Aminoimidazole FPR2 agonist

Abstract

The present disclosure relates to compounds of formula (I), which are formylpeptide 2 (FPR2) receptor agonists and / or formylpeptide 1 (FPR1) receptor agonists. The present disclosure also provides compositions and methods for using the compounds to treat, for example, atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases. TIFF2023546371000061.tif42140

Description

[Technical Field]

[0001] Cross-reference of related applications This application is granted priority to U.S. Provisional Patent Application No. 63 / 089,730, filed on 9 October 2020, in accordance with 35 U.S.SC §119(e), the entirety of which is incorporated herein by reference. [Background technology]

[0002] The present invention relates to a novel aminoimidazole compound represented by formula (I) that is a formylpeptide 2 (FPR2) receptor agonist, and to compositions containing the compound for the treatment of, for example, atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD) and related diseases, and to methods of using them for that purpose.

[0003] Formyl peptide receptor 2 (FPR2) belongs to a small group of seven-transmembrane domain G protein-binding receptors that are expressed in multiple human tissues (including immune cells) and are known to be important in host defense and inflammation. FPR2 shares significant sequence homology with FPR1 and FPR3 (Chen K. et al., Journal of Autoimmunity 85, 2017, 64-77). Comprehensively, these receptors bind to many structurally different agonists that act as chemoattractants and activate phagocytic cells, including N-formyl and non-formyl peptides. Endogenous peptide annexin A1 and its N-terminal fragment are examples of ligands that bind to human FPR1 and FPR2. Fatty acids, such as eicosanoids and lipoxin A4, which belong to the group of small pro-resolution mediators (SPMs), have also been reported as FPR2 agonists (Ye RD. et al., Pharmacol. Rev., 2009, 61, 119-61).

[0004] Endogenous FPR2 inflammation resolving ligands such as lipoxin A4 and annexin A1 are linked by Gi coupling and Ca2+ It has been reported to trigger diverse cytoplasmic cascades, including mobilization and β-arrestin replacement (Cattaneo, F. et al., Int J Mol Sci. 2013 April;14(4):7193-7230). FPR2 regulates both innate and adaptive immune systems, including neutrophils, macrophages, T cells, and B cells. In neutrophils, FPR2 ligands regulate activity, cytotoxicity, and lifespan. In macrophages, FPR2 activation inhibits apoptosis and enhances efferocytosis (Chandrasekharan JA, Sharma-Walia N, J. Inflamm. Res., 2015, 8, 181-92). The initiation of inflammation resolution through FPR2 activation is associated with enhanced anti-fibrous wound healing and the return of damaged tissue to homeostasis (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63).

[0005] Chronic inflammation is part of the pathways that lead to the development of many human diseases, and stimulating the inflammatory response pathway with FPR2 agonists may have both protective and reparative effects. Ischemia-reperfusion (I / R) injury is a common feature of several diseases associated with high morbidity and mortality, such as myocardial infarction and stroke. Unproductive wound healing associated with cardiomyocyte death and pathological remodeling resulting from ischemia-reperfusion injury leads to scarring, fibrosis, and progressive loss of cardiac function. FPR2 modulation has been proposed to enhance post-injury myocardial wound healing and reduce harmful myocardial remodeling (Kain V. et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). In addition, FPR2 inflammation-resolving agonists in the central nervous system may be useful therapeutic agents for treating various clinical I / R symptoms, including stroke (Gavins FN., Trends Pharmacol. Sci., 2010, 31, 266-76) and I / R-induced spinal cord injury (Liu ZQ. et al., Int. J. Clin. Exp. Med., 2015, 8, 12826-33).

[0006] In addition to the beneficial effects of targeting the FPR2 receptor with novel anti-inflammatory agonists to treat I / R-induced injury, the usefulness of these ligands may also be applicable to other diseases. In the cardiovascular system, both the FPR2 receptor and its anti-inflammatory agonist have been found to be involved in the stabilization and healing of atherosclerotic plaques (Petri MH. et al., Cardiovasc. Res., 2015, 105, 65-74; and Fredman G. et al., Sci. Trans. Med., 2015, 7(275);275ra20). FPR2 agonists have also been shown to be beneficial in preclinical models of chronic inflammatory human diseases, including infectious diseases, psoriasis, dermatitis, inflammatory bowel syndrome, Crohn's disease, ocular inflammation, sepsis, pain, metabolic / diabetes, cancer, COPD, asthma and allergic diseases, cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritis and other joint diseases, Alzheimer's disease, renal fibrosis, and organ transplantation (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63; Perrett, M. et al., Trends in Pharm. Sci., 2015, 36, 737-755). [Overview of the project]

[0007] The present invention encompasses a compound of formula (I) which is a formylpeptide 2 (FPR2) receptor agonist, compositions containing the compound, and methods of using them, for example, in the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD) and related diseases.

[0008] One aspect of the present invention is formula (I): [ka] [In formula: R 1 These include alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (alkoxycarbonyl)alkyl, alkoxycarbonyl, (NR 6 R 7 ) Carbonyl, Ar 1 , or (Ar1 ) is alkyl; Ar 1 is cycloalkyl, aryl, heteroaryl (containing 1 to 5 heteroatoms selected from carbon atoms and N, NR 5a , O, and S), heterocyclyl (containing 1 to 5 heteroatoms selected from carbon atoms and N, NR 5a , O, and S), or spiroheterocyclyl (containing 1 to 5 heteroatoms selected from carbon atoms and N, NR 5a , O, and S), each of which is substituted with 1 to 5 R 5 ; R 2 is hydrogen, alkyl, or haloalkyl; R 3 is phenyl or pyridinyl (substituted with 1 R 3a and 1 to 2 R 3b ); R 3a is halo, haloalkyl, alkoxy, or haloalkoxy; R 3b is hydrogen, halo, or haloalkyl; R 4 is phenyl or pyridinyl (substituted with 1 to 2 R 4a ); R 4a is halo, haloalkyl, alkoxy, or haloalkoxy; R 5 is hydrogen, hydroxyl, cyano, halo, alkyl, haloalkyl, amino, haloalkylamino, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, carboxamide, alkoxycarbonyl, alkylsulfonylamino, or hydroxyalkylcarbonyl; R 5a is hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroalkylcarbonyl, carboxamide, alkylaminocarbonyl, aminocarbonylalkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl; R 6and R 7 These are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl (carbon atoms and N, NR) 8a Heterocyclines (containing 1 to 4 heteroatoms selected from O, S, and N), (carbon atoms, N, NR) 8a (containing 1 to 4 heteroatoms selected from O, S, and N), arylalkyl, or heteroarylalkyl (containing carbon atoms, N, N, and N). 8a A cycloalkyl, aryl, heteroaryl, or heterocyclyl (containing 1 to 4 heteroatoms selected from O and S); where the cycloalkyl, aryl, heteroaryl, or heterocyclyl contains 1 to 5 R 8 Will it be replaced by; Or R 6 and R 7 These, together with the nitrogen they bind to, form heterocyclines or heteroaryls (carbon atoms and N, NR). 8a (containing 0 to 3 further heteroatoms selected from O and S), where the heteroaryl or heterocyclyl has 1 to 5 R 8 Replaced by; R 8 is hydrogen, halo, hydroxy, hydroxyalkyl, alkyl, alkoxy, or oxo; R 8a [is hydrogen, hydroxyalkyl, or alkyl] The compound shown, or a pharmaceutically acceptable salt thereof.

[0009] Another aspect of the present invention is a compound of formula (I), where R 3 Phenyl (1 R 3a and 1-2 R 3b (It is replaced by; R 3a However, the substituent is a halo, haloalkyl, or alkoxy substituent located in the para position relative to the imidazole moiety; R 3b is hydrogen, halo, or haloalkyl; The other variable groups are defined by formula (I) above. It is a compound.

[0010] Another aspect of the present invention is a compound of formula (I), where R 4 phenyl (one R at the para position relative to the amide portion) 4a (It is replaced by; R 4a is a halo, alkoxy, or haloalkoxy; and The other variable groups are defined by formula (I) above. It is a compound.

[0011] Another aspect of the present invention is formula (II): [ka] [In formula: R 1 These include alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (alkoxycarbonyl)alkyl, alkoxycarbonyl, (NR 6 R 7 ) Carbonyl, Ar 1 , or (Ar 1 ) is alkyl; Ar 1 These are cycloalkyl, aryl, and heteroaryl (carbon atoms and N, NR) 5a Heterocyclines (containing 1 to 4 heteroatoms selected from O, S, and N), heterocyclines (containing carbon atoms and N, NR) 5a Spiroheterocyclines (containing 1 to 4 heteroatoms selected from O, S, and N), (carbon atoms and N, NR) 5a (containing 1 to 4 heteroatoms selected from , O, and S), each containing 1 to 4 R 5 It has been replaced with; R 3a is an alkoxy; R 3b is hydrogen, halo, or haloalkyl; R 4a is a halo or haloalkoxy; R 5is hydrogen, hydroxyl, cyano, halo, alkyl, haloalkyl, amino, haloalkylamino, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, or alkylsulfonylamino; R 5a is hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroalkylcarbonyl, carboxyamide, alkylaminocarbonyl, aminocarbonylalkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl; R 6 and R 7 These are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heteroaryl (carbon atoms and N, NR) 8a (containing 1 to 4 heteroatoms selected from O, S, and N), arylalkyl, or heteroarylalkyl (containing carbon atoms, N, N, and N). 8a (containing 1 to 4 heteroatoms selected from O and S), where the cycloalkyl, heteroaryl, or heteroarylalkyl is 1 to 4 R 8 Will it be replaced by; Or R 6 and R 7 Together with the nitrogen they bind to, they become N, NR 8a It forms a heterocycline having 0 to 3 further heteroatoms selected from O and S, where the heterocycline or heteroaryl has 1 to 4 R 8 Replaced by; R 8 is hydrogen, halo, hydroxy, hydroxyalkyl, alkyl, alkoxy, or oxo; R 8a [is hydrogen, hydroxyalkyl, or alkyl] It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0012] Another aspect of the present invention is a compound of formula (II), where R 1 Ar 1 (1 to 3 R5 (It is replaced by; Ar 1 However, cycloalkyl, aryl, heteroaryl (carbon atoms and N, NR) 5a Heterocyclines (containing 1 to 3 heteroatoms selected from O, S, and N), (carbon atoms, N, NR) 5a Spiroheterocyclines (containing 1 to 3 heteroatoms selected from O, S, and N), (carbon atoms, N, NR) 5a (containing 1 to 3 heteroatoms selected from O and S), each containing 1 to 3 R 5 Replaced by; R 3a is an alkoxy; R 3b is hydrogen or halo; R 4a is a haloalkoxy; R 5 but which is hydrogen, hydroxyl, cyano, halo, alkyl, haloalkyl, amino, haloalkylamino, alkoxyalkyl, hydroxyalkyl, hydroalkylcarbonyl, alkoxy, haloalkoxy, alkoxycarbonyl, or alkylsulfonylamino; R 5a However, it is hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkylaminocarbonyl, aminocarbonylalkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl. It is a compound.

[0013] Another aspect of the present invention is a compound of formula (II), where Ar 1 but [ka] and; R 3a is an alkoxy; R 3b is hydrogen or halo; R 4a is a haloalkoxy; R 5is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, or haloalkoxy, a compound.

[0014] Another aspect of the present invention is a compound of formula (II), where Ar 1 is

Chemical formula

[0015] Another aspect of the present invention is a compound of formula (II), where Ar 1 is

Chemical formula

[0016] Another aspect of the present invention is a compound of formula (II), where Ar 1 but [ka] and; R 3a is an alkoxy; R 3b is hydrogen or halo; R 4a is a haloalkoxy; R 5 is hydrogen, hydroxyl, hydroxyalkyl, amino, haloalkylamino, or alkylsulfonylamino. It is a compound.

[0017] Another aspect of the present invention is a compound of formula (II), where R 1 But (Ar 1 ) is alkyl; R 3a is an alkoxy; R 3b is hydrogen or halo; R 4a It is a haloalkoxy. It is a compound.

[0018] Another aspect of the present invention is a compound of formula (II), where (Ar 1 ) Ar in alkyl 1 but [ka] and; R 3b is hydrogen or halo; R 4a is a haloalkoxy; R 5 but which is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, or haloalkoxy; R 5ais hydrogen or alkyl, It is a compound.

[0019] Another aspect of the present invention is a compound of formula (II), where R 1 is alkyl or haloalkyl; R 3a is an alkoxy; R 3b is hydrogen or halo; R 4a is a haloalkoxy It is a compound.

[0020] Another aspect of the present invention is a compound of formula (II), where R 1 is an alkoxycarbonyl or (alkoxycarbonyl)alkyl; R 3a is an alkoxy; R 3b is hydrogen or halo; R 4a is a haloalkoxy It is a compound.

