Compounds for treating respiratory diseases

Abstract

General formula (I) TIFF2022535980000230.tif43170 (wherein (AA) represents a single bond or a double bond, R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , X 5 , Y, and Z are as defined herein. The compounds of formula (I), and their tautomers, all enantiomeric and isotopic variants, and salts and solvates thereof, are useful in the treatment of respiratory disorders and other diseases and conditions modulated by TMEM16A.

Description

[Technical Field]

[0001] The present invention relates to compounds, including certain novel compounds, that have activity as positive modulators of the calcium-activated chloride channel (CaCC), TMEM16A. The invention also relates to methods for preparing the compounds and pharmaceutical compositions containing them, and to the use of these compounds in treating diseases and conditions modulated by TMEM16A, particularly respiratory diseases and conditions. [Background technology]

[0002] Humans can inhale up to 12,000 L of air each day, potentially introducing airborne pathogens (e.g., bacteria, viruses, and fungal spores) into the respiratory tract. To protect against these airborne pathogens, the lungs have evolved innate defense mechanisms to minimize the likelihood of respiratory tract infection and colonization. One such mechanism is the mucus clearance system, whereby secreted mucus is pushed up and expelled from the airways by coordinated ciliary beating in conjunction with cough clearance. This continuous lung "cleaning" constantly removes inhaled particles and microorganisms, reducing the risk of infection.

[0003] In recent years, it has become clear that the hydration of the mucus gel is important to enable mucus clearance (Boucher 2007; Matsui et al., 1998). In normal, healthy airways, the mucus gel is typically 97% water and 3% w / v solids, under which conditions mucus is cleared by mucociliary action. Airway mucosal hydration is regulated by the coordinated activity of many ion channels and transporters. Anion (Cl) transport is mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride conductance (CaCC; TMEM16A). - / HCO3 - ) secretion balance and epithelial Na + Na via the ENaC channel +Absorption determines the hydration state of the airway mucosa: as ions are transported across the epithelium, water is forced to follow osmotically, resulting in fluid secretion or absorption.

[0004] In respiratory diseases such as chronic bronchitis and cystic fibrosis, the % solids content of the mucus gel increases as hydration decreases and mucus clearance is reduced (Boucher, 2007). In cystic fibrosis, where loss-of-function mutations in CFTR impair the airway's ability to secrete fluid, the % solids content can increase to 15%, which is thought to contribute to small airway obstruction and failure of mucus clearance. Strategies to increase airway mucus hydration include stimulating anions and thereby fluid secretion or Na + To this end, stimulating TMEM16A channel activity increases anion secretion, increases fluid accumulation in the airway mucosa, hydrates mucus, and enhances mucus clearance mechanisms.

[0005] TMEM16A, also known as anoctamin-1 (Ano1), is the molecular identity of a calcium-activated chloride channel (Caputo et al., 2008; Yang et al., 2008). TMEM16A channels open in response to elevated intracellular calcium levels, allowing bidirectional flux of chloride, bicarbonate, and other anions across the plasma membrane. Functionally, TMEM16A channels have been proposed to regulate transepithelial ion transport, gastrointestinal peristalsis, nociception, and cell migration / proliferation (Pedemonte & Galietta, 2014).

[0006] TMEM16A channels are expressed by epithelial cells in various organs, including the lung, liver, kidney, pancreas, and salivary glands. In the airway epithelium, TMEM16A is expressed at high levels in mucus-producing goblet cells, ciliated cells, and submucosal glands. Physiologically, TMEM16A is activated by stimuli that mobilize intracellular calcium, particularly purinergic agonists (ATP, UTP), which are released from the respiratory epithelium in response to cyclic shear stress caused by breathing and other mechanical stimuli, such as coughing. In addition to increasing anion secretion, which promotes airway hydration, TMEM16A activation plays an important role in bicarbonate secretion. Bicarbonate secretion is a key regulator of mucus properties and has been reported to control airway luminal pH and, therefore, the activity of natural antibacterial agents such as defensins (Pezzulo et al., 2012).

[0007] Indirect modulation of TMEM16A via elevated intracellular calcium has been investigated clinically (Kunzelmann & Mall, 2003). Although promising initial results were observed in small patient cohorts, this approach failed to provide clinical benefit in larger patient cohorts (Accurso et al., 2011; Kellerman et al., 2008). This lack of clinical efficacy was attributed solely to transient increases in anion secretion, the short half-life of denufosol at epithelial surfaces, and the resulting desensitization of receptors / pathways, as well as undesirable effects of elevated intracellular calcium (e.g., increased mucus release from goblet cells) (Moss, 2013). Compounds that act directly on TMEM16A and enhance channel opening at low levels of elevated calcium are expected to durably enhance anion secretion and mucociliary clearance in patients, improving innate defenses. Because TMEM16A activity is independent of CFTR function, positive modulators of TMEM16A may have clinical benefit in all CF patients and non-CF respiratory diseases characterized by mucus congestion, such as chronic bronchitis and severe asthma.

[0008] Modulation of TMEM16A has been implicated as a treatment for dry mouth (xerostomia) resulting from salivary gland dysfunction, dry eye, cholestasis, and gastrointestinal motility disorders in Sjogren's syndrome and radiation therapy.

