Novel imidazole compounds, synthesis method thereof, and uses thereof

Abstract

To provide novel pharmaceutical agents and a preparation method thereof.SOLUTION: The present invention provides compounds represented by general formula I in the figure, and a preparation method thereof. The compounds of the invention are useful in the treatment and prevention of diseases related to cellular stress mediated immune regulation and homeostasis loss, including autoimmune diseases, cancers, metabolic diseases, dermatological diseases, cardiovascular diseases, and neurodegenerative diseases.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS REFERENCE TO RELATED APPLICATIONS: This application is the subject of International Patent Application No. PCT / IB2019 / 0 filed on November 1, 2019. § 371 of the national stage patent application No. 59389, filed on November 1, 2018. Benefit of priority of Indian Patent Application No. 201821041355 is claimed.

[0002] Field of the invention: The present invention relates to a novel pharmaceutical formulation and a method for producing the same. Compounds useful for the treatment and prevention of diseases associated with loss of immune regulation and homeostasis are disclosed. This includes autoimmune diseases, cancer, metabolic diseases, skin diseases, cardiovascular diseases and neurodegenerative diseases. Disease can be given. [Background technology]

[0003] The immune system is a collection of specialized cells and chemicals that fight against infectious agents such as bacteria and viruses. Autoimmune diseases occur when the human immune system mistakenly attacks the body's own cells and tissues. Autoimmune diseases are divided into two broad categories: those that affect only one organ "systemic" diseases, which affect multiple organs or body systems; To be classified.

[0004] Autoimmune diseases vary in severity depending on which organs of the body are attacked and to what extent. Women are more susceptible than men, especially during childbirth. It has also been observed that the age at which the condition develops is more pronounced. It is believed that...

[0005] Autoimmune diseases are characterized by an abnormal immune response involving either cells or antibodies. The adaptive immune response, including T cell-mediated immunity, and antibody-mediated immunity, Both immune and humoral responses, including the immune system, are involved in the induction and progression of autoimmune diseases.

[0006] The triggers of autoimmunity are poorly understood. Until recently, research into the pathogenesis of autoimmune diseases Most of the research has focused on the role of immune components. The synergistic role of target tissues in spreading immunity is emphasized. It was revealed that the cause was endoplasmic reticulum stress (ER stress). synthesis, folding and quality control, antigen processing and presentation, calcium regulation and redox Major subcellular microorganisms involved in important functions involved in cellular homeostasis, including cellular balance The physiological activity of the ER is tightly regulated by processes both inside and outside the cell. Damage to the ER triggers a stress response called ER stress, which activates intracellular signaling pathways. Thus, it is the unfolded protein response (UNRP) that is targeted to manage stress conditions. However, uncontrolled ER stress is a major risk factor for cancer, metabolic diseases, and It has been implicated in many pathological conditions, including skin diseases, cardiovascular diseases, and neurodegenerative diseases. In particular, abnormal regulation of ER stress is associated with early events in autoimmunity. Misfolding of proteins or alterations in antigen processing can lead to the formation of immunogenic neoantigens. In addition, stressed cells are less susceptible to programmed cell death. Type I diabetes, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, lupus, celiac disease, In diseases such as chronic anemia, tolerance mechanisms in autoreactive cells that sustain autoimmunity are not fully supported. The mechanism of endoplasmic reticulum stress is essential for the functioning of the epidermis, an organ that is constantly exposed to the external environment. It is of particular interest in skin physiology. Indeed, deregulation of the ER stress mechanism is a key factor in the pathogenesis of vitiligo, dry skin, and other skin diseases. It is associated with several autoimmune skin diseases, such as sclerosis, systemic lupus erythematosus, pemphigus, and scleroderma. Thus, targeting ER stress mechanisms may be a potential treatment for autoimmune diseases. It becomes a therapeutic target. Summary of the Invention [Problem to be solved by the invention]

[0007] Most of the existing treatments for autoimmune diseases are targeted and effective. It has been observed that, because of the lack of evidence, they can only aim to provide symptomatic benefit to patients. Administration of steroids is one of the most common treatments. However, long-term steroid use Its usefulness is limited by its non-specific nature and associated side effects. is an autoimmune disease in which dysregulation of immune function leads to increased levels of inflammatory cytokines within the lesions. Therefore, topical corticosteroids are the most common first-line treatment. Patients are also encouraged to get exposure to sunlight to increase melanin synthesis. Phototherapy (narrowband UVB or 311 nm laser) is generally used for better results. However, many patients are unable to achieve the desired level of pigmentation. If the dermatologist cannot inform you of the possibility of success of the treatment you have performed, The patient remains uncertain about the duration and outcome of treatment. New therapeutic approaches targeting relevant pathways involved in induction of inflammatory bowel disease are needed. Embodiments of the present invention provide chemical entities that modulate cellular stress. More specifically, The chemical protects cells from stress-mediated death, thus resulting in immune dysregulation. The chemicals thus disrupt the cascade of events, and thus play a key role in the prevention and treatment of immune-related diseases and disorders. This may result in treatment. [Means for solving the problem]

[0008] Summary of the Invention The present invention relates to a compound having the general formula I:

[0009] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen, linear or branched alkyl, linear or branched alkenyl, linear or branched alkoxyalkyl, phenyl, aryl, aralkyl, alkoxyalkyl, alkoxyaryl, aromatic or aliphatic heterocycle containing at least one heteroatom selected from the group of O, N, and S; any two adjacent R groups form a 5-6 membered aromatic or aliphatic ring containing at least one heteroatom selected from the groups O, N and S; R 6 are independently selected from hydrogen, linear or branched C1-C5 alkyl; X is selected from CH2 or C=O; where if X is CH2, then Y is C=O, and When X is C=O, Y does not exist); R 7 and R 8are each independently selected from hydrogen, linear or branched alkyl, linear or branched aralkyl, linear or branched alkenyl, linear or branched alkynyl, which together form a 3-7 membered aromatic or aliphatic heterocycle containing at least one heteroatom selected from O, N, and S, -CH2(CH2)nNRcRd (wherein n is 0-3, and Rc and Rd are both independently selected from alkyl), or form a 3-7 membered aromatic or aliphatic heterocycle containing at least one heteroatom selected from the group of O, N, and S). and their stereoisomerically pure or mixed forms, racemic mixtures, geometric isomers, tautomers, pharma- ceutically acceptable salts, hydrates, solvates, solid forms, and mixtures thereof. All the substituents R of the above general formula I 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may be further substituted or unsubstituted.

