Benzimidazole derivatives for the treatment of respiratory diseases

Abstract

Compounds of general formula (I): TIFF2023552638000112.tif44170 (in the above formula, R 1 , R 2 , R 3 , R 4 , R 5 , Y and Z are as indicated herein) are useful for treating respiratory diseases and other diseases and conditions modulated by TMEM16A.

Description

[Technical Field]

[0001] The present invention relates to compounds comprising certain novel compounds having activity as positive modulators of the calcium-dependent chlorine channel (CaCC) TMEM16A. The present invention also relates to methods for preparing such compounds and pharmaceutical compositions containing them, as well as to the use of these compounds modulated by TMEM16A in the treatment of diseases and conditions, particularly respiratory diseases and conditions. [Background technology]

[0002] Humans can inhale up to 12,000 liters of air per day, which means that airborne pathogens (bacteria, viruses, fungal spores, etc.) can enter the respiratory tract. To protect against these airborne pathogens, the lungs have evolved natural defense mechanisms to minimize the possibility of respiratory tract infection and colonization. One such mechanism is the mucous clearance system, in which secreted mucus is pushed up into the airways and expelled through the coordinated pulsation of cilia along with coughing. This continuous "cleaning" of the lungs constantly removes inhaled particles and microorganisms, thereby reducing the risk of infection.

[0003] In recent years, it has become clear that hydration of the mucous gel is important for enabling mucus clearance (Boucher 2007; Matsui et al, 1998). In healthy airways, the mucous gel is typically 97% water and 3 w / v% solids, and under these conditions, mucus is removed by mucociliary action. Hydration of the airway mucosa is controlled by the coordinated activity of several ion channels and transporters. This includes cystic fibrosis membrane conductance regulator (CFTR) and calcium-dependent chlorine conductance (CaCC; TMEM16A), which mediates anion (Cl - / HCO3 - ) secretion and epithelial Na + Na via channel (ENaC) +The balance with absorption determines the hydration state of the airway mucosa. As ions are transported through the epithelium, water follows due to osmotic pressure, and body fluids are secreted or absorbed.

[0004] In respiratory diseases such as chronic bronchitis and cystic fibrosis, hydration decreases and mucus clearance decreases, leading to an increase in the solids percentage of the mucus gel (Boucher, 2007). In cystic fibrosis, where loss-of-function mutations in CFTR weaken the airway's ability to secrete fluid, this solids percentage may increase to 15%, which is thought to lead to obstruction of narrowed airways and impaired mucus clearance. Strategies to increase airway mucus hydration include anion stimulation and the resulting fluid secretion or Na + This involves either inhibition of absorption. For this purpose, stimulating the activity of the TMEM16A channel increases anion secretion, which in turn increases fluid retention in the airway mucosa, hydrates mucus, and enhances the mucus clearance mechanism.

[0005] TMEM16A, also known as anoctamin 1 (Ano1), is molecularly identical to the calcium-dependent chloride channel (Caputo et al, 2008; Yang et al, 2008). The TMEM16A channel opens in response to an increase in intracellular calcium levels, allowing for the bidirectional flow of chloride ions, bicarbonate ions, and other anions across the cell membrane. Functionally, the TMEM16A channel has been proposed to regulate transepithelial ion transport, gastrointestinal peristalsis, nociception, and cell migration / proliferation (Pedemonte & Galietta, 2014).

[0006] The TMEM16A channel is expressed by epithelial cells in various organs, including the lungs, liver, kidneys, pancreas, and salivary glands. In the airway epithelium, TMEM16A is highly expressed in mucinous goblet cells, ciliated cells, and submucosal glands. Physiologically, TMEM16A is activated by purinergic agonists (ATP, UTP) released by the respiratory epithelium in response to stimuli that mobilize intracellular calcium, particularly periodic shear stress caused by respiration and other mechanical stimuli such as coughing. In addition to increasing anion secretion, which leads to improved airway hydration, TMEM16A also plays a crucial role in bicarbonate secretion. Bicarbonate secretion is an important regulator of mucin properties and has been reported to be important in controlling the pH of the airway lumen and, consequently, the activity of natural antimicrobial substances such as defensins (Pezzulo et al, 2012).

[0007] Indirect regulation of TMEM16A via elevated intracellular calcium has been clinically studied. For example, denufosol (Kunzelmann & Mall, 2003). This approach showed promising initial results in small patient cohorts but did not yield clinical utility in larger cohorts (Accurso et al 2011; Kellerman et al 2008). This lack of clinical efficacy was thought to be due to the short half-life of denufosol on the epithelial surface and the resulting transient increase in anion secretion, which is a consequence of receptor / pathway desensitization, as well as undesirable effects of elevated intracellular calcium, such as increased mucus release from goblet cells (Moss, 2013). Compounds that directly act on TMEM16A to promote channel opening at low levels of elevated calcium are expected to sustainably enhance anion secretion and mucociliary clearance in patients, thereby improving innate defense. A positive modulator of TMEM16A may offer clinical utility in all CF patients as well as in non-CF respiratory diseases characterized by mucous congestion, such as chronic bronchitis and severe asthma, because TMEM16A activity is independent of CFTR function.

[0008] TMEM16A modulation is involved as a treatment for salivary gland insufficiency in Sjogren's syndrome and dry mouth (xerostomia), dry eye, biliary stasis, and gastrointestinal motility disorders resulting from radiotherapy.

[0009] WO 2019 / 145726 relates to compounds that are positive modulators of TMEM16A and are thus useful in the treatment of diseases and conditions in which the modulation of TMEM16A plays a role, particularly respiratory diseases and conditions. The inventors have developed further compounds that are positive modulators of TMEM16A. SUMMARY OF THE INVENTION

[0010] In a first aspect of the invention, there is provided a compound of general formula (I), including all its tautomeric forms, all enantiomers and isotopic variants, as well as salts and solvates. TIFF0007853981000001.tif44170Where: R 1 is i. [CH(R 7 )] n -N(R 8 )-C(O)OR 9 (n is 1 or 2, each R 7 is independently H; phenyl; or C 1-3 alkyl optionally substituted with one or more substituents selected from OH and OCH3, R 8 is H; C 1-3 alkyl optionally substituted with one or more substituents selected from OH and methoxy, R 9 is C 2-4 alkyl); or ii. CH(R 11 )(R 12 ) (R 11 is H; OH; CH3; CH2OH; or a group that binds to a substituent on R 12 shown below, R 12 , which may be substituted with one or more substituents selected from OH and methoxy; and selected from phenyl or a 5-membered or 6-membered heteroaryl, wherein the phenyl or heteroaryl is OH, methoxy, methyl, fluoro, chloro, and R 11 And together with the atom to which it is bonded, the above phenyl or heteroaryl group R 12 (It may be substituted with one or more substituents selected from substituents that form a condensed 5-membered or 6-membered oxygen-containing heterocycle), or iii. OR 15 Even if replaced by C 2-6 Alkyl (R 15 is methyl or ethyl; or iv. 6-10 membered aryl or 5-10 membered heteroaryl (both may be substituted with one or more substituents selected from fluoro, chloro, OH, or methoxy) And, Z is selected from -NH-C(O)- and -C(O)-NH-; Y is selected from the bonds, -CH2- and -CH(CH3)-; or Y is R as shown below. 2 Combined with; R 2 teeth, Selected from a 3-10 membered carbocyclic system or a 6-10 membered aryl or 5-10 membered heteroaryl ring system, where the aryl, heteroaryl, or carbocyclic system is one or more substituents selected from the following: fluoro; chloro; CN; nitro; OH; C 1-6 Alkyl (may be substituted with one or more substituents selected from halo, OH, and CN); O(C 1-6 Alkyl) (may be substituted with one or more substituents selected from halo, OH, and CN); and CH2NH-C(O)OC 1-6 It may be substituted with alkyl (which may be substituted with one or more substituents selected from halo and OH); or Y and R 2 Together, they form a non-substituted C 3-8Alkyl group or group CH2-C(R 17 )(R 18 )-CH2-N(R 19 )R 20 (Here, R 17 , R 18 and R 19 Each of them is independently H or C1-4 alkyl; R 20 C 1-4 Alkyl or C 1-4 (Forms a haloalkyl) R 3 , R 4 and R 5 Each is independently either H or F; however: A. R 1 CH(R 11 )(R 12 ) when (where R 11 is H or methyl, and R 12 (The substituent is either unsubstituted or substituted with one or two substituents, the substituents being selected from halo and methoxy.) i. R 2 It is neither phenyl nor heteroaryl (where the phenyl or heteroaryl is a halo, C 1-4 Alkyl, C 1-4 It may be substituted with one or two substituents selected from alkoxy and five-membered heteroaryl rings; B. R 1 CH(R 11 )(R 12 ) when (where R 12 is phenyl, and R 11 R 12 Together with the substituents above and the atoms to which they are bonded, the phenyl ring R 12 A condensed 5 or 6-membered ring is formed, and the 5 or 6-membered ring is C 1-3 (May be substituted with alkyl) i. R 2 It is neither phenyl nor heteroaryl (where the phenyl or heteroaryl is a halo, C 1-4 Alkyl, C1-4 Haloalkyl and C 1-4 It may be substituted with one, two, or three substituents selected from alkoxy); and ii. Y and R 2 They combine to form C 3-10 It does not form alkyl groups; C. R 1 CH(R 1 )(R 12 ) when (where R 11 H is R 12 (It is cyclohexyl), R 2 is not a phenyl compound which may be substituted with one, two, or three substituents (where the substituents are selected from halo, methyl, methoxy; or unsubstituted 5- to 8-membered heteroaryl compounds).

[0011] The compound of general formula (I) is arbitrarily selected from the following: N-(2-benzyl-1H-benzimidazole-5-yl)-2-cyclohexyl-acetamide (compound 1.1); 2-benzyl-N-(cyclohexylmethyl)-1H-benzimidazole-5-carboxamide (compound 1.2); N-(1-adamantylmethyl)-2-benzyl-1H-benzimidazole-5-carboxamide (compound 1.2.1); 2-benzyl-N-[(1-methylcyclopentyl)methyl]-1H-benzimidazole-5-carboxamide (compound 1.2.2); 2-benzyl-N-[(1R)-1-cyclohexylethyl]-1H-benzimidazole-5-carboxamide (compounds 1, 2, and 3); N-(cycloheptylmethyl)-2-(1,1-dimethylpropyl)-3H-benzimidazole-5-carboxamide (compound 1.3); N-(cycloheptylmethyl)-2-[(1-hydroxycyclohexyl)methyl]-1H-benzimidazole-5-carboxamide (compound 1.3.1); N-(cycloheptylmethyl)-2-(2-hydroxy-1-phenylethyl)-1H-benzimidazole-5-carboxamide (compound 1.3.2); N-(cyclohexylmethyl)-2-[(3-hydroxyphenyl)methyl]-3H-benzimidazole-5-carboxamide (compound 1.4); 2-(1-adamantyl)-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.5); N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]-2-(1-methylcyclohexyl)acetamide (compound 1.5.1); 2-Cycloheptyl-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.5.2); 2-Cyclohexyl-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.5.3); 2-(1-adamantyl)-N-(2-benzyl-1H-benzoimidazole-5-yl)acetamide (compound 1.5.4); N-(2-benzyl-1H-benzimidazole-5-yl)-2-(2-hydroxy-2-adamantyl)acetamide (compound 1.6); 2-(2-adamantyl)-N-[2-[(3-methoxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.7); 2-(2-adamantyl)-N-[2-[(1S)-1-phenylethyl]-1H-benzimidazole-5-yl]acetamide (compound 1.7.1); 2-(2-adamantyl)-N-[2-[(1R)-1-phenylethyl]-1H-benzimidazole-5-yl]acetamide (compound 1.7.2); N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]methyl]carbamate tert-butyl (compound 1.7.3); 2-(1-adamantyl)-N-[2-[(2-methoxy-3-pyridyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.7.4); 2-(2-adamantyl)-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.8); 2-tert-butyl-N-[(5-chloro-2-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 1.9); N-[[5-(cycloheptylmethylcarbamoyl)-1H-benzimidazole-2-yl]methyl]carbamate tert-butyl (compound 1.10); 2-benzyl-N-[(1-methylcyclohexyl)methyl]-1H-benzimidazole-5-carboxamide (compound 1.10.1); 2-benzyl-N-(cyclooctylmethyl)-1H-benzimidazole-5-carboxamide (compound 1.10.2); N-[[1-[2-[(2-benzyl-1H-benzimidazole-5-yl)amino]-2-oxo-ethyl]cyclohexyl]methyl]carbamate tert-butyl (compound 2.1); N-(2-benzyl-1H-benzimidazole-5-yl)-2-(4,4-difluorocyclohexyl)acetamide (compound 2.1.1); N-[1-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzozmidazole-2-yl]-2-methoxy-ethyl]carbamate tert-butyl (compound 2.2); N-[(R)-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]-phenyl-methyl]-N-methylcarbamate tert-butyl (compound 2.2.1); N-[(S)-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]-phenyl-methyl]-N-methylcarbamate tert-butyl (compound 2.2.2); N-[[6-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]methyl]-N-ethylcarbamate tert-butyl (compound 2.2.3); N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]methyl]-N-(2-methoxyethyl)carbamate tert-butyl (compound 2.2.4); 2-(2-adamantyl)-N-[2-(2-methoxyethyl)-3H-benzoimidazole-5-yl]acetamide (compound 2.2.5); 2-(2-adamantyl)-N-[2-(3-methoxypropyl)-1H-benzoimidazole-5-yl]acetamide (compound 2.2.6); N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]methyl]-N-methylcarbamate tert-butyl (compound 2.3); N-(cycloheptylmethyl)-2-(2,3-dihydrobenzofuran-3-yl)-1H-benzimidazole-5-carboxamide (compound 2.4); 2-(2-adamantyl)-N-[2-[hydroxy(phenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 2.5); 2-Cyclohexyl-N-(2-phenyl-1H-benzimidazole-5-yl)acetamide (Compound 3.1); N-(2-benzyl-1H-benzimidazole-5-yl)adamantan-1-carboxamide (compound 3.2); N-(cycloheptylmethyl)-7-fluoro-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 3.3); N-(cycloheptylmethyl)-6-fluoro-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 3.3.1); N-(cycloheptylmethyl)-4-fluoro-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 3.3.2); N-[2-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]ethyl]carbamate tert-butyl (compound 3.4); 2-(2-adamantyl)-N-[2-[(3,5-dimethylisoxazole-4-yl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 3.4.1); 2-benzyl-N-(2,2-dimethylpropyl)-1H-benzimidazole-5-carboxamide (compound 3.5); 2-benzyl-N-(1,1,2,2-tetramethylpropyl)-1H-benzimidazole-5-carboxamide (compound 3.5.1); N-(cycloheptylmethyl)-2-[(5-fluoro-2-methoxyphenyl)methyl]-1H-benzimidazole-5-carboxamide; N-(cycloheptylmethyl)-2-[(3-fluoro-2-methoxyphenyl)methyl]-1H-benzimidazole-5-carboxamide; and These enantiomers, salts, and solvates.

[0012] Compounds of general formula (I) are modulators of TMEM16A and are therefore useful in the treatment or prevention of diseases and symptoms affected by the regulation of TMEM16A. [Brief explanation of the drawing]

[0013]

Figure 1

[0014] Throughout this specification and the following claims, unless otherwise required by context, the word “comprise,” and variations such as “comprises” and “comprising,” mean to include the integers, processes, groups of integers or processes described, but not to exclude any other integers, processes, groups of integers or processes.

[0015] In this specification, “pharmaceutical use” refers to use for the treatment or prevention of a disease or condition, for administration to humans or animals, in particular humans or mammals, such as livestock or domestic mammals. The term “pharmaceutical composition” refers to a composition suitable for a pharmaceutical use, and “pharmaceutically acceptable” refers to a drug suitable for use in a pharmaceutical composition. Other similar terms shall be interpreted accordingly.

[0016] In this specification, "C 1-6 The term "alkyl" refers to a straight-chain or branched fully saturated hydrocarbon group having 1 to 6 carbon atoms. This term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. Other alkyl groups, for example, C 1-10 Alkyl compounds, as shown above, contain a different number of carbon atoms.

[0017] The terms "carbocyclic" and "carbocyclyl" refer to non-aromatic hydrocarbon ring systems containing 3 to 10 ring carbon atoms and, optionally, one or more double bonds, unless otherwise specified. A carbocyclic group may be a single ring or may contain two or three rings that are condensed or bridged, with the carbon atoms in the bridges being included in the number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl, as well as bridged systems such as bicyclo[1.1.1]pentyl, bicyclo-[2.2.1]heptyl, bicyclo-[2.2.2]octyl, and adamantyl.

[0018] In the context of this specification, the terms “heterocyclic” and “heterocyclyl” refer, unless otherwise specified, to non-aromatic ring systems containing 3 to 10 ring atoms, each containing at least one heteroatom selected from N, O, and S. A heterocyclic group may be a single ring or may contain two or three rings that are condensed or bridged, with the bridged atom being counted as the number of ring atoms. Examples include tetrahydrofuran, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and thiomorpholinyl, as well as condensed systems such as cyclopropyl condensed pyrrolidine. References to oxygen-containing heterocyclics also include two rings where the only heteroatom is oxygen, e.g., tetrahydrofuran and tetrahydropyran, and rings where an additional heteroatom selected from N and S is present, e.g., morpholine.

[0019] In the context of this specification, the terms “aryl” and “aromatic” refer to aromatic ring systems having 5 to 14 ring carbon atoms and containing up to 3 rings, unless otherwise specified. If an aryl group contains multiple rings, not all rings need to be perfectly aromatic. Examples of aromatic moieties are benzene, naphthalene, fluorene, tetrahydronaphthalene, indane, and indene.

[0020] In the context of this specification, the terms “heteroaryl” and “heteroaromatic” mean, unless otherwise specified, a ring system having aromatic properties and containing up to three rings, with 5 to 14 ring atoms. At least one of these ring atoms is a heteroatom selected from N, O, and S. If a heteroaryl group contains multiple rings, not all rings need to be aromatic. Examples of heteroaryl groups include pyridine, pyrimidine, indole, indazole, thiophene, benzothiophene, benzoxazole, benzofuran, dihydrobenzofuran, tetrahydrobenzofuran, benzimidazole, benzimidazolin, quinoline, and indolene.

[0021] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, while the term "halo" refers to a fluoro group, chloro group, bromo group, or iodine group. Similarly, "halogenated compound" refers to a fluoride, chloride, bromide, or iodide.

[0022] The term "C" used herein 1-6 The term "haloalkyl" refers to a group in which one or more hydrogen atoms are replaced by a halo group, as shown above. 1-6 This refers to alkyl groups. Any number of hydrogen atoms may be substituted up to the maximum perhalo substitution. Examples include trifluoromethyl, chloroethyl, and 1,1-difluoroethyl. Fluoroalkyl groups are haloalkyl groups in which the halo is fluoro.

[0023] The term “isotope variant” refers to an isotope-labeled compound that is identical to that shown in formula (I), except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those most commonly found in nature, or that the proportion of atoms with atomic masses or mass numbers less common in nature is increased (the latter concept is called “isotope enrichment”). Examples of isotopes that can be incorporated into the compounds of the present invention include natural or unnatural isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, such as 2H (deuterium), 3H, 11C, 13C, 14C, 18F, 123I, or 125I (e.g., 3H, 11C, 14C, 18F, 123I, or 125I).

[0024] Compounds of general formula (I) may also be tautomers. TIFF0007853981000002.tif39170

[0025] In some compounds of the present invention, R 1 [CH(R 7 )] n -N(R 8 )-C(O)OR 9 Here, n, R 7 , R 8 and R9 is as shown above for the general formula (I).

[0026] In some compounds of this kind, n is 1, and in other such compounds, n is 2.

[0027] More preferably, in such compounds, R 7 is selected from H, phenyl, methyl, CH2OH and CH2OCH3, and even more preferably is selected from H, methyl, phenyl and CH2OCH3.

[0028] R 8 is more preferably selected from H; methyl optionally substituted with methoxy; and ethyl optionally substituted with methoxy.

[0029] R 9 is more preferably C 3-4 alkyl, especially n-butyl, i-butyl and t-butyl, especially t-butyl.

[0030] R 1 is [CH(R 7 )] n -N(R 8 )-C(O)OR 9 (where n is 1), in some compounds, both R 7 and R 8 are not H. For example, in some cases, R 7 is H and R 8 is C 1-3 alkyl optionally substituted with one or more substituents selected from OH and methoxy, especially methyl or ethyl. In other cases, R 7 is phenyl; or C 1-3 alkyl optionally substituted with one or more substituents selected from OH and OCH3, especially phenyl, methyl or CH2OCH3, and R 8 is H. In still other cases, R 7 is phenyl; or C 1-3It is alkyl, R 8 C may be substituted with one or more substituents selected from OH and methoxy. 1-3 It is alkyl; for example, R 7 R is CH2OCH3 or phenyl, 8 It is methyl or ethyl.

[0031] In some compounds of general formula (I), R 1 CH(R 11 )(R 12 ) and here, R 11 and R 12 The general formula (I) is as shown above.

[0032] In several suitable compounds of this type, R 12 This is a cyclohexyl which may be substituted with an OH group.

[0033] In other such compounds, R 12 is phenyl, pyridyl, or oxazolyl, and each may be substituted with one or more substituents selected from OH, methoxy, fluoro, and chloro.

[0034] In some cases, for example, R 12 This is a phenyl molecule that may have an OH group or a methoxy group at the 2-position and may have one or two further substituents, preferably one further substituent selected from fluoro and chloro. 12 Examples of the base include phenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-fluoro-2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 5-fluoro-2-methoxyphenyl, and 5-chloro-2-methoxyphenyl.

[0035] In other cases, R 12This is a pyridyl group which may be substituted with OH or methoxy, for example 2-methoxypyridine-3-yl, or an oxazolyl group which may be substituted with one or more methyl groups, particularly a dimethyloxazolyl group.

[0036] Alternatively, R 12 R 11 and together with the atom to which it is bonded, the phenyl group R 12 The phenyl group R has substituents that form a 5-membered or 6-membered oxygen-containing heterocycle when condensed. 12 This may include other substituents shown above. Preferably, R 11 R that combines with 12 The substituent is a phenyl group R 12 CH(R 11 The position where it connects to the adjacent phenyl group R 12 Located in the upper position, this bonded substituent is a two- or three-membered hydrocarbon chain in which the CH2 portion may be substituted with -O-. For example, R 11 and R 12 The above substituents may bond to form the groups -O-CH2-, -CH2-O-, -O-CH2-CH2-, and -CH2-CH2-O-. 11 Base and R 12 One example of the group is 2,3-dihydrobenzofuran-3-yl.

