL), extracted with ethyl acetate (2×25 mL), and the combined organic layers were washed with brine (25 mL), over anhydrous Na ₂ SO ₄ Dried, and concentrated to give a yellow viscous oil. The crude product was dissolved in trifluoroacetic acid (12 mL) and stirred at 45 ℃ for 16h. The reaction mixture was quenched with water (10 mL) and the product was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ Dried, and concentrated. The crude product was purified by FCC (on CH ₂ Cl ₂ From 0% to 10% MeOH) to afford the product as a white amorphous solid (0.260 g, 61% yield in two steps). ¹ H-NMR (400 MHz, chloroform-d) delta 8.00 (dd, j=8.2, 1.4hz, 1H), 7.53-7.47 (m,2H),7.45(d,J＝1.8Hz,1H),7.28(d,J＝1.8Hz,1H),7.17(d,J＝8.0Hz,2H),7.06(d,J＝1.8Hz,1H),7.02(d,J＝1.8Hz,1H),5.50(s,2H),4.68(s,br.2H),2.54(d,J＝7.2Hz,2H),1.99–1.83(m,1H),1.59(s,9H),0.92(d,J＝6.6Hz,6H)。

(d)((4 '- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -5-isobutyl- [1,1' -biphenyl)]-2-yl) Sulfonyl) carbamic acid methyl ester

The crude sulfonamide (55.3 mg,0.13mmol,1 eq.) was dissolved in DCM (0.05M). Triethylamine (90. Mu.L, 0.65mmol,5 eq.) and methyl chloroformate (11. Mu.L, 0.14mmol,1.1 eq.) were added. The reaction mixture was stirred at room temperature for 2h. The reaction mixture was diluted with ethyl acetate (10 mL), extracted with ethyl acetate (3X 5 mL), washed with brine (3 mL), and concentrated over MgSO ₄ Dried and concentrated. The crude product was purified by HPLC (30% to 70% ACN in water containing 0.05% formic acid). The product was obtained after lyophilization as a white amorphous solid (17 mg, 27% yield). ¹ H-NMR (500 MHz, acetone-d) ₆ )δ8.11(d,J＝8.2Hz,1H),7.43(dd,J＝8.3,1.8Hz,1H),7.41–7.36(m,2H),7.18–7.09(m,3H),6.91(d,J＝1.3Hz,1H),6.83(d,J＝1.3Hz,1H),5.48(s,2H),3.54(s,2H),2.62(d,J＝7.2Hz,2H),2.02–1.91(m,1H),1.41(s,9H),0.94(d,J＝6.6Hz,6H)。 ¹³ C-NMR (126 MHz, acetone-d) ₆ )δ154.6,152.7,148.1,141.5,139.7,138.6,136.7,134.0,131.1,130.3,129.1,126.8,126.7,122.8,53.1,51.2,45.3,34.1,30.8,30.4,22.6。C ₂₆ H ₃₄ N ₃ O ₄ S ⁺ [M+H] ⁺ HRMS (ESI) calculated 484.2270, found 484.2269.

(e)(4 '- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -5-isobutyl- [1,1' -biphenyl)]-2-yl) sulphone Acyl carbamic acid 2-hydroxy ethyl ester

The title compound was synthesized using the byproduct from step (d) above (37.2 mg,76.9 μmol) in anhydrous ethylene glycol (0.5 mL) at 120 ℃ for 10 minutes under MW irradiation. The reaction mixture was diluted with EtOAc (5 mL) and brine (5 mL) was added. The product was extracted with EtOAc (3×5 mL) and the combined organic layers were washed with brine (5×5 mL). The crude product was concentrated and purified by FCC (on CH ₂ Cl ₂ 3% to 8% MeOH) to afford the product as a white amorphous solid (32.0 mg, 81% yield). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.06(d,J＝8.2Hz,1H),7.44–7.38(m,2H),7.30(dd,J＝8.2,1.8Hz,1H),7.21–7.14(m,4H),7.03(d,J＝1.8Hz,1H),5.56(s,2H),3.93–3.84(m,2H),3.61–3.52(m,2H),2.55(d,J＝7.2Hz,2H),1.97–1.83(m,1H),1.52(s,9H),0.92(d,J＝6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ157.6,154.9,147.2,141.8,141.4,139.0,136.0,133.9,131.1,130.7,129.2,127.4,124.8,122.3,67.9,61.3,52.7,45.8,34.7,31.3,29.4,22.7。