[0010] The present invention also relates to a compound represented by the following general formula I

[0011] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen, linear or branched alkyl, linear or branched alkenyl, linear or branched alkoxyalkyl, phenyl, aryl, aralkyl, alkoxyalkyl, alkoxyaryl, aromatic or aliphatic heterocycle containing at least one heteroatom selected from the group of O, N, and S; any two adjacent R groups form a 5-6 membered aromatic or aliphatic ring containing at least one heteroatom selected from the groups O, N and S; R 6 are independently selected from hydrogen, linear or branched C1-C5 alkyl; X is selected from CH2 or C=O; where if X is CH2, then Y is C=O, and When X is C=O, Y does not exist); R 7 and R 8 are each independently selected from hydrogen, linear or branched alkyl, linear or branched aralkyl, linear or branched alkenyl, linear or branched alkynyl, which together form a 3-7 membered aromatic or aliphatic heterocycle containing at least one heteroatom selected from O, N, and S, -CH2(CH2)nNRcRd (wherein n is 0-3, and Rc and Rd are both independently selected from alkyl), or form a 3-7 membered aromatic or aliphatic heterocycle containing at least one heteroatom selected from the group of O, N, and S). and processes for preparing the compounds of the formula: DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present invention relates to a compound having the following general formula I:

[0013] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5are each independently selected from hydrogen, halogen, linear or branched alkyl, linear or branched alkenyl, linear or branched alkoxyalkyl, phenyl, aryl, aralkyl, alkoxyalkyl, alkoxyaryl, aromatic or aliphatic heterocycle containing at least one heteroatom selected from the group of O, N, and S; any two adjacent R groups form a 5-6 membered aromatic or aliphatic ring containing at least one heteroatom selected from the groups O, N and S; R 6 are independently selected from hydrogen, linear or branched C1-C5 alkyl; X is selected from CH2 or C=O; where if X is CH2, then Y is C=O, and When X is C=O, Y does not exist); R 7 and R 8 are each independently selected from hydrogen, linear or branched alkyl, linear or branched aralkyl, linear or branched alkenyl, linear or branched alkynyl, which together form a 3-7 membered aromatic or aliphatic heterocycle containing at least one heteroatom selected from O, N, and S, -CH2(CH2)nNRcRd (wherein n is 0-3, and Rc and Rd are both independently selected from alkyl), or form a 3-7 membered aromatic or aliphatic heterocycle containing at least one heteroatom selected from the group of O, N, and S). and their pure or mixed stereoisomers (diastereomers, enantiomers), racemic mixtures, geometric isomers, tautomers, pharma- ceutically acceptable salts, hydrates, solvates, solid forms, and mixtures thereof. All substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may be further substituted or unsubstituted.

[0014] The present invention discloses compounds of general formula I, where X is selected from C=O or CH2. In particular, when X is CH2, Y is C=O. Furthermore, when X is a carbonyl group, i.e., C= When N is O, there is no Y substitution on N, i.e., Y is not present at all. , a compound of general formula I, 1 , R 2 , R 3 , R 4 , R 5 is preferably Cl, Br , I and F), the present invention discloses compounds of the general formula I (formula Medium, R 6 The present invention discloses a compound in which R 6 However, preferably The present invention discloses a compound of general formula I, which may be a chiral compound.

[0015] Pharmaceutically acceptable salts of the compounds of the present invention include salts of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, Benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, formic acid Muamidinesulfonic acid, naphthalenedisulfonic acid, formic acid, fumaric acid, acetic acid, propionic acid , lactic acid, malic acid, citric acid, maleic acid, benzoic acid, malonic acid, tartaric acid, oxalic acid, co Vinyl chloride, or sodium, potassium, calcium, magnesium, ammonium The above group is used as an active ingredient, together with one or more pharma- ceutically acceptable carriers, diluents or excipients. Together, they are selected.

[0016] In the context of the present invention, the term "alkyl" includes methyl, trifluoromethyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Saturated, linear, branched or cyclic alkyl groups, especially those having 1 to 5 carbon atoms, such as pentyl, It denotes a saturated or unsaturated hydrocarbon group.

[0017] The term "alkenyl" refers to a group that is a carbon-carbon double bond, straight-chain, branched, halogenated, or especially carbon Unsaturated carbonized compounds having 2 to 5 ring atoms and one or more carbon-carbon double bonds. This refers to a hydrogen radical.

[0018] The term "alkynyl" refers to one or more carbon-carbon triple bonds, particularly those having 2 to 5 carbon atoms. An unsaturated hydrocarbon radical that may be linear, branched, halogenated, or cyclic.

[0019] The term "alkoxyalkyl" refers to an alkyl group attached to an oxygen atom forming an ether linkage. The alkyl chain corresponds to the above definition, and includes methoxy, trifluoromethoxy, ethoxy, and the like. , n-propyloxy, isopropyloxy, n-butoxy, isobutoxy, tert -butoxy, sec-butoxy, and other alkyl groups.

[0020] The term "aralkyl" refers to an aryl-substituted aryl group whose hydrocarbon group contains about 2 to 5 carbon atoms. The term "alkyl hydrocarbon group" refers to an alkyl group.

[0021] The term "cycloalkyl" refers to an alkyl group, as defined above, having at least one ring, e.g. For example, cycloalkyl groups having 3 to 8 carbon atoms: cyclopropyl, cyclobutyl, cyclo pentyl, cyclohexyl, cycloheptyl, and cycloctyl).

[0022] The term "aryl" preferably contains 6 to 10 carbon atoms, possibly including N, O or S. means an aromatic group interrupted by one or more heteroatoms selected from Specifically, they are referred to as "heteroaryls." They are generally monocyclic or bicyclic, and are preferably or those having 6 to 14 carbon atoms, such as phenyl, α-naphthyl, and β-naphthyl.

[0023] The term "alkoxyaryl" refers to an aryl group bonded to an oxygen atom via an ether linkage. It refers to an alkyl group formed by combining two or more groups.

[0024] The term "heterocycle" refers to an aliphatic aromatic ring, preferably 3 to 7 membered, including O, N and S. as defined above, interrupted by one or more heteroatoms selected from among It refers to any cycloalkyl group.

[0025] The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0026] The terms "effective amount," "pharmacologically effective amount," or "therapeutically effective amount" refer to an amount that is sufficient to treat a condition or one of its symptoms. or to bring about a further improvement or alteration in the condition or condition and / or to prevent the onset of a disease or disorder. and the normal clinical progression of the condition, the body surface area affected by the clinical condition. The dosage may be determined by the volume of the drug administered, as well as the type and concentration of the formulation administered.

[0027] The acronym "HATU" stands for 1-[bis(dimethylamino)methylene]-1H-1,2,3 -Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hexafluoro The acronym HBTU " is 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl- tetramethylbenzotriazole hexafluorophosphate The acronym "EDC" stands for 1-ethyl-3-(3-dimethylaminopropyl) The acronym "DMAP" refers to dimethylaminopyridine, The acronym "DMF" stands for dimethylformamide, and the acronym "TFA" stands for trifluoroacetate. The acronym "DCM" refers to dichloromethane, and the acronym "DIPEA" refers to Hun N,N-diisopropylethylamine, also known as ig base.