[0037] In some compounds of general formula (I), R 1 is OR 15 Even if replaced by C 2-6 It is alkyl, R 15 This is as shown in general formula (I). In some more preferable compounds of this type, R 1 is unsubstituted C 3-6 Alkyl, especially branched unsubstituted C 3-6 Alkyl, more specifically, branched unsubstituted C 4-6 It is an alkyl group. In other more suitable compounds of this type, R 1 is OR 15 , in particular, methyl or ethyl substituted with methoxy.

[0038] In other compounds of general formula (I), R 1 R is a 6-10 membered aryl or a 5-10 membered heteroaryl, and each may be substituted with one or more substituents selected from fluoro, chloro, OH, or methoxy. More preferably, 1 This is a phenyl or a 5-membered or 6-membered heteroaryl group, preferably a nitrogen or oxygen-containing heteroaryl group. The phenyl or heteroaryl group may be substituted as shown above, but more preferably unsubstituted. Unsubstituted phenyl is this type of R 1 This is an example of the basics.

[0039] In some compounds of general formula (I), R 2 This is a 3- to 10-membered carbon ring system that may be substituted as shown above.

[0040] In some compounds of this type, R 2 These are cross-linked carbocyclic systems such as bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo-[2.2.1]heptanyl, bicyclo-[2.2.2]octanyl, or adamantyl, particularly bicyclo-[2.2.1]heptanyl or adamantyl. 2 Compounds in which adamantyl is present are particularly suitable. In some cases, R 2 When it is a bridged carbocyclic system, it is unsubstituted. Alternatively, bridged carbocyclic system R 2 This can be substituted with, for example, OH. Such R 2 An example of the group is adamantyl substituted with an OH group.

[0041] In other compounds of this type, R 2 This is a carbocyclic system, particularly a 5- to 8-membered carbocyclic system selected from cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and any of them may be unsubstituted or substituted as shown above. 2 More preferred substituents for the group include OH, fluoro, and C. 1-6 Alkyl, O(C 1-6 Alkyl) and NH-C(O)OC1-6 Alkyl, especially OH, C 1-4 Alkyl, O(C 1-4 Alkyl) and NH-C(O)OC 1-4 Alkyl, and more preferably C 1-4 Alkyl (especially methyl) fluoro and NH-C(O)OC 1-4 It contains alkyl.

[0042] In other, more suitable compounds of this type, R 2 This is an unsubstituted cyclopentyl, cyclohexyl, or cycloheptyl ring, particularly unsubstituted cycloheptyl.

[0043] In other compounds of general formula (I), R 2 is a 6-10 membered aryl or 5-10 membered heteroaryl ring system, which may be substituted as shown above. In this case, more preferably R 2 is either phenyl, or fluoro, chloro, OH, C 1-6 Alkyl (may be substituted with one or more substituents selected from OH and halo), O(C 1-6 Alkyl) and O(C 1-6 Haloalkyl), more preferably fluoro, chloro, OH, C 1-4 C substituted with alkyl and OH groups 1-4 Alkyl, and O(C 1-4 alkyl; especially fluoro, chloro, OH, C 1-4 C substituted with alkyl, OH, and methoxy groups 1-4 A five-membered or six-membered heteroaryl ring which may be substituted with one or more substituents selected from alkyl groups. In particular, R 2 This is a phenyl molecule in which the 2-position is substituted with an OH group, and which may be further substituted with substituents selected from fluoro and chloro groups.

[0044] In some compounds of general formula (I), Y and R 2 They come together, non-substituted C 3-8 Alkyl alkyl groups, more preferably C 5-8 It forms an alkyl group.

[0045] In some compounds of general formula (I), Y and R 2 They combine to form the base CH2-C(R 17 )(R 18 )-CH2-N(R 19 )R 20 (Here, R 17 , R 18 , R 19 and R 20 Each of these forms (as shown above).

[0046] More preferably, R 17 , R 8 and R 19 Each of them is independently H or methyl, and R 20 is C 1-4 It is a haloalkyl. More preferably, R 17 and R 18 Each of them is independently H or methyl, and R 19 H is R 20 is C 1-4 It is a haloalkyl group.

[0047] In some particularly preferred compounds of general formula (I), R 2 It is an unsubstituted cyclohexyl, and R 1 CH(R 11 )(R 12 )(Here, R 11 and R 12 (As shown above). More specifically, R 11 As shown above, R 12 R is a phenyl which may be substituted with OH or methoxy. 2 is an unsubstituted cyclohexyl, and R 1 Compounds in which benzyl is unsubstituted are particularly preferred, especially N-(2-benzyl-1H-benzimidazole-5-yl)-2-cyclohexyl-acetamide; 2-benzyl-N-(cyclohexylmethyl)-1H-benzimidazole-5-carboxamide, as well as salts and solvates thereof.

[0048] In some compounds of general formula (I), R3 , R 4 and R 5 All of them are H.

[0049] In some compounds of general formula (I), R 3 , R 4 and R 5 One of them is a halo, and the others are H. In certain compounds, R 3 is a halo, R 4 and R 5 is H. In certain compounds, R 4 is a halo, R 3 and R 5 is H. In certain compounds, R 5 is a halo, R 3 and R 4 H is H.

[0050] In other compounds of general formula (I), R 3 , R 4 and R 5 One or more of them are F. For example: R 3 F is R 4 and R 5 is H; or R 4 F is R 3 and R 5 is H; or R 5 F is R 3 and R 4 H is H.

[0051] In some compounds of general formula (I), Z is -NH-C(O)-.

[0052] In some compounds of general formula (I), Z is -C(O)NH-.

[0053] In some compounds of general formula (I), Y is a bond.

[0054] In compounds of general formula (I), Y is -CH2-.

[0055] In some compounds of general formula (I), Y is -CH(CH3)-.

[0056] In certain embodiments, the compound of formula (I) is a compound of formula (IA) which includes all of its tautomeric forms, all enantiomers and isotopic variants, as well as salts and solvates. TIFF0007853981000003.tif46170 wherein R 2 , R 3 , R 4 , R 5 , Y and Z are as defined for general formula (I); R 1a is i. [CH(R 7a )] n -N(R 8a )-C(O)OR 9a (n is 1 or 2, each R 7a is independently H; phenyl; or C 1-3 alkyl optionally substituted with one or more substituents selected from OH and OCH3, R 8a is H; C 1-3 alkyl optionally substituted with one or more substituents selected from OH and methoxy, but when n is 1, both R 7a and R 8a are not H, R 9a is C 2-4 alkyl); or ii. CH(R 11a )(R 12a ) (R 11a is H; OH; CH3; CH2OH; or a group that binds to the substituent on R 12a shown below, R 12a is selected from phenyl or 5- or 6-membered heteroaryl, said phenyl or heteroaryl being OH, methoxy, methyl, fluoro, chloro, and R 11and together with the atom to which it is bonded, the above-mentioned phenyl or heteroaryl group R 12a It may be substituted with one or more substituents selected from substituents that form a condensed 5-membered or 6-membered oxygen-containing heterocycle, However, R 12a When R is a phenyl or 6-membered heteroaryl which may be substituted with one or more substituents selected from OH, methoxy, methyl, fluoro, or chloro, 11a is not H); or iii. OR 15a Methyl, ethyl, or n-propyl substituted with; (R 15a is methyl or ethyl; or iv. 6-10 membered aryl or 5-10 membered heteroaryl (both may be substituted with one or more substituents selected from fluoro, chloro, OH, or methoxy) However, A. R 1a CH(R 11a )(R 12a ) when (where R 11a is H or methyl, and R 12a (The substituent is either unsubstituted or substituted with one or two substituents, the substituents being selected from halo and methoxy.) i. R 2 It is neither phenyl nor heteroaryl (where the phenyl or heteroaryl is a halo, C 1-4 Alkyl, C 1-4 It may be substituted with one or two substituents selected from alkoxy and five-membered heteroaryl rings; B. R 1a CH(R 11a )(R 12a ) when (where R 12a is phenyl, and R 11a R 12a Together with the substituents above and the atoms to which they are bonded, the phenyl ring R 12a A condensed 5 or 6-membered ring is formed, and the 5 or 6-membered ring is C 1-3 (May be substituted with alkyl) i. R 2a It is neither phenyl nor heteroaryl (where the phenyl or heteroaryl is a halo, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 It may be substituted with one, two, or three substituents selected from alkoxy); and ii. Y and R 2 They combine to form C 3-10 It does not form alkyl groups.

[0057] In some compounds of general formula (IA), R 1a [CH(R 7a )] n -N(R 8a )-C(O)OR 9a Here, n, R 7a , R 8a and R 9a The general formula (IA) is as shown above.

[0058] In some compounds of this type, n is 1, and in other such compounds, n is 2.

[0059] More preferably, in such a compound, R 7a The compound is selected from H, phenyl, methyl, CH2OH, and CH2OCH3, and more preferably from H, methyl, phenyl, and CH2OCH3.

[0060] R 8a More preferably, the compound is selected from H; methyl which may be substituted with methoxy; and ethyl which may be substituted with methoxy.

[0061] R 9a More preferably, C 3-4 Alkyl compounds, particularly n-butyl, i-butyl, and t-butyl, are selected from t-butyl.

[0062] R 1 [CH(R 7 )] n-N(R 8 )-C(O)OR 9 In a compound of general formula (IA) where n is 1, R 7a and R 8a It is not possible for both to be H. In some cases, R 7a H is R 8a C may be substituted with one or more substituents selected from OH and methoxy. 1-3 Alkyl, especially methyl or ethyl. In other cases, R 7a C may be substituted with one or more substituents selected from phenyl, OH, and OCH3. 1-3 Alkyl, especially phenyl, methyl, or CH2OCH3, R 8a H is. In other cases, R 7a C may be substituted with one or more substituents selected from phenyl, OH, and methoxy. 1-3 It is alkyl, R 8a C may be substituted with one or more substituents selected from OH and methoxy. 1-3 It is alkyl; for example, R 7a R is CH2OCH3 or phenyl, 8a It is methyl or ethyl.

[0063] In some compounds of general formula (IA), R 1a CH(R 11a )(R 12a ) and here, R 11a and R 12a The general formula (IA) is as shown above.

[0064] In some such compounds, R 12a R is a 6-membered heteroaryl group such as phenyl or pyridyl, and each may be substituted with one or more substituents selected from OH, methoxy, fluoro and chloro. 11a The group is OH, CH3, or CH3OH.

[0065] For example, R 12aThis is a phenyl molecule that may have an OH group or a methoxy group at the 2-position and may have one or two further substituents, preferably one further substituent selected from fluoro and chloro. 12a Examples of the base include phenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-fluoro-2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 5-fluoro-2-methoxyphenyl, and 5-chloro-2-methoxyphenyl.

[0066] In other such compounds, R 12a This is a pyridyl group which may be substituted with OH or methoxy, for example, 2-methoxypyridine-3-yl.

[0067] R 1a CH(R 11a )(R 12a In other compounds of general formula (IA), R 12a R is a five-membered heteroaryl group such as oxazolyl, which may be substituted with one or two methyl groups, particularly a dimethyloxazolyl group. In this case, R 11a This can be H, OH, CH3, or CH3OH.

[0068] R 1a CH(R 11a )(R 12a In other compounds of the general formula (IA), R 12a R 11a And together with the atom to which it is bonded, the phenyl group R 12a The phenyl group R has substituents that form a 5-membered or 6-membered oxygen-containing heterocycle when condensed. 12a This may include other substituents shown above. Preferably, R 11a R that combines with 12a The substituent is a phenyl group R 12a CH(R 11a The position where it connects to the adjacent phenyl group R 12ais in the upper position, and this combined substituent is a 2- or 3-member hydrocarbon chain in which the CH2 moiety may be substituted with -O-. For example, R 11a and R 12a are bonded to form groups such as -O-CH2-, -CH2-O-, -O-CH2-CH2-, -CH2-CH2-O-. An example of this kind of bonded R 11 group and R 12 group is 2,3-dihydrobenzofuran-3-yl.

[0069] In some compounds of general formula (IA), R 1a is OR 15 , especially methyl, ethyl or n-propyl substituted with methoxy, especially ethyl or n-propyl.

[0070] In still other compounds of general formula (IA), R 1a is a 6- to 10-member aryl or 5- to 10-member heteroaryl, either of which may be substituted with one or more substituents selected from fluoro, chloro, OH or methoxy. More preferably, R 1a is a phenyl or 5- or 6-member heteroaryl group, preferably a nitrogen- or oxygen-containing heteroaryl group. The phenyl or heteroaryl group may be substituted as shown above, but more preferably is unsubstituted. Unsubstituted phenyl is an example of this kind of R 1a group.

[0071] In the compounds of general formula (IA), the more preferred values of R 2 , R 3 , R 4 , R 5 , Y and Z are as shown above for the compounds of general formula (I).

[0072] In a further embodiment, the compounds of general formula (I) are compounds of general formula (IB) including all their tautomeric forms, all their enantiomers and isotopic variants as well as salts and solvates. TIFF0007853981000004.tif48170 wherein R 1 , R3 , R 4 , R 5 Y and Z are as shown for general formula (I); R 2b teeth, i. Fluoro; chloro; CN; nitro; OH; C 1-6 Alkyl (may be substituted with one or more substituents selected from halo, OH, and CN); O(C 1-6 Alkyl) (may be substituted with one or more substituents selected from halo, OH, and CN); and CH2NH-C(O)OC 1-6 A 3- to 10-membered carbocyclic system substituted with one or more substituents selected from alkyl (which may be substituted with one or more substituents selected from halo and OH); or Y and R 2 Together, they form a non-substituted C 3-8 Alkyl group or group CH2-C(R 17b )(R 18b )-CH2-N(R 19b )R 20b (Here, R 17b , R 18b and R 19b Each of them is independently H or C1-4 alkyl; R 20b C 1-4 Alkyl or C 1-4 (Forms a haloalkyl) however: R 1 CH(R 11 )(R 12 ) when (where R 12 is phenyl, and R 11 R 12 Together with the substituents above and the atoms to which they are bonded, the phenyl ring R 12 A condensed 5 or 6-membered ring is formed, and the 5 or 6-membered ring is C 1-3 (May be substituted with alkyl) Y and R 2b They combine to form C 3-8 It does not form alkyl groups.

[0073] In some compounds of general formula (IB), R 2b This is a substituted 3- to 10-membered carbon ring system as shown above.

[0074] In some compounds of this type, R 2b These are cross-linked carbocyclic systems such as bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo-[2.2.1]heptanyl, bicyclo-[2.2.2]octanyl, or adamantyl, particularly bicyclo-[2.2.1]heptanyl or adamantyl substituted as shown above. 2 Compounds in which adamantyl is substituted, particularly adamantyl substituted with OH, are especially preferred.

[0075] In other compounds of general formula (IB), R 2b This is a carbocyclic system, particularly a 5- to 8-membered carbocyclic system selected from cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, all of which are substituted as shown above. 2 More preferred substituents for the group include OH, fluoro, and C. 1-6 Alkyl, O(C 1-6 Alkyl) and NH-C(O)OC 1-6 Alkyl, especially OH, C 1-4 Alkyl, O(C 1-4 Alkyl) and NH-C(O)OC 1-4 Alkyl, and more preferably C 1-4 Alkyl (especially methyl) fluoro and NH-C(O)OC 1-4 It contains alkyl.

[0076] In some compounds of general formula (IB), Y and R 2b They come together, non-substituted C 3-8 Alkyl alkyl groups, more preferably C 5-8 It forms an alkyl group.

[0077] In some compounds of general formula (I), Y and R 2b They combine to form the base CH2-C(R 17b )(R 18b )-CH2-N(R19b )R 20b (Here, R 17b , R 18b , R 19b and R 20b Each of these forms (as shown above).

[0078] More preferably, R 17b , R 8 and R 19b Each of them is independently H or methyl, and R 20b is C 1-4 It is a haloalkyl. More preferably, R 17b and R 18b Each of them is independently H or methyl, and R 19b H is R 20b is C 1-4 It is a haloalkyl group.

[0079] In the following discussion, references to compounds of general formula (I) include compounds of general formula (IA) and compounds of general formula (IB).

[0080] Compounds of general formula (I) where Z is -NH-C(O)- are compounds of general formula (II): TIFF0007853981000005.tif44170 (in the formula, R 1 , R 3 , R 4 and R 5 As shown for general formula (I), the compound of general formula (III): TIFF0007853981000006.tif23170(In the formula, Y and R 2 As shown for general formula (I), R 11 It can be prepared by reacting it with OH or a halogen (especially Cl).

[0081] R 11 When the reaction is carried out in an organic solvent in the presence of a base such as diisopropylethylamine.

[0082] R 11When it is OH, this reaction can be carried out in an organic solvent such as DMF under basic conditions, for example, in the presence of an amine such as diisopropylethylamine (DIPEA) or triethylamine (TEA), in the presence of a coupling reagent.

[0083] Suitable coupling reagents include known peptide coupling agents such as O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) carbodiimide such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and triazole such as 1-hydroxy-7-azabenzotriazole (HOAt) or hydroxybenzotriazole (HOBt). Preferably, this reaction is carried out under basic conditions, for example, in the presence of an amine such as diisopropylethylamine (DIPEA), in an organic solvent such as DMF.

[0084] The compounds of general formula (III) are commercially available or can otherwise be prepared by known methods. This also applies to some of the compounds of general formula (II). However, when the compounds of general formula (II) are not commercially available, the compounds of general formula (IV): TIFF0007853981000007.tif44170(where R 1 、R 3 、R 4 and R 5The compound can be prepared by the reaction as shown for the general formula (I).

[0085] The reduction can be carried out by hydrogenation with a palladium catalyst. Preferably, this kind of hydrogenation reaction is carried out in an alcohol solvent, such as ethanol.

[0086] Alternatively, the reduction may be carried out using a metal such as zinc and an acid such as acetic acid.

[0087] When R of the general formula (III) 1 contains an OH group, it may be protected as, for example, a benzyloxy group during the reaction. The protecting group can be removed during the reduction, especially when hydrogenation is used.

[0088] The compound of the general formula (IV) is a compound of the general formula (V): TIFF0007853981000008.tif23170(where R 1 is as shown for the general formula (I)) reacted with a compound of the general formula (VI): TIFF0007853981000009.tif44170(where R 3 , R 4 and R 5 are as shown for the general formula (I)) can be prepared by reacting with.

[0089] This reaction has two steps. Preferably, the first step is carried out in an organic solvent such as DMF under basic conditions, for example, in the presence of an amine such as diisopropylethylamine (DIPEA) or triethylamine (TEA), in the presence of a coupling reagent. The preferred coupling agent is as described above for the reaction between the compound of the general formula (II) and the compound of the general formula (III). The second step is a cyclization step of heating the product of the first step under acidic conditions, preferably in acetic acid, at a temperature of about 50 - 100 °C.

[0090] Compounds of general formula (V) and general formula (VI) are commercially available, or can be prepared by known methods.

[0091] An alternative synthetic method for compounds of general formula (I) where Z is -NH-C(O)- is to synthesize the compound of general formula (V) shown above into a compound of general formula (VII): TIFF0007853981000010.tif44170 (in the formula, R 2 , R 3 , R 4 and R 5 This is achieved by reacting it with the general formula (I) shown above.

[0092] Similar to the reaction between compounds of general formulas (V) and (VI), this reaction is a two-step process. The first step is carried out in an organic solvent such as DMF under basic conditions, in the presence of a coupling reagent, for example, in the presence of an amine such as diisopropylethylamine (DIPEA) or triethylamine (TEA). Suitable coupling agents are as described above for the reaction between compounds of general formula (II) and general formula (III). The second step is a cyclization step, which is carried out by heating the product of the first step with an acid such as acetic acid at a temperature of about 50-100°C.

[0093] Compounds of general formula (VII) are the same as compounds of general formula (VIII): TIFF0007853981000011.tif44170 (in the formula, R 2 , R 3 , R 4 and R 5 It can be prepared by reduction of the general formula (I) shown above.

[0094] The reduction may be carried out by catalytic hydrogenation using a palladium catalyst in an alcohol solvent such as ethanol.

[0095] The compounds of general formula (VIII) are the compounds of general formula (III) and general formula (IX) shown above: TIFF0007853981000012.tif44170 (in the formula, R 2 , R 3 , R 4 and R 5 It can be prepared by reaction with (as shown above for general formula (I)).

[0096] Preferably, this reaction is carried out in an organic solvent such as DMF, under basic conditions, in the presence of a coupling reagent, for example, in the presence of an amine such as diisopropylethylamine (DIPEA) or triethylamine (TEA). Suitable coupling agents are as described above for the reaction between a compound of general formula (II) and a compound of general formula (III).

[0097] Compounds of general formula (IX) are commercially available, or can be prepared by known methods.

[0098] Compounds of general formula (I) where Z is -C(O)-NH- are compounds of general formula (XII): TIFF0007853981000013.tif44170 (in the formula, R 1 , R 3 , R 4 and R 5 (As shown for general formula (I), Compounds of general formula (XIII): TIFF0007853981000014.tif16170 (in the formula, R 2 And Y can be prepared by reacting them with (as shown for general formula (I)).

[0099] Preferably, this reaction is carried out in an organic solvent such as DMF, under basic conditions, in the presence of a coupling reagent, for example, in the presence of an amine such as 4-dimethylaminopyridine (DMAP). Suitable coupling agents are as described above for the reaction between a compound of general formula (II) and a compound of general formula (III), with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) being particularly preferred.

[0100] The compounds of general formula (XIII) are commercially available or can be prepared by known methods. Some compounds of general formula (XII) are also commercially available.

[0101] Compounds of general formula (XII) that are not commercially available can be prepared by hydrolysis of a compound of general formula (XIV): TIFF0007853981000015.tif44170(wherein R 1 、R 3 、R 4 and R 5 are as defined for general formula (I) and R 15 is C 1-6 alkyl or benzyl).

[0102] This hydrolysis is preferably base hydrolysis using an alkali metal hydroxide, particularly lithium hydroxide, in an aqueous solution.

[0103] Compounds of general formula (XIV) can be prepared by reaction of a compound of general formula (V) shown above with a compound of general formula (XV): TIFF0007853981000016.tif44170(wherein R 1 、R 3 、R 4 and R 5 are as defined for general formula (I) and R 15 is as defined for general formula (XIV)).