[0021] Another aspect of the present invention is a compound of formula (II), where R 1 But (NR 6 R 7 )It is a carbonyl; R 3a is an alkoxy; R 3b is hydrogen or halo; R 4a is a haloalkoxy; R 6 and R 7 However, independently, hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heteroaryl (carbon atoms and N, NR) 8a Heteroaryls (containing 1 to 3 heteroatoms selected from O, S, and N, NR) are carbon atoms. 8a(containing 1 to 3 heteroatoms selected from O, S, and NR), or heteroarylalkyl (containing carbon atoms, N, NR) 8a (containing 1 to 3 heteroatoms selected from O and S), where the cycloalkyl, heteroaryl, or heteroarylalkyl is 1 to 3 R 8 Is it replaced by? Or R 6 and R 7 Together with the nitrogen to which they bind, [ka] form; R 8 However, it is hydrogen, halo, hydroxy, hydroxyalkyl, alkyl, alkoxy, or oxo; R 8a is hydrogen, hydroxyalkyl, or alkyl. It is a compound.

[0022] Another aspect of the present invention is a compound of formula (II), where R 1 But (NR 6 R 7 )It is a carbonyl; R 3a is an alkoxy; R 3b is hydrogen or halo; R 4a is a haloalkoxy; R 6 is hydrogen; R 7 but [ka] And; R 8 However, it is hydrogen, halo, hydroxy, hydroxyalkyl, alkyl, or alkoxy. It is a compound.

[0023] For compounds of formula (I) or (II), R 1 , R2 , R 3 , R 4 , and Ar 1 Examples of any range of variable substituents, including those mentioned above, can be used independently of other examples of any range of variable substituents. Thus, the present invention includes combinations of different embodiments.

[0024] Unless otherwise specified, these terms have the following meanings: "Halo" refers to fluoro, chloro, bromo, and iodine. "Hydroxyl" refers to the -OH group. "Oxo" means =O. "Carbonyl" refers to the -C=O group. "Alkyl" refers to linear or branched alkyl groups consisting of 1 to 7 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, and heptyl.

[0025] "Haloalkyl" and "haloalkoxy" refer to halo-substituted alkyl or alkoxy groups. Haloalkyl or haloalkoxy refers to alkyl or alkoxy groups that are single-substituted or multiple-substituted halo-substituted, up to perhalo-substituted alkyl or alkoxy groups. A "hydroxyalkyl" group is an alkyl group in which at least one hydrogen atom is substituted for a hydroxyl group. An "alkoxyalkyl" refers to an alkyl group in which at least one hydrogen atom is substituted with an alkoxy group as described above. "Alkylsulfonyl" refers to a group that is -SO2-alkyl, where alkyl is as defined herein.

[0026] "Alkylsulfonylamino" refers to a group "-NHSO2-alkyl," where alkyl is as defined herein. "Amine" refers to a group represented by formula -NRR', where R and R' are independently hydrogen, or alkyl, aryl, aralkyl, cycloalkyl, or haloalkyl groups, as described above. "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system containing approximately 3 to 10 ring carbon atoms. Examples of non-limited monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of non-limited polycyclic cycloalkyls include 1-decalinyl, norbornyl, and adamantyl.

[0027] "Aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms, or a bicyclic fused ring system in which one or both rings are aromatic. A "heteroaryl" is a 5-7 member monocyclic or 8-11 member bicyclic aromatic ring system having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. If the bond position is not specified, the bond may be at any appropriate position as understood by those skilled in the art.

[0028] A "heterocyclyl," "heterocycle," or "heterocyclic" refers to a non-aromatic monocyclic ring structure in which one or more atoms in the ring are heteroatoms, i.e., elements other than carbon. Heteroatoms are typically O, S, or N atoms. Examples of heterocyclyl groups include piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azetidine, oxirane, or aziridine. A "spiroheterocyclyl" is a spirocycle in which at least one of the rings is a heterocycle (for example, at least one of the rings is aziridinyl, azetidinyl, furanil, morpholinyl, or piperazinyl).

[0029] The combinations of substituents and bonding patterns are those that result in stable compounds, as will be understood by those skilled in the art. Terms in parentheses and multiple parentheses are intended to clarify the bonding relationships to those skilled in the art. For example, the term ((R)alkyl) means an alkyl substituent further substituted with substituent R.

[0030] R 3a However, some examples of compounds in which the substituent is located at the para position relative to imidazole are shown below. [ka]

[0031] R 4a However, some examples of compounds in which substituents are located in the para position relative to the amide moiety are shown below. [ka]

[0032] The present invention encompasses all forms of pharmaceutically acceptable salts of the compound. A pharmaceutically acceptable salt is one in which its counterion does not significantly contribute to the physiological activity or toxicity of the compound and functions as a pharmacological equivalent itself. These salts can be prepared using commercially available reagents according to common organic techniques. Some forms of anionic salts include acetate, ascilate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and quinowheate. Some forms of cationic salts include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0033] Some compounds of the present invention exist in stereoisomeric form, including those with a carbon atom below the specified carbon in their structure. The present invention encompasses compounds in all stereoisomeric forms, including enantiomers and diastereomers. Methods for producing and separating stereoisomers are known in the art. The present invention encompasses compounds in all tautomeric forms. The present invention encompasses atropisomers and rotational isomers.

[0034] This invention encompasses all isotopes of atoms present in a compound. Isotopes include atoms with the same atomic number but different mass numbers. Generally speaking, but not limited to, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 11 C, 13 C and 14 The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described herein, using appropriately isotope-labeled reagents instead of the unlabeled reagents used in other cases. Such compounds have a variety of potential uses, for example, as reagents for measuring standard and biological activity. If the isotope is stable, such compounds may preferably modify biological, pharmacological, or pharmacokinetic properties.

[0035] biological methods N-formyl peptide receptors (FPRs) are a group of chemoreceptor receptors that promote leukocyte responses during inflammation. FPRs belong to the seven-transmembrane G protein-binding receptor superfamily and bind to inhibitory G proteins (Gi). Three family members (FPR1, FPR2, and FPR3) have been identified in humans, found in diverse distributions primarily in bone marrow cells, and have also been reported in multiple organs and tissues. After binding to an agonist, FPRs facilitate intracellular signaling, Ca2+ 2. 2+It activates numerous physiological pathways, including recruitment and transcription. The family interacts with a diverse range of ligands, including proteins, polypeptides, and fatty acid metabolites, that activate both pro-inflammatory and resolving downstream responses. The activity of the compounds of the present invention was measured using cyclic adenosine monophosphate (cAMP) assays of FPR2 and FPR1.

[0036] FPR2 and FPR1 Cyclic Adenosine Monophosphate (cAMP) Assay A mixture of forskolin (final 5 μM for FPR2 or 10 μM for FPR1) and IBMX (final 200 μM) was added to 384-well proxiplates (Perkin-Elmer) pre-dotted with test compound / DMSO (final 1%) at final concentrations ranging from 0.020 nM to 100 μM. Chinese hamster ovary (CHO) cells overexpressing human FPR1 or human FPR2 receptors were cultured in F-12 (Ham) medium supplemented with 10% modified FBS, 250 μg / ml zeosin, and 300 μg / ml hygromycin (Life Technologies). The reaction was initiated by adding 2,000 human FPR2 cells / well or 4,000 human FPR1 cells / well to Dulbecco PBS (containing calcium and magnesium) (Life Technologies) supplemented with 0.1% BSA (Perkin-Elmer). The reaction mixture was incubated at room temperature for 30 minutes. Intracellular cAMP levels were measured using the HTRF HiRange cAMP assay reagent kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptotate conjugate anti-cAMP and d2 fluorohole-labeled cAMP were prepared separately in the supplied lysis buffer. After the reaction was complete, cells were lysed with equal volumes of d2 cAMP and anti-cAMP solutions. After incubation at room temperature for 1 hour, time-resolved fluorescence intensity was measured using Envision (Perkin-Elmer) for excitation at 400 nm and dual emission at 590 nm and 665 nm. Calibration curves were created by plotting the fluorescence ratio of the emission intensity at 665 nm and 590 nm against the cAMP concentration, using external cAMP standards at concentrations ranging from 1 μM to 0.1 pM. Next, the intensity and activity of compounds in inhibiting cAMP production were determined by fitting them to a four-parameter logistic coefficient equation, where the cAMP level was plotted against the compound concentration.

[0037] The examples disclosed below were tested in the above-mentioned FPR2 and FPR1 cAMP assays and were found to have FPR2 and / or FPR1 agonist activity. Table 1 below shows the EC2 levels measured in the FPR2 and FPR1 cAMP assays for the following examples. 50 List the values. Table 1 [Table 1] [Table 2] [Table 3]

[0038] Pharmaceutical composition and method of use The compounds of this invention are used to treat Behçet's disease, Sweethe's disease, systemic lupus erythematosus (SLE), Wegner granulomatosis, viral infections, diabetes, amputation, cancer, bacterial infections, physical injuries including trauma and radiation exposure, vasoconstriction, anaphylactic reactions, allergic reactions, rhinitis, shock (endotoxic, hemorrhagic, traumatic, splenic ischemic, and circulatory shock), rheumatoid arthritis, gout, psoriasis, benign prostatic hyperplasia, myocardial ischemia, myocardial infarction, heart failure, brain injury, lung disease, COPD, COAD, cold, and acute lung injury. It may be administered to mammals, preferably humans, to treat various symptoms and disorders related to the FPR2 receptor, such as acute respiratory distress syndrome, chronic bronchitis, emphysema, asthma (allergic and non-allergic asthma), cystic fibrosis, renal fibrosis, nephropathy, glomerular disease, ulcerative colitis, IBD, Crohn's disease, periodontitis, pain, Alzheimer's disease, AIDS, uveoid glaucoma, conjunctivitis, Sjögren's syndrome, rhinitis, neuroinflammatory diseases including atherosclerosis and multiple sclerosis, stroke, sepsis, etc.

[0039] Unless otherwise specified, the following terms have their defined meanings. The term “subject” means any human or other mammalian species that may benefit from treatment with FPR2 and / or FPR1 agonists, as understood by those skilled in the art. Some subjects include humans of an age with risk factors for cardiovascular disease. Common risk factors include age, sex, weight, family history, sleep apnea, alcohol or tobacco use, lack of exercise, arrhythmias, or signs of insulin resistance, such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). The term “patient” means a human being suitable for treatment, as defined by those skilled in the art. “To treat” or “treatment” extends to the treatment of a patient or subject, as understood by those skilled in the art. “To prevent” or “prevention” extends to the prophylactic treatment of an asymptomatic condition in a patient or subject (i.e., prevention and / or risk reduction), aimed at reducing the likelihood of the development of a clinical condition, as understood by those skilled in the art. Patients are selected for prophylactic treatment based on factors known to increase their risk of developing clinical conditions compared to the general population. “Therapeutably effective dose” means the amount of compound that is effective, as understood by those skilled in the art.

[0040] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) to (II) in combination with a pharmaceutical carrier. Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) to (II) in combination with at least one other therapeutic agent and pharmaceutical carrier.

[0041] "Pharmaceutical composition" means a composition comprising the compound of the present invention in combination with at least one further pharmaceutically acceptable carrier. "pharmaceutically acceptable carrier" means a medium generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal, and includes adjuvants, excipients, or vehicles such as diluents, preservatives, bulking agents, flow regulators, disintegrants, wetting agents, emulsifiers, anti-settling agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the characteristics of the administration method and dosage form.

[0042] Medicinally acceptable carriers are formulated according to a number of well-known factors within the scope of the art. These include, but are not limited to, the type and properties of the activator being formulated; the target to which the composition containing the activator is administered; the intended route of administration of the composition; and the therapeutic indicator being targeted. Medicinally acceptable carriers encompass both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers may contain, in addition to the activator, many different components and additives, which are incorporated into the composition for various reasons, such as stabilizing the activator. Such further components are binders, etc., well-known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in various readily available sources, such as Allen, LV, Jr., et al., Remington: The Science and Practice of Pharmacy (Vol. 2), 22nd edition, Pharmaceutical Press (2012).

[0043] In particular, when provided as a single dose unit, there is a possibility of chemical interactions between the combined active ingredients. For this reason, when the compound of the present invention and a second therapeutic agent are combined in a single dose unit, the active ingredients are combined in the single dose unit, but the active ingredients are formulated so that physical contact between them is minimized (i.e., reduced). For example, one of the active ingredients may be enterically coated. Enteric coating one of the active ingredients not only makes it possible to minimize contact between the combined active ingredients, but also makes it possible to regulate the release of one of these ingredients in the gastrointestinal tract so that one of these ingredients is released in the intestine rather than in the stomach. One of the active ingredients may be coated with a material that influences sustained release throughout the gastrointestinal tract and helps to minimize physical contact between the combined active ingredients. Furthermore, a sustained-release ingredient may be additionally enterically coated so that its release occurs only in the intestine. Another approach involves formulations of combination products in which, in order to further isolate the active ingredients, one component is coated with a sustained-release and / or enteric-release polymer, and the other component is also coated with a polymer such as low-viscosity grade hydroxypropyl methylcellulose (HPMC), or other suitable material known in the art. The polymer coating serves to form an additional barrier against interaction with the other component.

[0044] Another aspect of the present invention is a treatment for heart disease comprising administering a therapeutically effective amount of a compound of formulas (I) to (II) to a patient. Another aspect of the present invention is a method for treating a heart disease, wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and iatrogenic cardiac injury.