Example 17

(4 ' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl)]-2- Group) sulfonylcarbamic acid 2-hydroxyethyl ester

The title compound was synthesized by stirring the final compound (30.0 mg, 55.2. Mu. Mol) obtained according to the preparation described in example 4 in anhydrous ethylene glycol (0.5 mL). The crude product was purified by FCC (on CH ₂ Cl ₂ 4% to 10% meoh) to afford the product as a white amorphous solid (17.2 mg, 59% yield). ¹ H-NMR (400 MHz, methanol-d) ₄ )δ8.06(d,J＝8.2Hz,1H),7.34(dd,J＝8.2,1.8Hz,1H),7.29–7.17(m,4H),7.15–7.07(m,1H),7.06(d,J＝1.8Hz,1H),5.59(s,2H),3.97–3.81(m,2H),3.64–3.49(m,2H),2.56(d,J＝7.2Hz,2H),1.98–1.84(m,1H),1.55(d,J＝1.2Hz,9H),0.93(d,J＝6.6Hz,6H)。 ¹³ C-NMR (101 MHz, methanol-d) ₄ )δ160.9(d, ¹ J _C-F ＝246.7Hz),157.7,154.8,147.3,144.7(d, ³ J _C-F ＝8.6Hz),140.0(d, ⁴ J _C-F ＝1.8Hz),139.2,133.5,130.7,130.0(d, ³ J _C-F ＝3.9Hz),129.7,127.1(d, ⁴ J _C-F ＝3.2Hz),124.3,122.6(d, ² J _C-F ＝14.4Hz),122.2,118.0(d, ² J _C-F ＝22.0Hz),67.8,61.3,47.5(d, ³ J _C-F ＝4.1Hz),45.8,34.7,31.3,29.2,22.7。 ¹⁹ F-NMR (376 MHz, methanol-d) ₄ )δ-120.21(dd,J＝11.0,7.8Hz)。

Example 18

(5-isobutyl-4 '- ((2-methyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl)]-2-yl) sulphonyl-ammonia Methyl radical formate

To 5-isobutyl-4 '- ((2-methyl-1H-imidazol-1-yl) methyl) - [1,1' -biphenyl ]]2-sulfonamide (109 mg,0.284mmol,1 eq; synthesized according to example 35 except 2-ethyl-1H-imidazole was used instead of CH in step (a) ₂ Cl ₂ To the solution in (2 mL) was added triethylamine (198. Mu.L, 1.42mmol,5 eq.). The resulting white suspension was cooled to 0deg.C and butyl chloroformate (38.1 μL,0.298mmol,1.05 eq.) was added dropwise. After 10min, the reaction was brought to ambient temperature and stirred for a further 5min. The reaction was quenched with water, diluted with EtOAc, and the product was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (3 mL), and dried over Na ₂ SO ₄ Dried, and concentrated. The crude butyl carbamate was dissolved in MeOH (2 mL) and heated at 120 ℃ for 20min under MW irradiation. The crude product was concentrated and passed through FCC (2% to 6% MeOH in CH) ₂ Cl ₂ In (a) gradient) to give the product as a white amorphous solid (57.0 mg, 45% yield in two steps). ¹ H-NMR (400 MHz, methanol-d) ₄ Chloroform-d) delta 8.06 (d, j=8.1 hz, 1H), 7.42-7.36 (m, 2H), 7.28 (dd, j=8.2, 1.8hz, 1H), 7.24-7.14 (m, 3H), 7.07-6.98 (m, 2H), 5.23 (s, 2H), 3.48 (s, 3H), 2.53 (d, j=7.1 hz, 2H), 2.02-1.81 (m, 1H), 0.90 (d, j=6.6 hz, 6H). ¹³ C-NMR (101 MHz, methanol-d) ₄ Chloroform-d) delta 156.8,147.1,145.5,141.4,140.9,137.9,134.8,133.6,130.8,130.4,129.0,127.4,122.8,122.1,52.8,50.9,45.6,30.8,22.6,11.8.