[0104] Preferably, the first of the two steps is carried out in an organic solvent such as DMF under basic conditions, in the presence of a coupling reagent and in the presence of an amine such as diisopropylethylamine (DIPEA) or triethylamine (TEA). Suitable coupling agents are as described above for the reaction of a compound of general formula (II) with a compound of general formula (III). Thereafter, the product of the first step is treated with an acid such as acetic acid. <00​Compounds of general formula (XV) are commercially available, or can be prepared by known methods.

[0106] Compounds of general formula (I) where Z is -C(O)-NH- are the compounds of general formula (XIII) shown above, and compounds of general formula (XVI): TIFF0007853981000017.tif44170 (in the formula, R 1 , R 3 , R 4 and R 5 As shown for general formula (I), R 16 (These are halogens, especially bromine.) It can also be prepared by reacting it with carbon monoxide.

[0107] Carbon monoxide can be generated in situ, as described in Example 3.3 below.

[0108] Compounds of general formula (XVI) are those of general formula (V) and general formula (XIX) shown above: TIFF0007853981000018.tif44170 (in the formula, R 1 , R 3 , R 4 and R 5 As shown for general formula (I), R 16 It can be prepared by reaction with (as shown for general formula (XVI)).

[0109] Preferably, the first step of this reaction is carried out in an organic solvent such as DMF under basic conditions in the presence of a coupling reagent, for example, in the presence of an amine such as diisopropylethylamine (DIPEA) or triethylamine (TEA). Suitable coupling agents are as described above for the reaction between the compound of general formula (II) and the compound of general formula (III). Cyclization is achieved by treating the product of the first step with an acid such as acetic acid at a temperature of about 50 to 100°C.

[0110] Compounds of general formula (I) where Z is -C(O)-NH- are the compounds of general formula (V) shown above, and compounds of general formula (XX): TIFF0007853981000019.tif44170 (in the formula, R 2 , R 3 , R 4 and R 5 It can be prepared by reacting it with (as shown above for general formula (I)).

[0111] Preferably, the first step of this reaction is carried out in an organic solvent such as DMF under basic conditions in the presence of a coupling reagent, for example, in the presence of an amine such as diisopropylethylamine (DIPEA) or triethylamine (TEA). Suitable coupling agents are as described above for the reaction between the compound of general formula (II) and the compound of general formula (III). Cyclization is achieved by treating the product of the first step with an acid such as acetic acid at a temperature of about 50 to 100°C.

[0112] Compounds of general formula (XX) are the same as compounds of general formula (XIII) shown above, and compounds of general formula (XVIII): TIFF0007853981000020.tif44170 (in the formula, R 1 , R 3 , R 4 and R 5 The compound can be prepared by reacting it with the compound of general formula (I) as shown above. Preferably, this reaction is carried out in an organic solvent such as DMF under basic conditions in the presence of a coupling reagent, for example, in the presence of an amine such as diisopropylethylamine (DIPEA) or triethylamine (TEA). Suitable coupling agents are as described above for the reaction between the compound of general formula (II) and the compound of general formula (III).

[0113] Compounds of general formula (XVIII) can be prepared by hydrolysis of compounds of general formula (XV), particularly by base hydrolysis using an alkali metal hydroxide such as lithium hydroxide in an alcohol solvent such as methanol or a mixture of methanol, tetrahydrofuran, and water.

[0114] In the synthesis of compounds of general formula (I), protecting groups may be used as needed. Suitable protecting groups are well known (see Greene's Protective Groups in Organic Synthesis, Peter GM Wuts, Ed, John Wiley & Sons, Inc, 2014). For example, R 1 or R 2 If the compound contains an aromatic ring substituted with an OH group, protection may be necessary. For example, R 1 The base is CH(R 11 )(R 12 ) and here R 12 If it is an OH-substituted phenyl, the OH group is protected as a lactone, and the lactone is ring-opened by treatment with a reducing agent such as sodium borohydride or lithium borohydride, and the required R 12 It is possible to generate a group. Alternatively, the OH group is O(C 1-6 ) may be protected as an alkyl, particularly methoxy or benzyloxy. If the protecting group is methoxy, deprotection can be carried out by reaction with boron tribromide. The benzyloxy group can be removed by catalytic hydrogenation as shown in Examples 1.4, 1.5 and 3.3. Another method is to remove the OH group as tri(C 1-6 It can also be protected with an alkyl(silyl) group, which can be removed with an aqueous workup.

[0115] Since the compounds of general formula (I) are positive modulators of TMEM16A, further aspects of the present invention provide the compounds of general formula (I) shown above for use in medicine, particularly in the treatment or prevention of diseases and conditions affected by the modulation of TMEM16A.

[0116] Furthermore, the use of compounds of general formula (I) in the manufacture of pharmaceuticals for the treatment or prevention of diseases and symptoms affected by the modification of TMEM16A is also provided.

[0117] Furthermore, methods for treating or preventing diseases and conditions affected by the modification of TMEM16A are also provided, comprising administering an effective amount of a compound of general formula (I) to a patient in need of such treatment.

[0118] Diseases and symptoms affected by the regulation of TMEM16A include respiratory diseases and symptoms, dry mouth (xerostomia), hypermotility, cholestasis, and ocular symptoms.

[0119] The following will also be provided. • Compounds of general formula (I) for use in the treatment or prevention of respiratory diseases and symptoms. • A compound of general formula (I) for use in the treatment or prevention of dry mouth (xerostomia). • Compounds of general formula (I) for use in the treatment or prevention of excessive bowel motility. • Compounds of general formula (I) for use in the treatment or prevention of cholestasis. • Compounds of general formula (I) for use in the treatment or prevention of ocular symptoms.

[0120] The present invention also provides the following: • Use of compounds of general formula (I) in the manufacture of pharmaceuticals for the treatment or prevention of respiratory diseases and symptoms. • Use of compounds of general formula (I) in the manufacture of pharmaceuticals for the treatment or prevention of dry mouth (xerostomia). • Use of compounds of general formula (I) in the manufacture of pharmaceuticals for the treatment or prevention of excessive bowel motility. • Use of compounds of general formula (I) in the manufacture of pharmaceuticals for the treatment or prevention of cholestasis. • Use of compounds of general formula (I) in the manufacture of pharmaceuticals for the treatment or prevention of ocular symptoms.

[0121] Furthermore, the following will be provided: A method for the treatment or prevention of respiratory diseases and symptoms, comprising administering an effective amount of a compound of general formula (I) to a patient in need of such treatment. A method for treating or preventing dry mouth (xerostomia), comprising administering an effective amount of a compound of general formula (I) to a patient in need of such treatment. A method for treating or preventing excessive bowel motility, comprising administering an effective amount of a compound of general formula (I) to a patient in need of such treatment. A method for the treatment or prevention of cholestasis, comprising administering an effective amount of a compound of general formula (I) to a patient in need of such treatment. A method for the treatment or prevention of ocular symptoms, comprising administering an effective amount of a compound of general formula (I) to a patient in need of such treatment.

[0122] Respiratory diseases and conditions that can be treated or prevented by compounds of general formula (I) include cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis (including non-cystic fibrotic bronchiectasis), asthma, and primary ciliary dysfunction.

[0123] Dry mouth (xerostomia), which can be treated or prevented by compounds of general formula (I), may be caused by Sjögren's syndrome, radiation therapy, and xerogenic drugs.

[0124] Excessive bowel motility, which can be treated or prevented by compounds of general formula (I), may be associated with gastric dyspepsia, gastroparesis, chronic constipation, and irritable bowel syndrome.

[0125] Ocular conditions that can be treated or prevented by compounds of general formula (I) include dry eye disease.

[0126] The compounds of the present invention are typically administered as part of a pharmaceutical composition. Therefore, the present invention further provides pharmaceutical compositions comprising compounds of general formula (I) together with pharmaceutically acceptable additives.

[0127] This pharmaceutical composition can be formulated for oral, rectal, intranasal, bronchial (inhalation), topical (including skin, transdermal, ophthalmic, oral, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration, and can be prepared by any method well known in the field of pharmacy.

[0128] The compositions of the present invention can be prepared by combining the activators described above with additives. Generally, the formulations are prepared by uniformly and closely combining the activator with a liquid carrier, a pulverized solid carrier, or both, and then, if necessary, shaping the product. The present invention extends to methods for preparing pharmaceutical compositions, comprising combining or combining a compound of general formula (I) with a pharmaceutically acceptable carrier or vehicle.

[0129] The oral formulations of the present invention are provided as individual units such as capsules, sachets, or tablets, each containing a predetermined amount of the activator; as powder or granules; as a solution or suspension of the activator in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as a bolus, etc.

[0130] In the case of compositions for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes common additives, such as binders, vehicles such as syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose, and starch; fillers and carriers, such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid; and lubricants, such as magnesium stearate, sodium stearate, and other metal stearates, glycerol stearate, stearic acid, silicone fluids, talc wax, oils, and colloidal silica. Flavoring agents such as peppermint, wintergreen oil, and cherry flavoring may also be used. It may be desirable to add colorants to make the dosage form easily identifiable. Tablets may also be coated by methods well known in the art.

[0131] Tablets may be prepared by compression or molding, along with one or more auxiliary components as desired. Compressed tablets may be prepared by compressing an activator in a free-flowing form, such as a powder or granules, which is optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets may be prepared by molding a mixture of a moistened powdered compound and an inert liquid diluent in a suitable machine. Tablets may optionally be coated or perforated, and may be formulated to allow for the slow release, or sustained release, of the activator.

[0132] Other formulations suitable for oral administration include lozenges containing the activator in a flavored base, usually sucrose and gum arabic or tragacanth; flavored tablets containing the activator in an inert base such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes containing the activator in a suitable liquid carrier.

[0133] For topical administration to the skin, compounds of general formula (I) can be prepared as creams, ointments, jellies, solutions, or suspensions. Cream or ointment formulations that can be used as drugs are conventional formulations well known in the art, such as those described in standard compounding textbooks, such as the British Pharmacopoeia.

[0134] Local administration to the lungs can be achieved by the use of an aerosol formulation. The aerosol formulation typically contains an active ingredient suspended or dissolved in a suitable aerosol propellant such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC). Suitable CFC propellants include trichloromonofluoromethane (propellant 11), dichlorotetrafluoromethane (propellant 114), and dichlorodifluoromethane (propellant 12). Suitable HFC propellants include tetrafluoroethane (HFC-134a) and heptafluoropropane (HFC-227). The propellant typically constitutes 40% to 99.5% by weight, for example, 40% to 90% by weight, of the total inhalation composition. The formulation may include additives containing a cosolvent (e.g., ethanol) and a surfactant (e.g., lecithin, sorbitan trioleate, etc.). Other possible additives include polyethylene glycol, polyvinylpyrrolidone, and glycerin. The aerosol formulation is contained in a canister, and a suitable dose is delivered by a dispensing valve (e.g., supplied by Bespak, Valois, or 3M, or by Aptar, Coster, or Vari).

[0135] Local administration to the lungs can also be achieved by using non-pressurized formulations such as aqueous solutions or suspensions. These can be administered using a nebulizer, such as a handheld portable nebulizer, or a home or hospital (i.e., non-portable) nebulizer. The formulations may contain water, buffers, tonicity adjusters, pH adjusters, surfactants, and additives such as cosolvents. Suspensions and aerosol formulations (whether pressurized or non-pressurized) typically contain, for example, 0.5–10 μm, or for example, about 1–5 μm of D 50 The compound of the present invention is contained in a finely powdered form having the particle size distribution, D10 , D 50 and D 90 It can be expressed using a value. D of particle size distribution 50 The median is defined as the particle size in microns that divides the distribution in half. Since the measurements obtained from laser diffraction describe the volume distribution more accurately, the D obtained using this procedure is 50 The value is Dv 50 The term "value" (median of the volume distribution) is more meaningful. As used herein, the Dv value refers to the particle size distribution measured using laser diffraction. Similarly, D as used in the context of laser diffraction 10 Value and D 90 The value is Dv 10 Value and Dv 90 This represents the value, and each represents 10% of the distribution. 10 The values ​​are below the threshold, and 90% of the distribution is D 90 This likely refers to particle size below a certain value.

[0136] Local administration to the lungs can also be achieved by using a dry powder formulation. Dry powder formulations typically have a mass-average diameter (MMAD) of 1–10 μm or 0.5–10 μm, for example, about 1–5 μm. 50 The compound of the present disclosure is contained in a micronized form having the following characteristics. The powder of the compound of the present invention in a micronized form can be prepared by a micronization process or a similar size reduction process. Micronization may be performed using a jet mill such as that of Hosokawa Alpine. The resulting particle size distribution can be measured using laser diffraction (for example, with a Malvern Mastersizer 2000S instrument). The formulation of the present invention typically has relatively large particle sizes, for example, a mass-average diameter (MMAD) of 50 μm or more (e.g., 100 μm or more) or D 50These typically contain a topically acceptable diluent such as lactose, glucose, or mannitol (preferably lactose) in a 40-150 μm particle size. As used herein, the term “lactose” refers to lactose-containing components, including α-lactose monohydrate, β-lactose monohydrate, α-lactose anhydride, β-lactose anhydride, and amorphous lactose. Lactose components can be processed by micronization, sieving, grinding, compression, agglomeration, or spray drying. This also includes commercially available forms of lactose in various forms, such as Lactohale® (inhalation-grade lactose; DFE Pharma), InhaLac® 70 (sieved lactose for dry powder inhalation; Meggle), Pharmatose® (DFE Pharma), and Respitose® (sieved inhalation-grade lactose; DFE Pharma) products. In one embodiment, the lactose component is selected from the group consisting of α-lactose monohydrate, α-lactose anhydrous, and amorphous lactose. Preferably, the lactose is α-lactose monohydrate.

[0137] The dried powder formulation may also contain other additives. Therefore, in some embodiments, the dried powder formulation according to this disclosure contains magnesium stearate or calcium stearate. The dried powder formulation may have excellent chemical and / or physical stability, particularly if it also contains lactose.

[0138] Dry powder formulations are typically delivered using dry powder inhalers (DPIs). Examples of dry powder delivery systems include SPINHALER®, DISKHALER®, TURBOHALER®, DISKUS®, SKYEHALER®, ACCUHALER®, and CLICKHALER®. Further examples of dry powder delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER / NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X-CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR, and PROHALER.

[0139] In one embodiment, the compound of general formula (I) is provided as a micronized dry powder formulation containing, for example, a suitable grade of lactose.

[0140] Accordingly, in one aspect of the present invention, a pharmaceutical composition is provided which comprises a compound of general formula (I) in granular form combined with granular lactose, and optionally contains magnesium stearate.

[0141] In one embodiment, the compound of general formula (I) is provided as a micronized dry powder formulation containing a suitable grade of lactose and magnesium stearate, which is filled into a device such as a DISKUS. Preferably, such a device is a multi-unit dosing device, and for example, the formulation of the present invention is filled into a blister for use in a multi-unit dosing device such as a DISKUS.

[0142] In another embodiment, the compound of general formula (I) is provided as a micronized dry powder formulation containing a suitable grade of lactose, for example, filled into hard-shell capsules for use in single-dose devices such as AEROLISER.

[0143] In another embodiment, the compound of general formula (I) is provided as a micronized dry powder formulation containing a suitable grade of lactose and magnesium stearate, filled into hard-shell capsules for use in single-dose devices such as AEROLISER.

[0144] In another embodiment, the compound of general formula (I) is provided as a fine powder for use in an inhalation form, the powder being produced by a size reduction process other than atomization by jet milling, such as spray drying, spray freezing, microfluidization, high-pressure homogenization, supercritical fluid crystallization, ultrasonic crystallization or a combination thereof, or by other suitable particle formation methods known in the art used to produce fine particles with an aerodynamic particle size of 0.5 to 10 μm, for example, about 1 to 5 μm. 50 These are fine particles having [the specified characteristic]. The resulting particle size distribution can be measured using laser diffraction (for example, with a Malvern Mastersizer 2000S instrument). The particles may contain the compound of the present invention alone, or in combination with other suitable additives that can assist in processing. The resulting fine particles may form a final formulation for delivery to humans, or, optionally, be further formulated with other suitable additives to facilitate delivery in an acceptable dosage form.

[0145] The compounds of the present invention can also be administered rectally in the form of suppositories or enemas, including, for example, aqueous or oily solutions, suspensions, emulsions, and foams. Such compositions are prepared according to standard procedures well known to those skilled in the art. For example, suppositories can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides. In this case, the drug is mixed with a suitable non-irritating additive that is solid at room temperature but liquid at rectal temperature, and therefore dissolves in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0146] Generally, in the case of compositions intended for topical administration to the eye in the form of eye drops or eye ointments, the total amount of compound of general formula (I) will be less than about 0.0001 to 4.0% (w / w).

[0147] Preferably, for topical ocular administration, the composition administered according to general formula (I) is formulated as a solution, suspension, emulsion, or other dosage form. Aqueous solutions are generally preferred due to their ease of formulation and the fact that such a composition can be easily administered by the patient by dropping one or two drops of the solution onto the affected eye. However, the composition may also be a suspension, a viscous or semi-viscous gel, or other types of solid or semi-solid compositions. Suspensions may be preferred for compounds that are poorly soluble in water.

[0148] An alternative method of administration to the eye is intravitreal injection of a solution or suspension of the compound of general formula (I). Furthermore, the compound of general formula (I) can also be introduced using an ocular implant or insert.

[0149] The composition according to general formula (I) administered may also contain, but is not limited to, isotonic agents, buffers, surfactants, stabilizing polymers, preservatives, cosolvents, and viscosity enhancers. A preferred pharmaceutically acceptable composition of general formula (I) comprises the compound of the present invention formulated together with an isotonic agent and a buffer. The pharmaceutically acceptable composition of general formula (I) may optionally further contain a surfactant and / or a mitigating agent and / or a stabilizing polymer.

[0150] For ophthalmic compositions, the tonicity of the compositions of the present invention can be adjusted to preferably the tonicity of natural tears by using various isotonic agents. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride; monosaccharides such as dextrose, fructose, and galactose; and / or sugar alcohols such as mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrolyzed starch can be added to the compositions of the present invention to approximate physiological tonicity. The amount of such isotonic agent varies depending on the specific agent added. However, the compositions generally contain a sufficient amount of isotonic agent for the final composition to have an ophthalmologically acceptable osmolality by weight (generally about 150-450 mOsm, preferably 250-350 mOsm, most preferably about 290 mOsm). Generally, the isotonic agent of the present invention is present in the range of 2-4% (w / w). Preferred isotonic agents of the present invention include monosaccharides or sugar alcohols, such as D-mannitol.

[0151] A suitable buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate, or boric acid) can be added to the composition to prevent pH drift under storage conditions. The specific concentration will vary depending on the agent used. However, preferably, the buffer is selected to maintain the target pH within the range of pH 5 to 8, more preferably at a target pH of pH 5 to 7.

[0152] Optionally, surfactants may be used to deliver higher concentrations of the compound of general formula (I). The surfactants act to solubilize the compound and stabilize colloidal dispersions such as micellar solutions, microemulsions, emulsions, and suspensions. Examples of surfactants that can be optionally used include polysorbate, poloxamer, polyoxyl stearate (polyosyl) 40, polyoxyl castor oil, tyroxapole, Triton, and sorbitan monolaurate. Preferred surfactants used in the present invention have a hydrophilic-lipophilic balance "HLB" in the range of 12.4 to 13.2 and are acceptable for ophthalmic applications, such as Triton X114 and tyroxapole.

[0153] Additional agents that may be added to ophthalmic compositions of compounds of general formula (I) are stimulants that act as stabilizing polymers. The stabilizing polymer needs to be an ionic / charged example that is advantageous for topical ophthalmic use, and more specifically, it needs to be a polymer (i.e., water-soluble) having a negative charge on its surface, exhibiting a zeta potential of (-)10 to 50 mV for physical stability and capable of producing aqueous dispersions. Preferred stabilizing polymers of the present invention are 0.1 to 0.5% (w / w) of polyelectrolytes or (if more than one) multiple polyelectrolytes from the family of cross-linked polyacrylates such as carbomers and Pemulen®, particularly carbomer 974p (polyacrylic acid).

[0154] To increase the viscosity of the carrier, other compounds may be added to the ophthalmic composition of the compound of general formula (I). Examples of thickeners include, but are not limited to, hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, polysaccharides such as various polymers of the cellulose family, vinyl polymers, and acrylic acid polymers.

[0155] Topical ophthalmic products are typically packaged in multi-dose formulations. Therefore, preservatives are necessary to prevent microbial contamination during use. Suitable preservatives include benzalkonium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propylparaben, phenylethyl alcohol, disodium edentate, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. These preservatives are typically used at concentrations of 0.001–1.0% (w / v). Unit-dose compositions of general formula (I) are sterile but typically not preserved. Therefore, such compositions generally do not contain preservatives.

[0156] Parenteral formulations are generally sterile.

[0157] A physician or other person skilled in the art can determine a suitable dosage of the compound of general formula (I), and by extension, the amount of the compound of the present invention to be included in any particular pharmaceutical preparation (whether in unit dosage form or not).

[0158] Compounds of general formula (I) can be used in combination with one or more other active agents useful for the treatment or prevention of respiratory diseases and symptoms.

[0159] These additional activators may be included in the above-described pharmaceutical composition, but alternatively, they may be administered separately, simultaneously with, earlier than, or later than, the compound of general formula (I).

[0160] Accordingly, in a further aspect of the present invention, a product is provided comprising a compound of general formula (I) and an additional agent useful for the treatment or prevention of respiratory symptoms, as a combination preparation for simultaneous, sequential, or separate use in the treatment of a disease or condition affected by the modification of TMEM16A, particularly respiratory diseases or conditions, for example, the diseases and conditions described above.

[0161] Compounds of general formula (I) are also provided in combination with additional agents useful for the treatment or prevention of respiratory symptoms, as combination preparations for simultaneous, sequential, or separate use in the treatment of one of the diseases and symptoms described above, for example, diseases or symptoms affected by the modification of TMEM16A, particularly respiratory diseases or symptoms.

[0162] Suitable additional activators that may be included in a pharmaceutical composition or combination preparation with a compound of general formula (I) include the following: β2 adrenergic receptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, orodaterol, vilanterol, and avesiderol; Antihistamines, such as histamine H1 receptor antagonists or H4 receptor antagonists, including loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine, and chlorpheniramine; Dornaze alpha; Corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, and fluticasone furoate; Leukotriene antagonists such as montelukast and zaphirlukast; Anticholinergic compounds, particularly muscarinic antagonists such as ipratropium, tiotropium, glycopyrrolate, acridinium, and umeclidinium; CFTR repair therapies such as Ibacaftol, QBW251, Bamacaftor (VX659), Elexacaftor (VX445), VX561 / CPT-656, VX152, Olacaftor (VX440), GLP2737, GLP2222, GLP2451, PTI438, PTI801, PTI808, FDL-169 and FDL-176 (e.g., CFTR enhancers, correctors, or amplifiers), as well as CFTR correctors such as Lumacaftor and Tezacaftol, or combinations thereof (e.g., combinations of Ibacaftol, Tezacaftol, and Elexacaftor); ENaC modulators, especially ENaC inhibitors; antibiotics; Antiviral agents such as ribavirin and neuraminidase inhibitors such as zanamivir; Antifungal agents such as PUR1900; Hypertonic saline and mannitol (bronchitol®) and other airway hydration agents (osmotic regulators); and Mucolytic agents such as N-acetylcysteine.