[0028] Further embodiments of the present invention include compounds having the following general formula I:

[0029] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen, linear or branched alkyl, linear or branched alkenyl, linear or branched alkoxyalkyl, phenyl, aryl, aralkyl, alkoxyalkyl, alkoxyaryl, aromatic or aliphatic heterocycle containing at least one heteroatom selected from the group of O, N, and S; any two adjacent R groups form a 5-6 membered aromatic or aliphatic ring containing at least one heteroatom selected from the groups O, N and S; R 6 are independently selected from hydrogen, linear or branched C1-C5 alkyl; X is selected from CH2 or C=O; where if X is CH2, then Y is C=O, and When X is C=O, Y does not exist); R 7 and R 8are each independently selected from hydrogen, linear or branched alkyl, linear or branched aralkyl, linear or branched alkenyl, linear or branched alkynyl, which together form a 3-7 membered aromatic or aliphatic heterocycle containing at least one heteroatom selected from O, N, and S, -CH2(CH2)nNRcRd (wherein n is 0-3, and Rc and Rd are both independently selected from alkyl), or form a 3-7 membered aromatic or aliphatic heterocycle containing at least one heteroatom selected from the group of O, N, and S). The present invention discloses methods for preparing compounds represented by the formula:

[0030] The method for preparing the compound of formula I is as follows: (a) Chlorobenzamidine hydrochloride in the presence of 1,3-dihydroxyacetone dimer reacting to obtain imidazole compound II; (b) reacting the imidazole moiety formed in step (a) in the presence of a suitable reagent for chlorination; This gives compound III, which is then cyanated in the presence of a suitable reagent to give compound IV. The process of; (c) reacting said compound IV to hydrolyze the imidazole moiety containing the carboxylic acid V; generating a (d) reacting compound V with a desired reagent to effect amide coupling to obtain the compound of formula (I) producing a compound of formula (I); A method comprising: In some cases, (e) reacting the compound IV formed in step (b) with a suitable reagent to obtain the compound forming VII; (f) reacting said compound VII with a desired reagent to effect amide coupling to obtain the compound of formula producing the compound of formula (I); Includes.

[0031] An embodiment of the present invention is a method for preparing a compound of formula I comprising the steps of: (a) Chlorobenzamidine hydrochloride or is reacted with dichlorobenzamidine hydrochloride to give imidazole compound II or XVI. The process of; (b) reacting the imidazole compound II or XVI with a suitable reagent to obtain compound X or obtaining XVII; (c) reacting the imidazole compound X or XVII with a nitro group in the presence of a suitable reagent. introducing to obtain compound XI or XVIII; (d) hydrogenating the compound XI or XVIII in the presence of a suitable reagent to obtain compound X obtaining II or XIX; (e) reacting compound XII or XIX with Fe, NH4OH, and then di-tert -butyl dicarbonate is added and amination is performed to obtain compound XIII or XX. process; (f) treating the compound XIII or XX with a desired reagent by amide coupling to obtain a compound of the formula obtaining compound I; Includes.

[0032] Furthermore, the present invention relates to compounds of formula (I) and their stereoisomers (diastereomers). -, enantiomers) pure or mixed, racemic mixture, geometric isomers, tautomers, pharmaceutical The present invention discloses physiologically acceptable salts, hydrates, solvates, solid forms, and mixtures thereof.

[0033] Without being bound by theory, the present inventors have demonstrated that ER stroke in cells and / or in vivo We have contemplated novel and inventive methods for modulating the Res pathway.

[0034] Thus, the present invention unexpectedly and effectively affects the ER stress pathway in cells. The present invention discloses compounds of general formula I which have been found to be effective in treating rheumatoid arthritis. The compounds are useful in the treatment and prevention of diseases associated with deregulation of cellular stress pathways. More specifically, it is assumed that the cause is ER stress. The disease in question is limited to the following: However, autoimmune diseases, cancer, tumors, metabolic disorders, neurodegenerative diseases, cardiovascular diseases, and pulmonary These include diseases induced by cell stress, including inflammatory bowel diseases, eye diseases and skin diseases.

[0035] The inventors have demonstrated that the compound may be useful in the treatment of skin diseases due to the prevention of stress-mediated melanocyte death. The present inventors have found uses for the presently disclosed compounds that may be useful in treating chronic conditions such as heart failure, stroke, and stroke.

[0036] The compounds of the present invention can be used to treat, but are not limited to, autoimmune diseases, cancer, tumors, metabolic disorders, neurodegeneration, Cellular stress-induced diseases, including cardiovascular, pulmonary, ophthalmic and skin diseases It is contemplated that these compounds may be used separately or in combination with other therapies to treat various illnesses.

[0037] Other embodiments of the present invention are directed to treating psoriasis, lupus, vitiligo, scleroderma, dermatomyositis, epidermolysis bullosa, waterlogged ulcers, and other skin diseases. This includes, but is not limited to, bullous pemphigoid, vitiligo, dermatitis, Koebner phenomenon, and other skin disorders. Including, but not limited to, the treatment and prevention of autoimmune diseases of the skin.

[0038] The present invention also provides a method for the preparation of a pharmaceutical composition comprising administering an effective amount of the compound orally, parenterally, rectally, topically, or intramuscularly. Intranasal, intravenous, transdermal, sublingual, intramuscular, subcutaneous, ocular, and others and further adapted to be administered by any suitable method of administration, including topical administration of and a pharma- ceutically acceptable carrier.

[0039] The present invention discloses compounds of formula I that are useful for the treatment and prevention of ER stress-related diseases. The compounds of the invention are useful in therapeutic formulations or compositions, as well as in inhibiting ER stress via all modes of administration. It may also be used for prophylactic purposes in the treatment of associated diseases.

[0040] For example, oral, parenteral, rectal, topical, intranasal, intravenous, transdermal, Suitable for administration by topical, sublingual, intramuscular, subcutaneous, ocular and other local administration.

[0041] The compositions containing an effective amount of a compound of formula (I) as an active ingredient may be administered orally, parenterally, rectally or topically. This includes intranasal, intravenous, transdermal, sublingual, intramuscular, subcutaneous, intraocular, and any other method of topical administration. They are also intended to be administered by any suitable route, including, but not limited to, Tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions and oral solutions or suspensions Opacities, injections, syrups, liquids, microemulsions, topical creams, ointments, suppositories, Unit dosage forms such as sachets, lozenges and pastilles, and suitable amounts of the compound of formula I The compounds may be formulated and administered as oil-in-water emulsions or multiple dosage forms.

[0042] Suitable pharmaceutical formulations also include tablets, capsules, pills, powders, granules, sustained release formulations for oral administration. sterile solutions or suspensions in any suitable form for administration, as well as transdermal They can also be prepared from sachets and dry powder inhalers.

[0043] An embodiment of the present invention is a method for treating a patient suffering from atopic dermatitis, comprising administering to a patient a therapeutically effective amount of one or more compounds of general formula (I), Stereoisomers (diastereomers, enantiomers) pure or mixed, racemic mixture, Any isomers, tautomers, pharma- ceutically acceptable salts, hydrates, solvates, solid forms, and the like. The present invention relates to a method for treating a subject exhibiting symptoms of an ER stress-related disease, the method comprising administering the mixture to a subject. Regarding.

[0044] An embodiment of the present invention is a method for treating a patient suffering from atopic dermatitis, comprising administering to a patient a therapeutically effective amount of one or more compounds of general formula (I), Stereoisomers (diastereomers, enantiomers) pure or mixed, racemic mixture, Any isomers, tautomers, pharma- ceutically acceptable salts, hydrates, solvates, solid forms, and the like. The present invention relates to a method for treating skin cancer by reducing stress-mediated cell death, comprising administering a mixture of the above-mentioned compounds to a skin cell. for the treatment of autoimmune diseases.