[0009] Our application, PCT / GB2019 / 050209, relates to compounds that are positive modulators of TMEM16A and therefore have use in the treatment of diseases and conditions in which regulation of TMEM16A plays a role, particularly respiratory diseases and conditions. Summary of the Invention

[0010] The present inventors have developed additional compounds that are positive modulators of TMEM16A. In a first aspect of the present invention, there is provided a compound of general formula (I), including all tautomeric forms, all enantiomeric and isotopic variants: TIFF0007797206000001.tif31170[In the formula, TIFF0007797206000002.tif9170 represents a single or double bond; X 1 is N and X 3 is NH and X 2 and X 4 is C, a, c and d are single bonds, and b and e are double bonds; or X 1 is NH and X 3 is N and X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds; or X 1 is N and X 2 is N and X 3 is CR 3 or CN(R 3a )(R 3b ) and X 4 is C, b, c and e are single bonds, and a and d are double bonds; Each R 3 , R 3a , and R 3bare independently H or methyl; or X 1 is N and X 3 is O and X 2 and X 4 is C, a, c and d are single bonds, b and e are double bonds; X 1 and X 4 is N and X 2 is C and X 3 is CH, a and c are double bonds, and b, d and e are single bonds; X 1 is O and X 3 is N and X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds; X 5 is CH or N; R 1 teeth, i.-OR 5 , but X 2 is not N; (R 5 is a 5- or 6-membered carbocyclyl or heterocyclyl group optionally substituted with OH; or ii.CH(R 7 )-N(R 8 )-C(O)OR 9 R 7 is H, phenyl, or OH and O(C 1~4 C optionally substituted with one or more substituents selected from 1~3 is alkyl; R 8 is H, methyl, or C optionally substituted with one or more substituents selected from OH and methoxy; 2~3 is alkyl; R 9 is C optionally substituted with one or more substituents selected from halo, OH and methoxy; 1~4 is alkyl; or R 7 and R 8optionally include, in combination with the atom to which they are attached, further heteroatoms selected from N, O and S, and C 1~3 forming a 5- or 6-membered heterocycle optionally substituted with alkyl; or iii.CH(R 7 )-N(R 8 )-C(O)N(R 9 )(R 10 ); R 7 , R 8 and R 9 is as defined above, and R 10 is H or methyl; or iv.CH(R 11 )(R 12 ); R 11 is H, methyl, CH2OR 13 , OR 13 or N(R 13 )(R 14 ) and; Each R 13 and R 14 are independently H or methyl; R 12 teeth a 5- or 6-membered carbocyclyl or oxygen-containing heterocyclyl ring, said carbocyclyl or heterocyclyl ring optionally substituted with OH; and a 6-membered aryl or 6-membered heteroaryl ring optionally substituted with one or more substituents selected from OH; methoxy; chloro; fluoro; halo, OH, and CN; 1~6 the aryl or heteroaryl ring optionally substituted with one or more substituents selected from alkyl; 3- to 6-membered cycloalkyl or heterocyclyl groups optionally substituted with one or more substituents selected from halo, OH, CN, and C optionally substituted with one or more substituents selected from halo, OH, and CN; 1~6 the cycloalkyl or heterocyclyl group optionally substituted with one or more substituents selected from alkyl; and C 1~4 5-membered heteroaryl groups optionally substituted with one or more substituents selected from alkyl and halo; or R 12 When is a 6-membered aryl or heteroaryl ring, R 12 The substituent of R 11 and together with the atoms to which they are attached form said 6-membered aryl or heteroaryl ring R 12 forms a 5- or 6-membered ring fused to C 1~3 optionally substituted with alkyl; or v. Phenyl, OR 15 and N(R 15 )(R 16 C optionally substituted with one or more substituents selected from 2~6 alkyl; Each R 15 and R 16 are independently H or C 1~3 - alkyl; or vi. OH, CN, halo, and C optionally substituted with one or more substituents selected from halo, OH, and CN 1~4 a 3- to 8-membered cycloalkyl ring optionally substituted with one or more substituents selected from alkyl; Z is a linker selected from -NH-C(O)- and -C(O)-NH-; Y is -CH2- or -CH(CH3)-; R 2 is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, or a 3- to 10-membered carbocyclic ring system, wherein said aryl, heteroaryl, or carbocyclic ring system is optionally substituted with one or more substituents selected from fluoro; chloro; CN; nitro; OH; halo, OH, and CN. 1~6 alkyl; O(C) optionally substituted with one or more substituents selected from halo, OH, and CN; 1~6 alkyl), and NH—C(O)OC optionally substituted with one or more substituents selected from halo and OH. 1~6 optionally substituted with one or more substituents selected from alkyl; or Y and R 2 are both groups -CH2-C(R 17 )(R 18 )-CH2-N(R 19)-C(O)OR 20 Forming; Each R 17 , R 18 and R 19 are independently H or C 1~4 alkyl or R 18 and R 19 combine together with the atoms to which they are attached to form C 1~3 forming