[0163] If the additional activator is an ENaC modulator, it may be an ENaC inhibitor such as amiloride, VX-371, AZD5634, QBW276, SPX-101, BI443651, BI1265162, and ETD001. Other suitable ENaC blockers are disclosed in International Publications 2017 / 221008, 2018 / 096325, 2019 / 077340, and 2019 / 220147, and any of the exemplary compounds in these applications can be used in combination with the compound of general formula (I). Compounds particularly suitable for use in combination with the compound of general formula (I) include: 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)ethyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-6-{[2-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-yl)ethyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-5-[4-({bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}methyl)piperidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-6-[(3R)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-6-[(3S)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-1,3-diethyl-6-{[(1r,4r)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-1,3-diethyl-6-{[(1s,4s)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazole-3-ium A selected cation from; and Suitable anions include halides, sulfates, nitrates, phosphates, formates, acetates, trifluoroacetates, fumarates, citrates, tartrates, oxalates, succinates, mandelates, methanesulfonates, or p-toluenesulfonates. Examples of compounds having this feature include [Examples]

[0164] The present invention will be explained by the following embodiments.

[0165] Examples The present invention will be explained by the following non-limiting embodiments.

[0166] Example General conditions: Mass spectra were performed using an LC-MS system with electrospray ionization. Mass spectra were obtained using either a Waters Acquity uPLC system with Waters PDA and ELS detectors, or a Shimadzu LCMS-2010EV system. [M+H]+ refers to the monoisotopic molecular weight.

[0167] NMR spectra were recorded using a Bruker Avance III HD 500 MHz with a 5 mm broadband inverse probe, or a Bruker Avance III HD 250 MHz or 400 MHz Avance III HD Nanobay with a 5 mm broadband SmartProbe, with deuterium internal locking as the solvent. Unless otherwise specified, spectra were recorded at room temperature and referenced to the solvent peak.

[0168] With reference to the following examples, compounds of preferred embodiments were synthesized using the methods described herein or other methods known in the art.

[0169] Various starting materials, intermediates, and compounds of preferred embodiments can be isolated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography, as needed. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purification. Salts can be prepared from compounds by known salt-forming procedures.

[0170] The compounds were purified by flash column chromatography on normal-phase silica using a suitable SNAP or Sfar cartridge and gradient in a Biotage® Isolera system. Alternatively, the compounds were purified on reverse-phase silica using either a Biotage® Isolera or Biotage® Selekt system equipped with a suitable SNAP C18 or Sfar C18 cartridge and reverse-phase eluent, or by preparative HPLC (as otherwise stated).

[0171] Preparative HPLC using acidic pH, early elution method Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: RT) with a gradient of 10–95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) over 14.44 minutes, followed by 95% B for 2.11 minutes, at an injection volume of 1500 μL and flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0172] Preparative HPLC using acidic pH, standard elution method Purification by preparative HPLC (acidic pH, standard elution method) was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: RT) with a gradient of 30–95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) over 11 minutes, followed by 2.11 minutes of 95% B, at an injection volume of 1500 μL and flow rate of 40 mL / min. The UV spectrum was recorded at 215 nm using a Gilson detector.

[0173] Preparative HPLC using basic pH, early elution method Purification by preparative HPLC (basic pH, early elution method) was performed on a Gilson LC system using a Waters Xbridge C18 column (30 mm x 100 mm, 10 μM; temperature: RT) with a gradient of 10–95% (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) over 14.44 minutes, followed by 95% B over 2.11 minutes, at an injection volume of 1500 μL and flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0174] Preparative HPLC using basic pH, standard elution method Purification by preparative HPLC (basic pH, standard elution method) was performed on a Gilson LC system using a Waters Xbridge C18 column (30 mm x 100 mm, 10 μM; temperature: RT) with a gradient of 30–95% (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) over 11 minutes, followed by 95% B over 2.11 minutes, at an injection volume of 1500 μL and flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0175] Unless otherwise specified, the analytical HPLC conditions are as follows: Method A Column: Phenomenex Kinetix-XB C18 2.1x100mm, 1.7μm Column temperature: 40°C Eluting agents: A: H2O + 0.1% formic acid, B: Acetonitrile + 0.1% formic acid Flow rate: 0.6mL / min Gradient: 0-5.3 min 5-100%B, 5.3-5.8 min 100%B, 5.8-5.82 min 100-5%B, 5.82-7.00 min 5%B Method B Column: Waters UPLC(registered trademark) CSH TM C18 2.1 x 100 mm, 1.7 μm Column temperature: 40°C Eluting agents: A: 2 mM ammonium bicarbonate buffered to pH 10, B: acetonitrile Flow rate: 0.6mL / min Gradient: 0-5.3 min 5-100%B, 5.3-5.8 min 100%B, 5.8-5.82 min 100-5%B, 5.82-7.00 min 5%B Method C Column: Waters UPLC(registered trademark) BEH TM C18 2.1 x 100 mm, 1.7 μm Column temperature: 40°C Eluting agents: A: 2 mM ammonium bicarbonate buffered to pH 10, B: acetonitrile Flow rate: 0.6mL / min Gradient: 0-5.3 min 5-100%B, 5.3-5.8 min 100%B, 5.8-5.82 min 100-5%B, 5.82-7.00 min 5% B Method E Column: Kinetex Core-Shell C18 2.1 x 50 mm, 5 μm Column temperature: 40°C Eluting agents: A: H2O + 0.1% formic acid, B: Acetonitrile + 0.1% formic acid Flow rate: 1.2mL / min Gradient: 0-1.20 min 5-100%B, 1.20-1.30 min 100%B, 1.30-1.31 min 100-5%B, 1.31-1.7 min 5%B Method F Column: Phenomenex Gemini-NX C18 2 x 50mm 3μm Column temperature: 40°C Eluting agents: A: 2 mM ammonium bicarbonate buffered to pH 10, B: acetonitrile Flow rate: 1mL / min Gradient: 0-1.80 min 1-100%B, 1.80-2.10 min 100%B, 2.10-2.30 min 100-1%B, 2.30-3.50 min 1%B

[0176] The following examples are for illustrative purposes only and should not be construed as limitations on the present invention. Temperatures are expressed in Celsius. Unless otherwise specified, all evaporation is carried out in a vacuum, preferably between approximately 15 mm Hg and 100 mm Hg (=20-133 mbar). The structures of the final product, intermediates, and starting materials have been confirmed by standard analytical methods, e.g., trace analysis and spectroscopic properties, e.g., MS, IR, and NMR. Abbreviations used are those commonly used in the art. Unless otherwise specified, terms have their generally accepted meanings.

[0177] Abbreviation Acetic acid (ACOH) aq. aqueous solution br broad d doublet dd Double Doublet DCE Dichloroethane DCM Dichloromethane DIPEA Diisopropylethylamine DMAP 4-dimethylaminopyridine DMF (N,N-dimethylformamide) EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl ethyl acetate EtOH Ethanol HOAt 1-hydroxy-7-azabenzotriazole HATU 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HPLC (High-Pressure Liquid Chromatography) IPA Isopropyl Alcohol MeCN acetonitrile MeOH MeOH MS mass spectrometry m multiplex min mL (milliliter) m / z mass-to-charge ratio NMR nuclear magnetic resonance q quartet Rt Retention Time s singlet t triplet TBTU N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uroniumtetrafluoroborate TEA (Triethylamine) THF (Tetrahydrofuran)

[0178] Preparation example Example 1.1 N-(2-benzyl-1H-benzimidazole-5-yl)-2-cyclohexyl-acetamide TIFF0007853981000021.tif301702-Benzyl-1H-benzimidazole-5-amine (intermediate A) (75 mg, 0.34 mmol) and DIPEA (70 μL, 0.40 mmol) were mixed in a 2 mL chilled (0°C) DCM solution to which 2-chlorohexylacetyl chloride (57 μL, 0.37 mmol) was added. This solution was warmed to room temperature and stirred for 1 hour. The resulting mixture was diluted with 5 mL of DCM, washed with 5 mL of water and 5 mL of brine, dried over Na2SO4, and concentrated under vacuum. The crude residue was dissolved in 2 mL of MeOH and 0.5 mL of MeOH containing 7 M NH3, and the mixture was allowed to stand for 5 minutes. This methanol solution was purified by preparative HPLC (basic pH, early elution method) to obtain the title compound as an off-white powder. LC-MS (Method A): Rt 2.10 min; MS m / z 348.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.16 - 12.08 (m, 1H), 9.80 - 9.68 (m, 1H), 7.97 - 7.83 (m, 1H), 7.42 - 7.09 (m, 7H), 4.13 (s, 2H), 2.17 (d, J = 7.0 Hz, 2H), 1.82 - 1.74 (m, 1H), 1.72 - 1.59 (m, 5H), 1.27 - 1.11 (m, 3H), 1.02 - 0.93 (m, 2H).

[0179] Example 1.2 2-benzyl-N-(cyclohexylmethyl)-1H-benzimidazole-5-carboxamide TIFF0007853981000022.tif31170 A solution of commercially available 2-benzyl-1H-benzimidazole-5-carboxylic acid (75 mg, 0.30 mmol) in DMF (2 mL) was mixed with EDCI (63 mg, 0.33 mmol), DMAP (40 mg, 0.33 mmol), and HOAt (45 mg, 0.33 mmol). After stirring at room temperature for 5 minutes, cyclohexylmethaneamine (67 mg, 0.59 mmol) was added, and stirring was continued for 16 hours under an inert atmosphere. The resulting mixture was diluted with  (20 mL), washed with water (2 x 10 mL) and brine (2 x 10 mL), and concentrated under vacuum. The crude substance was purified by preparative HPLC (acidic pH, standard elution method) to obtain the title compound as a white solid. LC-MS (Method A): Rt 2.21 min; MS m / z 348.2 = [M+H]+ 1H NMR (500 MHz,Methanol-d4) δ 8.43 (t, J = 5.7 Hz, 1H), 8.01 (s, 1H), 7.70 (dd, J = 8.5, 1.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.35 - 7.30 (m, 4H), 7.28 - 7.23 (m, 1H), 4.26 (s, 2H), 3.26 - 3.21 (m, 2H), 1.85 - 1.73 (m, 4H), 1.71 - 1.62 (m, 2H), 1.34 - 1.17 (m, 3H), 1.07 - 0.97 (m, 2H).

[0180] Example 1.2.1 N-(1-adamantylmethyl)-2-benzyl-1H-benzimidazole-5-carboxamide TIFF0007853981000023.tif35170 The title compound was prepared from 2-benzyl-1H-benzimidazole-5-carboxylic acid and 1-adamantylmethaneamine, similar to Example 1.2. LC-MS (Method A): Rt 2.67 min; MS m / z 400.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.47 (br. s, 1H), 8.21 - 8.15 (m, 1H), 8.02 (br. s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 - 7.39 (m, 1H), 7.35 - 7.29 (m, 4H), 7.26 - 7.20 (m, 1H), 4.20 (s, 2H), 3.00 (d, J = 6.3 Hz, 2H), 1.96 - 1.89 (m, 3H), 1.69 - 1.56 (m, 6H), 1.54 - 1.46 (m, 6H).

[0181] Example 1.2.2 2-benzyl-N-[(1-methylcyclopentyl)methyl]-1H-benzimidazole-5-carboxamide TIFF0007853981000024.tif32170 The title compound was prepared from 2-benzyl-1H-benzimidazole-5-carboxylic acid and (1-methylcyclopentyl)methaneamine, similar to Example 1.2. LC-MS (Method A): Rt 2.22 min; MS m / z 348.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.48 (br s, 1H), 8.26 (t, J = 6.0 Hz, 1H), 8.19 - 7.80 (m, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.61 - 7.39 (m, 1H), 7.38 - 7.29 (m, 4H), 7.28 - 7.19 (m, 1H), 4.20 (s, 2H), 3.22 (d, J = 6.3 Hz, 2H), 1.69 - 1.51 (m, 6H), 1.32 - 1.17 (m, 2H), 0.98 (s, 3H).

[0182] Example 1.2.3 2-benzyl-N-[(1R)-1-cyclohexylethyl]-1H-benzimidazole-5-carboxamide TIFF0007853981000025.tif31170 The title compound was prepared from 2-benzyl-1H-benzimidazole-5-carboxylic acid and (1R)-1-cyclohexylethaneamine, similar to Example 1.2. LC-MS (Method A): Rt 2.38 min; MS m / z 362.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.45 (br s, 1H), 8.15 - 7.83 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.47 (br s, 1H), 7.36 - 7.28 (m, 4H), 7.27 - 7.17 (m, 1H), 4.19 (s, 2H), 3.89 - 3.79 (m, 1H), 1.78 - 1.66 (m, 4H), 1.63 - 1.57 (m, 1H), 1.46 - 1.38 (m, 1H), 1.24 - 1.07 (m, 6H), 1.00 - 0.89 (m, 2H).

[0183] Example 1.3 N-(cycloheptylmethyl)-2-(1,1-dimethylpropyl)-3H-benzimidazole-5-carboxamide TIFF0007853981000026.tif26170 Step 1: 3,4-Diamino-N-(cycloheptylmethyl)benzamide TIFF0007853981000027.tif27170 To a solution of THF (50 mL) and DMF (20 mL) containing cycloheptylmethaneamine (2.27 mL, 15.77 mmol) and 3,4-diaminobenzoic acid (2.0 g, 13.14 mmol), TBTU (5.06 g, 15.77 mmol) and TEA (5.5 mL, 39.43 mmol) were added. This mixture was stirred at room temperature for 19 hours and then concentrated under vacuum. The crude substance was dissolved in Depositphotos (50 mL) and washed with water (2 x 25 mL). The aqueous portion was back-extracted with Depositphotos (3 x 50 mL), and the combined organic extract was washed with brine (2 x 25 mL), dried over Na2SO4, and concentrated under vacuum to obtain a brownish syrup. The crude substance was purified by C18 reverse-phase chromatography, which elutes the crude substance in water with 10-100% MeCN, to obtain the title compound as a light brown solid. LC-MS (Method E): Rt 0.96 min; MS m / z 262.1 = [M+H]+ 1H NMR (250 MHz, Chloroform-d) δ 7.22 (d, J = 1.9 Hz, 1H), 7.08 (dd, J = 8.0, 2.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.13 - 5.92 (m, 1H), 3.81 - 2.90 (m, 6H), 1.85 - 1.33 (m, 11H), 1.32 - 1.14 (m, 2H). Step 2: N-(cycloheptylmethyl)-2-(1,1-dimethylpropyl)-3H-benzimidazole-5-carboxamide A mixture containing 2,2-dimethylbutanoic acid (34 μL, 0.28 mmol), HATU (105 mg, 0.28 mmol), and TEA (80 μL, 0.46 mmol) in DMF (1.9 mL) was stirred at room temperature for 1 hour, and then treated with DMF (1 mL) containing 3,4-diamino-N-(cycloheptylmethyl)benzamide (step 1) (60 mg, 0.23 mmol). This mixture was stirred at room temperature for 24 hours, then diluted with HCl (10 mL) and washed with saturated sodium bicarbonate aqueous solution (2 x 10 mL). The organic portion was dried over Na2SO4 and concentrated under vacuum, and the crude product was purified by chromatography on silica eluted with 0-100% HCl in heptane. The resulting residue was dissolved in acetic acid (1.9 mL) and stirred at 60°C for 3 hours. This mixture was diluted with HCl (20 mL) and washed with saturated sodium bicarbonate aqueous solution (3 x 20 mL). The organic portion was dried with Na2SO4 and concentrated under vacuum. The title compound was obtained as a colorless solid by purification of the residue using preparative HPLC (low pH, early elution method). LC-MS (Method A): Rt 2.22 min; MS m / z 342 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.27 - 12.17 (m, 1H), 8.41 - 8.25 (m, 1H), 8.11 - 7.86 (m, 1H), 7.70 - 7.58 (m, 1H), 7.58 - 7.39 (m, 1H), 3.11 (t, J = 6.3 Hz, 2H), 1.79 - 1.69 (m, 5H), 1.67 - 1.59 (m, 2H), 1.58 - 1.44 (m, 4H), 1.43 - 1.33 (m, 8H), 1.22 - 1.13 (m, 2H), 0.70 (t, J = 7.4 Hz, 3H).

[0184] Example 1.3.1 N-(cycloheptylmethyl)-2-[(1-hydroxycyclohexyl)methyl]-1H-benzimidazole-5-carboxamide TIFF0007853981000028.tif26170 The title compound was prepared from 3,4-diamino-N-(cycloheptylmethyl)benzamide (Example 1.3 Step 1) and 2-(1-hydroxycyclohexyl)acetic acid, similar to Step 2 of Example 1.3. LC-MS (Method A): Rt 2.19 min; MS m / z 384.4 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.21 (br. s, 1H), 8.35 (t, J = 5.6 Hz, 1H), 8.02 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 4.67 (br. s, 1H), 3.10 (t, J = 6.3 Hz, 2H), 2.92 (s, 2H), 1.80-1.70 (m, 3H), 1.68 - 1.34 (m, 17H), 1.23-1.12 (m, 3H).

[0185] Example 1.3.2 N-(cycloheptylmethyl)-2-(2-hydroxy-1-phenylethyl)-1H-benzimidazole-5-carboxamide TIFF0007853981000029.tif26170 The title compound was prepared from 3,4-diamino-N-(cycloheptylmethyl)benzamide (Example 1.3 Step 1) and 3-hydroxy-2-phenyl-propanoic acid, similar to Step 2 of Example 1.3. LC-MS (Method A): Rt 2.46 min; MS m / z 392.4 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.56 - 12.39 (m, 1H), 8.40 - 8.28 (m, 1H), 8.19 - 7.89 (m, 1H), 7.70 - 7.63 (m, 1H), 7.61 - 7.40 (m, 1H), 7.39 - 7.34 (m, 2H), 7.34 - 7.28 (m, 2H), 7.25 - 7.20 (m, 1H), 5.00 (br s, 1H), 4.35 (t, J = 7.2 Hz, 1H), 4.24 - 4.17 (m, 1H), 3.98 - 3.91 (m, 1H), 3.10 (t, J = 6.3 Hz, 2H), 1.82 - 1.68 (m, 3H), 1.67 - 1.59 (m, 2H), 1.57 - 1.34 (m, 6H), 1.23 - 1.12 (m, 2H).

[0186] Example 1.4 N-(cyclohexylmethyl)-2-[(3-hydroxyphenyl)methyl]-3H-benzimidazole-5-carboxamide TIFF0007853981000030.tif33170 Step 1: 2-[(3-benzyloxyphenyl)methyl]-1H-benzoimidazole-5-carboxylate methyl A solution of 2-(3-benzyloxyphenyl)acetic acid (2.01 g, 8.3 mmol), HATU (3.16 g, 8.3 mmol), and DIPEA (3.19 mL, 18.27 mmol) in DMF (50 mL) was stirred at room temperature for 45 minutes, and then treated with methyl 3,4-diaminobenzoate (1.38 g, 8.3 mmol). The reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was concentrated under vacuum, and the residue was partitioned into saturated NaHCO3 (100 mL) and HCl (125 mL). The organic layer was separated, washed with water (2 x 75 mL) and brine (2 x 75 mL), dried over Na2SO4, and concentrated under vacuum. This crude material was triturated with MeOH (40 mL), the solid was filtered, and dried in a vacuum oven at 40°C for 3 hours. The obtained solid was suspended in AcOH (25 mL) and stirred at 70°C for 6 hours. The resulting mixture was concentrated under vacuum, and the residue was partitioned into saturated NaHCO3 (100 mL) and ethylacetate (125 mL). The organic layer was washed with water (2 x 75 mL) and brine (2 x 75 mL), dried over Na2SO4, and concentrated under vacuum to obtain the title compound as an off-white powder. LC-MS (Method E): Rt 1.05 min; MS m / z 373.0 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 0.9 Hz, 1H), 7.79 (dd, J = 8.4, 1.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.38 - 7.33 (m, 2H), 7.32 - 7.28 (m, 1H), 7.24 (t, J = 7.9 Hz, 1H), 7.03 - 7.00 (m, 1H), 6.93 - 6.87 (m, 2H), 5.07 (s, 2H), 4.19 (s, 2H), 3.85 (s, 3H). Step 2: 2-[(3-hydroxyphenyl)methyl]-1H-benzoimidazole-5-carboxylate methyl TIFF0007853981000032.tif411702-[(3-benzyloxyphenyl)methyl]-1H-benzimidazole-5-carboxylate methyl (Step 1) (95%, 700 mg, 1.79 mmol) was added to a suspension of EtOH (20 mL) and 10% Pd-C (10%, 150 mg, 0.14 mmol). The reaction mixture was placed under a hydrogen atmosphere and stirred at room temperature for 6 hours. The resulting mixture was filtered through a Celite® (filter medium) plug and thoroughly washed with EtOH (45 mL). The filtrate was concentrated under vacuum to obtain the title compound as a pale orange / brown solid. LC-MS (Method E): Rt 0.83 min; MS m / z 283.1 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.78 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 6.72 - 6.69 (m, 1H), 6.62 (dd, J = 8.0, 1.8 Hz, 1H), 4.12 (s, 2H), 3.85 (s, 3H). Step 3: 2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxylic acid A 2.53 mL, 5.06 mmol aqueous solution of TIFF0007853981000033.tif391702M LiOH was added to an 8 mL THF solution of 2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxylate methyl (step 2) (95%, 501 mg, 1.69 mmol), and the reaction mixture was stirred at 50°C for 4 hours. After removing volatile organic compounds under vacuum, the resulting aqueous mixture was acidified to pH 4. This mixture was extracted with 3:1 chloroform:IPA (3 x 30 mL), the combined organic extract was dried over Na2SO4, and concentrated under vacuum to obtain the title compound as a pale orange powder. LC-MS (Method E): Rt 0.73 min; MS m / z 269.1 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 13.48 - 11.55 (m, 2H), 9.37 (s, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.81 (dd, J = 8.4, 1.5 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 6.73 - 6.70 (m, 1H), 6.64 (dd, J = 8.0, 1.8 Hz, 1H), 4.16 (s, 2H). Step 4: N-(cyclohexylmethyl)-2-[(3-hydroxyphenyl)methyl]-3H-benzimidazole-5-carboxamide A solution of 2-[(3-hydroxyphenyl)methyl]-3H-benzimidazole-5-carboxylic acid (step 3) (50 mg, 0.19 mmol), EDCI (33 mg, 0.21 mmol), DMAP (46 mg, 0.37 mmol), and HOAt (28 mg, 0.21 mmol) in DMF (1 mL) was stirred for 5 minutes and then treated with cyclohexylmethaneamine (48.5 μL, 0.37 mmol). The resulting mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was taken in  (5 mL), the organic matter was washed with water (3 x 5 mL) and brine (5 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by preparative HPLC (basic pH, standard elution method), followed by further purification by preparative HPLC (acidic pH, standard elution method) to obtain the title compound as an off-white solid. LC-MS (Method A): Rt 2.00 min; MS m / z 364.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.52 - 12.34 (m, 1H), 9.33 (s, 1H), 8.39 - 8.28 (m, 1H), 8.13 - 7.84 (m, 1H), 7.76 - 7.60 (m, 1H), 7.60 - 7.33 (m, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.71 - 6.66 (m, 1H), 6.63 (dd, J = 8.0, 2.1 Hz, 1H), 4.11 (s, 2H), 3.12 (t, J = 6.4 Hz, 2H), 1.77 - 1.65 (m, 4H), 1.65 - 1.51 (m, 2H), 1.28 - 1.08 (m, 3H), 1.00 - 0.85 (m, 2H).