[0045] Another embodiment of the present invention is in particular a pharmaceutical composition comprising essentially one or more compounds of general formula I Medicinal compositions or formulations comprising administering a therapeutically effective amount of the pharmaceutical composition or formulation. The present invention relates to the treatment of autoimmune skin diseases by reducing cell death.

[0046] Another aspect of the present invention is a method for the preparation of a compound of general formula (I), or a stereoisomer thereof, in a medicament. (Diastereomers, enantiomers) pure or mixed, racemic mixture, geometric isomers, Tautomers, Pharmacologically Acceptable Salts, Hydrates, Solvates, Solid Forms, and Mixtures thereof The present invention relates to a method for treating a subject suffering from vitiligo.

[0047] The present invention provides a method for the preparation of a compound of formula (I) by means of a pharmaceutical composition comprising an effective amount of the compound together with a pharma- ceutical acceptable carrier. Treatment of autoimmune diseases by administering a compound of formula I) is contemplated.

[0048] The present invention further provides the preparation of a pharmaceutical composition comprising an effective amount of the compound together with a pharma- ceutically acceptable carrier. A manufacturing method is contemplated. In particular, further aspects of the invention include oral, parenteral, rectal, topical, intranasal, intravenous, transdermal, lingual The drug may be administered by any suitable method of administration, including intramuscular, subcutaneous, ocular, and other topical modes of administration. A pharmaceutical composition comprising an effective amount of a compound together with an effective amount of a carrier, further adapted to be administered to Regarding the preparation of

[0049] The present invention relates to compounds of the general formula (I), their stereoisomers (diastereomers, enantiomers, Thiomers) pure or mixed, racemic mixture, geometric isomers, tautomers, pharma- ceutically acceptable The present invention relates to a method for treating ER stress-related disorders, comprising administering to said patient a therapeutically effective amount of the compound, comprising administering to said patient a therapeutically effective amount of the compound, and For medical, prophylactic, procedural, diagnostic, therapeutic, or surgical applications in the prevention or treatment of The intention is to

[0050] The present invention also relates to compounds of the general formula (I) or physiologically acceptable salts thereof, These stereoisomers (diastereomers, enantiomers) are available in pure or mixed form, racemic or mixed form. compounds, geometric isomers, tautomers, pharma- ceutically acceptable salts, hydrates, solvates, solid forms, The mixture is then administered to treat the disease, and the disease is regressed in the subject. The present invention is intended to provide preventive or maintenance therapy for

[0051] A preferred embodiment of the present invention is as follows: 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(4-fluoro (Orophenethyl)acetamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) Chilamid; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(2-mol (Horinoethyl)acetamide; N-Butyl-2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)acetate Toamide; N-Butyl-2-(2-(4-chlorophenyl)-1-methyl-1H-imidazole-4 -yl)acetamide; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N -(2-morpholinoethyl)acetamide; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N -(3-(trifluoromethyl)phenyl)acetamide; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N -(3-isopropoxypropyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(3-(trimethylsilyl) (trifluoromethyl)phenyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(3-isopropyl) (propoxypropyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(4-fluoro (Orophenyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-(4,4- Difluoropiperidin-1-yl)ethan-1-one; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N -(4-fluorophenyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(4-(trimethylsilyl) (trifluoromethyl)phenyl)acetamide; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N -(4-(trifluoromethyl)phenyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-(pyrrolidine) (1-yl)ethan-1-one; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-1 -(pyrrolidin-1-yl)ethan-1-one; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N -Cyclopentylacetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-cyclopentene Cetylacetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-(4-methyl Rupiperazin-1-yl)ethan-1-one; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-1 -(4-Methylpiperazin-1-yl)ethan-1-one; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N -(4-fluorophenethyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-morpholino Ethan-1-one; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-thiomorpho Linoethan-1-one; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 3,3-Dimethylbutanamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 2,2-Dimethylbutanamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 3-Methylbutanamide; N-(2-(2-phenyl-1H-imidazol-4-yl)ethyl)butyramide; N-(2-(3-(3-(1H-pyrazol-1-yl)phenyl)-1H-imidazo (4-yl)ethyl)butyramide; N-(2-(2-(4-methoxyphenyl)-1H-imidazol-4-yl)ethyl) Butyramide; N-(2-(2-(4-phenoxyphenyl)-1H-imidazol-4-yl)ethyl ) butyramide; N-(2-(2-(pyridin-4-yl)-1H-imidazol-4-yl)ethyl) Chilamid; N-(2-(1-methyl-2-(pyridin-4-yl)-1H-imidazol-4-yl) )ethyl)butyramide; N-(2-(2-(3-(1H-pyrrol-2-yl)phenyl)-1H-imidazole -4-yl)ethyl)butyramide; N-(2-(2-(p-tolyl)-1H-imidazol-4-yl)ethyl)butylamine D; N-(2-(2-(3,5-dichlorophenyl)-1H-imidazol-4-yl)ethyl l)Butylamide; N-(2-(2-([1,1'-biphenyl]-3-yl)-1H-imidazole-4- yl)ethyl)butyramide; N-(2-(2-(4-vinylphenyl)-1H-imidazol-4-yl)ethyl) Chilamid; N-(2-(2-(3-(1H-pyrrol-2-yl)phenyl)-1-methyl-1H- Imidazol-4-yl)ethyl)butyramide; N-(2-(2-(3-morpholinophenyl)-1H-imidazol-4-yl)ethyl ) butyramide; N-(2-(3-(3-(piperidin-1-yl)phenyl)-1H-imidazole-4 -yl)ethyl)butyramide; N-(2-(2-(3-(pyrimidin-5-yl)phenyl)-1H-imidazole-4 -yl)ethyl)butyramide; N-(2-(2-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl) Butyramide; N-(2-(2-(4-benzylphenyl)-1H-imidazol-4-yl)ethyl) Butyramide; N-(2-(1-methyl-2-(3-morpholinophenyl)-1H-imidazole-4- yl)ethyl)butyramide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) Chlopropanecarboxamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 4,4,4-Trifluorobutanamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)a Cetoamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 2-Methoxyacetamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) Clobutane carboxamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 4-Fluorobenzamide; 2-((1,S,4R)-Bicyclo[2.2.1]heptan-2-yl-N-(2-(4 -chlorophenyl)-1H-imidazol-4-yl)acetamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 4-(Trifluoromethyl)benzamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 3,5-Difluorobenzamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) Clopent-1-ene-1-carboxamide; N-(2-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)- 1H-imidazol-4-yl)ethyl)cyclopent-1-ene-1-carboxamide ; N-(2-(2-(benzo[d][1,3]dioxol-5-yl)-1H-imidazo (4-yl)ethyl)cyclopent-1-ene-1-carboxamide; (3r,5r,7r)-N-(2-(2-(4-chlorophenyl)-1H-imidazole -4-yl)ethyl)adamantane-1-carboxamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 4-Methyl-2-(pyridin-2-yl)thiazole-5-carboxamide; N-(2-(2-(2,4-dichlorophenyl)-1H-imidazol-4-yl)ethyl (trifluoromethyl)benzamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) Xanamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)o Ctanamide; N-(2-(2-(3,5-dichlorophenyl)-1H-imidazol-4-yl)ethyl l)-3,5-difluorobenzamide; N-(2-(2-(2,4-dichlorophenyl)-1H-imidazol-4-yl)ethyl (l)-4-fluorobenzamide; N-(2-(2-(2,4-dichlorophenyl)-1H-imidazol-4-yl)ethyl l)-3,5-difluorobenzamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 2-(4-(trifluoromethyl)phenyl)acetamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 3-(4(trifluoromethyl)phenyl)propenamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 2-(4-fluorophenyl)acetamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 3-(4-fluorophenyl)propenamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 2-(3,5-difluorophenyl)acetamide; N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)- 3-(3,5-difluorophenyl)propenamide The present invention relates to a compound of formula I provided by:

[0052] Without limiting the scope of the invention, other advantageous embodiments of the invention include the following:

[0053] [Table 1]

[0054] [Table 2]

[0055] [Table 3]

[0056] [Table 4]

[0057] [Table 5]

[0058] [Table 6]

[0059] [Table 7]

[0060] [Table 8] The present invention relates to a preferred compound selected from the group consisting of:

[0061] The present invention further describes novel and inventive methods for the preparation of the compounds of the present invention. Compounds of formula I can be prepared by a novel and inventive method having the general scheme shown below: This is synthesized as follows:

[0062] [ka] Procedure A Synthesis of Compound II: (3.15 g, 49%) (2-(4-chlorophenyl)-1H-isopropyl Midazol-4-yl)methanol: 4-Chlorobenzamidine hydrochloride (0.19 mol) in NH4OH (380 ml) and A stirred solution of NH4Cl (54 g) was added to 1,3-dihydroxyacetone dimer (0.40 m ol) was added at room temperature and the reaction was stirred at reflux for 30 minutes, cooled and the reaction mass was cooled. Filter through a Hookner funnel and wash the solid twice with diethyl ether (40 mL) and It was then thoroughly dried.

[0063] [ka] Synthesis of compound III: 4-(chloromethyl)-2-(4-chlorophenyl)-1H-isopropyl Midazole (4.8 g, 89%). Hydrochloric acid: A stirred solution of II (0.023 mol) and SOCl2 (0.23 mol) was refluxed for 2 h. The mixture was then concentrated, washed with diethyl ether (30 ml) and dried thoroughly.

[0064] [ka] Synthesis of compound IV: (1.54 g, 55%) 2-(2-(4-chlorophenyl)-1H -imidazol-4-yl)acetonitrile: DMF (30 ml) and the free salt of compound III (0.013 mol) (NaHCO 3 ) To a stirred solution of 1,2-dichlorophenyl ether (1,2-dichlorophenyl ether), NaCN (0.015 mol) was added at room temperature and the reaction The mass was stirred for 12 hours. Water was added to the reaction mass and the compound was extracted with ethyl acetate, organic layer. did Dried over Na2SO4 and concentrated.

[0065] Step B:

[0066] [ka] Synthesis of compound V: 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl ) Acetic acid: To a stirred solution of compound IV (0.0069 mol) in ethanol (30 ml), add NaOH (0.0276 mol) and water (10 ml) were added and the reaction mixture was refluxed for 4 hours. Cool to warm, concentrate, and acidify to pH ~3. Dilute with ethyl acetate and hydrochloric acid. The layer was dried over Na2SO4 and concentrated.

[0067] Step C:

[0068] [ka] Synthesis of general compound VI: Acid (compound V) (0.54 mmol), amine (R-NH2 To a stirred solution of 0.33 mmol) and HATU (0.60 mmol) was added DIPEA ( 1.09 mmol) was added at 0° C. and the reaction was stirred overnight. The reaction mass was concentrated and ethyl acetate was added. Dilute with chill. Wash with 1N HCl, saturated NaHCO3 solution, and saturated brine. The organic layer was dried over Na2SO4, concentrated, and purified by column chromatography. Ta.

[0069] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(4-fluorophenyl) (fluorophenethyl)acetamide (001): Compound 001 (66 mg, 35%) was synthesized from compound V by procedure C below.

[0070] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(2-molybdenum (Furyloxyethyl)acetamide (Compound 003): Compound 003 (38 mg, 30%) was synthesized from compound V by procedure C below.

[0071] [ka] N-Butyl-2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)a Cetoamide (compound 004): Compound 004 (30 mg, 28%) was synthesized from compound V by procedure C below.

[0072] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(3-( (Trifluoromethyl)phenyl)acetamide (Compound 009): Compound 009 (110 mg, 52%) was synthesized from compound V by procedure C below.

[0073] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(3-methylphenyl) (isopropoxypropyl)acetamide (compound 010): Compound 010 (152 mg, 83%) was synthesized from compound V by procedure C below.

[0074] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(4-fluorophenyl) (fluorophenyl)acetamide (Compound 011) Compound 011 (60 mg, 33%) was synthesized from compound V by procedure C below.

[0075] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-(4,4 -difluoropiperidin-1-yl)ethan-1-one (compound 012): Compound 012 (35 mg, 28%) was synthesized from compound V by procedure C below.

[0076] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(4-( (Trifluoromethyl)phenyl)acetamide (Compound 014): Compound 014 (47 mg, 33%) was synthesized from compound V by procedure C below.

[0077] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-(pyrrolidine) Diphenyl-1-yl)ethan-1-one (Compound 016): Compound 016 (72 mg, 45%) was synthesized from compound V by procedure C below.

[0078] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-cyclopentadiene N-butylacetamide (Compound 019): Compound 019 (76 mg, 46%) was synthesized from compound V by procedure C below.

[0079] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-(4-methylphenyl) Tylpiperazin-1-yl)ethan-1-one (Compound 020): Compound 020 (63 mg, 36%) was synthesized from compound V by procedure C below.

[0080] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-morpholino Noethan-1-one (Compound 023): Compound 023 (170 mg, 76%) was synthesized from compound V by procedure C below.

[0081] [ka] 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-thiomol Homoethan-1-one (compound 024): Compound 024 (70 mg, 40%) was synthesized from compound V by procedure C below.

[0082] [ka] Scheme II: Compound VII: (0.95 g, 45%) 2-(2-(4-chlorophenyl)-1-methyl Synthesis of (1H-imidazol-4-yl)acetonitrile: To a stirred solution of compound IV (0.0092 mol) and DMF (20 ml), K2CO3 ( Then, MeI (0.0184 mol) and MeI (0.0184 mol) were added and stirred for 2 hours. Water was added to the reaction mass and extracted with ethyl acetate. The organic layer was washed with water and a saturated solution of brine. The organic layer was dried over sodium sulfate and concentrated.

[0083] [ka] Compound VIII: 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazo Synthesis of (4-yl)acetic acid: Compound VIII was synthesized from compound VII by the following procedure B.

[0084] [ka] Synthesis of General Compound IX: General compound IX can be synthesized from compound VIII by the following procedure C. It was done.

[0085] [ka] N-Butyl-2-(2-(4-chlorophenyl)-1-methyl-1H-imidazole 4-yl)acetamide (Compound 005): Compound 005 (35 mg, 33%) was synthesized from compound VIII by the following procedure C. Ta.