a 5- or 6-membered heterocyclyl ring optionally substituted with alkyl; R 20 is C optionally substituted with one or more halo substituents 1~6 is alkyl; or Y and R 2 are both C substituted with one or more substituents selected from halo, OH, and CN. 3~10 forming an alkyl group; or Y and R 2 are both halo, OH, CN, and C optionally substituted with one or more substituents selected from halo, OH, and CN. 1~6 forming a 3- to 8-membered carbocyclic ring optionally substituted with one or more substituents selected from alkyl; however, IX 1 is N and X 3 is NH and X 2 and X 4 When is C, a, c and d are single bonds, and b and e are double bonds: AR 1 is CH(R 11 )(R 12 ) and R 11 is H or methyl, and R 12 When is unsubstituted or phenyl substituted with one or two substituents, said substituents being selected from halo and methoxy: iR 2 is not phenyl or heteroaryl, and said phenyl or heteroaryl is selected from halo, C 1~4 Alkyl, C 1~4 optionally substituted with one or two substituents selected from alkoxy and a 5-membered heteroaryl ring; ii.Y and R 2are combined to form a 3- to 8-membered cycloalkyl ring optionally substituted with methyl; or C optionally substituted with CN. 3~10 Does not form alkyl groups BR 1 is CH(R 11 )(R 12 ) if R 12 is phenyl and R 11 is R 12 and the atoms to which they are attached combine to form the phenyl ring R 12 forming a 5- or 6-membered ring fused to C 1~3 Optionally substituted with alkyl: iR 2 is not phenyl or heteroaryl, and said phenyl or heteroaryl is selected from halo, C 1~4 Alkyl, C 1~4 Haloalkyl and C 1~4 optionally substituted with 1, 2, or 3 substituents selected from alkoxy; ii.Y and R 2 is a C substituted with CN in combination 3~10 Does not form alkyl; CR 1 is CH(R 11 )(R 12 ) and R 11 is H and R 12 If is cyclohexyl: R 2 is not phenyl optionally substituted with 1, 2, or 3 substituents selected from halo, methyl, methoxy; unsubstituted 5-8 membered heteroaryl; DR 1 C optionally substituted with a single substituent selected from OH and phenyl 2~6 If it is alkyl: R 2 is not phenyl or 5-10 membered heteroaryl, any of which is optionally substituted with one or two substituents, said substituents being halo, methyl, trifluoromethyl, O(C 1~4 alkyl) or a 5-membered heteroaryl ring; ER 1When is an unsubstituted 3- to 8-membered cycloalkyl ring: R 2 is halo, OH, methyl, trifluoromethyl, O(C 1~4 is not phenyl optionally substituted with one substituent selected from alkyl) or a 5-membered heteroaryl ring; II.X 1 is N and X 2 is N and X 3 is CR 3 or CN(R 3a )(R 3b ) and X 4 is C; b, c, and e are single bonds, a and d are double bonds; and each R 3 , R 3a and R 3b When are independently H or methyl: AR 1 is CH(R 11 )(R 12 ) and R 11 is H and R 12 When is phenyl unsubstituted or substituted with one or two substituents selected from halo and methoxy: R 2 is not phenyl optionally substituted with one halo substituent; BR 1 C optionally substituted with phenyl 2~6 If it is alkyl: R 2 is not phenyl or naphthyl optionally substituted with one or two substituents selected from halo, methoxy, and a 5-membered heteroaryl group; III.X 1 is N and X 3 is O and X 2 and X 4 When is C, a, c and d are single bonds, and b and e are double bonds: AR 1 is CH(R 11 )(R 12 ) and R 11 is H and R 12When is phenyl unsubstituted or substituted with one or two substituents selected from halo and methoxy: iR 2 is not phenyl or heteroaryl, and said phenyl or heteroaryl is selected from halo, C 1~4 Alkyl, C 1~4 optionally substituted with one or two substituents selected from alkoxy and 5-membered heteroaryl groups; ii.Y and R 2 is C substituted with one or more substituents selected in combination from halo and OH 3~10 does not form an alkyl group, BR 1 is CH(R 11 )(R 12 ) and R 12 is phenyl and R 12 The substituent of R 11 and together with the atoms to which they are attached form a 6-membered aryl or heteroaryl ring R 12 forms a 5- or 6-membered ring fused to C 1~3 When optionally substituted with alkyl; Y and R 2 C substituted with one or more halo substituents in combination 3~10 Does not form alkyl; IV.X 1 is O and X 3 is N and X 2 and X 4 is C, a, b and d are single bonds, c and e are double bonds; R 1 is CH(R 11 )(R 12 ) and R 11 is H and R 12 When is phenyl unsubstituted or substituted with one or two substituents selected from halo and methoxy: iR 2 is not phenyl or heteroaryl, and said phenyl or heteroaryl is selected from halo, C 1~4 Alkyl, C 1~4optionally substituted with 1, 2, or 3 substituents selected from alkoxy and 5-membered heteroaryl groups; ii.Y and R 2 are combined to form an unsubstituted 3- to 8-membered cycloalkyl ring; or C optionally substituted with one or more substituents selected from halo and OH. 3~10 does not form an alkyl group] and salts and solvates thereof.