[0045] It will be understood that the treatment or prevention of heart failure may also encompass the treatment or prevention of cardiovascular events. The treatment or prevention referred to herein means the treatment or prevention of specific negative signs or symptoms that are associated with or result from the consequences of a cardiovascular event. For example, treatment or prevention includes reducing or preventing negative changes in left ventricular diameter reduction, cardiac weight, lung weight, myocyte cross-sectional area, pressure-load-induced cardiac fibrosis, stress-induced cellular senescence, and / or cardiac hypertrophic characteristics, or any combination thereof, that are associated with or result from a cardiovascular event. Treatment may be administered with or in response to a cardiovascular event formulation to mitigate negative effects. Prevention encompasses proactive or prophylactic treatments that can prevent cardiovascular events or reduce the development of negative effects of cardiovascular events.

[0046] In one embodiment, the present invention provides the use of compounds of formulas (I) to (II) or pharmaceutically acceptable salts thereof for the manufacture of pharmaceutical compositions for treating or preventing heart failure, such as heart failure derived from hypertension, ischemic heart disease, non-ischemic heart disease, exposure to cardiotoxic compounds, myocarditis, Kawasaki disease, type 1 and type 2 diabetes, thyroid disease, viral infection, periodontitis, drug poisoning, alcohol poisoning, pericarditis, atherosclerosis, vascular disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial infarction, atrial fibrosis, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, coronary artery bypass surgery, pacemaker implantation, starvation, eating disorders, muscular dystrophy, and genetic defects. Preferably, the heart failure to be treated is diastolic heart failure, heart failure with reduced left ventricular systolic function (HF). R EF), heart failure with preserved left ventricular systolic function (HF) P This includes EF, acute heart failure, and chronic heart failure of ischemic and non-ischemic origin.

[0047] In one embodiment, the present invention provides a use of compounds of formulas (I) to (II) for the treatment of systolic and / or diastolic dysfunction, wherein the compounds are administered in a therapeutically effective amount to increase the ability of cardiomyocytes to contract and relax, thereby increasing the filling and emptying capacity of both the right and left ventricles, preferably the left ventricle. In yet another embodiment, the present invention provides a use of the compounds of formulas (I) to (II) for the treatment of heart failure, wherein the compounds are administered in a therapeutically effective amount to increase the contractility of the left ventricle.

[0048] In yet another embodiment, the present invention provides a use of the compounds of formulas (I) to (II) for the treatment of heart failure, wherein the compounds are administered in a therapeutically effective amount to reduce fibrosis in cardiac tissue. Another aspect of the present invention is a method for treating heart disease in which the treatment of heart disease occurs after a myocardial infarction. Another aspect of the present invention is a method for treating heart disease, comprising administering to a patient a therapeutically effective amount of a compound of formulas (I) to (II) in combination with other therapeutic agents.

[0049] The compounds of the present invention may be administered by any suitable means, for example, orally; sublingually; buccally; parenterally by techniques such as subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion (e.g., as sterile injection aqueous or non-aqueous solution or suspension), including administration into the nasal mucosa, by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository. The compounds may be administered alone, but will generally be administered with a pharmaceutical carrier selected based on a chosen route of administration and standard pharmacoagulation.

[0050] The dosage regimen of the compounds of the present invention will naturally vary depending on known factors such as the pharmacokinetic properties of the particular drug and its method and route of administration; the recipient's species, age, sex, health status, medical condition, and weight; the characteristics and severity of symptoms; the type of treatment currently being administered; the frequency of treatment; the route of administration, the patient's renal and hepatic function, and the desired effect.

[0051] As a general guideline, the daily oral dose of each active ingredient, when used for the intended effect, ranges from about 0.01 to about 5000 mg per day, preferably from about 0.1 to about 1000 mg, and most preferably from about 0.1 to about 250 mg. For intravenous administration, the most preferred dose would be in the range of about 0.001 to about 10 mg / kg / min during continuous metered infusion. The compounds of the present invention may be administered as a single dose per day, or the total daily dose may be divided into 2, 3, or 4 doses per day.

[0052] Suitable dosage forms (pharmaceutical compositions) may contain approximately 1 milligram to approximately 2000 milligrams of the active ingredient per dose unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of approximately 0.1 to 95% by weight, based on the total weight of the composition. A typical capsule for oral administration contains at least one compound of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and packed into No. 1 gelatin capsules. A typical injectable formulation is prepared by aseptically placing at least one compound of the present invention (250 mg) into a vial, aseptically lyophilizing and sealing it. When ready for use, the contents of the vial are mixed with 2 mL of physiological saline to prepare the injectable formulation.

[0053] The compounds of the present invention may be used in combination with other suitable therapeutic agents useful for treating the above-mentioned diseases or disorders, such as anti-atherosclerotic agents, anti-dyslipidemia agents, antidiabetic agents, antihyperglycemic agents, anti-hyperinsulinemia agents, antithrombotic agents, anti-retinopathy agents, antineuropathy agents, antinephropathy agents, anti-ischemic agents, antihypertensive agents, anti-obesity agents, anti-hyperlipidemia agents, anti-hypertriglyceridemia agents, anti-hypercholesterolemia agents, anti-restenosis agents, anti-pancreatic agents, lipid-lowering agents, appetite suppressants, memory enhancers, anti-dementia agents, cognitive enhancers, appetite suppressants, agents for treating heart failure, agents for treating peripheral artery disease, agents for treating malignant tumors, and anti-inflammatory agents.

[0054] The compounds of the present invention may be used in combination with at least one heart failure agent selected from the following: loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists, nitroxyl donors, RXFP1 agonists, APJ agonists, and inotropic agents. These agents include, but are not limited to, furosemide, bumetanide, torsemide, sacvitoral valsartan, thiazide diuretics, captopril, enalapril, lisinopril, carvedilol, metoporol, bisoprolol, celeracin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irvestalin, losartan, olmesartan, telmisartan, and valsartan.

[0055] The compounds of the present invention may be used in combination with at least one of the following therapeutic agents for treating atherosclerosis: hyperlipidemia agents, agents that increase plasma HDL, anti-hypercholesterolemia agents, cholesterol biosynthesis inhibitors (such as HMG-CoA reductase inhibitors), LXR agonists, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid chelating agents (such as anion exchange resins or quaternary amines (e.g., cholestylamine or colestipol)), low-density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, sipofibrate, gemfibrizol, vitamin B6, vitamin B12, antioxidant vitamins, β-blockers, antidiabetic agents, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin, and fibric acid derivatives.

[0056] The compounds of the present invention may be used in combination with at least one of the following therapeutic agents when treating with a cholesterol biosynthesis inhibitor, particularly an HMG CoA reductase inhibitor. Examples of suitable HMG CoA reductase inhibitors include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin.

[0057] The compounds of the present invention may be used in combination with at least one of the following antidiabetic agents, depending on the desired targeted therapy. Studies have shown that the regulation of diabetes and hyperlipidemia can be further improved by adding a second agent to the treatment regimen. Examples of antidiabetic agents include sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, trazamide, glibride, gliclazide, glinase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as siglitazone, pioglitazone, troglitazone, and rosiglitazone), and related insulin sensitizers such as selective and non-selective activators of PPARα, PPARβ, and PPARγ; dehydroepiandrosterone (DHEA or its conjugated sulfate ester, also known as DHEA·SO4). This includes, but is not limited to; antiglucocorticoids; TNFα inhibitors; dipeptidyl peptidase IV (DPP4) inhibitors (such as sitagliprin and saxagliptin); GLP-1 agonists or analogs (such as exenatide); α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose); pramulintide (a synthetic analog of the human hormone amylin); other insulin secretagogues (such as repaglinide, glikidone, and nateglinide); insulin; and the aforementioned therapeutic agents for treating atherosclerosis.

[0058] The compounds of the present invention may be used in combination with at least one anti-obesity agent selected from the following: phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, fentyramine, β3-adrenergic receptor agonist; sibutramine, gastrointestinal lipase inhibitor (such as orlistat), and leptin. Other agents used in the treatment of obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholecystokinin, bombesin, amylin, histamine H3 receptor, dopamine D2 receptor modulator, melanocyte-stimulating hormone, corticotrophin-releasing factor, galanin, and gamma-aminobutyric acid (GABA).

[0059] The compounds of the present invention are also useful as standard or reference compounds, for example, as quality standards or controls, in tests or assays involving FPR2. Such compounds may be provided in commercially available kits for use, for example, in pharmaceutical research involving FPR2 activity. For example, the compounds of the present invention may be used as a reference in an assay to compare the known activity of a compound with unknown activity. This assures the experimenter that the assay was performed properly and provides a standard for comparison, especially when the test compound is a derivative of the reference compound. When a novel assay or protocol is developed, its effectiveness can be tested using the compounds of the present invention. The compounds of the present invention may also be used in diagnostic assays involving FPR2.

[0060] The present invention also encompasses manufactured products. As used herein, manufactured products include, but are not limited to, kits and packages. A manufactured product of the present invention includes (a) a first container; (b) a pharmaceutical composition contained in the first container (the composition comprising a first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof); and (c) a statement indicating that the pharmaceutical composition can be used for the treatment of dyslipidemia and its sequelae. In another embodiment, the statement indicates that the pharmaceutical composition can be used in combination with a second therapeutic agent (as above) for the treatment of dyslipidemia and its sequelae. The manufactured product may further include (d) a second container (where components (a) and (b) are placed in the second container, and component (c) is placed inside or outside the second container). To place in the first and second containers means that each container holds the components within its area. The first container is the container used to hold the pharmaceutical composition. This container may be for manufacturing, storage, transport, and / or individual / bulk sales. The first container shall include bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other container used in the manufacturing, holding, storage, or distribution of pharmaceutical formulations. The second container is used to hold the first container and, optionally, to hold the accompanying documentation. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The accompanying documentation may be physically attached to the outside of the first container by tape, adhesive, staples, or other means of attachment, or it may be placed inside the second container without any physical means of attachment to the first container. Alternatively, the accompanying documentation may be placed outside the second container. If placed outside the second container, it is preferable that the accompanying documentation be physically attached by tape, adhesive, staples, or other means of attachment. Alternatively, it can be brought close to or in contact with the outside of the second container without physically adhering to it.The package insert is a label, tag, marker, etc., that contains information relating to the pharmaceutical composition contained in the first container. This information will typically be determined by the regulatory authority that controls the region in which the product is sold (e.g., the U.S. Food and Drug Administration). Preferably, the package insert specifically contains a statement of the matters for which the pharmaceutical composition is authorized. The package insert may be made of any material on which a person can read the information contained therein or on it. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, wheel, or a paper or plastic seal, etc.) on which the desired information is formed (e.g., printed or pasted).

[0061] chemical method The abbreviations used herein are defined as follows: "1x" for one, "2x" for two, "3x" for three, "℃" for degrees Celsius, "aq" for aqueous solution, "Col" for column, "eq" for equivalent, "g" for gram, "mg" for milligram, "L" for liter, "mL" for milliliter, "μL" for microliter, "N" for normal, "M" for mole, "nM" for nanomoles, and for moles "mol" is used for millimoles, "mmol" for millimoles, "min" for minutes, "h" for hours, "rt" for room temperature, "ON" for overnight, "atm" for air, "psi" for pounds per square inch, "conc." for concentrates, "aq" for aqueous solutions, "sat" or "sat'd" for saturation, "MW" for molecular weight, "mw" or "μwave" for microwaves, "mp" for melting point, "Wt" for weight, and "MS" or "Mass" for mass spectrometry. "Spec" is used for electron jet ionization mass spectrometry, "ESI" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high-pressure liquid chromatography, "RP HPLC" for reversed-phase HPLC, "TLC" or "tlc" for thin-layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser spectroscopy, "1H" for proton, "δ" for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quadrant, "m" for multiplet, "br" for broad, and "Hz" for Hertz. "α", "β", "R", "S", "E", and "Z" are stereochemical designations familiar to those skilled in the art.

[0062] [Table 4]

[0063] The compounds of the present invention can be produced by many methods known to those skilled in the art in the field of organic synthesis. The compounds of the present invention can be produced by the methods described below, along with synthetic methods known in the field of organic synthesis chemistry, or by modifications thereof as understood to those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for the transformation to take place. Those skilled in the art in organic synthesis will understand that the functional groups present on the molecule must be compatible with the proposed transformation. This will sometimes necessitate the decision to modify the order of the synthetic steps or to choose a particular process scheme in preference to other schemes in order to obtain the desired compound of the present invention.

[0064] The novel compounds of the present invention can be prepared using the reactions and techniques described in this section. Furthermore, in the description of the synthesis methods below, all proposed reaction conditions, including solvent selection, reaction environment, reaction temperature, experimental duration, and workup procedures, are understood to be selected as standard conditions for the reaction, readily apparent to those skilled in the art. Limitations on substituents suitable for the reaction conditions will be obvious to those skilled in the art, and alternative methods must be used in such cases.

[0065] synthesis R 1 , R 2 , R 3 , and R 4Compounds of formula (I), as defined below, can be prepared by the exemplary methods described in the following scheme and examples, as well as by procedures in relevant published literature used by those skilled in the art. Exemplary reagents and procedures for these reactions are shown below and in the examples. Protection and deprotection in the following methods can be carried out by procedures well known in the art (see, for example, Wuts, PGM et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007)). General methods of organic synthesis and functional group transformation are described in the following: Trost, BM et al. (eds.), Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, NY (1991); Smith, MB et al., March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 6th Edition, Wiley & Sons, New York, NY (2007); Katritzky, AR et al. (eds.), Comprehensive Organic Functional Groups Transformations II, 2nd Edition, Elsevier Science Inc., Tarrytown, NY (2004); Larock, RC, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, NY (1999), and the references listed therein. [ka]

[0066] R 3 The aminoimidazole compounds of the present invention, in which is a substituted phenyl compound, can be produced using a general route as described in Scheme 1.