[0187] Example 1.5 2-(1-adamantyl)-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide TIFF0007853981000034.tif31170 Step 1: 2-[(3-benzyloxyphenyl)methyl]-5-nitro-1H-benzimidazole A solution of 2-(3-benzyloxyphenyl)acetic acid (2.99 g, 12.34 mmol), HATU (4.69 g, 12.34 mmol), and DIPEA (5.27 mL, 30.17 mmol) in DMF (50 mL) was stirred at room temperature for 45 minutes, and then treated with 4-nitrobenzene-1,2-diamine (2.1 g, 13.71 mmol). The reaction mixture was stirred at room temperature for 60 hours, and then diluted with saturated NaHCO3 (50 mL) and siRNA (100 mL). The phases were separated, the organic portion was washed with water (2 x 50 mL) and brine (2 x 50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was dissolved in acetic acid (40 mL) and stirred at 70°C for 2.5 hours. An additional 20 mL of AcOH was added, and the mixture was stirred at 70°C for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was partitioned into saturated NaHCO3 (50 mL) and HCl (100 mL). The organic portion was separated, washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by chromatography on silica eluting with 20–75% HCl in heptane, followed by C18 reverse-phase chromatography eluting with 10–100% MeCN (0.1% formic acid) in water, yielding the title compound as a bright orange solid. LC-MS (Method E): Rt 1.17 min; MS m / z 360.0 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.94 (br s, 1H), 8.41 (br s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.65 (br s, 1H), 7.47 - 7.19 (m, 6H), 7.01 (s, 1H), 6.94 - 6.88 (m, 2H), 5.07 (s, 2H), 4.23 (s, 2H). Step 2: 3-[(5-amino-1H-benzimidazole-2-yl)methyl]phenol TIFF0007853981000036.tif341702-[(3-benzyloxyphenyl)methyl]-5-nitro-1H-benzimidazole (Step 1) (89%, 250 mg, 0.62 mmol) was added to a suspension of EtOH (30 mL) to 10% Pd-C (10%, 66 mg, 0.06 mmol). The reaction mixture was placed under a hydrogen atmosphere and stirred at room temperature for 6 hours. The resulting mixture was passed through a Celite® filter plug and thoroughly washed with EtOH (approximately 35 mL). The filtrate was concentrated under vacuum and then azeotropically mixed with Et2O (3 x 15 mL) to obtain the title compound as a gray powder. LC-MS (Method F): Rt 1.19 min; MS m / z 240.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 11.61 (br. s, 1H), 9.28 (br. s, 1H), 7.22 - 7.04 (m, 2H), 6.75 - 6.37 (m, 5H), 4.74 (br. s, 2H), 3.95 (s, 2H). Step 3: 2-(1-adamantyl)-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide A solution of HATU (119 mg, 0.31 mmol), 2-(1-adamantyl)acetic acid (55 mg, 0.28 mmol), and DIPEA (109 μL, 0.63 mmol) in DMF (2 mL) was stirred at room temperature for 30 minutes, and then treated with 3-[(5-amino-1H-benzimidazole-2-yl)methyl]phenol (step 2) (80%, 85 mg, 0.28 mmol). The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was taken into  (5 mL), washed with water (3 x 5 mL) and brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC (basic pH, standard elution method) to obtain the title compound as an off-white powder. LC-MS (Method A): Rt 2.28 min; MS m / z 416.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.14 - 12.03 (m, 1H), 9.73 - 9.57 (m, 1H), 9.31 (s, 1H), 7.99 - 7.81 (m, 1H), 7.46 - 7.04 (m, 3H), 6.75 - 6.56 (m, 3H), 4.03 (s, 2H), 2.05 (s, 2H), 1.93 (s, 3H), 1.71 - 1.52 (m, 12H).

[0188] Example 1.5.1 N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]-2-(1-methylcyclohexyl)acetamide TIFF0007853981000037.tif30170 The title compound was prepared from 3-[(5-amino-1H-benzimidazole-2-yl)methyl]phenol (Example 1.5 Step 2) and 2-(1-methylcyclohexyl)acetic acid, similar to Step 3 of Example 1.5. LC-MS (Method A): Rt 2.11 min; MS m / z 378.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.07 (br s, 1H), 9.69 (s, 1H), 9.39 (br s, 1H), 7.90 (s, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.25 - 7.12 (m, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.69 - 6.66 (m, 1H), 6.60 dd, J = 8.0, 1.9 Hz, 1H), 4.03 (s, 2H), 2.21 (s, 2H), 1.53 - 1.38 (m, 7H), 1.35 - 1.26 (m, 3H), 1.03 (s, 3H).

[0189] Example 1.5.2 2-Cycloheptyl-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide TIFF0007853981000038.tif31170 The title compound was prepared from 3-[(5-amino-1H-benzimidazole-2-yl)methyl]phenol (Example 1.5 Step 2) and 2-cycloheptylacetic acid, similar to Step 3 of Example 1.5. LC-MS (Method A): Rt 2.11 min; MS m / z 378.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.17 - 12.04 (m, 1H), 9.80 - 9.68 (m, 1H), 9.30 (s, 1H), 7.96 - 7.83 (m, 1H), 7.45 - 7.10 (m, 2H), 7.08 (t, J = 7.8 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.69 - 6.65 (m, 1H), 6.63 - 6.58 (m, 1H), 4.05 - 4.00 (m, 2H), 2.24 - 2.13 (m, 2H), 2.06 - 1.92 (m, 1H), 1.75 - 1.65 (m, 2H), 1.65 - 1.51 (m, 4H), 1.51 - 1.34 (m, 4H), 1.27 - 1.16 (m, 2H).

[0190] Example 1.5.3 2-Cyclohexyl-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide TIFF0007853981000039.tif33170 The title compound was prepared from 3-[(5-amino-1H-benzimidazole-2-yl)methyl]phenol (Example 1.5 Step 2) and 2-cyclohexylacetic acid, similar to Step 3 of Example 1.5. LC-MS (Method A): Rt 1.89 min; MS m / z 364.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.12 - 12.04 (m, 1H), 9.80 - 9.67 (m, 1H), 9.30 (s, 1H), 7.96 - 7.83 (m, 1H), 7.45 - 7.04 (m, 3H), 6.72 (d, J = 7.5 Hz, 1H), 6.69 - 6.65 (m, 1H), 6.61 (dd, J = 8.0, 1.8 Hz, 1H), 4.05 - 4.01 (m, 2H), 2.20 - 2.15 (m, 2H), 1.86 - 1.55 (m, 6H), 1.32 - 1.06 (m, 3H), 1.06 - 0.91 (m, 2H).

[0191] Example 1.5.4 2-(1-adamantyl)-N-(2-benzyl-1H-benzoimidazole-5-yl)acetamide TIFF0007853981000040.tif30170 Example 1.5 The title compound was prepared from 2-benzyl-1H-benzimidazole-5-amine (intermediate A) and 2-(1-adamantyl)acetic acid, similar to step 3. LC-MS (Method C): Rt 3.51 min; MS m / z 400.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.10 (s, 1H), 9.84 - 9.40 (m, 1H), 8.02 - 7.78 (m, 1H), 7.48 - 7.05 (m, 7H), 4.13 (s, 2H), 2.04 (s, 2H), 1.93 (s, 3H), 1.75 - 1.48 (m, 12H).

[0192] Example 1.6 N-(2-benzyl-1H-benzimidazole-5-yl)-2-(2-hydroxy-2-adamantyl)acetamide TIFF0007853981000041.tif41170 Step 1: 2-(2-hydroxy-2-adamantyl)acetic acid TIFF0007853981000042.tif23170 Diisopropylamine (350 μL, 2.5 mmol) was mixed with THF (4 mL) at -78°C, to which n-BuLi (1.6 M in hexane) (1.56 mL, 2.5 mmol) was added. The mixture was heated to 0°C, stirred for 30 minutes, and then recooled to -78°C. Acetic acid (95 μL, 1.66 mmol) was added, followed by n-BuLi (1.6 M in hexane) (1.04 mL, 1.66 mmol). This solution was heated to 0°C, stirred for 30 minutes, and then recooled to -78°C. THF (1.5 mL) containing adamantan-2-one (751 mg, 5.0 mmol) was added. The resulting solution was heated to room temperature and stirred for 1 hour. The reaction was rapidly cooled by adding saturated NH4Cl solution (1 mL). This mixture was diluted with diethyl ether (10 mL) and washed with 2 M NaOH solution (10 mL). The ether layer was separated and discarded. This aqueous layer was acidified to pH 2 with 2 M HCl solution and extracted with SiO (10 mL). The SiO solution was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated in vacuum to obtain the title compound as a colorless powder. LC-MS (Method E): Rt 0.98 min; MS m / z 209.0 = [MH]- 1H NMR (250 MHz, DMSO-d6) δ 11.99 (br s, 1H), 4.48 (br s, 1H), 2.55 (s, 2H), 2.20 (d, J = 12.5 Hz, 2H), 1.92 - 1.57 (m, 10H), 1.40 (d, J = 12.2 Hz, 2H). Step 2: N-(2-benzyl-1H-benzimidazole-5-yl)-2-(2-hydroxy-2-adamantyl)acetamide TIFF0007853981000043.tif401702-(2-hydroxy-2-adamantyl)acetic acid (Step 1) (120 mg, 0.57 mmol), DIPEA (209 μL, 1.2 mmol), and 2-benzyl-1H-benzimidazole-5-amine (Intermediate A) (127 mg, 0.57 mmol) were dissolved in DMF (3 mL), to which HATU (239 mg, 0.63 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with SiO (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was triturated with a mixture of MeCN / MeOH / water (1:1:1), and the resulting solid was collected by filtration. The solid was washed with MeCN / water (1:1) and ether, and then dried under a nitrogen stream to obtain the title compound as an off-white powder. LC-MS (Method A): Rt 2.20 min; MS m / z 416.3 = [M+H]+ 1H NMR (250 MHz, DMSO-d6) δ 12.23 - 12.11 (m, 1H), 10.01 - 9.89 (m, 1H), 7.96 - 7.80 (m, 1H), 7.46 - 7.10 (m, 7H), 5.13 - 5.03 (m, 1H), 4.14 (s, 2H), 2.69 (s, 2H), 2.28 - 2.19 (m, 2H), 1.92 (d, J = 12.4 Hz, 2H), 1.80 (s, 1H), 1.75 - 1.61 (m, 7H), 1.42 (d, J = 11.9 Hz, 2H).

[0193] Example 1.7 2-(2-adamantyl)-N-[2-[(3-methoxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide TIFF0007853981000044.tif441702-(3-methoxyphenyl)acetic acid (83 mg, 0.50 mmol), HATU (210 mg, 0.55 mmol), and DIPEA (0.18 mL, 1.00 mmol) were dissolved in DMF (1.5 mL), and the mixture was stirred at room temperature for 30 minutes. A solution of 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (intermediate B) (150 mg, 0.50 mmol) in DMF (1 mL) was added, and the reaction mixture was stirred overnight at room temperature. Additional 2-(3-methoxyphenyl)acetic acid (42 mg, 0.25 mmol), HATU (105 mg, 0.28 mmol), and DIPEA (0.09 mL, 0.5 mmol) were stirred in DMF (0.5 mL) for 10 minutes, and then added to the main reaction mixture. After stirring at room temperature for 45 hours, the resulting mixture was diluted with HCl (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL). The phases were separated, the organic portion was washed with water (2 x 20 mL) and brine (10 mL), and concentrated under vacuum. The crude substance was purified by chromatography on silica eluting with a gradient of 0-100% HCl in heptane to obtain a brown oil. This oil was triturated in HCl to obtain an off-white solid. This solid was suspended in acetic acid (1 mL) and stirred at 60°C for 5 hours. After cooling to room temperature, the mixture was concentrated under vacuum, and the residue was partitioned into HCl (5 mL) and saturated sodium bicarbonate aqueous solution (5 mL). The layers were separated, the organic layer was washed with saturated sodium bicarbonate aqueous solution (3 x 5 mL), passed through hydrophobic frit, and concentrated under vacuum. The resulting oil was azeotropically mixed three times with MeCN to obtain the title compound as a colorless solid. LC-MS (Method A): Rt 2.83 min; MS m / z 430 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.91 - 9.70 (m, 1H), 8.06 - 7.79 (m, 1H), 7.49 - 7.05 (m, 3H), 6.97 - 6.85 (m, 2H), 6.84 - 6.74 (m, 1H), 4.10 (s, 2H), 3.73 (s, 3H), 2.45 (d, J = 7.5 Hz, 2H), 2.28 - 2.21 (m, 1H), 1.99 - 1.65 (m, 12H), 1.56 - 1.49 (m, 2H).

[0194] The compounds shown in the following table (Example 1.7 in the table) were prepared in the same manner as in Example 1.7, from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (intermediate B) and a suitable commercially available acid. TIFF0007853981000045.tif136170

[0195] Example 1.7.3 N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]methyl]carbamate tert-butyl The title compound TIFF0007853981000046.tif30170 was prepared from 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide (intermediate C) and 2-(tert-butoxycarbonylamino)acetic acid, in the same manner as in Example 1.7. LC-MS (Method A): Rt 2.69 min; MS m / z 439.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.02 (br. s, 1H), 9.67 (s, 1H), 7.94 (s, 1H), 7.46 - 7.26 (m, 2H), 7.19 (s, 1H), 4.31 (d, J = 5.8 Hz, 2H), 2.05 (s, 2H), 1.94 (s, 3H), 1.71 - 1.57 (m, 12H), 1.41 (s, 9H).

[0196] Example 1.7.4 2-(1-adamantyl)-N-[2-[(2-methoxy-3-pyridyl)methyl]-1H-benzimidazole-5-yl]acetamide The title compound was prepared from 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide (intermediate C) and 2-(2-methoxy-3-pyridyl)acetic acid, in the same manner as in Example 1.7. LC-MS (Method A): Rt 2.37 min; MS m / z 431.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.03 (br s, 1H), 9.73 - 9.59 (m, 1H), 8.09 (dd, J = 5.0, 1.8 Hz, 1H), 8.01 - 7.79 (m, 1H), 7.55 (dd, J = 7.2, 1.7 Hz, 1H), 7.41 - 7.07 (m, 2H), 6.96 (dd, J = 7.2, 5.0 Hz, 1H), 4.09 (s, 2H), 3.87 (s, 3H), 2.05 (s, 2H), 1.94 (s, 3H), 1.69 - 1.58 (m, 12H).

[0197] Example 1.8 2-(2-adamantyl)-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide TIFF0007853981000048.tif451701M DCM (0.20 mL, 0.20 mmol) containing BBr3 was added dropwise to a 3 mL ice-cold solution of 2-(2-adamantyl)-N-[2-[(3-methoxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide (Example 1.7) (44 mg, 0.10 mmol) in DCM. The mixture was stirred in an ice bath for 5 minutes, then at room temperature overnight. The reaction mixture was recooled in an ice bath and treated with an additional 0.10 mL, 0.10 mmol DCM containing 1 M BBr3, and stirred at room temperature for 6 hours. Water (5 mL) was slowly added to the stirring reaction mixture. The majority of the aqueous layer was carefully removed with a pipette. The remaining DCM / aqueous suspension was filtered under vacuum to obtain a white solid. This solid was dissolved in MeOH and purified by C18 reverse-phase chromatography using elution with 10-100% MeCN (+0.1% formic acid) in water to obtain the title compound as a colorless solid. LC-MS (Method A): Rt 2.57 min; MS m / z 416 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.10 (s, 1H), 9.82 (s, 1H), 9.33 (s, 1H), 7.92 (s, 1H), 7.48 - 7.04 (m, 3H), 6.74 - 6.70 (m, 1H), 6.69 - 6.66 (m, 1H), 6.62 - 6.58 (m, 1H), 4.03 (s, 2H), 2.45 (d, J = 7.7 Hz, 2H), 2.26 - 2.19 (m, 1H), 1.99 - 1.91 (m, 2H), 1.88 - 1.63 (m, 10H), 1.56 - 1.46 (m, 2H).

[0198] Example 1.9 2-tert-butyl-N-[(5-chloro-2-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide TIFF0007853981000049.tif25170 Step 1: 2-tert-butyl-1H-benzimidazole-5-carboxylate methyl TIFF0007853981000050.tif251703,4-methyl diaminobenzoate (200 mg, 1.2 mmol), 2,2-dimethylpropanoic acid (148 mg, 1.44 mmol), and DIPEA (0.25 mL, 1.44 mmol) were mixed in DMF (7 mL) with HATU (503 mg, 1.32 mmol) added, and the mixture was stirred at room temperature for 1 hour. Additional 2,2-dimethylpropanoic acid (148 mg, 1.44 mmol), DIPEA (0.25 mL, 1.44 mmol), and HATU (503 mg, 1.32 mmol) were added, and stirring was continued overnight. The resulting mixture was diluted with HCl (15 mL), washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude residue was dissolved in acetic acid (7 mL), heated at 60°C for 2 hours, and then at 70°C for 2 hours. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was dissolved in HCl (10 mL), washed with saturated NaHCO₃ solution (10 mL) and brine (10 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude residue was purified by chromatography on silica eluted with 30-100% HCl in heptane to obtain the title compound as a light brown glassy solid. LC-MS (Method E): Rt 0.80 min; MS m / z 233.3 = [M+H]+ 1H NMR (500 MHz,Chloroform-d) δ 10.01 (br s, 1H), 8.48 - 8.10 (m, 1H), 7.96 - 7.90 (m, 1H), 7.79 - 7.32 (m, 1H), 3.92 (s, 3H), 1.52 (s, 9H). Step 2: 2-tert-butyl-1H-benzimidazole-5-carboxylic acid TIFF0007853981000051.tif231702-tert-butyl-1H-benzimidazole-5-carboxylate methyl (Step 1) (213 mg, 0.92 mmol) was added to a solution of MeOH (1.5 mL), THF (1.5 mL), and water (1.5 mL) with LiOH (26 mg, 1.1 mmol) and the mixture was stirred overnight at room temperature. Additional LiOH (26 mg, 1.1 mmol) was added and the reaction was stirred at room temperature for 8 hours. Further LiOH (79 mg, 3.3 mmol) was added and the mixture was stirred for 30 hours. The reaction was rapidly cooled by adding 1 M HCl solution to pH 4. The aqueous mixture was extracted with SiO2 (10 mL) and CHCl3 / IPA (1:1) (10 mL), the combined organic extract was dried over Na2SO4, and concentrated under vacuum to obtain the title compound as a pale pink powder. LC-MS (Method E): Rt 0.77 min; MS m / z 219.0 = [M+H]+ Step 3: (5-chloro-2-methoxyphenyl)methaneamine A solution of 5-chloro-2-methoxy-benzonitrile (2.0 g, 11.93 mmol) in THF (30 mL) was added dropwise to a solution of lithium aluminum hydride (2.4 M in THF, 7.46 mL, 17.9 mmol) in THF (22.5 mL) (0°C). After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. The reaction was rapidly cooled by slowly adding 1 M NaOH solution (10 mL) (0°C). The resulting mixture was diluted with ELISA (50 mL) and 1 M NaOH solution (50 mL), filtered, and the suspended solid was removed. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain the title compound as a yellow oil. LC-MS (Method E): Rt 0.72 min; MS m / z 172.0 / 174.0 = [M+H]+ 1H NMR (250 MHz, Chloroform-d) δ 7.23 - 7.13 (m, 2H), 6.77 (d, J = 8.5 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 2H). Step 4: 2-tert-butyl-N-[(5-chloro-2-methoxyphenyl)methyl]-1H-benzimidazole-5-carboxamide To a 1 mL solution of DMF containing 2-tert-butyl-1H-benzimidazole-5-carboxylic acid (Step 2) (80 mg, 0.37 mmol), DIPEA (57 mg, 0.44 mmol) and HATU (167 mg, 0.44 mmol), followed by a 1 mL solution of DMF containing (5-chloro-2-methoxyphenyl)methaneamine (Step 3) (90%, 84 mg, 0.44 mmol), the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with 10 mL of siRNA, washed with 10 mL of water and 10 mL of brine, dried over Na₂SO₄, and concentrated under vacuum. The crude residue was purified by chromatography on silica eluted with 50-100% siRNA in heptane to obtain the title compound as a pale pink glass. LC-MS (Method E): Rt 1.02 min; MS m / z 372.0 / 374.0 = [M+H]+ 1H NMR (250 MHz, Methanol-d4) δ 8.08 (br s, 1H), 7.75 (dd, J = 8.4, 1.6 Hz, 1H), 7.63 - 7.52 (m, 1H), 7.27 - 7.18 (m, 2H), 6.97 (d, J = 8.4 Hz, 1H), 4.57 (s, 2H), 3.89 (s, 3H), 1.49 (s, 9H). Step 5: 2-tert-butyl-N-[(5-chloro-2-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide To a solution of 2-tert-butyl-N-[(5-chloro-2-methoxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (Step 4) (94%, 124 mg, 0.31 mmol) in DCM (1 mL) (0°C), DCM containing 1 M BBr3 (0.47 mL, 0.47 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction was rapidly cooled by the dropwise addition of saturated NaHCO3 solution (5 mL), and the resulting mixture was diluted with ELISA (10 mL) and saturated NaHCO3 solution (5 mL). The organic moiety was separated, washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by preparative HPLC (basic pH, standard elution method) to obtain the title compound as a colorless powder. LC-MS (Method A): Rt 1.77 min; MS m / z 358.1 / 360.1 = [M+H]+ 1H NMR (500 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.74 (dd, J = 8.4, 1.6 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 2.6 Hz, 1H), 7.08 (dd, J = 8.6, 2.6 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 4.54 (s, 2H), 1.49 (s, 9H).