[0011] In some suitable compounds of general formula (I): X 1 is N and X 2 is N and X 3 is CR 3 or CN(R 3a )(R 3b ) and X 4 is C; b, c, and e are single bonds, a and d are double bonds; and each R 3 , R 3a and R 3b When are independently H or methyl: AR 1 is CH(R 11 )(R 12 ) and R 11 is H and R 12 When is phenyl unsubstituted or substituted with one or two substituents selected from halo and methoxy: R 2 is not phenyl optionally substituted with one halo substituent; BR 1 C optionally substituted with phenyl 2~6 If it is alkyl: R 2 is not phenyl, thienyl or naphthyl optionally substituted with one or two substituents selected from halo, methoxy, and 5-membered heteroaryl groups.

[0012] The compounds of general formula (I) are modulators of TMEM16A and are therefore useful in the treatment or prevention of diseases and conditions affected by the modulation of TMEM16A.

[0013] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated integer or step, or group of integers or steps, but not the exclusion of any other integer or step, or group of integers or groups of steps.

[0014] As used herein, reference to "medical use" refers to use for administration to humans or animals, particularly humans or mammals, such as domestic animals or domestic mammals, for the treatment or prevention of a disease or condition. The term "pharmaceutical composition" refers to a composition suitable for medical use, and "pharmaceutically acceptable" refers to an agent suitable for use in a pharmaceutical composition. Other similar terms should be construed accordingly.

[0015] As used herein, "C 1~6 The term alkyl refers to a straight-chain or branched, fully saturated hydrocarbon group having from 1 to 6 carbon atoms. This term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. Other alkyl groups, such as C 1~10 Alkyl is as defined above but containing a different number of carbon atoms.

[0016] The terms "carbocyclic" and "carbocyclyl," unless otherwise specified, refer to a non-aromatic hydrocarbon ring system containing 3 to 10 ring carbon atoms and, optionally, one or more double bonds. A carbocyclic group may be a single ring or may contain two or three rings, which may be fused or bridged, with the carbon atoms in the bridge 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.

[0017] In the context of this specification, the terms "heterocyclic" and "heterocyclyl," unless otherwise specified, refer to a non-aromatic ring system containing 3 to 10 ring atoms, including at least one heteroatom selected from N, O, and S. A heterocyclic group can be a single ring, or it can contain two or three rings, which can be fused or bridged, and the bridging atom is included in the number of ring atoms. Examples include tetrahydrofuran, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and thiomorpholinyl, as well as fused systems such as cyclopropyl-fused pyrrolidine. A reference to an oxygen-containing heterocycle includes both rings in which the only heteroatom is oxygen, e.g., tetrahydrofuran and tetrahydrofuran, and rings in which an additional heteroatom selected from N and S is present, e.g., morpholine.

[0018] In the context of this specification, the terms "aryl" and "aromatic," unless otherwise specified, refer to a ring system having aromatic character, having 5 to 14 ring carbon atoms and containing up to three rings. When an aryl group contains multiple rings, not all rings need to be fully aromatic. Examples of aromatic moieties include benzene, naphthalene, fluorene, tetrahydronaphthalene, indene, and indene.

[0019] In the context of this specification, the terms "heteroaryl" and "heteroaromatic," unless otherwise specified, refer to a ring system having aromatic character having 5 to 14 ring atoms, at least one of which is a heteroatom selected from N, O, and S, and including up to three rings. When a heteroaryl group contains multiple rings, not all of the rings need be aromatic. Examples of heteroaryl groups include pyridine, pyrimidine, indole, indazole, thiophene, benzothiophene, benzoxazole, benzofuran, dihydrobenzofuran, tetrahydrobenzofuran, benzimidazole, benzimidazoline, quinoline, and indolene.

[0020] The term "oxo" refers to a C=O substituent, where the carbon atom is a ring atom of a carbocyclyl, heterocyclyl group, or a ring of an aryl or heteroaryl group that is not aromatic.

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

[0022] As used herein, "C 1~6 The term "haloalkyl" refers to a C group, as defined above, in which one or more hydrogen atoms are replaced by a halo group. 1=6 This refers to an alkyl group. Any number of hydrogen atoms can be substituted, up to perhalo substitution. Examples include trifluoromethyl, chloroethyl, and 1,1-difluoroethyl. A fluoroalkyl group is a haloalkyl group where the halo is fluoro.

[0023] The term "isotopic variant" refers to a compound identical to that described in formula (I), but is isotopically labeled due to the fact that one or more atoms are replaced by atoms with an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature, or the proportion of atoms with an atomic mass or mass number less commonly found in nature is increased (the latter concept is referred to as "isotopic enrichment"). Examples of isotopes that can be incorporated into the compounds of the present invention include 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), which may be naturally occurring or non-naturally occurring isotopes.