[0067] Scheme 1 [ka]

[0068] Substituted alpha-bromoketone G1a can be subjected to a substitution reaction with aniline in a suitable solvent such as DMF in the presence of an inorganic base such as sodium bicarbonate, and then subjected to a condensation reaction with an excess amount of cyanamide in a solvent such as MeOH or NMP to obtain G1b. Substituted aminoimidazole G1c can be obtained by coupling it with an aryl carboxylic acid activated, for example, by HATU or BOP, in the presence of a tertiary amine base (e.g., TEA, DIEA).

[0069] Experimental method In the illustrative examples, unless otherwise specified, the following methods were used. Purification of intermediates and final products was carried out by either normal-phase or reverse-phase chromatography. Unless otherwise specified, normal-phase chromatography was performed using pre-packed SiO2 cartridges and eluting with either a hexane and ƒ or DCM and MeOH gradient.

[0070] The reversed-phase preparative HPLC in the examples was performed using a Waters XBridge C18 column (19 x 200 mm, 5 μm particles) and with UV and LC-MS detection using a variable gradient of mobile phase A (95% water, 5% ACN) and mobile phase B (5% water, 95% ACN) containing 0.1% TFA or 10 mM NH4OAc.

[0071] Reverse-phase analytical HPLC / MS was performed using a Waters Acquity system coupled with a Waters Micromass® ZQ Mass Spectrometer.

[0072] Method A: Apply a linear gradient from 0 to 100% B over 3 minutes, with a holding time of 0.75 minutes at 100% B; UV visualization (220nm) Column: Waters BEH C18 2.1x50mm Flow rate: 1.0mL / min Solvent A: 10 mM NH4OAc, 95% water, 5% ACN Solvent B: 10 mM NH4OAc, 5% water, 95% ACN

[0073] Method B: Apply a linear gradient from 0 to 100% B over 3 minutes, with a holding time of 0.75 minutes at 100% B; UV visualization (220nm) Column: Waters BEH C18 2.1x50mm Flow rate: 1.0mL / min Solvent A: 0.1% TFA, 95% water, 5% ACN Solvent B: 0.1% TFA, 5% water, 95% ACN

[0074] Method C: Apply a linear gradient from 2% to 98% B over 1 minute, with a holding time of 0.50 minutes at 100% B; UV visualization (220nm) Column: Waters BEH C18 2.1x50mm Flow rate: 0.8mL / min Solvent A: Water containing 0.05% TFA Solvent B: ACN containing 0.05% TFA

[0075] 1 ¹H NMR spectra were obtained using a Bruker spectrometer operated at frequencies of 300 MHz, 400 MHz, or 500 MHz. Spectral data are reported in the format of chemical shifts (multiplicity, coupling constant, and number of hydrogen atoms). Chemical shifts are identified in downfield ppm of the internal standard tetramethylsilane (d unit, tetramethylsilane = 0 ppm), and / or 1It is identified by mentioning the solvent peaks that appear in the 1H NMR spectrum at 2.50 ppm for (CD3)2SO, 3.31 ppm for CD3OD, 1.94 ppm for CD3CN, and 7.26 ppm for CDCl3.

[0076] Example 1: N-[1-(2,6-difluoro-4-methoxyphenyl)-4-phenyl-1H-imidazole-2-yl]-4-(difluoromethoxy)benzamide [ka]

[0077] Intermediate 1: 1-(2,6-difluoro-4-methoxyphenyl)-4-phenyl-1H-imidazole-2-amine [ka]

[0078] To a stirred solution of 2,6-difluoro-4-methoxyaniline in DMF (3.8 mL), sodium bicarbonate (71 mg, 0.85 mmol) was added at room temperature, followed by 2-bromo-1-phenylethanone (180 mg, 0.88 mmol). The resulting solution was stirred at room temperature for 16 hours. Cyanamide (264 mg, 6.28 mmol) was added to the resulting intermediate. The resulting solution was heated at 95°C for 16 hours. The crude material was purified by reverse-phase HPLC to obtain intermediate 1 (25 mg, 0.084 mmol, yield 13%). MS(ESI) m / z: 302.3(M+H) + ; 1 H NMR (500MHz, DMSO-d6) δ 7.65(brd,J=7.6Hz,2H), 7.31(t,J=7.6Hz,2H), 7.23-7.10(m,2H), 6.96(brd,J=9.8Hz,2H), 5.60(s,2H), 3.84(s,3H)

[0079] Example 1: N-[1-(2,6-difluoro-4-methoxyphenyl)-4-phenyl-1H-imidazole-2-yl]-4-(difluoromethoxy)benzamide To a stirred solution of 4-(difluoromethoxy)benzoic acid (79 mg, 0.42 mmol) in DMF (0.25 mL), BOP (190 mg, 0.42 mmol) was added, followed by DIEA (0.15 mL, 0.84 mmol). The resulting solution was stirred at room temperature for 15 minutes. To the resulting mixture, a solution of intermediate 1 (25 mg, 0.084 mmol) in DMF (0.25 mL) was added, and the reaction product was heated at 50°C for 16 hours. The crude material was purified by reverse-phase HPLC to obtain Example 1 (18 mg, 0.038 mmol, yield 45%). MS(ESI) m / z: 472.2(M+H) +

[0080] The following examples listed in Table 2 were manufactured as described for Example 1.

[0081] Table 2 [Table 5] [Table 6] [Table 7] [Table 8] [Table 9]

[0082] [Table 10] [Table 11] [Table 12] [Table 13]

[0083] Example 44: 1-(2,6-difluoro-4-methoxyphenyl)-2-[4-(difluoromethoxy)benzamide]-N-[(1H-pyrazole-3-yl)methyl]-1H-imidazole-4-carboxamide [ka]

[0084] Intermediate 2: 1-(2,6-difluoro-4-methoxyphenyl)-2-(4-(difluoromethoxy)benzamide)-1H-imidazole-4-carboxylic acid [ka]

[0085] Compound 38 (130 mg, 0.27 mmol) was mixed in THF (1 mL) and MeOH (0.25 mL) and then 1N NaOH solution (2.7 mL, 2.7 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH=1 using 1N HCl, and the mixture was extracted with SiO(3x). The extracts were combined, dried (Na2SO4), filtered, and evaporated under reduced pressure to obtain intermediate 2, which was used without further purification.

[0086] Example 44: 1-(2,6-difluoro-4-methoxyphenyl)-2-[4-(difluoromethoxy)benzamide]-N-[(1H-pyrazole-3-yl)methyl]-1H-imidazole-4-carboxamide To a stirred solution of intermediate 2 (10 mg, 0.023 mmol) in DMF (0.40 mL), BOP (15 mg, 0.034 mmol) was added, followed by DIEA (0.020 mL, 0.11 mmol). The resulting solution was stirred at room temperature for 15 minutes. (1H-pyrazole-3-yl)methanamine (4 mg, 0.046 mmol) was added to the resulting mixture, and the reaction was stirred at room temperature for 16 hours. The crude material was purified by reverse-phase HPLC to obtain the indicated compound (5 mg, 0.009 mmol, 40% yield). MS(ESI) m / z: 519.1(M+H) + ; 1 H NMR (500MHz, DMSO-d6) δ 8.33(s,1H), 7.94(s,1H), 7.86(brd,J=8.5Hz,2H), 7.58(brs,1H), 7.34(t,J=73.6Hz,1H), 7.26 (brd,J=8.5Hz,2H), 6.94(brd,J=10.4Hz,2H), 6.17(s,1H), 4.46(brd,J=5.8Hz,2H), 3.79(s,3H)

[0087] The following embodiments listed in Table 3 were manufactured as described in Example 44.

[0088] Table 3 [Table 14] [Table 15] [Table 16] [Table 17] [Table 18]

[0089] Example 63: N-[1-(2,6-difluoro-4-methoxyphenyl)-4-(piperidine-4-yl)-1H-imidazole-2-yl]-4-(difluoromethoxy)benzamide [ka]

[0090] Intermediate 3: tert-butyl 4-(1-(2,6-difluoro-4-methoxyphenyl)-2-(4-difluoromethoxy)benzamide)-1H-imidazole-4-yl)piperidine-1-carboxylate To a solution of intermediate 3 (prepared as described in Example 1) (29 mg, 0.50 mmol) in DCM (0.5 mL), TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature for 16 hours. The material was purified by reverse-phase HPLC to obtain Example 63 (14 mg, 0.29 mmol, 57% yield). MS(ESI) m / z: 479.2(M+H) + ; 1 H NMR (500MHz, DMSO-d6) δ 7.89(brd,J=8.5Hz,2H), 7.29(t,J=73.9Hz,1H), 7.19(brd,J=8.5Hz,2H), 7.00(s ,1H), 6.95(brd,J=10.1Hz,2H), 3.82(s,3H), 3.30-3.24(m,1H), 3.20-3.14(m,1H) , 3.09(brd,J=11.9Hz,2H), 2.79-2.65(m,3H), 2.56(brs,4H), 2.52(brs,6H), 1.97 (brd,J=11.6Hz,2H), 1.83(s,3H), 1.54(brd,J=10.4Hz,2H), 1.01(d,J=6.4Hz,2H)

[0091] Example 64: 4-(difluoromethoxy)-N-[1-(4-methoxyphenyl)-4-(piperidine-3-yl)-1H-imidazole-2-yl]benzamide was prepared as described in Example 63. [ka]

[0092] The material was purified by reverse-phase HPLC to obtain Example 64 (21.3 mg, 0.05 mmol, yield 87%). MS(ESI)m / z:443.1(M+H) + ; 1 H NMR (500MHz, DMSO-d6) δ 7.95(brd,J=7.3Hz,2H), 7.46(brs,2H), 7.31(t,J=73.8Hz,1H), 7.22(brd,J=8.2Hz,2H), 7.17(brs,1H), 7.15(brs,1H), 7.02(brd,J=8.2Hz, 2H), 3.77(s,3H), 3.30(brs,1H), 3.05(brd,J=8.9Hz,1H), 2.84(brs,1H), 2.78-2.63(m,2H), 2.07-2.01(m,1H), 1.74(brs,1H), 1.58(brs,2H)

[0093] Example 65: N-[1-(2,6-difluoro-4-methoxyphenyl)-4-[1-(ethanesulfonyl)piperidine-4-yl]-1H-imidazole-2-yl]-4-(difluoromethoxy)benzamide [ka]

[0094] To a solution of compound 63 (10 mg, 0.021 mmol) in DCM (0.4 mL), ethanesulfonyl chloride (16 mg, 0.12 mmol), followed by DIEA (0.027 mL, 0.16 mmol), was added. The resulting solution was stirred overnight at room temperature. The crude material was purified by reverse-phase HPLC to obtain Example 65 (2 mg, 0.003 mmol, yield 13%). MS(ESI) m / z: 571.2(M+H) + ; 1H NMR (500MHz, DMSO-d6) δ 7.89(brs,2H), 7.30(s,2H), 7.20(s,2H), 7.10(s,1H), 3.81(brs,1H), 3.68(brd,J=11.9Hz,2H), 3.08(q,J=7.3Hz,2H), 3.00(s,1 H), 2.97-2.89(m,3H), 2.55(s,6H), 2.51(brs,8H), 2.10-2.05(m,2H), 1.80(brd,J=6.4Hz,1H), 1.24(t,J=7.3Hz,4H), 1.18(s,1H)

[0095] Example 66: 4-[1-(2,6-difluoro-4-methoxyphenyl)-2-[4-(difluoromethoxy)benzamide]-1H-imidazole-4-yl]-N-ethylpiperidine-1-carboxamide [ka]

[0096] To a solution of compound 63 (10 mg, 0.021 mmol) in DCM (0.4 mL), ethyl isocyanate (13 mg, 0.13 mmol), followed by DIEA (0.027 mL, 0.16 mmol), was added. The resulting solution was stirred overnight at room temperature. The crude material was purified by reverse-phase HPLC to obtain Example 66 (3.0 mg, 0.004 mmol, yield 15%). MS(ESI) m / z: 550.22(M+H) + ; 1 H NMR (500MHz, DMSO-d6) δ 7.90(brd,J=7.7Hz,2H), 7.39(s,1H), 7.24(s,1H), 7.17(brd,J=8.0Hz,2H), 7 .09(s,1H), 6.98-6.89(m,3H), 4.01(brd,J=13.2Hz,2H), 3.89(s,1H), 3.83(br s,2H), 3.11-3.03(m,2H), 2.94(q,J=7.3Hz,1H), 2.78(brt,J=11.9Hz,2H), 1.9 8-1.91(m,2H), 1.50-1.39(m,2H), 1.19(t,J=7.3Hz,1H), 1.03(t,J=7.1Hz,3H)

[0097] Example 67: N-{4-[1-(3-carbamoylpropanoyl)piperidin-4-yl]-1-(2,6-difluoro-4-methoxyphenyl)-1H-imidazol-2-yl}-4-(difluoromethoxy)benzamide

Chem.