[0086] [ka] 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)- N-(2-morpholinoethyl)acetamide (Compound 006): Compound 006 (44 mg, 35%) was synthesized from compound VIII by the following procedure C. Ta.

[0087] [ka] 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)- N-(3(trifluoromethyl)phenyl)acetamide (Compound 007): Compound 007 (85 mg, 62%) was synthesized from compound VIII by the following procedure C. Ta.

[0088] [ka] 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)- N-(3-isopropoxypropyl)acetamide (Compound 008): Compound 008 (95 mg, 78%) was synthesized from compound VIII by the following procedure C. Ta.

[0089] [ka] 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)- N-(4-fluorophenyl)acetamide (Compound 013): Compound 013 (60 mg , 31%) was synthesized from compound VIII by the following procedure C.

[0090] [ka] 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)- N-(4-(trifluoromethyl)phenyl)acetamide (Compound 015): Compound 015 (47 mg, 33%) was synthesized from compound VIII by the following procedure C. Ta.

[0091] [ka] 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)- 1-(Pyrrolidin-1-yl)ethan-1-one (Compound 017): Compound 017 (67 mg, 40%) was synthesized from compound VIII by the following procedure C.

[0092] [ka] 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)- N-Cyclopentylacetamide (Compound 018): Compound 018 (111 mg, 64%) was synthesized from compound VIII by the following procedure C. It was.

[0093] [ka] 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)- 1-(4-Methylpiperazin-1-yl)ethan-1-one (Compound 021): Compound 021 (59 mg, 32%) was synthesized from compound VIII by the following procedure C. Ta.

[0094] [ka] 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)- N-(4-fluorophenethyl)acetamide (Compound 022): Compound 022 (180 mg, 88%) was synthesized from compound VIII by the following procedure C. It was.

[0095] [ka] Scheme III: Step D: Compound X: (84%, 7.5 g) 2-(4-chlorophenyl)-1H-imidazole- Synthesis of 4-carbaldehyde: To a stirred solution of compound II (0.043 mol) and THF (100 ml) was added MnO2 (0. 65 mol) was slowly added, stirred at room temperature for 3 hours, filtered through a bed of celite, and The bed was washed with 10% MeOH in DCM (60 ml), concentrated and thoroughly dried. did.

[0096] Step D:

[0097] [ka] Compound XI: (3 g, 93%) (E)-2-(4-chlorophenyl)-4-(2-dichlorophenyl) Synthesis of 1H-imidazole (vinyl) To a stirred solution of compound X (0.013 mol) and THF (50 ml) was added nitromethane (0 .026mol), pyrrolidine (0.0013mol) and acetic acid (0.0013mol) The reaction mass was stirred for 3 hours and then heated at low temperature (350°C) to 90%. Concentrate, add water to the concentrate, filter the solid through a Buckner funnel, and add the solid to ethyl acetate. (30 ml), filtered and thoroughly dried.

[0098] [ka] Compound XII: (0.45 mg, 44%) 2-(4-chlorophenyl)-4-(2-dichlorophenyl) Synthesis of triethyl-1H-imidazole: To a stirred solution of compound XI (0.0016 mol) in THF:methanol (10:1 ml) Sodium borohydride (0.0018 moles) was slowly added under cooling conditions and the mixture was stirred. The reaction mixture was added slowly for 30 minutes, and 1N HCl was added slowly (12 ml) under low temperature conditions. Ethyl acetate was added and the organic layer was washed with water and saturated brine solution. The organic layer was dried over ethyl acetate, concentrated under reduced pressure, and purified by column chromatography.

[0099] [ka] Compound XIII: (1.2 g, 48%) tert-butyl (2-(2-(4-chlorophenyl)- Synthesis of phenyl-1H-imidazol-4-ylethyl carbamate: A stirred solution of compound XII (0.0048 mol) and ethanol:water (24 ml:8 ml) NH4Cl (0.048 mol) was added to the mixture, followed by Fe (0.048 mol) at room temperature. The reaction mass was cooled to room temperature and passed through a bed of Celite. The bed of Celite was diluted with ethyl acetate. The concentrated mass was then washed with ethyl acetate (15 ml) and water (10 ml), and concentrated ethyl acetate. In a stirred solution of tert-butanol (20 ml), NaHCO3 (0.019 mol) and B Octanhydride (di-tert-butyl dicarbonate) (0.019 mol) was added. The mixture was stirred overnight. Stir the reaction mass, concentrate the reaction mass, add ethyl acetate (30 ml) and wash the organic layer with water. The saturated brine solution, concentrate and crude product were washed twice with diethyl ether (20 ml). Ta.

[0100] [ka] Synthesis of compound XIV: To a stirred solution of compound XIII (0.43 mmol) and DCM (10 ml) was added TFA ( ml) was stirred at 00°C for 2 hours, the concentrated reaction mass was added and washed with diethyl ether (5 ml). DMF (8 ml), EDC-HCl (0.47 mmol), DMAP (1.43 mmol), mol) and acid (0.47 mmol) were added to the above stirred solution. The reaction mass was stirred overnight. The mixture was stirred, ethyl acetate was added, and the organic layer was washed with saturated NaHCO3, water, and saturated saline solution. It was dried over sodium sulfate, concentrated and purified by column chromatography.

[0101] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) Butyramide (Compound 002): Compound 002 (18 mg, 51%) was synthesized from compound XIII by the following procedure H. Ta.

[0102] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) -3,3-Dimethylbutanamide (Compound 025): Compound 025 (77 mg, 54%) was synthesized from compound XIII by the following procedure H. Ta.

[0103] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) -2,2-Dimethylbutanamide (Compound 026): Compound 026 (75 mg, 35%) was synthesized from compound XIII by the following procedure H. Ta.

[0104] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) -3-Methylbutanamide (Compound 027): Compound 027 (58 mg, 28%) was synthesized from compound XIII by the following procedure H. Ta.

[0105] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) -4-Fluorobenzamide (Compound 051): Compound 051 (45 mg, 28%) was synthesized from compound XIII by the following procedure H. was.

[0106] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) Cyclobutanecarboxamide (Compound 050): Compound 050 (60 mg, 42%) was synthesized from compound XIII by the following procedure H. Ta.

[0107] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) Cyclopropanecarboxamide (Compound 046): Compound 046 (95 mg, 70%) was synthesized from compound XIII by the following procedure H. Ta.

[0108] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) Cyclopent-1-ene-1-carboxamide (Compound 055): Compound 055 (52 mg, 35%) was synthesized from compound XIII by the following procedure H. Ta.

[0109] [ka] (3r,5r,7r)-N-(2-(2-(4-chlorophenyl)-1H-imidazo (4-yl)ethyl)adamantane-1-carboxamide (Compound 064): Compound 064 (61 mg, 33%) was synthesized from compound XIII by the following procedure H. Ta.

[0110] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) -4-(trifluoromethyl)benzamide (compound 053): Compound 053 (61 mg, 33%) was synthesized from compound XIII by the following procedure H. Ta.

[0111] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) -3,5-difluorobenzamide (compound 054): Compound 054 (76 mg, 38%) was synthesized from compound XIII by the following procedure H. Ta.