[0024] In an alternative embodiment of the present invention, there is provided a compound of general formula (Ix), including all tautomeric forms, all enantiomeric and isotopic variants thereof: TIFF0007797206000003.tif31170 (in the formula, TIFF0007797206000004.tif7170 represents a single or double bond; X 1 is N and X 3 is NH and X 2 and X 4 is C, a, c and d are single bonds, and b and e are double bonds; or X 1 is NH and X 3 is N and X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds; or X 1 is N and X 2 is N and X 3 is CR 3 or CN(R 3a )(R 3b ) and X 4 is C, b, c and e are single bonds, and a and d are double bonds; Each R 3 , R 3a , and R 3b are independently H or methyl; or X 1 is N and X 3 is O and X 2 and X 4 is C, a, c and d are single bonds, b and e are double bonds; X 1 and X 4 is N and X 2 is C and X 3 is CH, a and c are double bonds, and b, d and e are single bonds; X 1 is O and X 3 is N and X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds; X 5 is CH or N; R 1 teeth, i.-OR 5 or N(R5 )(R 6 ), but X 2 is not N; (R 5 is a 5- or 6-membered carbocyclyl or heterocyclyl group optionally substituted with OH; R 6 is H, methyl or ethyl); or ii.CH(R 7 )-N(R 8 )-C(O)OR 9 R 7 is H, phenyl, or OH and O(C 1~4 C optionally substituted with one or more substituents selected from 1~3 is alkyl; R 8 is H, methyl, or C optionally substituted with one or more substituents selected from OH and methoxy; 2~3 is alkyl; R 9 is C optionally substituted with one or more substituents selected from halo, OH and methoxy; 1~4 is alkyl; or R 7 and R 8 optionally include, in combination with the atom to which they are attached, further heteroatoms selected from N, O and S, and C 1~3 forming a 5- or 6-membered heterocycle optionally substituted with alkyl; or iii.CH(R 7 )-N(R 8 )-C(O)N(R 9 )(R 10 ); R 7 , R 8 and R 9 is as defined above, and R 10 is H or methyl; or iv.CH(R 11 )(R 12 ); R 11 is H, methyl, CH2OR 13 , OR 13 or N(R13 )(R 14 ) and; Each R 13 and R 14 are independently H or methyl; R 12 is a 5- or 6-membered carbocyclyl or heterocyclyl ring optionally substituted with OH; or is a 5- or 6-membered carbocyclyl or heterocyclyl ring optionally substituted with OH, methoxy, chloro, fluoro and C 1~3 a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from alkyl; or C 1~4 a 5-membered heteroaryl group optionally substituted with one or more substituents selected from alkyl and halo; or R 12 When is a 6-membered aryl or heteroaryl ring, R 12 The substituent of R 11 and together with the atoms to which they are attached form a 6-membered aryl or heteroaryl ring R 12 forms a 5- or 6-membered ring fused to C 1~3 optionally substituted with alkyl; or v. Phenyl, OR 15 and N(R 15 )(R 16 C optionally substituted with one or more substituents selected from 2~4 alkyl; (Each R 15 and R 16 are independently H or C 1~3 - alkyl); Z is a linker selected from -NH-C(O)- and -C(O)-NH-; Y is -CH2- or -CH(CH3)-; R 2 is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered carbocyclic ring system, any of which may be fluoro, chloro, CN, nitro, OH, C 1~6 Alkyl C 1-6 Haloalkyl, O(C 1~6 alkyl), O(C 1~6 haloalkyl) and NH-C(O)OC1~6 optionally substituted with one or more substituents selected from alkyl; or Y and R 2 are both groups -CH2-C(R 17 )(R 18 )-CH2-N(R 19 )-C(O)OR 20 Forming; (Each R 17 , R 18 and R 19 are independently H or C 1~4 alkyl or R 18 and R 19 combine together with the atoms to which they are attached to form C 1~3 forming a 5- or 6-membered heterocycle optionally substituted with alkyl; R 20 is C optionally substituted with one or more halo substituents 1~6 alkyl); or Y and R 2 are both unsubstituted C 5~10 Forms an alkyl group; provided that: (i)R 1 is arbitrarily substituted C as defined above 2~4 If it is alkyl, R 2 is not an optionally substituted aryl or heteroaryl as defined above; (ii)R 1 is CH(R 11 )(R 12 ), then R 11 is H or methyl, and R 12 is phenyl or cyclohexyl, either of which is optionally substituted as defined above; R 2 is not an optionally substituted aryl or heteroaryl as defined above; Y and R 2 combines to form C 5~10 (does not form alkyl groups) and salts and solvates thereof.

[0025] More suitably, there is provided a compound of general formula (I) or (Ix) as defined above, provided that: R 1 but 2~6 If it is alkyl, R 2 is not an optionally substituted aryl or heteroaryl as defined above; R 1 is CH(R 11 )(R 12 ), then R 11 is H or methyl; R 2 is not an optionally substituted aryl or heteroaryl as defined above; and / or Y and R 2 are combined and substituted as defined above 5~10 It does not form an alkyl group.

[0026] Suitably, there is provided a compound of general formula (I) or (Ix) as defined above, provided that: R 1 but 2~6 If it is alkyl, R 2 is not an optionally substituted aryl or heteroaryl as defined above; R 1 is CH(R 11 )(R 12 ), then R 11 is H or methyl; R 2 is not an optionally substituted aryl or heteroaryl as defined above; and / or Y and R 2 are combined and substituted as defined above 5~10 It does not form an alkyl group.

[0027] Alternatively, there is provided a compound of general formula (I) or (Ix) as defined above, provided that: R 1 but 2~4 If it is alkyl, R 2is not an optionally substituted aryl or heteroaryl as defined above; R 1 is CH(R 11 )(R 12 ), then R 11 is H or methyl; R 2 is not an optionally substituted aryl or heteroaryl as defined above; and / or Y and R 2 are combined and substituted as defined above 5~10 It does not form an alkyl group.

[0028] In some suitable compounds of general formula (I) and (Ix): X 1 is N and X 3 is NH and X 2 and X 4 is C, a, c and d are single bonds, and b and e are double bonds; or X 1 is NH and X 3 is N and X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds; or X 1 is N and X 2 is N and X 3 is CR 3 or CN(R 3a )(R 3b ) and X 4 is C, b, c and e are single bonds, and a and d are double bonds; Each R 3 , R 3a , and R 3b are independently H or methyl; or X 1 is N and X 3 is O and X 2 and X 4 is C, a, c and d are single bonds, b and e are double bonds; X 1 and X 4is N and X 2 is C and X 3 is CH, a and c are double bonds, and b, d and e are single bonds.

[0029] More appropriately X 1 is N and X 3 is NH and X 2 and X 4 is C, a, c and d are single bonds, and b and e are double bonds; or X 1 is NH and X 3 is N and X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds; or X 1 is N and X 2 is N and X 3 is CR 3 or CN(R 3a )(R 3b ) and X 4 is C, b, c and e are single bonds, and a and d are double bonds; Each R 3 , R 3a , and R 3b are independently H or methyl.

[0030] Particularly suitable compounds of general formula (I) are: X 1 is N and X 3 is NH and X 2 and X 4 is C, a, c and d are single bonds, b and e are double bonds; or a tautomer thereof X 1 is NH and X 3 is N and X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds.