[0098] To a solution of 4-amino-4-oxobutanoic acid (5 mg, 0.042 mmol) in DMF (0.2 mL) was added BOP (12 mg, 0.026 mmol), followed by DIEA (0.018 mL, 0.11 mmol). The resulting solution was stirred at room temperature for 10 minutes. To this mixture was added a solution of Example 63 (10 mg, 0.021 mmol) in DMF (0.2 mL). The reaction mixture was stirred at room temperature overnight. The crude material was purified by reverse-phase HPLC to give Example 67 (1 mg, 0.002 mmol, 9% yield). MS (ESI) m / z: 578.14 (M+H)<清 + ;<清 1 H NMR (500 MHz, DMSO-d6) δ 7.90 (brd, J = 8.5 Hz, 2H), 7.45 (s, 1H), 7.29 (brd, J = 13.4 Hz, 1H), 7.19 (brd, J = 8.5 Hz, 2H), 7.16 (s, 1H), 7.02 (s, 1H), 6.96 (brd, J = 10.4 Hz, 2H), 6.71 (brs, 1H), 4.44 (brd, J = 13.1 Hz, 1H), 3.96 (brd, J = 13.1 Hz, 1H), 3.82 (s, 3H), 3.12 (brt, J = 12.7 Hz, 1H), 2.92 - 2.83 (m, 1H), 2.67 (brt, J = 12.5 Hz, 1H), 2.36 - 2.28 (m, 2H), 2.04 (brd, J = 13.1 Hz, 1H), 1.97 (brd, J = 11.9 Hz, 1H), 1.90 (s, 2H), 1.58 - 1.48 (m, 1H), 1.45 - 1.35 (m, 1H)

[0099] Examples 68 and 69 (Table 3) were prepared as described in Example 67.

[0100] Example 70: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-isopropyl-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide [ka]

[0101] Intermediate 4: 1-(2,6-difluoro-4-methoxyphenyl)guanidine To a solution of N,N'-di-Boc-1H-pyrazole-1-carboxamidine (780 mg, 2.5 mmol) in chloroform (5 mL), 2,6-difluoro-4-methoxyaniline (400 mg, 2.5 mmol) was added, and the mixture was stirred at 55°C for 16 hours. Another 200 mg of N,N'-di-Boc-1H-pyrazole-1-carboxamidine was added, and heating was continued for a further 24 hours. The mixture was cooled to room temperature, then subjected to silica gel chromatography, and purified by elution with 2-20% siRNA / hexane to obtain di-tert-butyl [(2,6-difluoro-4-methoxyphenyl)carbonimidoyl]biscarbamate (370 mg, yield 37%) as a white solid.

[0102] Next, the white solid was treated with 4N HCl (2.3 mL, 9.1 mmol) in dioxane, and the mixture was left to stand for 48 hours. The mixture was evaporated, then co-evaporated with ACN, and subsequently with diethyl ether to obtain 1-(2,6-difluoro-4-methoxyphenyl)guanidine·HCl (230 mg, 100% yield) as a white solid. MS(ESI)m / z:202.1(M+H) + ; 1 H NMR (500MHz, DMSO-d6) δ 9.29(brs,1H), 7.57(brs,4H), 6.92(d,J=9.6Hz,2H), 3.81(s,3H)

[0103] Intermediate 5: 1-(2,6-difluoro-4-methoxyphenyl)-4-isopropyl-1H-imidazole-2-amine: Intermediate 4 (24 mg, 0.10 mmol) and potassium carbonate (42 mg, 0.30 mmol) were mixed in EtOH (0.33 mL). 1-bromo-3-methylbutan-2-one (12 μl, 0.10 mmol) was added to the mixture, and the mixture was heated under reflux temperature for 10 minutes. The mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was subjected to silica gel column chromatography and purified by elution with 0.5-15% MeOH / DCM to obtain the denoted compound (15 mg, 0.06 mmol, yield 56%) as a white solid. MS(ESI) m / z: 268.1(M+H) + ; 1 H NMR (500MHz, chloroform-d) δ 6.69-6.55(m,2H), 6.27(s,1H), 4.31(brs,2H), 3.85(s,3H), 2.79(spt,J=6.7Hz,1H), 1.25(d,J=6.9Hz,6H)

[0104] Example 70: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-isopropyl-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide) To a solution of intermediate 5 (15 mg, 0.06 mmol) and 4-(difluoromethoxy)benzoic acid (16 mg, 0.084 mmol) in DMF (0.5 mL), DIPEA (0.035 mL, 0.20 mmol) was added, followed by HATU (38 mg, 0.10 mmol), and the mixture was stirred for 16 hours. The mixture was diluted with 70% HCl / hexane, washed with saturated NH4Cl and 1.5 M K2HPO4, then dried (Na2SO4), filtered, and concentrated. The residue was subjected to silica gel column chromatography, eluted with 5-40% HCl / hexane, and then purified by reverse-phase HPLC to obtain the denoted compound (10 mg, 0.022 mmol, 40% yield). MS(ESI) m / z: 438.2(M+H) + ; 1H NMR (500MHz, DMSO-d6) δ 7.91(brd,J=8.5Hz,2H), 7.30(t,J=73.6Hz,1H), 7.20(brd,J=8.2Hz,2H), 7.05(s,1H), 6 .98(brd,J=10.1Hz,2H), 3.84(s,3H), 2.95(dt,J=13.8, 6.7Hz,1H), 1.25(d,J=7.0Hz,6H)

[0105] Examples 71 and 72 (Table 3) were manufactured as described in Example 70.

[0106] Example 73: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-((5-methyl-1,3,4-oxadiazole-2-yl)methyl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide [ka]

[0107] To a solution of compound 72 (prepared as described in Example 70) (30 mg, 0.062 mmol) in DCM (0.6 mL), hydrazine (0.020 mL, 0.62 mmol) was added, and the mixture was stirred for 16 hours. The mixture was evaporated twice from the DCM and placed under vacuum to obtain N-(1-(2,6-difluoro-4-methoxyphenyl)-4-(2-hydrazinyl-2-oxoethyl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide (29 mg, 0.062 mmol, 99% yield) as a white solid. To a solution of the solid (14 mg, 0.030 mmol) and acetic acid (2.1 μl, 0.036 mmol) in dioxane (0.25 mL), 50% cyclic 1-propanephosphonic anhydride (in Â) (0.045 mL, 0.075 mmol) was added, and the reaction mixture was heated at 70°C for 1.5 hours. Fresh 50% cyclic 1-propanephosphonic anhydride (in Â) (0.045 mL, 0.075 mmol) was added, and the reaction mixture was heated at 105°C for 1.5 hours. The reaction mixture was cooled to room temperature, evaporated under a stream of nitrogen, and then filtered. The crude material was purified by reverse-phase HPLC to obtain the compound (4 mg, 7.4 micromoles, yield 25%). MS(ESI) m / z: 492.12(M+H) + ; 1 H NMR (500MHz, DMSO-d6) δ 7.82(brd,J=7.6Hz,2H), 7.31(t,J=72.9Hz,1H), 7.23(brd,J=7.3Hz,2H),7. 16(s,1H), 6.88(brd,J=11.0Hz,2H), 4.16(brs,2H), 3.76(s,3H), 2.48(s,3H)

[0108] Example 74: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-(3-hydroxycyclobutyl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide [ka]

[0109] Intermediate 6: 1-(3-(benzyloxy)cyclobutyl)-2-bromoethane-1-one A solution of 1-(3-(benzyloxy)cyclobutyl)ethane-1-one (430 mg, 2.1 mmol) in EtOH (5.3 mL) at 0°C was added dropwise to a solution of bromine (110 μl, 2.1 mmol) in EtOH (1 mL). The mixture was stirred at 0°C for 2 hours, then heated to room temperature and stirred for 16 hours. The mixture was poured into a saturated NaHCO3 solution and extracted with DCM. The organic extracts were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography and purified by elution with 0-100% siRNA / hexane to obtain intermediate 6 (280 mg, 1.0 mmol, yield 47%) as cis and trans isomers, which were used directly in the next step.

[0110] Intermediate 7: 4-(3-(benzyloxy)cyclobutyl)-1-(2,6-difluoro-4-methoxyphenyl)-1H-imidazole-2-amine Intermediate 6 (280 mg, 1.0 mmol) was added to a mixture of intermediate 4 (210 mg, 0.77 mmol) and potassium carbonate (320 mg, 2.30 mmol) in EtOH (2.6 mL), and the mixture was stirred at 80°C for 2.5 hours. The mixture was cooled to room temperature, diluted with DCM, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel flash chromatography. Purification was achieved by elution with 0-20% MeOH / DCM to obtain intermediate 7 (270 mg, 0.7 mmol, yield 91%). LCMS (Method B): Rt = 0.77 min, (M+H) + =386.1

[0111] Intermediate 8: N-(4-(3-(benzyloxy)cyclobutyl)-1-(2,6-difluoro-4-methoxyphenyl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide A solution of intermediate 7 (270 mg, 0.7 mmol) and 4-(difluoromethoxy)benzoic acid (160 mg, 0.84 mmol) in DMF (2 mL) was treated with DIPEA (0.37 mL, 2.1 mmol), followed by the addition of HATU (400 mg, 1.05 mmol), and the mixture was stirred at 80 °C for 3 days. The mixture was diluted with EtOAc, washed with water, 1N HCl and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography and eluted with 0 - 100% EtOAc / hexane for purification to obtain intermediate 8 (185 mg, 0.33 mmol, 47% yield) as a mixture of cis and trans isomers. LCMS (method B): Rt = 0.93 min, (M+H) + =556.0

[0112] Example 74: N-(1-(2,6-Difluoro-4-methoxyphenyl)-4-(3-hydroxycyclobutyl)-1H-imidazol-2-yl)-4-(difluoromethoxy)benzamide To a solution of intermediate 8 (180 mg, 0.33 mmol) in EtOH (5 mL) was added 10% Pd - C (35 mg, 0.033 mmol). The reaction was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through a Celite pad and concentrated under reduced pressure. The material was purified by reverse phase HPLC to afford the title compound (7.7 mg, 0.016 mmol, 5% yield). MS (ESI) m / z: 466.1 (M+H) + : 1 H NMR (500 MHz, DMSO - d6) δ 8.00 - 7.81 (m, 2H), 7.09 (brs, 5H), 6.95 - 6.82 (m, 1H), 4.51 - 4.32 (m, 1H), 4.31 - 4.20 (m, 1H), 3.94 - 3.86 (m, 3H), 2.45 - 2.28 (m, 2H), 2.29 - 2.14 (m, 2H)

[0113] Example 75: N-(1-(2,6-Difluoro-4-methoxyphenyl)-4-(2-azaspiro[3.3]heptan-6-yl)-1H-imidazol-2-yl)-4-(difluoromethoxy)benzamide [ka]

[0114] Intermediate 9: tert-butyl 6-acetyl-2-azaspiro[3,3]heptane-2-carboxylate To a stirred solution of N,O-dimethylhydroxylamine hydrochloride (200 mg, 2.1 mmol), 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (250 mg, 1.04 mmol), and TEA (0.7 mL, 5.18 mmol) in DCM (10 mL) at 0°C, T3P (50% in Â, 1.2 mL, 2.1 mmol) was added dropwise under an argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with Â, washed with water, 1N HCl solution, and brine, and dried over sodium sulfate to concentrate. The crude product was subjected to silica gel column chromatography and purified by elution with 0-100% EtAOc / hexane. This was then treated with methylmagnesium brominated (3M in THF) (1.1 mL, 3.2 mmol) to obtain the descriptive compound (227 mg, 0.95 mmol, 90% yield).