Bioassays

The biological activity of example compounds as described herein above (and compared to C21) was assessed using the following bioassays.

Metabolic stability

Human liver microsomes at a concentration of 0.5mg/mL in PBS were incubated at 37℃for 70min with or without 1mM NADPH. After 10 minutes the test compound was added to give a final concentration of 1. Mu.M. Samples were taken at 0, 5, 15 and 60 minutes and added to the acetonitrile containing tube to stop the reaction and terfenadine was added as an internal standard. After centrifugation at 10000 Xg for 5 minutes, the supernatant was diluted 1:1 with 1% formic acid. The samples were separated on reverse phase columns and detected by triple quadrupole MSMS (Agilant model 6540). The concentrations of the parent compound at different time points were measured by external standard curves using terfenadine as internal standard, and the initial metabolic rate in the presence or absence of NADPH was calculated.

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Binding to AT1 and AT2 receptors

The binding of compounds to human recombinant AT2 and AT1 receptors was evaluated using radioscintillation assays according to the Eurofins protocols ITEM26 and ITEM 24.

Briefly, for IC ₅₀ The recombinant proteins were incubated with the test compounds (1 nM, 10nM, 100nM and 1000nM for the AT2 receptor; 1. Mu.M and 10. Mu.M for the AT1 receptor) for 2 to 4h AT 37℃as measured. Ki values for AT2 receptors were determined using seven-point dose response curves. Will be ¹²⁵ I (sar 1, IIe 8) -AT-II is used as a ligand for the AT1 receptor, and ¹²⁵ ICGP 42112A is used as a ligand for AT2 receptor. The percent inhibition of control specific binding was calculated as 100- (measured specific binding/control specific binding) x 100.

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Asterisks indicate the average of the data obtained from the two runs.

CYP inhibition

Inhibition of major cytochrome P450 isoforms (CYP 1A, CYP B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A4& 5) by 10 μm compounds was evaluated using an isoform specific substrate incubated with human liver microsomes (Eurofins protocol ITEMG 232). The following substrates were used; CYP1A phenacetin, CYP2B6 bupropion, CYP2C8 taxol and amodiaquine, CYP2C9 diclofenac, CYP2C19 omeprazole, CYP2D6 dextromethorphan, CYP3A midazolam and testosterone.

At the end of incubation, metabolite formation was monitored by HPLC-MS/MS as a response to peak area.

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	CYP3A4 Midazolam inhibition%	CYP3A4&5 testosterone inhibition%
			Example 4	18.1	23.5
Example 5	3.8	15.1
			Example 6	19.9	31.0
Example 7	9.7	29.7
			Example 8	-4.7	19.4
Example 9	-4.9	17.5
			Example 10	11.5	24.5
Example 11	5.6	30.5
			Example 12	8.6	12.6
Example 13	9.3	14.5
			Example 14	-4.2	21.9
Example 15	-5.3	18.4
			C21	95	94

Abbreviations (abbreviations)

The following abbreviations may be used herein.

DBU 1, 8-diazabicyclo (5.4.0) undec-7-ene

DCM dichloromethane

DMF dimethylformamide

FCC flash column chromatography

HPLC high performance liquid chromatography

MeCN acetonitrile

MeOH methanol

MW microwave

NMR nuclear magnetic resonance

THF tetrahydrofuran

TLC thin layer chromatography

Claims

1. A compound of the formula I,

wherein:

R ² and R is ³ Each independently represents H or C _1-6 Alkyl group, itOptionally substituted with one or more halogen atoms; y is Y ¹ 、Y ² 、Y ³ And Y ⁴ Independently represents-CH-or-CF-;

z represents-O-, -N (R) ⁵ ) -or a direct bond;

R ⁴ represent C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, the alkyl portion of each of which is optionally substituted with one or more substituents selected from-OH and halogen, or

x represents ch= CH, CH, N, NH, O or S;

y represents ch= CH, CH, N, NH, O or S,

the conditions are as follows:

(a) X and Y are not the same and are not the same,

(b) When X represents ch=ch, then Y represents only CH,

(c) When Y represents ch=ch, then X represents only CH, and

(d) When Y represents O or S, then X does not represent CH or ch=ch;