[0031] In some compounds of general formula (I): R1 is arbitrarily substituted C as defined above 2~4 If it is alkyl, R 2 is not an optionally substituted aryl or heteroaryl as defined above; R 1 is CH(R 11 )(R 12 ), then R 11 is H or methyl, and R 12 is phenyl or cyclohexyl, either of which is optionally substituted as defined above; R 2 is not an optionally substituted aryl or heteroaryl as defined above; and / or Y and R 2 are combined and substituted as defined above 5~10 It does not form an alkyl group.

[0032] In other compounds of general formula (I): R 1 but 2~4 If it is alkyl, R 2 is not an optionally substituted aryl or heteroaryl as defined above; R 1 is CH(R 11 )(R 12 ), then R 11 is H or methyl; R 2 is not an optionally substituted aryl or heteroaryl as defined above; Y and R 2 combines to form C 5~10 It does not form an alkyl group.

[0033] The compound of general formula (I) is represented by the general formula (IA): TIFF0007797206000005.tif176170 (in the formula, R 1 , X 5 , Z, Y and R 2 is as defined for general formula (I) or general formula (Ix) The compound may be:

[0034] Compounds of general formula (IA) may also exist in the tautomeric form: It could be TIFF0007797206000006.tif25170.

[0035] In some cases, the compound of general formula (I) is a compound of general formula (IA).

[0036] In some cases, the compound of general formula (I) is a compound of general formula (IB).

[0037] In some cases, the compound of general formula (I) is a compound of general formula (IC).

[0038] In some cases, the compound of general formula (I) is a compound of general formula (ID).

[0039] In some cases, the compound of general formula (I) is a compound of general formula (IE).

[0040] The present invention also provides: R 1 , X 5 , Z, Y and R 2 is as defined for general formula (I) or general formula (Ix), with the proviso that: AR 1 is CH(R 11 )(R 12 ) if R 11 is H or methyl, and R 12 is phenyl unsubstituted or substituted with one or two substituents, the substituents being selected from halo and methoxy: iR 2 is not phenyl or heteroaryl, and said phenyl or heteroaryl is selected from halo, C 1~4 Alkyl, C 1~4 optionally substituted with one or two substituents selected from alkoxy and a 5-membered heteroaryl ring; ii.Y and R 2are combined to form a 3- to 8-membered cycloalkyl ring optionally substituted with methyl; or C substituted with CN 3~10 Does not form alkyl groups BR 1 is CH(R 11 )(R 12 );R 11 is H and R 12 is phenyl and R 12 The substituent of R 11 and together with the atoms to which they are attached form a 6-membered aryl or heteroaryl ring R 12 forms a 5- or 6-membered ring fused to C 1~3 When optionally substituted with alkyl; iR 2 is not phenyl or heteroaryl, and said phenyl or heteroaryl is selected from halo, C 1~4 Alkyl, C 1~4 Haloalkyl and C 1~4 optionally substituted with 1, 2, or 3 substituents selected from alkoxy; ii.Y and R 2 is a C substituted with CN in combination 3~10 Does not form alkyl; CR 1 is CH(R 11 )(R 12 ) and R 11 is H and R 12 If is cyclohexyl: R 2 is not phenyl optionally substituted with 1, 2, or 3 substituents, the substituents being selected from halo, methyl, methoxy; unsubstituted 5-8 membered heteroaryl; DR 1 C optionally substituted with a single substituent selected from OH and phenyl 2~6 If it is alkyl: R 2 is not phenyl or 5-10 membered heteroaryl, any of which is optionally substituted with one or two substituents, the substituents being halo, methyl, trifluoromethyl, O(C 1~4 alkyl) or a 5-membered heteroaryl ring; ER 1 When is an unsubstituted 3- to 8-membered cycloalkyl ring: R 2 is halo, OH, methyl, trifluoromethyl, O(C 1-4 is not phenyl optionally substituted with one substituent selected from alkyl) or a 5-membered heteroaryl ring; R 1 , X 5 , Z, Y and R 2 is as defined for general formula (I) or general formula (Ix), with the proviso that: AR 1 is CH(R 11 )(R 12 ) and R 11 is H and R 12 When is phenyl unsubstituted or substituted with one or two substituents selected from halo and methoxy: R 2 is not phenyl optionally substituted with one halo substituent; BR 1 C optionally substituted with phenyl 2~6 If it is alkyl, R 2 is not phenyl, thienyl or naphthyl optionally substituted with one or two substituents selected from halo, methoxy, and 5-membered heteroaryl groups; R 1 , X 5 , Z, Y and R 2 is as defined for general formula (I) or general formula (Ix), with the proviso that: R 1 is CH(R 11 )(R 12 ), then R 11 is H or methyl, and R 12 is phenyl optionally substituted as defined above; R 2 is not an optionally substituted aryl or heteroaryl as defined above; R 1, X 5 , Z, Y and R 2 is as defined for general formula (I) or general formula (Ix), with the proviso that: AR 1 is CH(R 11 )(R 12 ) and R 11 is H and R 12 When is phenyl unsubstituted or substituted with one or two substituents selected from halo and methoxy: iR 2 is not phenyl or heteroaryl, and said phenyl or heteroaryl is selected from halo, C 1~4 Alkyl, C 1~4 optionally substituted with one or two substituents selected from alkoxy and 5-membered heteroaryl groups; ii.Y and R 2 is C substituted with one or more substituents selected in combination from halo and OH 3~10 does not form an alkyl group, BR 1 is CH(R 11 )(R 12 ) and R 11 is H and R 12 is phenyl and R 12 The substituents of R 11 and together with the atoms to which they are attached form a 6-membered aryl or heteroaryl ring R 12 forms a 5- or 6-membered ring fused to C 1~3 optionally substituted with alkyl; Y and R 2 C substituted with one or more halo substituents in combination 3~10 Does not form alkyl; Compounds of general formula (ID); and R 1 , X 5 , Z, Y and R 2 is as defined for general formula (I) or general formula (Ix), with the proviso that: iR 2is not phenyl or heteroaryl, and said phenyl or heteroaryl is selected from halo, C 1~4 Alkyl, C 1~4 optionally substituted with 1, 2, or 3 substituents selected from alkoxy and 5-membered heteroaryl groups; ii.Y and R 2 are combined to form an unsubstituted 3- to 8-membered cycloalkyl ring; or C substituted with one or more substituents selected from halo and OH. 3~10 It does not form an alkyl group.