[0115] Intermediate 10: tert-butyl 6-(2-amino-1-(2,6-difluoro-4-methoxyphenyl)-1H-imidazole-4-yl)-2-azaspiro[3.3]heptan-2-carboxylate Intermediate 9 (220 mg, 0.92 mmol) and carbon tetrabromide (300 mg, 0.92 mmol) were added to a mixture of intermediate 4 (210 mg, 0.77 mmol) and potassium carbonate (212 mg, 1.532 mmol) in ACN (7.6 mL). The mixture was heated overnight at 70°C. The mixture was diluted with DCM and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC to obtain intermediate 10 (67 mg, 0.16 mmol, yield 21%). MS(ESI) m / z: 421.1(M+H) +

[0116] Example 75: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-(2-azaspiro[3,3]heptan-6-yl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide To a solution of intermediate 10 (67 mg, 0.16 mmol) and 4-(difluoromethoxy)benzoic acid (45 mg, 0.24 mmol) in DMF (2 mL), DIPEA (0.083 mL, 0.47 mmol) was added, followed by HATU (91 mg, 0.24 mmol), and the mixture was stirred at 80°C for 6 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was treated with 50% TFA / DCM (1.0 mL) for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC to obtain the indicated compound (18 mg, 0.036 mmol, yield 23%). MS(ESI) m / z: 491.2(M+H) + ; 1 H NMR (500MHz, methanol-d4) δ 7.88(brd,J=8.7Hz,2H), 7.23-7.15(m,2H), 7.04-6.72(m,4H), 3.85(s,3H) , 3.51-3.41(m,1H), 2.79-2.70(m,2H), 2.58-2.50(m,2H), 1.50-1.26(m,4H)

[0117] Example 76: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-(4-hydroxycyclohexyl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide [ka]

[0118] Intermediate 11: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide Intermediate 11 was prepared from intermediate 4 and 1-(1,4-dioxaspiro[4.5]decane-8-yl)ethane-1-one as described in Example 74, to obtain intermediate 11 (390 mg, 0.72 mmol, yield 63%). LCMS (Method A, Rt=0.83 min), MS(ESI) m / z: 536.0(M+H) + ; 1 H NMR (500MHz, DMSO-d6) δ 8.04-7.79(m,2H), 7.38-6.82(m,6H), 3.97-3.70(m,7H), 2.82-2.66(m,1H), 1.79-1.44(m,8H)

[0119] Intermediate 12: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-(4-oxocyclohexyl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide A mixture of intermediate 11 (390 mg, 0.73 mmol) and TFA (3 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to obtain intermediate 12 (310 mg, 0.64 mmol, yield 87%). LC-MS (Method A, Rt=0.80 min), MS(ESI) m / z: 492.0 (M+H) +

[0120] Example 76: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-(4-hydroxycyclohexyl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide To a solution of intermediate 12 (40 mg, 0.081 mmol) in MeOH (2 mL) at room temperature, NaBH4 (5 mg, 0.13 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain Example 76 (6 mg, 0.011 mmol, yield 14%). MS(ESI) m / z: 494.03 (M+H) + ; 1H NMR (500MHz, DMSO-d6) δ 7.90(brd,J=8.6Hz,2H), 7.39-7.03(m,3H), 6.95-6.84(m,3H), 3.83(s,3H), 3.71-3. 59(m,1H), 2.71-2.64(m,1H), 1.85-1.76(m,2H), 1.74-1.63(m,4H), 1.62-1.52(m,2H)

[0121] Example 77: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-((6-fluoro-1H-imidazo[4,5-b]pyridine-2-yl)methyl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide [ka]

[0122] Intermediate 13: Methyl 2-(1-(2,6-difluoro-4-methoxyphenyl)-2-(4-(difluoromethoxy)benzamide)-1H-imidazole-4-yl)-2-methylpropanoate Intermediate 13 was prepared as described in Example 74.

[0123] Intermediate 14: 2-(1-(2,6-difluoro-4-methoxyphenyl)-2-(4-(difluoromethoxy)benzamide)-1H-imidazole-4-yl)-2-methylpropanoate·Na salt To a stirred solution of intermediate 13 (210 mg, 0.42 mmol) in THF / MeOH (3:1, 4 mL), 1N NaOH (0.85 mL, 0.85 mmol) was added. The mixture was stirred at room temperature for 3 days. The mixture was concentrated and used directly in the next step.

[0124] Intermediate 15: N-(4-(2-((2-amino-5-fluoropyridine-3-yl)amino)-2-oxoethyl)-1-(2,6-difluoro-4-methoxyphenyl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide A mixture of intermediate 14 (47 mg, 0.1 mmol), 5-fluoropyridine-2,3-diamine (16 mg, 0.13 mmol), HATU (49 mg, 0.13 mmol), and DIPEA (0.052 mL, 0.30 mmol) in ACN (2 mL) was stirred overnight at room temperature. The crude material was diluted with DCM, washed with brine, dried, and concentrated. The residue was subjected to flash chromatography and purified by elution with 0-100% ethyl acetate to obtain intermediate 14 (12 mg, 0.021 mmol, yield 22%).

[0125] Example 77: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-((6-fluoro-1H-imidazo[4,5-b]pyridine-2-yl)methyl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide A mixture of intermediate 15 (12 mg, 0.021 mmol) and AcOH (1 mL) was heated at 95°C for 3 hours. The mixture was cooled to room temperature, diluted with DMF, and purified by reverse-phase HPLC to obtain the denoted compound (3 mg, 0.005 mmol, 5% yield). MS(ESI) m / z: 545.2(M+H) + ; 1 H NMR (500MHz, CD3OD) δ 8.23(brs,1H), 7.84(brd,J=7.8Hz,2H), 7.70(brd,J=8.5Hz,1H), 7.33-6.63(m,6H), 4.31(s,2H), 3.82(s,3H)

[0126] Examples 78-81 (Table 3) were manufactured as described in Example 75.

[0127] Example 82: N-(1-(2,6-difluoro-4-methoxyphenyl)-4-(3-((2,2,2-trifluoroethyl)amino)cyclobutyl)-1H-imidazole-2-yl)-4-(difluoromethoxy)benzamide [ka]

[0128] To a solution of Example 81 (20 mg, 0.040 mmol) in THF (0.4 mL) and TEA (56 μl, 0.40 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (23 mg, 0.10 mmol) was added. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was diluted with DMF and purified by reverse-phase HPLC to obtain Example 82 (16 mg, 0.028 mmol, 70% yield). MS(ESI) m / z: 547.3(M+H) + ; 1 H NMR (500MHz, CD3OD) δ 8.05-7.76(m,2H), 7.21-7.08(m,2H), 7.05-6.63(m,4H), 4.24-4.03(m,1H), 3.8 8-3.81(m,3H), 3.52-3.43(m,1H), 2.91(s,3H), 2.63-2.54(m,2H), 2.49(brs,2H)

[0129] Example 83: N-[1-(2,6-difluoro-4-methoxyphenyl)-4-(3-methanesulfonamidecyclobutyl)-1H-imidazole-2-yl]-4-(difluoromethoxy)benzamide (Table 3) was prepared as described in Example 82.

[0130] The following examples listed in Table 4 were synthesized according to the operations described above. Table 4 [Table 19] [Table 20] [Table 21]

[0131] NMR data for the examples shown in the table: Example 2: 1H NMR (500MHz, DMSO-d6) δ 7.95-7.87(m,3H), 7.81(brd,J=7.2Hz,2H), 7.39(brd,J=7.4Hz,4H), 7.32( t,J=73.4Hz,1H), 7.29-7.20(m,3H), 7.00(brd,J=8.1Hz,2H), 3.74(brs,3H) Example 3: 1 H NMR (500MHz, DMSO-d6) δ 7.89(s,1H), 7.84(brd,J=8.0Hz,2H), 7.39-7.34(m,2H), 7.33-7.27(m,2H), 7.24(br d,J=8.2Hz,2H), 6.90(brd,J=10.4Hz,2H), 6.82(brd,J=7.2Hz,1H), 3.70-3.67(m,6H) Example 4: 1 H NMR (500MHz, DMSO-d6) δ 7.88-7.78(m,5H), 7.27(t,J=73.5Hz,1H), 7.25-7.19(m,4H), 6.89(brd,J=10.4Hz,2H), 3.77(s,3H) Example 5: 1 H NMR (500MHz, DMSO-d6) δ 10.91(brs,1H), 7.91-7.81(m,3H), 7.77(s,1H), 7.62(brd,J=8.3Hz,1H), 7.41(brd,J=8.3Hz,1H), 7 .30(t,J=73.5Hz,1H), 7.24(brd,J=8.3Hz,2H), 6.90(brd,J=10.3Hz,2H), 3.75(brs,3H), 2.35(s,3H) Example 6: 1 H NMR (500MHz, DMSO-d6) δ 8.07(brs,1H), 8.00(brd,J=8.0Hz,2H), 7.85(brd,J=8.2Hz,2H), 7.75(brd,J=8.0Hz,2H ), 7.30(t,J=73.5Hz,1H), 7.24(brd,J=8.5Hz,2H), 6.92(brd,J=10.4Hz,2H), 3.76(s,3H) Example 7: 1H NMR (500MHz, DMSO-d6) δ 7.92-7.78(m,5H), 7.36-7.06(m,1H), 7.30(t,J=73.5Hz,1H), 7.22(brdd,J=16.1, 8.3Hz,4H), 6.90(brd,J=10.2Hz,2H), 3.76(brs,3H) Example 8: 1 H NMR (500MHz, DMSO-d6) δ 7.82(brd,J=7.5Hz,2H), 7.68(brd,J=7.1Hz,2H), 7.49-7.39(m,2H), 7.32-7.11(m,4H), 6.93(brd,J=9.9Hz,2H), 3.76(brs,3H), 2.21(brs,3H) Example 9: 1 H NMR (500MHz, DMSO-d6) δ 8.32(s,1H), 8.01(brs,1H), 7.97-7.82(m,6H), 7.58-7.40(m,2H), 7.31(t,J= 73.4Hz,1H), 7.25(brd,J=8.2Hz,2H), 6.93(brd,J=10.1Hz,2H), 3.77(brs,3H) Example 10: 1 H NMR (500MHz, DMSO-d6) δ 7.95(s,1H), 7.83(brd,J=8.1Hz,2H), 7.63(brd,J=7.7Hz,1H), 7.56(brd,J=10.3Hz,1H), 7.47-7.39(m,1H), 7 .27(t,J=73.2Hz,1H), 7.23(brd,J=8.4Hz,2H), 7.07(brt,J=7.4Hz,1H), 6.89(brd,J=10.4Hz,2H), 3.77(s,3H)

[0132] Example 11: 1 H NMR (500MHz, DMSO-d6) δ 7.89(brs,1H), 7.81(brdd,J=14.7, 8.4Hz,4H), 7.48-7.40(m,2H), 7.27(t,J= 73.5Hz,1H), 7.23(brd,J=8.3Hz,2H), 6.89(brd,J=10.3Hz,2H), 3.77(brs,3H) Example 12: 1H NMR (500MHz, DMSO-d6) δ 7.99(brs,1H), 7.87-7.80(m,3H), 7.75(brd,J=7.4Hz,1H), 7.43(brt,J=7.7Hz,1H), 7.34-7.09(m,4H), 6.91(brd,J=10.4Hz,2H), 3.76(brs,3H) Example 13: 1 H NMR (500MHz, DMSO-d6) δ 7.82(brd,J=7.7Hz,2H), 7.71(brd,J=8.0Hz,2H), 7.48(brd,J=8.0Hz,2H), 7.29(t,J=73. 2Hz,1H), 7.22(brd,J=8.1Hz,2H), 6.93(brd,J=9.9Hz,2H), 3.76(brs,3H), 2.21(brs,3H) Example 14: 1 H NMR (500MHz, DMSO-d6) δ 7.87(brd,J=7.6Hz,2H), 7.75-7.71(m,4H), 7.33(t,J=73.6Hz,1H), 7.25(brd ,J=7.9Hz,2H), 6.98(brd,J=8.2Hz,2H), 6.92(brd,J=9.8Hz,2H), 3.78(s,6H) Example 15: 1 H NMR (500MHz, DMSO-d6) δ 7.91-7.78(m,3H), 7.69(brd,J=7.7Hz,2H), 7.33(t,J=73.3Hz,1H), 7.23(b rdd,J=18.6,8.0Hz,4H), 6.92(brd,J=10.3Hz,2H), 3.77(s,3H), 2.31(s,3H) Example 16: 1 H NMR (500MHz, DMSO-d6) δ 8.10(brs,1H), 7.97(brd,J=7.9Hz,2H), 7.83(brd,J=7.3Hz,4H), 7.28(t,J=7 3.5Hz,1H), 7.23(brd,J=6.4Hz,2H), 6.91(brd,J=10.4Hz,2H), 3.76(brs,3H) Example 17: 11H NMR (500 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.13 (brd, J = 8.2 Hz, 1H), 8.06 (s, 1H), 7.85 (brd, J = 8.5 Hz, 2H), 7.70 (brd, J = 7.6 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.30 (t, J = 73.6 Hz, 1H), 7.24 (brd, J = 8.5 Hz, 2H), 6.92 (brd, J = 10.1 Hz, 2H), 3.77 (s, 3H) Example 18: 1 1H NMR (500 MHz, DMSO-d6) δ 8.02 (brs, 2H), 7.85 (brd, J = 7.4 Hz, 2H), 7.77 (brd, J = 6.6 Hz, 1H), 7.65 (brd, J = 7.9 Hz, 1H), 7.30 (t, J = 73.5 Hz, 1H), 7.23 (brd, J = 6.7 Hz, 2H), 6.92 (brd, J = 10.1 Hz, 2H), 3.76 (brs, 3H) Example 19: 1 1H NMR (500 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.90 (brd, J = 7.0 Hz, 2H), 7.75 (s, 1H), 7.68 (brs, 1H), 7.55 (brd, J = 7.6 Hz, 1H), 7.43 - 7.42 (m, 1H), 7.38 (brd, J = 7.6 Hz, 1H), 7.35 (t, J = 73.4 Hz, 1H), 7.27 (brd, J = 7.6 Hz, 2H), 7.00 (brd, J = 8.2 Hz, 2H), 6.77 (brd, J = 8.2 Hz, 1H), 4.54 (brt, J = 8.2 Hz, 2H), 3.75 (brs, 3H), 3.20 (brt, J = 8.2 Hz, 2H) Example 20: 1 1H NMR (500 MHz, DMSO-d6) δ 8.38 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 7.90 (brd, J = 8.5 Hz, 2H), 7.84 (s, 1H), 7.78 (brd, J = 4.6 Hz, 1H), 7.41 (brd, J = 8.5 Hz, 2H), 7.34 (t, J = 73.4 Hz, 1H), 7.27 (brd, J = 8.5 Hz, 2H), 7.02 (brd, J = 8.5 Hz, 2H), 3.75 (s, 3H)