[0199] Example 1.10 N-[[5-(cycloheptylmethylcarbamoyl)-1H-benzimidazole-2-yl]methyl]carbamate tert-butyl TIFF0007853981000054.tif28170 Step 1: 2-[(tert-butoxycarbonylamino)methyl]-1H-benzoimidazole-5-carboxylate methyl TIFF0007853981000055.tif281702-(tert-butoxycarbonylamino)acetic acid (3.45 g, 19.70 mmol) was mixed with HATU (8.24 g, 21.67 mmol) and DIPEA (3.78 mL, 21.67 mmol) in a stirred solution of DMF (100 mL), and the mixture was stirred at room temperature for 10 hours. Methyl 3,4-diaminobenzoate (3.60 g, 21.67 mmol) was added, and the mixture was stirred for 17 hours. The resulting mixture was diluted with water (100 mL) and extracted with SiO2 (6 x 100 mL). The combined organic extract was washed with brine (3 x 100 mL), dried over Na2SO4, and concentrated under vacuum. This intermediate was dissolved in acetic acid (50 mL) and heated to 60°C for 80 minutes. The resulting mixture was concentrated under vacuum, and the residue was dissolved in HCl (50 mL). The organic matter was washed with saturated sodium bicarbonate aqueous solution (2 x 30 mL) and brine (2 x 30 mL), dried over Na₂SO₄, and concentrated under vacuum. The title compound was obtained by purification by chromatography on silica that elutes in heptane at 50-100% HCl. LC-MS (Method E): Rt 0.91 min; MS m / z 306.1 = [M+H]+ 1H NMR (250 MHz, DMSO-d6) δ 12.54 (br s, 1H), 8.12 (d, J = 1.1 Hz, 1H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.47 (t, J = 5.4 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 1.41 (s, 9H). Step 2: 2-[(tert-butoxycarbonylamino)methyl]-1H-benzimidazole-5-carboxylic acid TIFF0007853981000056.tif291702-[(tert-butoxycarbonylamino)methyl]-1H-benzimidazole-5-carboxylate methyl (Step 1) (500 mg, 1.64 mmol) was added to a solution of MeOH (5 mL), THF (5 mL), and water (5 mL) with LiOH (39 mg, 1.64 mmol) added, and the mixture was stirred at 50°C for 1 hour and 40 minutes. Additional LiOH (39 mg, 1.64 mmol) was added, and stirring continued at 50°C for 3 hours and 35 minutes. Further LiOH (117 mg, 4.91 mmol) was added, the temperature was raised to 60°C, and the reaction was allowed to continue overnight. Additional LiOH (390 mg, 16.4 mmol) was added, and stirring continued at 60°C for 6 hours. The last portion of LiOH (390 mg, 16.4 mmol) was added, and the mixture was heated and stirred at 60°C for a further 23 hours. The resulting mixture was acidified to pH 4 with 1 M HCl and extracted with ELISA (5 x 10 mL). The combined organic extract was concentrated under vacuum to obtain the title compound as a colorless powder. LC-MS (Method E): Rt 0.83 min; MS m / z 292.0 = [M+H]+ 1H NMR (250 MHz, Methanol-d4) δ 8.47 - 8.38 (m, 1H), 8.28 - 8.16 (m, 1H), 7.90 - 7.81 (m, 1H), 4.80 - 4.70 (m, 2H), 1.68 - 1.07 (m, 9H). Step 3: N-[[5-(cycloheptylmethylcarbamoyl)-1H-benzimidazole-2-yl]methyl]carbamate tert-butyl To a solution of cycloheptylmethaneamine (74 μL, 0.51 mmol) and 2-[(tert-butoxycarbonylamino)methyl]-1H-benzimidazole-5-carboxylic acid (Step 2) (85%, 160 mg, 0.47 mmol) in DMF (3 mL), HATU (195 mg, 0.51 mmol) was added, and the mixture was stirred for 10 minutes. DIPEA (90 μL, 0.51 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours and 30 minutes. The resulting mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic extract was washed with brine (2 x 5 mL), dried over Na2SO4, and concentrated under vacuum. The residue was redissolved in ethyl acetate (2 mL), washed with saturated sodium bicarbonate aqueous solution (2 x 2 mL), and concentrated under vacuum. The title compound was purified by C18 reverse-phase chromatography using elution with 10-100% water (0.1% ammonium hydroxide) in MeCN to obtain a colorless solid. LC-MS (Method A): Rt 2.52 min; MS m / z 401.3 = [M+H]+ 1H NMR (500 MHz, Methanol-d4) δ 8.03 (s, 1H), 7.71 (dd, J = 8.4, 1.3 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 4.51 (s, 2H), 3.24 (d, J = 7.0 Hz, 2H), 1.91 - 1.78 (m, 3H), 1.76 - 1.68 (m, 2H), 1.67 - 1.59 (m, 2H), 1.59 - 1.42 (m, 12H), 1.33 - 1.23 (m, 3H).

[0200] Example 1.10.1 2-benzyl-N-[(1-methylcyclohexyl)methyl]-1H-benzimidazole-5-carboxamide TIFF0007853981000057.tif32170 Example 1.10 The title compound was prepared from 2-benzyl-1H-benzimidazole-5-carboxylic acid and (1-methylcyclohexyl)methaneamine in the same manner as in step 3. LC-MS (Method A): Rt 2.43 min; MS m / z 362.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.46 (br s, 1H), 8.17 (t, J = 6.2 Hz, 1H), 8.01 (br s, 1H), 7.70 - 7.61 (m, 1H), 7.57 - 7.39 (m, 1H), 7.36 - 7.28 (m, 4H), 7.27 - 7.20 (m, 1H), 4.20 (s, 2H), 3.17 (d, J = 6.4 Hz, 2H), 1.55 - 1.46 (m, 2H), 1.46 - 1.18 (m, 8H), 0.88 (s, 3H).

[0201] Example 1.10.2 2-benzyl-N-(cyclooctylmethyl)-1H-benzimidazole-5-carboxamide TIFF0007853981000058.tif31170 Example 1.10 The title compound was prepared from 2-benzyl-1H-benzimidazole-5-carboxylic acid and cyclooctylmethaneamine in the same manner as in step 3. LC-MS (Method A): Rt 2.62 min; MS m / z 376.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.36 (t, J = 5.7 Hz, 1H), 8.01 (br s, 1H), 7.67 (dd, J = 8.4, 1.3 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.35 - 7.31 (m, 4H), 7.28 - 7.20 (m, 1H), 4.20 (s, 2H), 3.10 (t, J = 6.6 Hz, 2H), 1.86 - 1.78 (m, 1H), 1.70 - 1.60 (m, 4H), 1.57 - 1.38 (m, 8H), 1.30 - 1.22 (m, 2H).

[0202] Example 2.1 N-[[1-[2-[(2-benzyl-1H-benzimidazole-5-yl)amino]-2-oxo-ethyl]cyclohexyl]methyl]carbamate tert-butyl TIFF0007853981000059.tif321702-Benzyl-1H-benzimidazole-5-amine (intermediate A) (50 mg, 0.22 mmol) was added to a solution of 2-[1-[(tert-butoxycarbonylamino)methyl]cyclohexyl]acetic acid (67 mg, 0.25 mmol), HATU (102 mg, 0.27 mmol), and DIPEA (0.12 mL, 0.67 mmol) in DMF (2 mL), and the reaction mixture was stirred for 18 hours. The resulting mixture was partitioned into SiO (10 mL) and water (10 mL) and phase separation was performed. The organic phase was washed with 1 M LiOH aqueous solution (10 mL) and brine (10 mL). The combined organic extract was dried over MgSO4 and concentrated under vacuum to obtain a yellow oil. This oil was purified by preparative HPLC (basic pH, initial elution method) to obtain the title compound as a colorless solid. LC-MS (Method A): Rt 2.61 min; MS m / z 477.3 = [M+H]+ 1H NMR (500 MHz,Methanol-d4) δ 7.95 (s, 1H), 7.59 - 7.15 (m, 7H), 4.23 (s, 2H), 3.21 (s, 2H), 2.33 (s, 2H), 1.67 - 1.55 (m, 4H), 1.53 - 1.44 (m, 13H), 1.44 - 1.31 (m, 2H).

[0203] Example 2.1.1 N-(2-benzyl-1H-benzimidazole-5-yl)-2-(4,4-difluorocyclohexyl)acetamide TIFF0007853981000060.tif29170 The title compound was prepared from 2-benzyl-1H-benzimidazole-5-amine (intermediate A) and 2-(4,4-difluorocyclohexyl)acetic acid, similar to Example 2.1. LC-MS (Method A): Rt 1.95 min; MS m / z 384.2 = [M+H]+ 1H NMR (500 MHz, Methanol-d4) δ 7.92 (s, 1H), 7.43 (br. s, 1H), 7.34 - 7.28 (m, 4H), 7.28 - 7.11 (m, 2H), 4.20 (s, 2H), 2.32 (d, J = 7.2 Hz, 2H), 2.10 - 1.92 (m, 3H), 1.91 - 1.70 (m, 4H), 1.44 - 1.31 (m, 2H).

[0204] Example 2.2 N-[1-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]-2-methoxyethyl]tert-butyl carbamate TIFF0007853981000061.tif391702-(tert-butoxycarbonylamino)-3-methoxypropanoic acid (36 mg, 0.16 mmol), 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (intermediate B) (95%, 50 mg, 0.16 mmol), and DIPEA (36 μL, 0.21 mmol) were mixed in DMF (1 mL) and HATU (60 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum, and the residue was diluted with saturated NaHCO3 (10 mL) and ethyl acetate (10 mL). The organic layer was separated, washed with water (2 x 5 mL) and brine (2 x 5 mL), dried over Na2SO4, and concentrated under vacuum. The crude substance was dissolved in acetic acid (1 mL) and stirred at 70°C for 2 hours. The resulting mixture was concentrated under vacuum, and the residue was partitioned into saturated NaHCO3 (10 mL) and HCl (10 mL). The organic layer was separated, washed with water (2 x 5 mL), and dried over Na2SO4. The crude material was purified by preparative HPLC (acidic pH, early elution method) to obtain the title compound as an off-white powder. LC-MS (Method A): Rt 2.80 min; MS m / z 483.3 = [M+H]+ 1H NMR (500 MHz, Methanol-d4) δ 7.98 (d, J = 1.4 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.25 (dd, J = 8.7, 1.8 Hz, 1H), 5.16 - 4.97 (m, 1H), 3.85 - 3.65 (m, 2H), 3.36 (s, 3H), 2.56 (d, J = 7.7 Hz, 2H), 2.36 (t, J = 7.6 Hz, 1H), 2.09 - 2.01 (m, 2H), 1.96 - 1.82 (m, 6H), 1.82 - 1.74 (m, 4H), 1.68 - 1.58 (m, 2H), 1.52 - 1.24 (m, 9H).

[0205] The compounds shown in the following table (Example 2.2 in the table) were prepared in the same manner as in Example 2.2, from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (intermediate B) and a suitable commercially available acid. TIFF0007853981000062.tif232170TIFF0007853981000063.tif240170

[0206] Example 2.3 N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]methyl]-N-methylcarbamate tert-butyl TIFF0007853981000064.tif38170 Step 1: N-methyl-N-[(5-nitro-1H-benzimidazole-2-yl)methyl]carbamate tert-butyl A 15 mL solution of 2-[tert-butoxycarbonyl(methyl)amino]acetic acid (1.4 g, 7.4 mmol) and HATU (3.38 g, 8.88 mmol) in DMF (15 mL) was treated with 4-nitrobenzene-1,2-diamine (1.36 g, 8.88 mmol) and DIPEA (2.58 mL, 14.8 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with HCl (25 mL) and washed with water (3 x 25 mL). The combined aqueous portion was back-extracted with HCl (25 mL), and the combined organic extract was washed with saturated NaHCO3 aqueous solution (25 mL) and brine (25 mL), dried over MgSO4, and concentrated under vacuum. The residue was dissolved in acetic acid (10 mL) and stirred at 70°C for 3 hours. The resulting mixture was concentrated under vacuum, and the residue was partitioned into NaHCO3 (50 mL) and HCl (50 mL). The organic portion was separated, washed with water (3 x 50 mL) and brine (50 mL), dried over MgSO4, and concentrated under vacuum. The title compound was purified by chromatography on silica eluted in heptane with 0-100% HCl to obtain an orange solid. LC-MS (Method A): Rt 2.67 min; MS m / z 307 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.97 (br. s, 1H), 8.43 (s, 1H), 8.08 (dd, J = 8.9, 2.3 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 4.66 (s, 2H), 2.96 (s, 3H), 1.58 - 1.19 (m, 9H). Step 2: N-[(5-amino-1H-benzimidazole-2-yl)methyl]-N-methylcarbamate tert-butyl A solution of tert-butyl N-methyl-N-[(5-nitro-1H-benzimidazole-2-yl)methyl]carbamate (Step 1) (99%, 500 mg, 1.62 mmol) in EtOH (10 mL) was purged with nitrogen (3 times) and treated with 10% Pd / C (50% wet) (5%, 86 mg, 0.04 mmol). The mixture was placed under a hydrogen atmosphere and stirred at room temperature for 16 hours. The resulting mixture was filtered through Celite® (filter medium) and concentrated under vacuum to obtain the title compound. LC-MS (Method E): Rt 0.71 min; MS m / z 277.1 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 11.84 - 11.53 (m, 1H), 7.27 - 7.05 (m, 1H), 6.75 - 6.40 (m, 2H), 4.91 - 4.60 (m, 2H), 4.46 (s, 2H), 2.86 (s, 3H), 1.53 - 1.25 (m, 9H). Step 3: N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]methyl]-N-methylcarbamate tert-butyl A solution of 2-(2-adamantyl)acetic acid intermediate B (step 3) (103 mg, 0.53 mmol) and HATU (243 mg, 0.64 mmol) in DMF (3 mL) was treated with DIPEA (0.19 mL, 1.06 mmol) and N-[(5-amino-1H-benzimidazole-2-yl)methyl]-N-methylcarbamate tert-butyl (step 2) (98%, 150 mg, 0.53 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with ELISA (20 mL) and washed with water (3 x 20 mL). The organic portion was dried over MgSO4 and concentrated under vacuum. The title compound was purified by C18 reverse-phase chromatography eluting with 10-100% MeCN (0.1% formic acid) in water to obtain an off-white solid. LC-MS (Method A): Rt 2.86 min; MS m / z 453.4 = [M+H]+ 1H NMR (500 MHz, Methanol-d4) δ 7.98 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.30 - 7.22 (m, 1H), 4.65 (s, 2H), 3.06 - 2.94 (m, 3H), 2.57 (d, J = 7.7 Hz, 2H), 2.40 - 2.33 (m, 1H), 2.09 - 2.01 (m, 2H), 1.96 - 1.83 (m, 6H), 1.82 - 1.75 (m, 4H), 1.64 (d, J = 12.6 Hz, 2H), 1.57 - 1.29 (m, 9H).

[0207] Example 2.4 N-(cycloheptylmethyl)-2-(2,3-dihydrobenzofuran-3-yl)-1H-benzimidazole-5-carboxamide TIFF0007853981000067.tif311702-(2,3-dihydrobenzofuran-3-yl)-1H-benzimidazole-5-carboxylic acid (intermediate D) (90%, 61 mg, 0.20 mmol) was mixed with DIPEA (38 μL, 0.22 mmol) and HATU (82 mg, 0.22 mmol), followed by cycloheptylmethanamine (27 mg, 0.22 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water and extracted with SiO (5 mL). The organic extract was washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by preparative HPLC (basic pH, early elution method) to obtain the title compound as a colorless powder. LC-MS (Method A): Rt 2.91 min; MS m / z 390.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.38 (t, J = 5.2 Hz, 1H), 8.04 (br s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 6.90 - 6.84 (m, 2H), 5.08 (dd, J = 9.6, 6.9 Hz, 1H), 5.05 - 5.00 (m, 1H), 4.98 - 4.93 (m, 1H), 3.11 (t, J = 6.3 Hz, 2H), 1.80 - 1.70 (m, 3H), 1.66 - 1.61 (m, 2H), 1.58 - 1.52 (m, 2H), 1.51 - 1.43 (m, 2H), 1.42 - 1.35 (m, 2H), 1.21 - 1.14 (m, 2H).

[0208] Example 2.5 2-(2-adamantyl)-N-[2-[hydroxy(phenyl)methyl]-1H-benzimidazole-5-yl]acetamide TIFF0007853981000068.tif38170 Step 1: 2-(2-adamantyl)-N-[2-[methoxy(phenyl)methyl]-1H-benzimidazole-5-yl]acetamide TIFF0007853981000069.tif36170 The title compound was prepared from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (intermediate B) and 2-methoxy-2-phenyl-acetic acid, similar to Example 2.2. LC-MS (Method A): Rt 2.88 min; MS m / z 430.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.42 - 12.32 (m, 1H), 9.94 - 9.70 (m, 1H), 8.06 - 7.80 (m, 1H), 7.51 - 7.06 (m, 7H), 5.61 - 5.49 (m, 1H), 3.36 (s, 3H), 2.48 - 2.41 (m, 2H), 2.27 - 2.19 (m, 1H), 1.98 - 1.91 (m, 2H), 1.88 - 1.64 (m, 10H), 1.56 - 1.47 (m, 2H). Step 2: 2-(2-adamantyl)-N-[2-[hydroxy(phenyl)methyl]-1H-benzimidazole-5-yl]acetamide DCM (0.37 mL, 0.37 mmol) containing 1 M BBr3 is mixed with 2-(2-adamantyl)-N-[2-[methoxy(phenyl) 53 mg, 0.12 mmol of methyl-1H-benzimidazole-5-yl]acetamide (Step 1) was added dropwise to a 3 mL solution of DCM, and the mixture was stirred overnight at room temperature. The resulting mixture was left at room temperature for 2 days, after which the solvent was evaporated to obtain a white / yellow solid. This solid was suspended in 5 mL of water and sonicated. The acidic aqueous solution was adjusted to pH 8 using an aqueous solution of sodium bicarbonate. 10 mL of toluene was added, and the mixture was sonicated until all solids were dissolved. The organic layer was separated, washed with water, and passed through a phase separation column. The mixture was concentrated under vacuum, the crude product was suspended in 1 mL of MeOH, and filtered. The filtrate was concentrated under vacuum, the residue was suspended in 1 mL of MeOH, heated briefly, and sonicated. After cooling to room temperature, the suspension was filtered and the solid was discarded. The filtrate was purified by C18 reverse-phase chromatography using 10-100% MeCN (+0.1% formic acid) in water to obtain the title compound as a colorless solid. LC-MS (Method A): Rt 2.53 min; MS m / z 416.3 = [M+H]+ 1H NMR (500 MHz, Methanol-d4) δ 7.93 (d, J = 1.8 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.45 (d, J = 8.6 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.31 - 7.25 (m, 1H), 7.25 - 7.20 (m, 1H), 5.97 (s, 1H), 2.59 - 2.52 (m, 2H), 2.39 - 2.32 (m, 1H), 2.09 - 2.00 (m, 2H), 1.95 - 1.73 (m, 10H), 1.68 - 1.58 (m, 2H).

[0209] Example 3.1 2-Cyclohexyl-N-(2-phenyl-1H-benzimidazole-5-yl)acetamide TIFF0007853981000070.tif211702-Phenyl-1H-benzimidazole-5-amine (50 mg, 0.24 mmol) and DIPEA (84 μL, 0.48 mmol) were dissolved in 5 mL of chilled DCM (0°C), to which 2-cyclohexylacetyl chloride (42 mg, 0.26 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with saturated sodium bicarbonate solution (5 mL), dried over Na2SO4, and concentrated under vacuum. The title compound was obtained by purification by preparative HPLC (basic pH, early elution method). LC-MS (Method A): Rt 2.29 min; MS m / z 334.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ = 12.96 - 12.55 (m, 1H), 9.98 - 9.71 (m, 1H), 8.27 - 7.95 (m, 3H), 7.66 - 7.06 (m, 5H), 2.29 - 2.15 (m, 2H), 1.88 - 1.54 (m, 6H), 1.38 - 1.09 (m, 3H), 1.06 - 0.90 (m, 2H).

[0210] Example 3.2 N-(2-benzyl-1H-benzimidazole-5-yl)adamantan-1-carboxamide TIFF0007853981000071.tif341702-Benzyl-1H-benzimidazole-5-amine (intermediate A) (60 mg, 0.27 mmol) and DIPEA (56 μL, 0.32 mmol) were cooled in DMF (1 mL) at 0°C, to which adamantane-1-carbonyl chloride (59 mg, 0.30 mmol) was added. This solution was heated to room temperature and stirred for 1 hour. The resulting mixture was diluted with HCl (5 mL), washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The residue was suspended in water (1.5 mL) and MeCN (0.5 mL), filtered, washed with ether and heptane, and then dried under a nitrogen stream to obtain the title compound. LC-MS (Method A): Rt 2.50 min; MS m / z 386.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.14 (s, 1H), 9.06 - 8.97 (m, 1H), 7.92 - 7.82 (m, 1H), 7.41 - 7.21 (m, 7H), 4.13 (s, 2H), 2.04 - 1.99 (m, 3H), 1.93 - 1.90 (m, 6H), 1.72 - 1.69 (m, 6H).