[0041] Compounds of general formulae (IA), (IB), (IC) and (ID), in particular compounds of general formulae (IA), (IB) and (IC), more particularly compounds of general formulae (IA) and (IB), are more suitable.

[0042] Compounds of general formula (IA) are particularly suitable.

[0043] Suitably, in the compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) and (IE), X 5 is CH.

[0044] In some compounds of the invention, Z is —NHC(O)—, such that the nitrogen atom is connected to the central ring and C(O) is connected to Y.

[0045] In other compounds of the invention, Z is —C(O)NH—, such that —C(O) is attached to the central ring and the nitrogen atom is attached to Y.

[0046] In some more suitable compounds of the invention, Y is -CH2-.

[0047] In some suitable compounds of the present invention, particularly compounds of general formula (IA), (IC), (ID) and (IE), R 1 is OR 5 In these compounds, R 5is suitably an unsubstituted 5- or 6-membered heterocyclyl group, especially an oxygen-containing heterocyclyl group, suitably tetrahydrofuran or a tetrahydrofuran group, especially tetrahydrofuran, eg tetrahydrofuran-3-yl.

[0048] In other suitable compounds of the invention, R 1 is CH(R 7 )-N(R 8 )-C(O)OR 9 In such compounds, the more suitable group R 7 methoxy-substituted H, phenyl and C 1~3 Alkyl, especially H, phenyl or CH2OCH3 are included.

[0049] R 8 is suitably H, methyl or ethyl optionally substituted with OH or OCH3. 8 Specific examples include H, methyl, ethyl, CH2CH2OCH3, and CH2CH2OH.

[0050] R 9 is suitably C optionally substituted with one or more halo substituents 2~4 More suitably, R 9 is i-propyl or t-butyl, etc. 2~4 Branched alkyl groups or C such as 2,2,2-trifluoroethyl 2~4 It is a haloalkyl group.

[0051] R 7 and R 8 may combine with the atoms to which they are attached to form a 5- or 6-membered heterocyclic ring, optionally containing additional heteroatoms. In this case, the 5- or 6-membered heterocyclic ring is 8 a heterocycle containing only nitrogen atoms bonded to R 8 and one further heteroatom, such as a nitrogen or oxygen atom. The ring thus formed may be a heterocycle containing a nitrogen atom bonded to C 1~3It may be substituted by alkyl, especially methyl or ethyl, but is more suitably unsubstituted. Examples of such rings include pyrrolidine, piperidine, piperazine and morpholine, especially pyrrolidine and morpholine.

[0052] In still other suitable compounds of the invention, R 1 is CH(R 7 )-N(R 8 )-C(O)N(R 9 )(R 10 In these compounds, the more appropriate R 7 , R 8 and R 9 The part is R 1 is CH(R 7 )-N(R 8 )-C(O)OR 9 As defined above for compounds in which R 10 is H or methyl.

[0053] In further compounds of the invention, R 1 is CH(R 11 )(R 12 )

[0054] In some such compounds, R 12 is a 5- or 6-membered carbocyclic or oxygen-containing heterocyclic ring optionally substituted with OH.

[0055] In these compounds, R 11 is suitably H or methyl, more suitably H.

[0056] R 12 is more suitably cyclopentyl or cyclohexyl, or an oxygen-containing 5- or 6-membered heterocycle, optionally containing a further heteroatom, such as tetrahydrofuran, tetrahydrofuran or morpholinyl. Even more suitably, R 12 is cyclopentyl, cyclohexyltetrahydrofuranyl or tetrahydropyranyl.

[0057] As discussed above, R 12 is optionally substituted with OH. Typically, R 12 is unsubstituted or has a single OH substituent. 12 If has a single OH substituent, it is CH(R 11 ) may be located on a ring atom attached to the

[0058] R 1 is CH(R 11 )(R 12 ), in other compounds where R 12 is a 6-membered aryl or heteroaryl ring, the aryl or heteroaryl ring being a C optionally substituted with OH, methoxy, chloro, fluoro, halo, or OH. 1~6 Alkyl and C 1~4 Optionally substituted with one or more substituents selected from a 5-membered heteroaryl group optionally substituted with one or more substituents selected from alkyl and halo.

[0059] More suitably in these compounds, R 11 is H, methyl or methoxy, especially H.

[0060] More appropriately, R 12 is selected from phenyl or pyridyl, e.g., pyridin-3-yl, suitably unsubstituted or optionally substituted with OH, methoxy, fluoro, chloro and OH; 1~4 alkyl; even more suitably substituted with one or more substituents, suitably one, two or three substituents selected from phenyl or pyridyl groups; R 12 is unsubstituted or optionally substituted with OH, methoxy, fluoro, chloro and C 3~4 and substituted with 1, 2 or 3 substituents selected from alkyl.