[0133] Example 21: 1H NMR (500MHz, DMSO-d6) δ 10.64(s,1H), 8.13-7.99(m,1H), 7.91(brd,J=8.5Hz,2H), 7.68(d,J=3.4Hz,1H), 7.41(brd,J=8.9Hz,1H), 7.36(t,J=73.6Hz ,1H), 7.33(brs,1H), 7.32(brs,1H), 7.28(brd,J=8.5Hz,2H), 7.17(brt,J=7.6Hz,1H), 7.01(brd,J=8.5Hz,2H), 3.75(s,3H) Example 22: 1 H NMR (500MHz, DMSO-d6) δ 8.34(s,1H), 8.05-7.97(m,2H), 7.97-7.91(m,2H), 7.85(brd,J=7.9Hz,1H), 7.76(brd,J=5. 2Hz,1H), 7.58-7.40(m,3H), 7.36-7.12(m,3H), 7.14(s,1H), 7.07-7.00(m,2H), 3.77(s,3H) Example 23: 1 H NMR (500MHz, DMSO-d6) δ 8.22(s,1H), 8.10(d,J=7.6Hz,1H), 7.96(brd,J=7.9Hz,1H), 7.91(brd,J=8.5Hz,2H), 7.54-7.3 9(m,5H), 7.34(t,J=73.6Hz,1H), 7.28(brd,J=8.5Hz,2H), 7.02(brd,J=8.5Hz,2H), 3.75(s,3H) Example 24: 1 H NMR (500MHz, DMSO-d6) δ 7.96(s,1H), 7.90(brd,J=8.5Hz,2H), 7.83(d,J=3.1Hz,1H), 7.64(d,J=3.1Hz,1H), 7.42(brd,J= 8.5Hz,2H), 7.35(t,J=73.6Hz,1H), 7.28(brd,J=8.2Hz,2H), 7.01(brd,J=8.9Hz,2H), 3.75(s,3H) Example 25: 11H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.05 (brt, J = 6.7 Hz, 1H), 7.91 (brd, J = 8.2 Hz, 2H), 7.69 (brd, J = 3.1 Hz, 1H), 7.42 (brd, J = 8.9 Hz, 2H), 7.35 (t, J = 73.5 Hz, 1H), 7.28 (brd, J = 7.9 Hz, 5H), 7.01 (brd, J = 8.9 Hz, 2H), 3.75 (s, 3H) Example 26: 1 1H NMR (500 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.90 (brd, J = 8.5 Hz, 2H), 7.71 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.43 (brd, J = 8.5 Hz, 2H), 7.34 (t, J = 73.6 Hz, 1H), 7.32 - 7.25 (m, 3H), 7.07 (s, 1H), 7.02 (brd, J = 8.5 Hz, 2H), 3.75 (s, 3H) Example 27: 1 1H NMR (500 MHz, DMSO-d6) δ 8.13 - 7.85 (m, 3H), 7.65 (brs, 1H), 7.31 - 6.99 (m, 6H), 3.85 (s, 3H), 2.72 - 2.61 (m, 1H), 2.00 (brs, 2H), 1.77 (brs, 2H), 1.69 (brd, J = 11.3 Hz, 1H), 1.36 (brt, J = 9.6 Hz, 4H), 1.23 (brs, 1H) Example 29: 1 1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.89 (brd, J = 8.5 Hz, 2H), 7.41 (brd, J = 8.5 Hz, 2H), 7.33 (t, J = 73.6 Hz, 1H), 7.27 (brd, J = 8.5 Hz, 2H), 7.02 (brd, J = 8.5 Hz, 3H), 4.39 (q, J = 6.9 Hz, 2H), 3.75 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H) Example 30: 1H NMR (500MHz, DMSO-d6) δ 10.67(s,1H), 8.10(s,1H), 7.88(brd,J=8.5Hz,2H), 7.39(brd,J=8.9Hz,2H), 7.35(t,J=73.6Hz,1H), 7. 27(brd,J=8.5Hz,2H), 7.00(brd,J=8.9Hz,2H), 4.26(q,J=7.0Hz,2H), 3.74(s,3H), 1.29(t,J=7.0Hz,3H)

[0134] Example 32: 1 H NMR (500MHz, DMSO-d6) δ 8.05(brd,J=11.1Hz,1H), 7.88(brd,J=4.5Hz,1H), 7.74-7.61(m,1H), 7.49-6.91(m,7H), 3.90-3.67(m,3H), 1.33-1.23(m,9H) Example 33: 1 H NMR (500MHz, DMSO-d6) δ 10.82(s,1H), 8.05(brt,J=6.9Hz,1H), 7.87(brd,J=8.6Hz,2H), 7.65(brd,J=3.3Hz, 1H), 7.36-7.20(m,5H), 7.29(t,J=73.6Hz,1H), 6.89(brd,J=10.1Hz,2H), 3.79(s,3H) Example 34: 1 H NMR (500MHz, DMSO-d6) δ 8.39(d,J=5.2Hz,1H), 8.24(s,1H), 7.86(brd,J=8.7Hz,2H), 7.82(s,1H), 7.76(d,J=5.1Hz ,1H), 7.28(t,J=73.5Hz,1H), 7.24(d,J=8.6Hz,2H), 6.91(brd,J=10.0Hz,2H), 3.79(s,3H) Example 36: 1 H NMR (500MHz, DMSO-d6) δ 7.92-7.84(m,3H), 7.82-7.74(m,1H), 7.65(brs,1H), 7.50-7.41(m,1H), 7.29(t ,J=73.5Hz,1H), 7.25(brd,J=8.6Hz,2H), 6.91(brd,J=10.1Hz,2H), 3.80(s,3H) Example 37: 1 H NMR (500MHz, DMSO-d6) δ 7.96-7.78(m,2H), 7.24-7.10(m,3H), 7.10-6.99(m,2H), 6.87(brs,1H), 3.92-3.70(m,3H), 2.04-1.77(m,1H), 0.82(brs,2H), 0.69(brs,2H) Example 38: 1 H NMR (500MHz, DMSO-d6) δ 8.04(s,1H), 7.84(d,J=8.7Hz,2H), 7.26(t,J=73.6Hz,1H), 7.22(brd,J=8.6Hz,2H) , 6.88(brd,J=10.2Hz,2H), 4.28(q,J=7.1Hz,2H), 3.79(s,3H), 1.30(t,J=7.1Hz,3H) Example 39: 1 H NMR (500MHz, DMSO-d6) δ 8.03-7.80(m,2H), 7.36(brs,1H), 7.27-7.06(m,3H), 7.04-6.80(m,3H), 3.89(brd,J=4.5Hz,3H), 2.61(brs,2H), 1.22(t,J=7.5Hz,3H) Example 40: 1 H NMR (500MHz, DMSO-d6) δ 7.98(s,1H), 7.85(brd,J=8.2Hz,3H), 7.66(brs,1H), 7.31(t,J=73.5Hz,1H), 7.25(brd,J=8.5Hz,2H), 6.92(brd,J=10.1Hz,2H), 3.77(s,3H)

[0135] Example 42: 1 H NMR (500MHz, DMSO-d6) δ 8.11(s,1H), 7.88(brd,J=8.7Hz,2H), 7.40(brd,J=8.8Hz,2H), 7.31(t,J=73.5Hz,1H), 7.26(brd,J=8.7Hz,2H), 7.01(brd,J=8.9Hz,2H), 3.76(s,3H) Example 43: 1H NMR (500MHz, DMSO-d6) δ 8.13(s,1H), 7.87(brd,J=8.5Hz,2H), 7.39(d,J=8.9Hz,2H), 7.34(t,J=73.4Hz,1H),7.27(brd,J=8.5Hz,2H), 7.01(d,J=8.9Hz,2H), 3.74(s,3H) Example 45: 1 H NMR (500MHz, DMSO-d6) δ 7.89(brd,J=7.9Hz,2H), 7.82(s,1H), 7.39(brd,J=8.9Hz,2H), 7.35(t,J=73.4Hz,1H), 7.26(brd,J= 8.5Hz,2H), 7.01(s,2H), 3.89(s,1H), 3.74(s,3H), 3.17(s,1H), 2.89(s,1H), 2.73(brd,J=6.4Hz,5H) Example 46: 1 ¹H NMR (500MHz, DMSO-d6) δ 8.11(brs,1H), 7.89(brd,J=8.2Hz,2H), 7.85(s,1H), 7.39(brd,J=8.5Hz,2H), 7.35(t,J=73.4Hz,1H), 7.27(brd,J=8.5Hz,2H), 7.01(brd,J=8.9Hz,2H), 3.75(s,3H), 3.46(brt,J=6.1Hz,1H), 1.65(brt,J=6.4Hz,2H); The protons of the three alkyl groups are obscured by the DMSO solvent peak. Example 47: 1 H NMR (500MHz, DMSO-d6) δ 8.79(brs,1H), 8.54(s,1H), 8.44(brd,J=4.3Hz,1H), 7.92(s,1H), 7.83(brd,J=8.5Hz,2H), 7.73(brd,J=7.6Hz,1H), 7.35(dd,J= 7.3, 4.9Hz,1H), 7.31(t,J=73.5Hz,1H), 7.24(brd,J=8.5Hz,2H), 6.92(brd,J=10.1Hz,2H), 4.46(brd,J=6.1Hz,2H), 3.77(s,3H) Example 49: 1H NMR (500MHz, DMSO-d6) δ 7.87(s,1H), 7.83(brd,J=8.2Hz,2H), 7.67(brd,J=7.3Hz,1H), 7.32(t,J=73.4Hz,1H), 7.24(brd,J=8.2Hz,2H), 6.91(brd,J=10.1Hz,2H), 3.89(s,1H), 3.77(s,3H) ,3.74-3.68(m,1H),1.86-1.76(m,4H),1.47-1.36(m,2H),1.29-1.20(m,2H) Example 50: 1 H NMR (500MHz, DMSO-d6) δ 7.90-7.82(m,3H), 7.32(t,J=73.4Hz,1H), 7.24(brd,J=8.2Hz,2H), 6.90(brd,J=10.4Hz,2H), 4.18(brs,1H), 3. 89(s,1H), 3.76(s,3H), 3.66-3.54(m,1H), 3.45(s,1H), 3.16(s,1H), 2.91(brd,J=7.0Hz,2H), 1.97-1.82(m,4H)

[0136] Example 51: 1 H NMR (500MHz, DMSO-d6) δ 7.86-7.80(m,4H), 7.31(t,J=73.6Hz,1H), 7.24(brd,J=8.2Hz,2H), 6.90(brd,J=10.4Hz,2H), 3.76(s,3H), 3.46(brs,1H), 3.16( brs,1H), 2.91(q,J=7.0Hz,1H), 1.90(brd,J=4.6Hz,1H), 1.73(brs,1H), 1.41(brs,2H), 1.27-1.21(m,1H), 1.15(t,J=7.3Hz,2H) Example 52: 1H NMR (500MHz, DMSO-d6) δ 7.86-7.81(m,3H), 7.32(t,J=73.4Hz,1H), 7.24(brd,J=8.5Hz,2H), 6.90(brd,J=10.4Hz,2H), 4.12-3.92(m,1H), 3.76(s,3H), 3.4 9-3.42(m,1H), 3.16(brd,J=4.3Hz,1H), 2.95-2.87(m,1H), 1.79(brd,J=9.2Hz,2H), 1.36(brd,J=8.5Hz,2H), 1.15(t,J=7.2Hz,1H) Example 53: 1 H NMR (500MHz, DMSO-d6) δ 7.94-7.88(m,2H), 7.84(brd,J=8.2Hz,2H), 7.33(t,J=73.6Hz,1H), 7.25(brd,J=8.5Hz,2H), 6.93(brd,J=10.4Hz,2H), 4.78 (brt,J=5.2Hz,1H), 3.77(s,3H), 3.50(q,J=5.8Hz,1H), 3.34(brd,J=8.9Hz,1H), 3.17(d,J=5.2Hz,1H), 2.92(q,J=7.2Hz,1H) Example 54: 1 H NMR (500MHz, DMSO-d6) δ 7.91(s,1H), 7.84(brd,J=8.2Hz,2H), 7.33(t,J=73.4Hz,1H), 7.24(brd,J=8.2Hz,2H), 6.91(brd,J=10.1Hz,2H), 3.7 7(s,3H), 3.64(brs,2H), 3.43-3.34(m,1H), 3.17(brd,J=4 .6Hz, 1H), 2.97-2.87 (m, 1H); 4 pieces of water suppression. Example 55: 1¹H NMR (500MHz, DMSO-d6) δ 7.99(s,1H), 7.84(brd,J=8.2Hz,2H), 7.33(t,J=73.6Hz,1H), 7.25(brd,J=8.5Hz,2H), 6.92(brd,J=10.4Hz,2H), 3.77(s,3H), 3.48-3.40(m,1H), 3.16(s,1H), 2.92(brd,J=6.1Hz,1H), 2.74-2.62(m,3H); Four alkyl protons are obscured by the DMSO solvent peak. Example 56: 1 H NMR (500MHz, DMSO-d6) δ 8.69(brs,1H), 8.47(s,2H), 7.94(s,1H), 7.84(brd,J=8.5Hz,2H), 7.33(t,J=73.6Hz,1H), 7.25 (brd,J=8.5Hz,2H), 6.93(brd,J=10.1Hz,2H), 4.57(brd,J=5.8Hz,2H), 3.77(s,3H), 2.47(s,3H) Example 57: 1 H NMR (500MHz, DMSO-d6) δ 7.84(brd,J=10.4Hz,3H), 7.27(t,J=73.6Hz,1H), 7.23(brd,J=7.8Hz,2H), 6.89(brd,J=6.4Hz,2H), 4.33(brd,J= 19.5Hz,1H), 3.91(brs,1H), 3.79(brs,3H), 3.63-3.52(m,1H), 3.50-3.38(m,1H), 2.98(s,1H), 2.02-1.76(m,3H) Example 58: 1 ¹H NMR (500MHz, DMSO-d6) δ 8.09 (brs, 1H), 7.97 (s, 1H), 7.85 (brd, J=8.5Hz, 2H), 7.33 (t, J=73.6Hz, 1H), 7.24 (brd, J= 8.5Hz, 2H), 6.92 (brd, J= 10.1Hz, 2H), 3.77 (s, 3H), 1.90 (s, 1H), 1.23 (s, 1H); alkyl protons are obscured by DMSO peaks and water suppression. Example 59: 1H NMR (500MHz, DMSO-d6) δ 7.92-7.83(m,3H), 7.34(t,J=73.2Hz,1H), 7.24(brd,J=7.9Hz,2H), 6.92(br d,J=9.2Hz,2H), 4.13-4.05(m,1H), 3.78(brs,3H), 3.65-3.55(m,1H), 3.51-3 .39(m,1H), 2.38(brdd,J=12.1, 7.5Hz,1H), 2.33-2.22(m,1H), 1.99(brd,J= 7.3Hz,1H), 1.94-1.86(m,1H), 1.71(brs,1H), 1.66-1.55(m,1H), 1.23(s,1H) Example 60: 1 H NMR (500MHz, DMSO-d6) δ 8.08(brs,1H), 7.87(s,1H), 7.83(brd,J=8.2Hz,2H), 7.32(t,J=73.5Hz,1H), 7.24(brd,J= 8.2Hz,2H), 6.91(brd,J=10.4Hz,2H), 4.58(t,J=5.2Hz,1H), 3.77(s,3H), 3.31(q,J=6.7Hz,1H), 3.16(d,J=5.2Hz,1H), 1.66(quin,J=6.5Hz,3H)