[0211] Example 3.3 N-(cycloheptylmethyl)-7-fluoro-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide TIFF0007853981000072.tif32170 Step 1 :2-[(3-benzyloxyphenyl)methyl]-5-bromo-7-fluoro-1H-benzoimidazole TIFF0007853981000073.tif261702-(3-benzyloxyphenyl)acetic acid (650 mg, 2.68 mmol) was dissolved in DMF (10 mL) to which HATU (1113 mg, 2.93 mmol) was added, followed by DIPEA (0.85 mL, 4.88 mmol). The mixture was stirred under nitrogen at room temperature for 30 minutes, and then 5-bromo-3-fluorobenzene-1,2-diamine (500 mg, 2.44 mmol) was added. After stirring overnight at room temperature, the resulting mixture was diluted with RINKAN (50 mL) and washed with water (3 x 50 mL) and brine (3 x 50 mL). The organic portion was dried over Na2SO4 and concentrated under vacuum. The resulting black oil was placed in acetic acid (10 mL), heated at 70°C for 3 hours, and then cooled to room temperature. This mixture was diluted with water (100 mL) and then extracted with ethyl acetate (50 mL). The organic extract was washed with water (2 x 50 mL), saturated aqueous NaHCO3 solution (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by chromatography on silica eluted with 0-100% ethyl acetate in heptane to obtain the title compound as a light brown solid. LC-MS (Method E): Rt 1.31 min; MS m / z 411.0 / 413.0 = [M+H]+ 1H NMR (250 MHz, DMSO-d6) δ 12.71 (br. s, 1H), 7.51 (s, 1H), 7.45 - 7.29 (m, 5H), 7.28 - 7.19 (m, 2H), 7.01-6.97 (m, 1H), 6.93-6.86 (m, 2H), 5.07 (s, 2H), 4.15 (s, 2H). Step 2: 2-[(3-benzyloxyphenyl)methyl]-N-(cycloheptylmethyl)-7-fluoro-1H-benzimidazole-5-carboxamide TIFF0007853981000074.tif31170 All reagents were loaded into the COware instrument (carbon monoxide generation system) according to the following procedure. Chamber A was charged with 2-[(3-benzyloxyphenyl)methyl]-5-bromo-7-fluoro-1H-benzimidazole (Step 1) (83%, 200 mg, 0.40 mmol), sodium carbonate (128 mg, 1.21 mmol), and XantPhos Pd-G3 (third-generation (G3) Buchwald catalyst precursor) (19 mg, 0.020 mmol). Toluene (5 mL), followed by cycloheptylmethanamine (77 mg, 0.61 mmol), was added. This mixture was degassed with nitrogen for 5 minutes. Then, toluene (5 mL) containing formic acid (46 μL, 1.15 mmol), followed by mesyl chloride (94 μL, 1.21 mmol), was added to Chamber B. The apparatus was further degassed with nitrogen for 2 minutes and then sealed. TEA (338 μL, 2.42 mmol) was added to chamber B (to generate CO gas). This sealed system was heated overnight at 100°C. The mixture obtained from chamber A was concentrated under vacuum, and the residue was taken in HCl (50 mL). This mixture was washed with water (2 x 25 mL) and brine (25 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by chromatography on silica eluting 0–100% HCl in heptane to obtain the title compound as a pale yellow solid. LC-MS (Method E): Rt 1.35 min; MS m / z 486.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 13.20-12.70 (m, 1H), 8.46 (t, J = 5.6 Hz, 1H), 8.00 - 7.74 (m, 1H), 7.48 (d, J = 11.5 Hz, 1H), 7.43 (d, J = 7.1 Hz, 2H), 7.36 (t, J = 7.3 Hz, 2H), 7.33-7.29 (m, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.01 (s, 1H), 6.94 - 6.88 (m, 2H), 5.08 (s, 2H), 4.19 (s, 2H), 3.11 (t, J = 6.3 Hz, 2H), 1.80 - 1.67 (m, 3H), 1.67-1.59 (m, 2H), 1.58 - 1.34 (m, 6H), 1.22-1.13 (m, 2H). Step 3: N-(cycloheptylmethyl)-7-fluoro-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide To a solution of 2-[(3-benzyloxyphenyl)methyl]-N-(cycloheptylmethyl)-7-fluoro-1H-benzimidazole-5-carboxamide (Step 2) (75 mg, 0.15 mmol) in EtOH (25 mL), 10% Pd / C (50% wet) (5%, 33 mg, 0.015 mmol) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The resulting mixture was filtered through Celite® (filter medium) and washed with EtOH (20 mL). The filtrate was concentrated under vacuum, and the crude product was purified by preparative HPLC (basic pH, early elution method) to obtain the title compound as a white solid. LC-MS (Method A): Rt 2.96 min; MS m / z 396.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.69 (br. s, 1H), 9.35 (s, 1H), 8.45 (t, J = 5.7 Hz, 1H), 7.83 (br. s, 1H), 7.47 (d, J = 11.8 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 6.71-6.69 (m, 1H), 6.63 (dd, J = 8.0, 1.9 Hz, 1H), 4.12 (s, 2H), 3.10 (t, J = 6.3 Hz, 2H), 1.80 - 1.67 (m, 3H), 1.67-1.58 (m, 2H), 1.58 - 1.33 (m, 6H), 1.21-1.12 (m, 2H).

[0212] Example 3.3.1 N-(cycloheptylmethyl)-6-fluoro-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide The title compound was prepared in the same manner as in Example 3.3 (Steps 1-3), by replacing 5-bromo-3-fluorobenzene-1,2-diamine (Step 1) with 4-bromo-5-fluorobenzene-1,2-diamine. LC-MS (Method A): Rt 2.71 min; MS m / z 396.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 9.44 (br s, 1H), 8.28 - 8.23 ​​(m, 1H), 7.75 (d, J = 6.2 Hz, 1H), 7.48 (d, J = 10.5 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 6.73 - 6.71 (m, 1H), 6.67 (dd, J = 8.0, 1.8 Hz, 1H), 4.21 (s, 2H), 3.10 (t, J = 6.2 Hz, 2H), 1.75 - 1.70 (m, 3H), 1.67 - 1.61 (m, 2H), 1.57 - 1.52 (m, 2H), 1.50 - 1.45 (m, 2H), 1.42 - 1.36 (m, 2H), 1.22 - 1.15 (m, 2H).

[0213] Example 3.3.2 N-(cycloheptylmethyl)-4-fluoro-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide The title compound was prepared in the same manner as in Example 3.3 (Steps 1-3), by replacing 5-bromo-3-fluorobenzene-1,2-diamine (Step 1) with 4-bromo-3-fluorobenzene-1,2-diamine. LC-MS (Method A): Rt 2.90 min; MS m / z 396.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 9.35 (br s, 1H), 8.14 (br s, 1H), 7.37 - 7.33 (m, 1H), 7.31 - 7.26 (m, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 6.71 - 6.67 (m, 1H), 6.62 (dd, J = 8.0, 1.9 Hz, 1H), 4.10 (s, 2H), 3.11 (t, J = 6.2 Hz, 2H), 1.77 - 1.70 (m, 3H), 1.67 - 1.60 (m, 2H), 1.58 - 1.52 (m, 2H), 1.51 - 1.44 (m, 2H), 1.43 - 1.35 (m, 2H), 1.22 - 1.14 (m, 2H).

[0214] Example 3.4 N-[2-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]ethyl]carbamate tert-butyl TIFF0007853981000077.tif431703-(tert-butoxycarbonylamino)propanoic acid (75 mg, 0.40 mmol), 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (intermediate B) (95%, 125 mg, 0.40 mmol), and DIPEA (90 μL, 0.52 mmol) were mixed in DMF (2 mL) and HATU (151 mg, 0.40 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum, and the residue was partitioned into saturated NaHCO3 (10 mL) and SiO (10 mL). The organic layer was separated, washed with water (2 x 5 mL) and brine (2 x 5 mL), dried over Na2SO4, and concentrated under vacuum. The resulting crude substance was dissolved in acetic acid (2 mL) and stirred at 70°C for 2 hours. The mixture was concentrated under vacuum, and the residue was partitioned into saturated NaHCO3 (10 mL) and HCl (10 mL). The organic layer was washed with water (2 x 5 mL) and dried over Na2SO4. The crude material was purified by preparative HPLC (basic pH, early elution method) to obtain the title compound as an off-white powder. LC-MS (Method A): Rt 2.46 min; MS m / z 453.3 = [M+H]+ 1H NMR (500 MHz, Methanol-d4) δ 7.92 (s, 1H), 7.43 (br s, 1H), 7.18 (br s, 1H), 3.50 (t, J = 7.0 Hz, 2H), 3.02 (t, J = 6.9 Hz, 2H), 2.56 (d, J = 7.7 Hz, 2H), 2.36 (t, J = 7.7 Hz, 1H), 2.05 (d, J = 14.6 Hz, 2H), 1.98 - 1.83 (m, 6H), 1.83 - 1.73 (m, 4H), 1.64 (d, J = 12.5 Hz, 2H), 1.45 - 1.20 (m, 9H).

[0215] Example 3.4.1 2-(2-adamantyl)-N-[2-[(3,5-dimethylisoxazole-4-yl)methyl]-1H-benzimidazole-5-yl]acetamide TIFF0007853981000078.tif37170 The title compound was obtained from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (intermediate B) and 2-(3,5-dimethylisoxazole-4-yl)acetic acid, similar to Example 3.4. LC-MS (Method A): Rt 2.56 min; MS m / z 419.4 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.06 (br. s, 1H), 9.82 (br. s, 1H), 8.07 - 7.78 (m, 1H), 7.48 - 7.03 (m, 2H), 3.90 (s, 2H), 2.45 (d, J = 7.7 Hz, 2H), 2.32 (s, 3H), 2.26 - 2.20 (m, 1H), 2.08 (s, 3H), 1.98 - 1.90 (m, 2H), 1.89 - 1.66 (m, 10H), 1.56 - 1.47 (m, 2H).

[0216] Example 3.5 2-benzyl-N-(2,2-dimethylpropyl)-1H-benzimidazole-5-carboxamide A solution of 2-benzyl-1H-benzimidazole-5-carboxylic acid (75 mg, 0.3 mmol) in DMF (2 mL) was treated with EDCI (63 mg, 0.33 mmol), DMAP (40 mg, 0.33 mmol), and HOAt (45 mg, 0.33 mmol). After stirring at room temperature for 5 minutes, 2,2-dimethylpropane-1-amine (52 mg, 0.59 mmol) was added, and the reaction mixture was stirred at room temperature under an inert atmosphere for 16 hours. The resulting mixture was diluted with  (20 mL), washed with water (2 x 10 mL) and brine (2 x 10 mL), and concentrated under vacuum. The crude product was purified by HPLC (acidic pH, standard elution method) to obtain the title compound as a colorless solid. LC-MS (Method A): Rt 1.89 min; MS m / z 322.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.69 - 12.33 (m, 1H), 8.29 - 8.20 (m, 1H), 8.16 - 7.86 (m, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.59 - 7.39 (m, 1H), 7.36 - 7.28 (m, 4H), 7.27 - 7.20 (m, 1H), 4.20 (s, 2H), 3.12 (d, J = 6.4 Hz, 2H), 0.90 (s, 9H).

[0217] Example 3.5.1 2-benzyl-N-(1,1,2,2-tetramethylpropyl)-1H-benzimidazole-5-carboxamide ET4146 TIFF0007853981000080.tif31170 The title compound was prepared from 2-benzyl-1H-benzimidazole-5-carboxylic acid and 2,3,3-trimethylbutane-2-amine, similar to Example 3.5. LC-MS (Method A): Rt 2.31 min; MS m / z 350.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.89 (s, 1H), 7.55 (dd, J = 8.4, 1.4 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.34 - 7.29 (m, 4H), 7.26 - 7.21 (m, 1H), 7.05 (s, 1H), 4.19 (s, 2H), 1.42 (s, 6H), 0.99 (s, 9H).

[0218] Preparation of intermediates Intermediate A 2-benzyl-1H-benzimidazole-5-amine TIFF0007853981000081.tif26170 Step 1: 2-benzyl-6-nitro-1H-benzimidazole A solution of DIPEA (4.56 mL, 26.12 mmol), 2-phenylacetic acid (1.60 g, 11.75 mmol), HATU (4.47 g, 11.75 mmol), and 4-nitrobenzene-1,2-diamine (2.0 g, 13.06 mmol) in DMF (50 mL) was stirred at room temperature for 72 hours. The resulting mixture was diluted with HCl (60 mL), washed with water (2 x 20 mL) and brine (2 x 50 mL), dried over MgSO4, and concentrated under vacuum. The crude substance was taken in acetic acid (5 mL) and stirred at 60°C for 20 hours. This mixture was concentrated under vacuum, and the resulting residue was partitioned into HCl (30 mL) and cooled saturated NaHCO3 aqueous solution (30 mL). The phases were separated, the organic matter was washed with water (2 x 30 mL) and brine (30 mL), dried with MgSO4, and concentrated in vacuum to obtain the title compound as a red viscous oil. LC-MS (Method E): Rt 1.00 min; MS m / z 254.0 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 12.98 (br s, 1H), 8.40 (s, 1H), 8.07 (dd, J = 8.9, 2.3 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.40 - 7.30 (m, 4H), 7.30 - 7.21 (m, 1H), 4.26 (s, 2H). Step 2: 2-benzyl-1H-benzimidazole-5-amine Zinc powder (4.8 g, 73.44 mmol) was added to a chilled (0°C) solution of MeOH (40.5 mL) and acetic acid (13.5 mL) containing 2-benzyl-5-nitro-1H-benzimidazole (Step 1) (3.1 g, 12.24 mmol). The reaction mixture was heated to room temperature and stirred for 20 minutes. The resulting mixture was filtered through Celite® (filter medium) and thoroughly washed with MeOH. The filtrate was concentrated under vacuum, and the crude residue was dissolved in HCl (50 mL) and saturated NaHCO3 aqueous solution (50 mL). The resulting two-phase mixture was filtered, and the phases of the filtrate were separated. The aqueous layer was extracted with CHCl3 / IPA (2:1, 3 x 20 mL), and the combined organic portion was concentrated under vacuum. The crude substance was dissolved in 3 M HCl aqueous solution (heating was required for dissolution), and then treated with 2 M NaOH until a solid precipitate remained. Since the product could not be isolated by filtration, the combined solid and filtrate were concentrated under vacuum to obtain a brown oil. The title compound was purified by C18 reverse-phase chromatography, which elutes the oil in 10-100% MeCN (0.1% formic acid) water, to obtain a pink glassy solid. LC-MS (Method E): Rt 0.65 min; MS m / z 224.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 7.41 - 7.28 (m, 6H), 6.82 (d, J = 1.7 Hz, 1H), 6.78 (dd, J = 8.7, 2.0 Hz, 1H), 4.35 (s, 2H).

[0219] Intermediate B 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide TIFF0007853981000083.tif27170 Step 1: 2-(2-adamantylidene)ethyl acetate TIFF0007853981000084.tif22170 NaH (60% dispersion in mineral oil) (1.86 g, 46.6 mmol) was added dropwise to a THF (100 mL) cooled (0°C) suspension to ethyl 2-diethoxyphosphoryl (7.26 mL, 36.61 mmol). After stirring at 0°C for 30 minutes, adamantan-2-one (5.0 g, 33.28 mmol) was added, and the mixture was heated to room temperature and stirred for 2 hours. The resulting mixture was diluted with DCM (100 mL) and washed with water (100 mL). The aqueous portion was extracted with DCM (100 mL), and the combined organic extract was dried over MgSO4 and concentrated under vacuum to obtain a colorless oil. This oil was purified by chromatography on silica eluted with 0-20% siRNA in heptane to obtain the title compound as a colorless oil. LC-MS (Method B): Rt 1.43 min; MS m / z 221.3 = [M+H]+ 1H NMR (500 MHz, Chloroform-d) δ 5.58 (s, 1H), 4.14 (q, J = 7.1 Hz, 2H), 4.06 (s, 1H), 2.43 (s, 1H), 2.00 - 1.90 (m, 6H), 1.88 - 1.78 (m, 6H), 1.27 (t, J = 7.1 Hz, 3H). Step 2: 2-(2-adamantyl)ethyl acetate TIFF0007853981000085.tif221702-(2-adamantylidene)ethyl acetate (Step 1) (95%, 14.0 g, 60.37 mmol) and Pd / C (10%, 6.42 g, 6.04 mmol) were suspended in EtOH (125 mL) and stirred under a hydrogen atmosphere for 18 hours. The resulting mixture was filtered through glass filter paper, and the filter cake was washed with EtOH (2 x 10 mL). The filtrate was concentrated under vacuum to obtain the title compound as a colorless oil. LC-MS (Method B): Rt 1.47 min; MS m / z 223.0 = [M+H]+ 1H NMR (500 MHz, Chloroform-d) δ 4.12 (q, J = 7.1 Hz, 2H), 2.44 (d, J = 7.6 Hz, 2H), 2.23 (t, J = 7.6 Hz, 1H), 1.91 - 1.75 (m, 8H), 1.71 (d, J = 10.9 Hz, 4H), 1.62 - 1.50 (m, 3H), 1.25 (t, J = 7.1 Hz, 3H). Step 3: 2-(2-adamantyl)acetic acid A solution of 2-(2-adamantyl)ethyl acetate (step 2) (100%, 18.3g, 82.31 mmol) in MeOH (200 mL) and a 2M aqueous sodium hydroxide solution (82.31 mL, 164.63 mmol) were stirred at 70°C for 2 hours. The mixture was cooled to room temperature and concentrated in vacuum. The resulting solution was diluted with water (200 mL), and when 6M aqueous HCl (approximately 30 mL) was added, a white precipitate was formed. HCl (300 mL) was added to separate the phases. The aqueous portion was further extracted with HCl (200 mL), the combined organic extract was washed with brine (200 mL), dried over MgSO4, and concentrated in vacuum to obtain the title compound as a white solid. LC-MS (Method B): Rt 1.15 min; MS m / z 193.4 = [M+H]+ 1H NMR (500 MHz, Chloroform-d)δ 2.50 (d, J = 7.6 Hz, 2H), 2.24 (t, J = 7.5 Hz, 1H), 1.93 - 1.77 (m, 8H), 1.74 (d, J = 11.2 Hz, 4H), 1.56 (d, J = 12.5 Hz, 2H). 2-(2-adamantyl)-N-(4-amino-3-nitrophenyl)acetamide 13.66 g, 35.91 mmol of HATU was added to a 60 mL cooled (0°C) solution of 2-(2-adamantyl)acetic acid (step 3) (6.34 g, 32.65 mmol) in DMF (60 mL). 8.53 mL, 48.97 mmol of DIPEA was added dropwise over 1 minute, and the resulting solution was stirred at 0°C for 5 minutes and at room temperature for 10 minutes. The solution was recooled to 0°C, and 5.0 g, 32.65 mmol of 2-nitrobenzene-1,4-diamine was added. The resulting solution was stirred at 0°C for 1 hour, warmed to room temperature, and then diluted with water (60 mL). 100 mL of ethyl acetate and an additional 40 mL of water were added, and the layers were separated. The aqueous layer was extracted with toluene (100 mL), and the combined organic extract was washed with saturated sodium bicarbonate aqueous solution (2 x 100 mL) and 10% potassium carbonate solution (2 x 100 mL), and filtered under vacuum. The two-phase filtrate was placed in a separatory funnel, and the layers were separated. The organic layer was passed through an Isolute® phase separation cartridge and concentrated under vacuum to obtain a dark black / brown / red gum. Approximately 80 mL of DCM was added, and the suspension was stirred. Further DCM was added, the suspension was filtered under vacuum, washed with DCM, and dried under vacuum to obtain the title compound as a red / brown solid. LC-MS (Method B): Rt 1.22 min; MS m / z 330.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.40 (d, J = 2.5 Hz, 1H), 7.52 (dd, J = 9.1, 2.5 Hz, 1H), 7.31 (s, 2H), 7.03 - 6.90 (m, 1H), 2.41 (d,J= 7.6 Hz, 2H), 2.21 (t, J = 7.5 Hz, 1H), 1.95 - 1.60 (m, 12H), 1.56 - 1.46 (m, 2H). Step 4: 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide A solution of 2-(2-adamantyl)-N-(4-amino-3-nitrophenyl)acetamide (step 4) (4.0 g, 12.14 mmol) in EtOH (60 mL) was purged with nitrogen and treated with Pd / C (10%, 1.03 g, 0.97 mmol). The mixture was placed under a hydrogen atmosphere and stirred overnight at room temperature. The resulting mixture was filtered through Celite® (filter medium), washed with SiO2, and concentrated under vacuum to obtain the title compound as a brown foam. LC-MS (Method B): Rt 0.97 min; MS m / z 300.2 = [M+H]+ (100% @ 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 9.27 (s, 1H), 6.81 (d, J=2.3 Hz, 1H), 6.53 (dd, J= 2.3, 6.5 Hz, 1H), 6.38 (d, J= 6.4 Hz, 1H), 4.60 - 4.07 (m, 4H), 2.33 (d, J= 7.6 Hz, 2H), 2.20 - 2.13 (m, 1H), 1.95 - 1.62 (m, 12H), 1.55 - 1.42 (m, 2H).

[0220] Intermediate C 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide TIFF0007853981000089.tif20170 Step 5: 2-(1-adamantyl)-N-(4-amino-3-nitrophenyl)acetamide TIFF0007853981000090.tif241702-Nitrobenzene-1,4-diamine (3.15 g, 20.59 mmol) was added to a solution of 2-(1-adamantyl)acetic acid (4.0 g, 20.59 mmol), HATU (8.61 g, 22.65 mmol), and DIPEA (5.38 mL, 30.88 mmol) in DMF (20 mL). After stirring at room temperature for 18 hours, the reaction mixture was partitioned into siRNA (100 mL) and water (100 mL). A black precipitate formed in the two-phase mixture. This solid was filtered off and discarded. The phases were separated, the organic layer was washed with water (100 mL) and brine (2 x 50 mL), dried over MgSO4, and concentrated under vacuum to obtain a brown / black oil. This oil was tritulated in DCM (approximately 40 mL), and the resulting suspension was filtered to obtain the title compound as a red / black solid. LC-MS (Method B): Rt 1.24 min; MS m / z 330.2 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 7.50 (dd, J = 9.1, 2.5 Hz, 1H), 7.29 (s, 2H), 6.96 (d, J = 9.1 Hz, 1H), 2.00 (s, 2H), 1.93 (s, 3H), 1.69 - 1.63 (m, 3H), 1.63 - 1.54 (m, 9H). Step 1: 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide TIFF0007853981000091.tif211702-(1-adamantyl)-N-(4-amino-3-nitrophenyl)acetamide (Step 1) (4.82 g, 14.63 mmol) and Pd / C (10%, 1.24 g, 1.17 mmol) were suspended in EtOH (50 mL) and stirred under a hydrogen atmosphere for 18 hours. The resulting mixture was filtered through Celite® (filter medium), and the solid was washed with EtOH (3 x 10 mL). The filtrate was concentrated under vacuum to obtain the title compound as a purple solid. LC-MS (Method B): Rt 0.93 min; MS m / z 300.3 = [M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.52 (dd, J = 8.2, 2.3 Hz, 1H), 6.38 (d, J = 8.2 Hz, 1H), 4.54 - 4.22 (m, 4H), 1.96 - 1.88 (m, 5H), 1.70 - 1.54 (m, 12H).