[0112] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) -4-Methyl-2-(pyridin-2-yl)thiazole-5-carboxamide (Compound 0 65): Compound 065 (75 mg, 38%) was synthesized from compound XIII by the following procedure H. Ta.

[0113] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) Hexanamide (Compound 067): Compound 067 (75 mg, 50%) was synthesized from compound XIII by the following procedure H. Ta.

[0114] [ka] N-(2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl) Octanamide (Compound 068): Compound 068 (70 mg, 43%) was synthesized from compound XIII by the following procedure H. Ta.

[0115] [ka] Scheme IV: Compound XVI (51%): (2-(2,4-dichlorophenyl)-1H-imidazole Synthesis of (4-yl)methanol: Compound XVI was synthesized from 2,4-dichlorobenzamidine hydrochloride by the following procedure A. .

[0116] [ka] Compound XVII (80%): 2-(2,4-dichlorophenyl)-1H-imidazole Synthesis of 4-carbaldehyde: Compound XVII was synthesized from compound XVI by the following procedure D.

[0117] [ka] Compound XVIII (85%): (E)-2-(2,4-dichlorophenyl)-4-(2 Synthesis of (-nitrovinyl)-1H-imidazole: Compound XVIII was synthesized from compound XVII by the following procedure E.

[0118] [ka] Compound XIX (35%): 2-(2,4-dichlorophenyl)-4-(2-nitroethyl) Synthesis of 1H-imidazole: Compound XIX was synthesized from compound XVIII by the following procedure F.

[0119] [ka] Compound XX (40%): s-tert-butyl (2-(2-(2,4-dichlorophenyl) Synthesis of 1H-imidazol-4-ylethyl carbamate: Compound XX was synthesized from compound XIX by the following procedure G.

[0120] [ka] Synthesis of general compound XXI: Compound XXI is synthesized from compound XX by the following procedure H. Ta.

[0121] [ka] N-(2-(2-(2,4-dichlorophenyl)-1H-imidazol-4-yl)ethyl (ethyl)-4-(trifluoromethyl)benzamide (Compound 066): Compound 066 (52 mg, 29%) was synthesized from compound XX by procedure H below.

[0122] [ka] N-(2-(2-(2,4-dichlorophenyl)-1H-imidazol-4-yl)ethyl (ethyl)-4-fluorobenzamide (compound 070): Compound 070 (50 mg, 31%) was synthesized from compound XX by procedure H below.

[0123] [ka] N-(2-(2-(2,4-dichlorophenyl)-1H-imidazol-4-yl) (ethyl)-3,5-difluorobenzamide (compound 071): Compound 071 (62 mg, 31%) was synthesized from compound XX by procedure H below.

[0124] [ka] Scheme V: Compound XXIII (52%): (2-(3,5-dichlorophenyl)-1H-imidazo Synthesis of (4-yl)methanol: Compound XXIII was synthesized from 3,5-dichlorobenzamidine hydrochloride by the following procedure A: did.

[0125] [ka] Compound XXIV (85%): 2-(3,5-dichlorophenyl)-1H-imidazole Synthesis of 4-carbaldehyde: Compound XXIV can be converted to Compound XXII by the following procedure D. It was synthesized from I.

[0126] [ka] Compound XXV (90%): (E)-2-(3,5-dichlorophenyl)-4-(2-dichlorophenyl) Synthesis of 1H-imidazole (vinyl) Compound XXV was synthesized from compound XXIV by the following procedure E.

[0127] [ka] Compound XXVI (35%): 2-(3,5-dichlorophenyl)-4-(2-nitrophenyl) Synthesis of (ethyl)-1H-imidazole: Compound XXVI was synthesized from compound XXV by procedure F below.

[0128] [ka] Compound XXVII (45%): tert-Butyl (2-(2-(3,5-dichlorophenyl) Synthesis of 1H-imidazol-4-ylethyl carbamate: Compound XXVII was synthesized from compound XXXVI by procedure G below.

[0129] [ka] Synthesis of general compound XXVIII: Compound XXVIII can be synthesized by the following procedure H from compound X Synthesized from XVII.

[0130] [ka] N-(2-(2-(3,5-dichlorophenyl)-1H-imidazol-4-yl) (ethyl)-3,5-difluorobenzamide (compound 069): Compound 069 (57 mg, 34%) was synthesized from compound XXVII by the following procedure H. Ta.

[0131] [ka] In addition to the general preparation schemes described herein, the present invention relates to the preparation of The present invention contemplates all known reaction mechanisms and general reaction schemes, and the results are As a result, the presently claimed compounds are prepared. EXAMPLES

[0132] Testing Data: Biological activity of synthetic compounds The compounds synthesized according to the present invention were tested for in vitro efficacy. The ability of endoplasmic reticulum stress to protect melanocytes from stress-induced cell death was examined. The results were compared with those of mouse B16F10 cells, human Tables I, II and II for A375 cells and human primary melanocytes, respectively. Tables IV and V show the dose of compound required to obtain 50% of the maximum effect. The potency of the compounds at the mean effective concentration 50 (EC50) is shown.

[0133] The following data finally demonstrate that the compound improves cell viability under ER stress conditions. Since ER stress is a causative factor in the initiation of autoimmunity, the compound The compound is non-cytotoxic and is believed to be effective in the management of vitiligo and other diseases. Protects cells from stress-induced damage, a condition seen in some autoimmune diseases.

[0134] Melanocytes are gradually lost due to the high cell stress in vitiligo patients, but Survival and avoidance from stress is achieved by the imidazole compounds. The compounds may be used to treat autoimmune vitiligo.

[0135] Furthermore, elevated cellular stress is a mechanism for the initiation of autoimmunity, and The compound is effective against vitiligo, psoriasis, atopic dermatitis, alopecia areata, SLE, bullous dermatitis, pemphigus, and scleroderma. autoimmune diseases of the skin, including rheumatoid arthritis, type I diabetes, celiac disease, and inflammatory bowel disease , and other autoimmune diseases, including Crohn's disease, etc. The present invention relates to the unexpected use of imidazole compounds to treat and prevent such diseases. Clearly establish efficacy. Table I: List of compounds and their potency (25-30 μM concentrations) in mouse B16F10 cells. Strike

[0136] [Table 9]

[0137] [Table 10] Table II: List of compounds and their potency (25-30 μM concentrations) in human A375 cells.

[0138] [Table 11]

[0139] [Table 12] Table III: In human primary melanocytes (NHEM: normal human epidermal melanocytes) List of compounds and their potencies (25-30μM concentration)

[0140] [Table 13] Table IV: EC50 (μM) of NCEs in mouse B16F10 cells

[0141] [Table 14]

[0142] [Table 15] Table V: EC50 (μM) of NCEs in human A375 cells

[0143] [Table 16] To estimate efficacy, mouse B16F10, human A375 or human primary melanocyte (N HEM) cells were pretreated with the compounds for 6 hours in quadruplicate. After incubation, the concentration was 300ng / ml for B16F10 cells and 100ng / ml for A375 cells. Tunicamycin was added to either 200 ng / ml for NHEM or 200 ng / ml for NHEM. Stress-mediated cell death was induced and the cells were further cultured for a total of 72 h. The concentration of α-heptane was kept constant for each well. After 72 hours of treatment, MTT assay was performed to assess cell proliferation. The effect of compound treatment was measured after tunicamycin treatment and the solvent control was kept at 100%. To estimate the effective concentration 50 (EC50), cells were The cells were treated with different concentrations of compounds together with tunicamycin and then subjected to MTT assay. EC50 Values ​​were calculated using GraphPad Prism 7 software.