[0137] Example 61: 1 ¹H NMR (500MHz, DMSO-d6) δ 7.88(s,1H), 7.85(brd,J=8.5Hz,2H), 7.34(t,J=73.6Hz,1H), 7.25(d,J=8.5Hz,2H), 6.93(brd,J=10.1Hz,2H), 3.78(s,3H), 2.85-2.78(m,4H); Four protons are obscured by the DMSO solvent peak. Example 64: 11H NMR (500 MHz, DMSO-d6) δ 7.95 (brd, J = 7.3 Hz, 2H), 7.46 (brs, 2H), 7.31 (t, J = 73.8 Hz, 1H), 7.22 (brd, J = 8.2 Hz, 2H), 7.17 (brs, 1H), 7.15 (brs, 1H), 7.02 (brd, J = 8.2 Hz, 2H), 3.77 (s, 3H), 3.30 (brs, 1H), 3.05 (brd, J = 8.9 Hz, 1H), 2.84 (brs, 1H), 2.78 - 2.63 (m, 2H), 2.07 - 2.01 (m, 1H), 1.74 (brs, 1H), 1.58 (brs, 2H) Example 68: 1 1H NMR (500 MHz, DMSO-d6) δ 7.97 - 7.81 (m, 2H), 7.35 - 6.80 (m, 7H), 4.53 (brt, J = 5.5 Hz, 1H), 4.45 (brd, J = 3.1 Hz, 1H), 3.97 (brd, J = 11.6 Hz, 1H), 3.91 - 3.74 (m, 3H), 3.65 (q, J = 6.4 Hz, 2H), 3.19 - 3.08 (m, 1H), 2.99 - 2.90 (m, 1H), 2.80 (brs, 1H), 2.67 (brd, J = 19.8 Hz, 1H), 2.08 (s, 1H), 2.06 - 1.94 (m, 2H), 1.92 (s, 1H), 1.52 (brs, 1H), 1.41 (brd, J = 10.7 Hz, 1H), 1.24 (s, 1H) Example 69: 1 1H NMR (500 MHz, DMSO-d6) δ 7.87 - 7.81 (m, 3H), 7.34 (t, J = 73.5 Hz, 1H), 7.24 (brd, J = 8.5 Hz, 2H), 6.91 (brd, J = 10.4 Hz, 2H), 5.16 - 5.03 (m, 1H), 4.50 (brd, J = 5.5 Hz, 1H), 3.90 (s, 1H), 3.77 (s, 3H), 3.31 - 3.24 (m, 1H), 3.17 (d, J = 4.9 Hz, 1H), 1.91 (s, 1H), 1.78 - 1.63 (m, 4H), 1.11 (brs, 2H)

[0138] Example 71: 1H NMR (500MHz, DMSO-d6) δ 8.00-7.76(m,2H), 7.38-7.27(m,4H), 7.29-6.78(m,8H), 4.03-3.72(m,5H). Example 72: 1 H NMR (500MHz, CDCl3) δ 8.10(brd,J=8.3Hz,2H), 7.06(brd,J=8.3Hz,2H), 6.66(s,1H), 6.64(s,2H), 6.54(t, J=73.7Hz,1H), 4.25(q,J=7.0Hz,2H), 3.87(s,3H), 3.65(s,2H), 1.32(t,J=7.2Hz,3H) Example 78: 1 H NMR (500MHz, DMSO-d6) δ 8.40(brs,1H), 8.03-7.74(m,4H), 7.38(brd,J=7.6Hz,1H), 7.30-7.07(m,4H), 6.92-6.62(m,2H), 3.83(brs,2H), 3.73(brs,3H) Example 79: 1 H NMR (500MHz, DMSO-d6) δ 7.91-7.86(m,2H), 7.31(s,1H), 7.24-7.17(m,3H), 6.98-6.92(m,2H), 3.98-3.84(m,4H), 3.81(s,3H), 3.29-3.21(m,1H) Example 80: 1 H NMR (500MHz, CD3OD) δ 8.01-7.80(m,3H), 7.31-7.20(m,3H), 7.13-6.61(m,4H), 3.87(s,3H) Example 81: 1 H NMR (500MHz, DMSO-d6) δ 7.96-7.73(m,2H), 7.41-7.08(m,3H), 7.07-7.03(m,1H), 6.91(brd,J=10.3Hz,2H), 3.82(s,3H), 3.70(brs,1H), 3.41-2.92(m,1H), 2.67-2.59(m,2H), 2.36-2.26(m,2H) Example 83: 1H NMR (500MHz, CD3OD) δ 8.05-7.76(m,2H), 7.21-7.08(m,2H), 7.05-6.63(m,4H), 4.24-4.03(m,1H), 3.8 8-3.81(m,3H), 3.52-3.43(m,1H), 2.91(s,3H), 2.63-2.54(m,2H), 2.49(brs,2H)

[0139] It will be apparent to those skilled in the art that this disclosure is not limited to the exemplary embodiments described above and can be embodied in other specific forms without departing from its essential attributes. Therefore, it is desirable that the embodiments be considered illustrative and non-restrictive in all respects, and that references are made to the appended claims rather than to the embodiments described above, and that all modifications falling within the meaning of the claims and their equivalents are therefore encompassed therein.

Claims

1. Formula (II): 【Chemistry 1】 [In the formula: R １ Alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (alkoxycarbonyl)alkyl, alkoxycarbonyl, (NR ６ R ７ ) Carbonyl, Ar １ , or (Ar １ ) is alkyl; Ar １ is cycloalkyl, aryl, heteroaryl (including 1 to 4 heteroatoms selected from carbon atoms and N, NR ５ａ , O, and S), heterocyclyl (including 1 to 4 heteroatoms selected from carbon atoms and N, NR ５ａ , O, and S), spiroheterocyclyl (including 1 to 4 heteroatoms selected from carbon atoms and N, NR ５ａ , O, and S), each of which is substituted with 1 to 4 R ５ ; R ３ａ is an alkoxy; R ３ｂ is hydrogen, halo, or haloalkyl; R ４ａ is a halo or haloalkoxy; R ５ is hydrogen, hydroxyl, cyano, halo, alkyl, haloalkyl, amino, haloalkylamino, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, or alkylsulfonylamino; R ５ａ is hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroalkylcarbonyl, carboxyamide, alkylaminocarbonyl, aminocarbonylalkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl; R ６ and R ７ These are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heteroaryl (carbon atoms and N, NR ８ａ (containing 1 to 4 heteroatoms selected from , O, and S), arylalkyl, or heteroarylalkyl (carbon atoms, N, NR ８ａ (containing 1 to 4 heteroatoms selected from O and S), where the cycloalkyl, heteroaryl, or heteroarylalkyl is 1 to 4 R ８ Will it be replaced by; Or R ６ and R ７ Together with the nitrogen they bind to, they become N, NR ８ａ A heterocycline or heteroaryl is formed comprising 0 to 3 further heteroatoms selected from O and S, where the heterocycline or heteroaryl comprises 1 to 4 R ８ Replaced by; R ８ is hydrogen, halo, hydroxy, hydroxyalkyl, alkyl, alkoxy, or oxo; R ８ａ [is hydrogen, hydroxyalkyl, or alkyl] The compound indicated by or a pharmaceutically acceptable salt thereof.

2. R １ Ar １ (1 to 3 R ５ (It is replaced by; Ar １ However, cycloalkyl, aryl, heteroaryl (carbon atoms and N, NR ５ａ Heterocyclines (containing 1 to 3 heteroatoms selected from , O, and S), and N, NR ５ａ Spiroheterocyclils (containing one to three heteroatoms selected from O and S), carbon atoms, and N, NR ５ａ (containing 1 to 3 heteroatoms selected from , O, and S), each containing 1 to 3 R ５ Replaced by; R ３ａ is an alkoxy; R ３ｂ is hydrogen or halo; R ４ａ is a haloalkoxy; R ５ but which is hydrogen, hydroxyl, cyano, halo, alkyl, haloalkyl, amino, haloalkylamino, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, or alkylsulfonylamino; R ５ａ However, it is hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroalkylcarbonyl, alkylaminocarbonyl, aminocarbonylalkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. Ar １ but 【Chemistry 2】 And; R ５ However, it is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, or haloalkoxy. The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

4. Ar １ but 【Transformation 3】 And; R ５ However, it is hydrogen, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, alkoxycarbonyl, or haloalkoxy. The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

5. Ar １ but 【Chemistry 4】 And; R ５ However, it is hydrogen, alkyl, or hydroxyalkyl; R ５ａ However, it is hydrogen, alkyl, hydroalkylcarbonyl, alkylaminocarbonyl, aminocarbonylalkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl. The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

6. Ar １ but 【Transformation 5】 And; R ５ However, it is hydrogen, hydroxyl, hydroxyalkyl, amino, haloalkylamino, or alkylsulfonylamino. The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

7. R １ But (Ar １ ) is alkyl; R ３ａ is an alkoxy; R ３ｂ is hydrogen or halo; R ４ａ It is a haloalkoxy. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. Ar １ but 【Transformation 6】 And; R ５ but which is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, or haloalkoxy; R ５ａ is hydrogen or alkyl, The compound according to claim 7 or a pharmaceutically acceptable salt thereof.

9. R １ is alkyl or haloalkyl; R ３ａ is an alkoxy; R ３ｂ is hydrogen or halo; R ４ａ It is a haloalkoxy. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. R １ However, it is an alkoxycarbonyl or (alkoxycarbonyl)alkyl; R ３ａ is an alkoxy; R ３ｂ is hydrogen or halo; R ４ａ It is a haloalkoxy. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. R １ But (NR ６ R ７ ) is a carbonyl; R ６ and R ７ However, independently, hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heteroaryl (carbon atoms and N, NR ８ａ Heteroaryls (containing 1 to 3 heteroatoms selected from , O, and S) (carbon atoms and N, NR ８ａ (containing 1 to 3 heteroatoms selected from , O, and S), or heteroarylalkyl (containing carbon atoms, N, NR ８ａ (containing 1 to 3 heteroatoms selected from , O, and S), where the cycloalkyl, heteroaryl, or heteroarylalkyl is 1 to 3 R ８ Will it be replaced by; Or R ６ and R ７ However, together with the nitrogen they bind to, 【Transformation 7】 Forming; R ８ but which is hydrogen, halo, hydroxy, hydroxyalkyl, alkyl, alkoxy, or oxo; R ８ａ is hydrogen, hydroxyalkyl, or alkyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. R ６ is hydrogen; R ７ but 【Transformation 8】 And; R ８ However, it is hydrogen, halo, hydroxy, hydroxyalkyl, alkyl, or alkoxy. The compound according to claim 11 or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

14. A pharmaceutical composition according to claim 13 for treating heart disease.

15. The pharmaceutical composition according to claim 14, wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and iatrogenic cardiac injury.

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