[0221] Intermediate D 2-(2,3-dihydrobenzofuran-3-yl)-1H-benzoimidazole-5-carboxylic acid TIFF0007853981000092.tif32170 Step 2: 2-(2,3-dihydrobenzofuran-3-yl)-1H-benzoimidazole-5-carboxylate methyl TIFF0007853981000093.tif321702,3-Dihydrobenzofuran-3-carboxylic acid (50 mg, 0.30 mmol) was dissolved in DMF (2 mL), to which DIPEA (59 μL, 0.34 mmol) and HATU (127 mg, 0.34 mmol), followed by methyl 3,4-diaminobenzoate (56 mg, 0.34 mmol). The mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (5 mL) and extracted with HCl (2 x 5 mL). The combined organic extract was washed with brine (5 mL) and concentrated under vacuum. The crude residue was dissolved in acetic acid (2 mL) and heated at 60°C for 3 hours. The resulting mixture was diluted with HCl (10 mL), washed with saturated NaHCO3 solution (2 x 10 mL), dried over Na2SO4, and concentrated under vacuum. The crude residue was purified by chromatography on silica eluted with 0-100% siRNA in heptane, yielding the title compound as a pale orange glass. LC-MS (Method E): Rt 0.97 min; MS m / z 294.9 = [M+H]+ 1H NMR (500 MHz, Methanol-d4) δ 8.22 (br s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.55 (br s, 1H), 7.23 - 7.14 (m, 2H), 6.92 - 6.84 (m, 2H), 5.09 - 5.03 (m, 1H), 4.96 (t, J = 9.4 Hz, 1H), 4.87-4.83 (obscured m, 1H), 3.91 (s, 3H). Step 1: 2-(2,3-dihydrobenzofuran-3-yl)-1H-benzoimidazole-5-carboxylic acid A solution containing 2-(2,3-dihydrobenzofuran-3-yl)-1H-benzimidazole-5-carboxylate methyl (Step 1) (90%, 69 mg, 0.21 mmol) in MeOH (0.3 mL), THF (0.3 mL), and water (0.3 mL) was prepared. LiOH (5.6 mg, 0.23 mmol) was added to this solution, and the mixture was stirred at room temperature for 2 hours. Further LiOH (5.6 mg, 0.23 mmol) was added, and the mixture was heated to 50°C overnight. The resulting mixture was cooled to room temperature and acidified to pH 4 using 1 M HCl. The mixture was diluted with water and extracted with chloroform / IPA (2:1). The combined organic extract was passed through a hydrophobic frit and concentrated under vacuum to obtain the title compound. LC-MS (Method E): Rt 0.84 min; MS m / z 280.9 = [M+H]+

[0222] Biological examples Whole-cell automated patch-clamp assay for detecting TMEM16A activity in recombinant cells Cell culture and preparation Fisher rat thyroid (FRT) cells stably expressing human TMEM16A (TMEM16Aabc variant; Dr. Luis Galietta, Insituto Giannina, Italy) were cultured in T-75 flasks on Coon-modified Ham F-12 medium (Sigma) supplemented with 10% (v / v) fetal bovine serum, penicillin-streptomycin (10,000 U / mL / 10,000 μg / mL), G-418 (750 μg / mL), L-glutamine (2 mM), and sodium bicarbonate solution (7.5% v / v). At approximately 90% confluence, cells were harvested for experimental use by detachment using a 2:1 (v / v) mixture of Detachin (BMS Biotechnology) and 0.25% (w / v) trypsin-EDTA. Cells were cultured in a medium consisting of CHO-S-SFM II (Sigma), 25 mM HEPES (Sigma), and a soy trypsin inhibitor (Sigma) at a rate of 3.5–4.5 x 10⁻¹⁴. 6 Diluted to a density of cells / mL.

[0223] Whole cell patch clamp record Whole-cell patch clamping of FRT-TMEM16A cells was performed using an automated planar patch clamp system (Qpatch, Sophion). Briefly, once a high-resistance (GOhm) seal was established between the cells and the planar recording array, the patch was ruptured using a suction pulse to establish the whole-cell recording configuration of the patch clamp technique. This assay used the following solutions (all reagents from Sigma).

[0224] Intracellular solution (mM): N-methyl-D-glucamine 130, CaCl2 18.2, MgCl2 1, HEPES 10, EGTA 10, BAPTA 20, Mg-ATP 2, pH 7.25, sucrose 325 mOsm.

[0225] Extracellular solution (mM): N-methyl-D-glucamine 130, CaCl22, MgCl21, HEPES 10, pH 7.3, sucrose 320 mOsm.

[0226] The intracellular solution buffers intracellular calcium at a level necessary to activate the maximum TMEM16A mediated current by approximately 20% (for calcium ions, EC2). 20 Cells were voltage-clamped at a holding potential of -70mV, and a synthesis voltage step (up to +70mV) / ramp (-90mV to +90mV) was applied at 0.05Hz. After a period of current stabilization, the test compound was solubilized in 100% (v / v) DMSO and then diluted in extracellular solution to generate a cumulative concentration-response curve. After incubating each concentration of the test compound for 5 minutes, the next concentration was added. After testing the final concentration, the upper and lower limits of the assay were defined by adding either a known active positive modulator or the TMEM16A inhibitor CaCCinhA01 (Del La Fuente et al, 2008) at ultramaximal concentrations.

[0227] Compound activity was quantified by measuring the increase in current upon compound addition and expressing this as the percentage increase in the baseline TMEM16A current level. The percentage increase in current was determined for each concentration, and the data was plotted as a function of concentration using either Qpatch software or Graphpad Prism v6.05, with the maximum effect at 50% (EC2). 50 ) and concentrations that provide maximum efficacy (rate of increase from baseline) were obtained.

[0228] The method for calculating the results is shown in Figure 1, which shows an example of tracing the Qpatch TMEM16A assay. In Figure 1, I BL This is equal to the baseline current, I [#1] This is equal to the peak current during the incubation period of the test compound at a concentration of 1, and so on.

[0229] The peak TMEM16A current at +70mV was plotted as a function of time over the assay period. Baseline current (I BLThe current was measured after the stabilization period. The increase in current due to the addition of each compound was determined by obtaining the peak current during the incubation period, subtracting the current from the previous recording period, and then expressing this as a percentage of the baseline current. For test compound concentration 1 in Figure 1, the results are as follows. (I [#1] -I BL / I BL ) x 100 The increase in current for each additional test concentration was determined by subtracting the current from the previous incubation period and normalizing the baseline value. For test concentration 2 in Figure 1, the following applies. (I [#2] - I [#1} / I BL ) x 100 The values ​​for each test concentration were plotted as a cumulative function of concentration. For example, in the case of test concentration 2, this represents the sum of the peak changes measured at concentration 1 plus concentration 2.

[0230] Table 2 shows the enhancement percentage results at 3.33 μM obtained for the compounds in the examples. From this table, it can be seen that the compounds of the present invention can significantly increase the TMEM16A current level.

[0231] TIFF0007853981000094.tif254170TIFF0007853981000095.tif127170

[0232] Sheep mucociliary clearance (MCC) MCC in sheep was measured as described in Coote et al., “NVP-QBE170: an inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia,” Br J Pharmacol. 2015 Jun; 172(11): 2814-2826. Briefly, adult ewes were intubated with the test compound, delivered as a dry powder lactose mixture. Hypertonic saline and control water were administered to the sheep by spray through an endotracheal tube. Aerosolized technetium-labeled sulfur colloid ( 99m Tc-SC is used to measure the effect of various doses of test compounds or controls on MCC by gamma machinography. In female sheep, after administration of the test substance, at selected time intervals... 99m Tc-SC is administered. Sequential images are taken regularly, and the count from the right lung is attenuated and expressed as the percentage of radioactivity removed relative to the baseline image (removal%). 99mThe differences in Tc-SC clearance will be compared based on the time interval after radioactive aerosol administration. See also Hirsh et al., “Pharmacological properties of N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N'-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine methanesulfonate, a novel epithelial sodium channel blocker with potential clinical efficacy for cystic fibrosis lung disease,” J Pharmacol Exp Ther. 2008 Apr;325(1):77-88 and Coote et al., Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease,” J Pharmacol Exp Ther. 2009 May;329(2):764-74.

[0233] All references and patent documents used herein are incorporated by reference to the greatest extent possible.

[0234] Step 2: References Accurso FJ,Moss RB,Wilmott RW,Anbar RD,Schaberg AE,Durham TA,RamsayBW;TIGER-1 Investigator Study Group(2011)Denufosol tetrasodium in patients with cystic fibrosis and normal to mildly impaired lung function.Am J Respir Crit Care Med,183(5):627-634. Boucher RC(2007) Evidence for airway surface dehydration as the initiating event in CF airway disease.J Intern Med.,261(1):5-16. Caputo A,Caci E,Ferrera L,Pedemonte N,Barsanti C,Sondo E,Pfeffer U,Ravazzolo R,Zegarra-Moran O & Galietta LJ(2008) TMEM16A,a membrane protein associated with calcium-dependent chloride channel activity.Science,322(5901):590-594. Del La Fuente R,Namkung W,Mills A & Verkman AS(2008) Small molecule screen identifies inhibitors of a human intestinal calcium-activated chloride channel.Mol Pharmacol,73(3):758-768. Kellerman D,Rossi Mospan A,Engels J,Schaberg A,Gorden J & Smiley L(2008) Denufosol:a review of studies with inhaled P2Y(2) agonists that led to Phase 2.Pulm Pharmacol Ther,21(4):600-607. Kunzelmann K & Mall M (2003) Pharmacotherapy of the ion transport defect in cystic fibrosis:role of purinergic receptor agonists and other potential therapeutics.Am J Respir Med,2(4):299-309. Matsui H,Grubb BR,Tarran R,Randell SH,Gatzy JT,Davis CW and Boucher RC(1998) Evidence for periciliary liquid layer depletion,not abnormal ion composition,in the pathogenesis of cystic fibrosis airways disease.Cell,95(7):1005-15. Moss RB(2013) Pitfalls of drug development:lessons learned from trials of denufosol in cystic fibrosis.J Pediatr,162(4):676-680. Pedemonte N & Galietta LJ(2014) Structure and function of TMEM16 proteins(anoctamins).Physiol Rev,94(2):419-459. Pezzulo AA,Tang XX,Hoegger MJ, Abou Alaiwa MH,Ramachandran S,Moninger TO,Karp PH,Wohlford-Lenan CL,Haagsman HP,van Eijk M,Banfi B,Horswill AR,Stoltz DA,McCray PB Jr,Welsh MJ & Zabner J(2012) redcued airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung.Nature,487(7405):109-113. Yang YD,Cho H,Koo JY,Tak MH,Cho Y,Shim WS,Park SP,Lee J,Lee B,Kim BM,Raouf R,Shin YK & Oh U(2008) TMEM16 confers receptor-activated calcium-dependent chloride conductance.Nature,455(7217):1210-1215.

Claims

1. Compounds of general formula (I), including all tautomers, enantiomers and isotopic variants, as well as salts and solvates: {In the formula: R １ teeth, i. [CH(R ７ )] ｎ -N(R ８ )-C(O)OR ９ (n is 1 or 2, Each R ７ These are independently H; phenyl; or OH and OCH ３ C may be substituted with one or more substituents selected from １－３ It is alkyl, R ８ is C １－３ alkyl optionally substituted with one or more substituents selected from H; OH and methoxy, R ９ is C ２－４ (It is alkyl); or ii. CH(R １１ )(R １２ ) (R １１ H;OH;CH ３ CH ３ OH; or R as shown below １２ It is a group that bonds to the substituent above, R １２ , cyclohexyl which may be substituted with one or more substituents selected from OH and methoxy; and phenyl or a five-membered or six-membered heteroaryl, wherein the phenyl or heteroaryl is OH, methoxy, methyl, fluoro, chloro, and R １１ and together with the atom to which it is bonded, the phenyl or heteroaryl group R １２ (May be substituted with one or more substituents selected from substituents that form a condensed 5-membered or 6-membered oxygen-containing heterocycle), or iii. OR １５ C may be replaced with ２－６ Alkyl (R １５ (is methyl or ethyl); or iv. 6-10 membered aryl or 5-10 membered heteroaryl (both may be substituted with one or more substituents selected from fluoro, chloro, OH, or methoxy) And, Z is selected from -NH-C(O)- and -C(O)-NH-; Y is a bond, -CH ２ - and -CH(CH ３ ) - selected from; or Y is R as shown below ２ Combined with; R ２ teeth, i. Selected from a 3-10 membered carbocyclic system or a 6-10 membered aryl or 5-10 membered heteroaryl ring system, where the aryl, heteroaryl, or carbocyclic system is one or more substituents selected from the following: fluoro; chloro; CN; nitro; OH; C １－６ Alkyl (may be substituted with one or more substituents selected from halo, OH, and CN); O (C １－６ (alkyl) (may be substituted with one or more substituents selected from halo, OH, and CN); and CH ２ NH-C(O)OC １－６ They may be substituted with alkyl groups (which may be substituted with one or more substituents selected from halo and OH); or Y and R ２ Together, they form a non-substituted C ３－８ Alkyl group or CH group ２ -C(R １７ ) (Caution １８ ) - CH ２ -N(R) １９ ) R ２０ (Here, R １７ , R １８ and R １９ Each of these is independently H or C １－４ It is alkyl; R ２０ C １－４ Alkyl or C １－４ Forms a haloalkyl (which is a haloalkyl); R ３ , R ４ and R ５ Each of these is independently either H or F. And, N-(2-benzyl-1H-benzimidazole-5-yl)-2-cyclohexyl-acetamide (compound 1.1); 2-benzyl-N-(cyclohexylmethyl)-1H-benzimidazole-5-carboxamide (compound 1.2); N-(1-adamantylmethyl)-2-benzyl-1H-benzimidazole-5-carboxamide (compound 1.2.1); 2-benzyl-N-[(1-methylcyclopentyl)methyl]-1H-benzimidazole-5-carboxamide (compound 1.2.2); 2-benzyl-N-[(1R)-1-cyclohexylethyl]-1H-benzimidazole-5-carboxamide (compounds 1, 2, and 3); N-(cycloheptylmethyl)-2-(1,1-dimethylpropyl)-3H-benzimidazole-5-carboxamide (compound 1.3); N-(cycloheptylmethyl)-2-[(1-hydroxycyclohexyl)methyl]-1H-benzimidazole-5-carboxamide (compound 1.3.1); N-(cycloheptylmethyl)-2-(2-hydroxy-1-phenylethyl)-1H-benzimidazole-5-carboxamide (compound 1.3.2); N-(cyclohexylmethyl)-2-[(3-hydroxyphenyl)methyl]-3H-benzimidazole-5-carboxamide (compound 1.4); 2-(1-adamantyl)-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.5); N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]-2-(1-methylcyclohexyl)acetamide (compound 1.5.1); 2-Cycloheptyl-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.5.2); 2-Cyclohexyl-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.5.3); 2-(1-adamantyl)-N-(2-benzyl-1H-benzimidazole-5-yl)acetamide (compound 1.5.4); N-(2-benzyl-1H-benzimidazole-5-yl)-2-(2-hydroxy-2-adamantyl)acetamide (compound 1.6); 2-(2-adamantyl)-N-[2-[(3-methoxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.7); 2-(2-adamantyl)-N-[2-[(1S)-1-phenylethyl]-1H-benzimidazole-5-yl]acetamide (compound 1.7.1); 2-(2-adamantyl)-N-[2-[(1R)-1-phenylethyl]-1H-benzimidazole-5-yl]acetamide (compound 1.7.2); N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]methyl]carbamate tert-butyl (compound 1.7.3); 2-(1-adamantyl)-N-[2-[(2-methoxy-3-pyridyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.7.4); 2-(2-adamantyl)-N-[2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 1.8); 2-tert-butyl-N-[(5-chloro-2-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 1.9); N-[[5-(cycloheptylmethylcarbamoyl)-1H-benzoimidazole-2-yl]methyl]carbamate tert-butyl (Compound 1.10); 2-benzyl-N-[(1-methylcyclohexyl)methyl]-1H-benzimidazole-5-carboxamide (compound 1.10.1); 2-benzyl-N-(cyclooctylmethyl)-1H-benzimidazole-5-carboxamide (compound 1.10.2); N-[[1-[2-[(2-benzyl-1H-benzimidazole-5-yl)amino]-2-oxo-ethyl]cyclohexyl]methyl]carbamate tert-butyl (compound 2.1); N-(2-benzyl-1H-benzimidazole-5-yl)-2-(4,4-difluorocyclohexyl)acetamide (compound 2.1.1); N-[1-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]-2-methoxyethyl]carbamate tert-butyl (compound 2.2); N-[(R)-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]-phenyl-methyl]-N-methylcarbamate tert-butyl compound 2.2.1; N-[(S)-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]-phenyl-methyl]-N-methylcarbamate tert-butyl (compound 2.2.2); N-[[6-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]methyl]-N-ethyl-carbamate tert-butyl (compound 2.2.3); N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]methyl]-N-(2-methoxyethyl)carbamate tert-butyl (compound 2.2.4); 2-(2-adamantyl)-N-[2-(2-methoxyethyl)-3H-benzimidazole-5-yl]acetamide (compound 2.2.5); 2-(2-adamantyl)-N-[2-(3-methoxypropyl)-1H-benzimidazole-5-yl]acetamide (compound 2.2.6); N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]methyl]-N-methylcarbamate tert-butyl (compound 2.3); N-(cycloheptylmethyl)-2-(2,3-dihydrobenzofuran-3-yl)-1H-benzimidazole-5-carboxamide (compound 2.4); 2-(2-adamantyl)-N-[2-[hydroxy(phenyl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 2.5); 2-Cyclohexyl-N-(2-phenyl-1H-benzimidazole-5-yl)acetamide (compound 3.1); N-(cycloheptylmethyl)-7-fluoro-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 3.3); N-(cycloheptylmethyl)-6-fluoro-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 3.3.1); N-(cycloheptylmethyl)-4-fluoro-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 3.3.2); N-[2-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazole-2-yl]ethyl]carbamate tert-butyl (compound 3.4); 2-(2-adamantyl)-N-[2-[(3,5-dimethylisoxazole-4-yl)methyl]-1H-benzimidazole-5-yl]acetamide (compound 3.4.1); 2-benzyl-N-(2,2-dimethylpropyl)-1H-benzimidazole-5-carboxamide (compound 3.5); 2-benzyl-N-(1,1,2,2-tetramethylpropyl)-1H-benzimidazole-5-carboxamide (compound 3.5.1); and These salts and solvates A compound selected from among them.

2. N-(2-benzyl-1H-benzimidazole-5-yl)-2-cyclohexyl-acetamide; 2-benzyl-N-(cyclohexylmethyl)-1H-benzimidazole-5-carboxamide; and These salts and solvates A compound according to claim 1, selected from the following.

3. A pharmaceutical agent for the treatment or prevention of diseases and symptoms affected by the regulation of TMEM16A, comprising an effective amount of the compound described in claim 1.

4. The pharmaceutical product according to claim 3, wherein the diseases and symptoms affected by the regulation of TMEM16A are selected from respiratory diseases and symptoms, dry mouth (xerostomia), hypermotility, cholestasis, and ocular symptoms.

5. A pharmaceutical product according to claim 4, The aforementioned respiratory diseases and symptoms are selected from cystic fibrosis; chronic obstructive pulmonary disease (COPD); chronic bronchitis; emphysema; bronchiectasis including non-cystic fibrosis bronchiectasis; asthma and primary ciliary dysfunction, and / or Dry mouth (xerostomia) caused by Sjögren's syndrome, radiation therapy, or xerogenic drugs, and / or Excessive bowel motility is associated with gastric indigestion, gastroparesis, chronic constipation, or irritable bowel syndrome, and / or The eye symptoms are due to dry eye disease. Pharmaceuticals.

6. A pharmaceutical composition comprising the compound described in claim 1 and a pharmaceutically acceptable additive.

7. The pharmaceutical composition according to claim 6, further comprising an additional activator useful for the treatment or prevention of respiratory symptoms, as a combination preparation for simultaneous, sequential, or separate use in the treatment of diseases or symptoms affected by the modification of TMEM16A.

8. The pharmaceutical composition according to claim 7, wherein the additional activator is β2 adrenergic receptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, orodaterol, vilanterol, and avesiderol; Antihistamines, such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine, and chlorpheniramine, are histamine H2. １ Receptor antagonist or H ４ Receptor antagonist; Dornase alpha; Corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, and fluticasone furoate; Leukotriene antagonists such as montelukast and zaphirlukast; Anticholinergic compounds, particularly muscarinic antagonists such as ipratropium, tiotropium, glycopyrrolate, acridinium, and umeclidinium; CFTR repair therapies such as Ibacaftol, QBW251, Bamacaftol (VX659), Elexacaftol (VX445), VX561 / CPT-656, VX152, Olacaftol (VX440), GLP2737, GLP2222, GLP2451, PTI438, PTI801, PTI808, FDL-169 and FDL-176 (e.g., CFTR enhancers, correctors or amplifiers), as well as CFTR correctors such as Lumacaftol and Tezacaftol, or combinations thereof (e.g., combinations of Ibacaftol, Tezacaftol and Elexacaftol); ENaC modulators, particularly ENaC inhibitors such as amiloride, VX-371, AZD5634, QBW276, SPX-101, BI443651, BI1265162 and ETD001, and cations selected from the following: 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)ethyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-6-{[2-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-yl)ethyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-5-[4-({bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}methyl)piperidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-6-[(3R)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-6-[(3S)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-1,3-diethyl-6-{[(1r,4r)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazole-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazine-2-yl}formamide)methyl]-1,3-diethyl-6-{[(1s,4s)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazole-3-ium and suitable anions, such as halides, sulfates, nitrates, phosphates, formates, acetates, trifluoroacetates, fumarates, citrates, tartrates, oxalates, succinates, mandelates, methanesulfonates, or p-toluenesulfonates. Compounds having; Antibiotics; Antiviral agents such as ribavirin and neuraminidase inhibitors such as zanamivir; Antifungal agents such as PUR1900; Hypertonic saline and mannitol (bronchitol®), and other airway hydration agents (osmotic regulators); and Mucolytic agents such as N-acetylcysteine A pharmaceutical composition selected from the following.

9. A compound selected from the above, or an enantiomer or pharmaceutically acceptable salt thereof.

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