R ⁶ represent C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 alkoxy-C _1-6 Alkyl groups, each of which is optionally substituted with one or more halogen atoms; and is also provided with

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein Z represents-O-or-N (R) ⁵ )-。

3. The compound of claim 1, wherein R ¹ Represents methyl, ethyl, isopropyl, or tert-butyl, optionally substituted by up to three fluorine atoms, or R ¹ Represents OR ⁷ 。

4. The compound of any one of the preceding claims, wherein R ² And R is ³ Independently represents H or methyl.

5. The compound of any one of the preceding claims, wherein R ⁴ Represents C optionally substituted by one or more-OH groups and/or fluorine atoms _1-4 An alkyl group; a phenyl group; a benzyl group; 2-methylpyridinyl, 2-methylthiophenyl, or 2-methylfuryl.

6. The compound of any one of the preceding claims, wherein R ⁵ Represents H, methyl, ethyl, n-propyl, n-butyl, or isobutyl.

7. A compound according to any one of the preceding claims, wherein X represents CH and Y represents ch=ch, or X represents N and Y represents S.

8. The compound of any one of the preceding claims, wherein R ⁶ Represents n-propyl, n-butyl, or isobutyl.

9. The compound of any one of the preceding claims, wherein R ⁷ Represents H or methyl.

10. A compound according to any one of the preceding claims, wherein X represents CH and Y represents S.

11. A compound according to any one of the preceding claims, which is:

4'- ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -5-isobutyl-N- ((thiophen-2-ylmethyl) carbamoyl) - [1,1' -biphenyl ] -2-sulfonamide, or

(4 ' - ((2- (tert-butyl) -1H-imidazol-1-yl) methyl) -3' -fluoro-5-isobutyl- [1,1' -biphenyl ] -2-yl) sulfonylcarbamic acid 2-hydroxyethyl ester,

12. A compound according to any one of claims 1 to 10 for use as a medicament.

13. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 10 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

14. A compound according to any one of claims 1 to 10 for use in the treatment of autoimmune diseases, viral respiratory infections and/or pneumonia caused thereby, fibrotic diseases, chronic kidney diseases, pulmonary arterial hypertension, heart failure and/or myocardial infarction.

15. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of autoimmune diseases, viral respiratory infections and/or pneumonia caused thereby, fibrotic diseases, chronic kidney diseases, pulmonary arterial hypertension, heart failure and/or myocardial infarction.

16. A method of treating autoimmune diseases, viral respiratory infections and/or pneumonia caused thereby, fibrotic diseases, chronic kidney diseases, pulmonary hypertension, heart failure and/or myocardial infarction, comprising administering a compound according to any one of claims 1 to 10 to a patient in need of such treatment.

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

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

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

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

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

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

23. The compound for use according to claim 13, the use according to claim 14 or the method of treatment according to claim 15, wherein the viral respiratory infection results in a virus-induced pneumonia.

24. A process for preparing a compound of formula I according to any one of the preceding claims, the process comprising:

(i) The compound of the formula II is allowed to react,

wherein R is ¹ 、R ² 、R ³ 、R ⁶ 、Y ¹ 、Y ² 、Y ³ 、Y ⁴ X and Y are as defined in any one of claims 1 to 10, and L represents C _1-6 Alkyl or aryl, with a compound of formula III,

NHR ⁴ R ⁵ III

wherein R is ⁴ And R is ⁵ The reaction according to any one of claims 1 to 10; or alternatively

(ii) For those wherein Z represents-N (R ⁵ ) -and R ⁵ A compound of formula I, which represents H, reacting a compound of formula IV,

wherein R is ¹ 、R ² 、R ³ 、R ⁶ 、Y ¹ 、Y ² 、Y ³ 、Y ⁴ X and Z are as defined in any of claims 1 to 10, with a compound of formula V,

R ⁴ -N＝C＝O V

or a compound of the formula VI,

wherein X is ¹ Is a suitable leaving group, and wherein in each case R ⁴ The reaction according to any one of claims 1 to 10;

(iii) For compounds of formula I wherein Z represents-O-, reacting said compounds of formula II with a compound of formula VII,

R ⁴ OH VII

wherein R is ⁴ The reaction according to any one of claims 1 to 10.