Claims

1. Formula I below: 【Chemistry 1】 (In the formula, R １ , R ２ , R ３ , R ４ , R ５ are each independently selected from hydrogen, halogen, linear or branched alkyl, linear or branched alkenyl, linear or branched alkoxyalkyl, phenyl, aryl, aralkyl, alkoxyalkyl, alkoxyaryl, aromatic or aliphatic heterocycle containing at least one heteroatom selected from the group of O, N, and S; any two adjacent R groups form a 5-6 membered aromatic or aliphatic ring containing at least one heteroatom selected from the groups O, N, and S; R ６ are independently selected from hydrogen, linear or branched C1-C5 alkyl; X is CH ２ or C=O, When X is C=O, Y is absent; R ７ and R ８ are each independently selected from hydrogen, linear or branched alkyl, linear or branched aralkyl, linear or branched alkenyl, linear or branched alkynyl, both of which contain at least one heteroatom selected from O, N, and S, —CH ２ (CH ２ ) forming a 3-7 membered aromatic or aliphatic heterocycle containing nNRcRd, where n is 0-3 and Rc and Rd are both independently selected from alkyl, or forming a 3-7 membered aromatic or aliphatic heterocycle containing at least one heteroatom selected from the group of O, N, and S; and their pure or mixed stereoisomers (diastereomers, enantiomers), racemic mixtures, geometric isomers, tautomers, pharma- ceutically acceptable salts, hydrates, solvates, solid forms, and mixtures thereof.

2. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The pharmaceutical compounds of claim 1, wherein R is substituted or unsubstituted, as well as their stereoisomeric (diastereomers, enantiomers) pure or mixed forms, racemic mixtures, geometric isomers, tautomers, pharma- ceutically acceptable salts, hydrates, solvates, solid forms, and mixtures thereof.

3. below: 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(4-fluorophenethyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(2-morpholinonethyl)acetamide; N-butyl-2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)acetamide; N-butyl-2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)acetamide; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N-(2-morpholinoethyl)acetamide; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N-(3-(trifluoromethyl)phenyl)acetamide 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N-(3-isopropoxypropyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(3-(trifluoromethyl)phenyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(3-isopropoxypropyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(4-fluorophenyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N-(4-fluorophenyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-(4-(trifluoromethyl)phenyl)acetamide; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N-(4-(trifluoromethyl)phenyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-(pyrrolidin-1-yl)ethan-1-one; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-1-(pyrrolidin-1-yl)ethan-1-one; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N-cyclopentylacetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-N-cyclopentylacetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one; 2-(2-(4-chlorophenyl)-1-methyl-1H-imidazol-4-yl)-N-(4-fluorophenethyl)acetamide; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-morpholinoethan-1-one; 2-(2-(4-chlorophenyl)-1H-imidazol-4-yl)-1-thiomorpholinoethan-1-one; The pharmaceutical compounds according to claim 1, as well as their stereoisomers (diastereoisomers), isomers, enantiomers) pure or mixed, racemic mixture, geometric isomers, tautomers , pharma- ceutically acceptable salts, hydrates, solvates, solid forms, and mixtures thereof.

4. 10. A method for preparing a compound of formula I according to claim 1, comprising the steps of: (a) reacting chlorobenzamidine hydrochloride in the presence of 1,3-dihydroxyacetone dimer to obtain imidazole compound II; (b) reacting the imidazole moiety formed in step (a) in the presence of a suitable reagent for chlorination to give compound III, which is then cyanated in the presence of a suitable reagent to give compound IV; (c) reacting said compound IV to hydrolyze and generate an imidazole moiety containing carboxylic acid V; (d) reacting said compound V with a desired reagent to effect amide coupling to produce a compound of formula (I); A method comprising: In some cases, (e) reacting the compound IV formed in step (b) with a suitable reagent to form compound VII; (f) reacting said compound VII with a desired reagent to effect amide coupling to produce a compound of formula (I); A method comprising:

5. A method for obtaining a compound of formula I according to claim 1, comprising the steps of: (a) reacting chlorobenzamidine hydrochloride or dichlorobenzamidine hydrochloride in the presence of 1,3-dihydroxyacetone dimer to obtain imidazole compound II or XVI; (b) reacting said imidazole compound II or XVI with a suitable reagent to obtain compound X or XVII; (c) introducing a nitro group into said imidazole compound X or XVII in the presence of a suitable reagent to obtain compound XI or XVIII; (d) hydrogenating said compound XI or XVIII in the presence of a suitable reagent to obtain compound XII or XIX; (e) adding Fe, NH to the compound XII or XIX ４ OH, followed by addition of di-tert-butyl dicarbonate to give compound XIII or XX; (f) amide coupling of said compound XIII or XX with a desired reagent to obtain a compound of formula I; A method comprising:

6. A pharmaceutical composition for treating and / or preventing diseases and disorders involving stress-mediated cell death comprising an effective amount of a compound of formula (I) as defined in claim 1, as well as its stereoisomeric (diastereomers, enantiomers) pure or mixed forms, racemic mixtures, geometric isomers, tautomers, pharma- ceutically acceptable salts, hydrates, solvates, solid forms and mixtures thereof, together with a pharma- ceutically acceptable carrier, as an active ingredient.

7. 7. The pharmaceutical composition of claim 6, wherein the disease or disorder is selected from the group consisting of an autoimmune disease, a cancer, a tumor, a metabolic disorder, a neurodegenerative disease, a cardiovascular disease, a pulmonary ophthalmological disease and a skin disease.

8. 8. The pharmaceutical composition of claim 7, wherein the autoimmune disease is selected from the group consisting of autoimmune skin diseases, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, lupus, celiac disease and pernicious anemia.

9. 9. The pharmaceutical composition according to claim 8, wherein the autoimmune skin disease is selected from the group consisting of psoriasis, lupus, vitiligo, scleroderma, dermatomyositis, epidermolysis bullosa, bullous pemphigoid, albinism, dermatitis, Koebner phenomenon and other autoimmune skin diseases.

10. The pharmaceutical composition according to any one of claims 6 to 9, wherein the mode of administration is selected from the group consisting of oral, parenteral, rectal, topical, intranasal, intravenous, transdermal, sublingual, intramuscular, subcutaneous, intraocular, and any other topical mode of administration.

11. 7. The pharmaceutical composition of claim 6, in the form of tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, injections, syrups, liquids, microemulsions, topical creams, ointments, suppositories, sachets, troches and lozenges, and oil-water emulsions containing an appropriate amount of the compound of formula I, or a formulation to be administered in unit dosage form in a multiple dosage form.

12. Use of the compounds according to claims 1 to 3 for the preparation of a pharmaceutical composition for the treatment and / or prevention of diseases and disorders associated with stress-mediated cell death.

Images