[0061] In some such compounds, R 12 is unsubstituted phenyl; or R 12is phenyl with a single OH or methoxy substituent at the 2-, 3-, or 4-position of the phenyl ring. 12 is a first substituent selected from OH and methoxy, particularly OH, and halogen, CN, or C optionally substituted with halo, OH, or CN; 1~4 It may be phenyl having one or two further substituents selected from alkyl.

[0062] In some particularly suitable compounds, R 12 is phenyl substituted with a first substituent selected from OH and methoxy, particularly OH; a second substituent selected from fluoro and chloro. In this case, the first substituent may be at the 2-position and the second substituent may be at the 3-, 4-, 5- or 6-position. Even more suitably, R 12 is a phenyl having an OH substituent at the 2-position and a fluoro at the 3-, 4-, 5- or 6-position.

[0063] In alternative particularly suitable compounds, R 12 with a first substituent selected from OH and methoxy, especially OH; with a second substituent selected from fluoro and chloro; C optionally substituted with OH or CN 1~4 Alkyl, but especially C with a single OH substituent 3~4 and a third substituent selected from alkyl. More suitably, R 12 is phenyl having a first substituent that is OH, a second substituent that is fluoro, and a third substituent selected from t-butyl, —C(CH)OH, and —C(CH)CHOH. In some examples, the third substituent is at the 4-position, the fluoro substituent is at the 2-position, and the OH is at the 5-position.

[0064] In a further alternative compound, R 12 with a first substituent selected from OH and methoxy, particularly OH; C optionally substituted with one or more substituents selected from halo, OH and CN 1~6 alkyl; and 3-6 membered cycloalkyl or heterocyclyl optionally substituted with one or more substituents selected from halo, OH, CN, and halo, OH, and CN 1~6 the cycloalkyl or heterocyclyl group optionally substituted with one or more substituents selected from alkyl, and a second substituent selected from phenyl substituted with a second substituent selected from phenyl.

[0065] In this case, more appropriately, the phenyl group R 12 is also substituted with a third substituent selected from chloro and fluoro, particularly fluoro.

[0066] In other such compounds, R 12 is one or more C 1~4 and phenyl substituted with a 5-membered heteroaryl ring optionally substituted with one or two alkyl groups, suitably one or two methyl groups. Suitable 5-membered heteroaryl groups include nitrogen-containing heteroaryl groups such as pyrrole, oxazole, thiazole, and imidazole.

[0067] In other such compounds, R 12 is unsubstituted pyridyl, typically unsubstituted pyridin-3-yl. Alternatively, R 12 is CH(R 11 R is a pyridyl having a single substituent selected from OH, methoxy, fluoro, and chloro at the ring position adjacent to the atom bonded to R. 12 When R is pyridin-3-yl, the substituent may be at the 2-position. 2 is halo, OH, and C optionally substituted with OH 1~4 and pyridyl having 1 to 3 substituents selected from alkyl, for example, C, optionally having a single OH substituent and one or two further substituents selected from OH and halo. 3~4 and pyridyl having a substituent selected from alkyl groups.

[0068] R 1 is CH(R 11 )(R 12) and R 12 is a 6-membered aryl or heteroaryl ring, and R 12 The substituent of R 11 in combination with a 6-membered aryl or heteroaryl ring R 12 When a 5- or 6-membered ring is formed fused to a group CH(R 11 )(R 12 ) is suitably saturated, for example benzofuran, indoline or indane, especially dihydrobenzofuran.

[0069] As mentioned above, R 1 is phenyl, OR 15 and N(R 15 )(R 16 C optionally substituted with one or more substituents selected from 2~6 In more suitable compounds of this type, R 1 is phenyl, OR 15 and N(R 15 )(R 16 C optionally substituted with one or more substituents selected from 2~3 alkyl, and each R 15 and R 16 are independently defined above, but are in particular H or methyl.

[0070] Suitably, the alkyl group R 1 is unsubstituted or is selected from phenyl and OR 15 substituted with one or more substituents, typically a single substituent, selected from 15 is as defined above, but more suitably is H or methyl.

[0071] Alternatively, R 1 is OH, CN, halo, and C optionally substituted with one or more substituents selected from halo and OH; 1~4 It may be a 3- to 8-membered cycloalkyl ring optionally substituted with one or more substituents selected from alkyl. In this case, more suitably, R 1is a 3- to 6-membered ring, or even more suitably a 3- to 4-membered ring optionally substituted with one or more substituents, for example one or two substituents, especially one substituent, as described above. 12 Particularly suitable substituents for the cycloalkyl group include C 1~4 Alkyl and C 1~4 Haloalkyl, even more appropriately C 1~2 Alkyl and C 1~2 Haloalkyl includes, for example, methyl and trifluoromethyl.

[0072] In some suitable compounds of the invention, R 2 is a 3- to 10-membered carbocyclic ring system optionally substituted as defined above.

[0073] In some compounds of this type, R 2 is a bridged carbocyclic ring system such as bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo-[2.2.1]heptanyl, bicyclo-[2.2.2]octanyl or adamantyl, in particular bicyclo-[2.2.1]heptanyl or adamantyl. 2 Particularly suitable are compounds in which R is adamantyl. 2 When is a bridged carbocyclic ring system, it is unsubstituted.

[0074] In other compounds of this type, R 2 is a carbocyclic ring system selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, any of which may be unsubstituted or substituted as defined above. 2 More suitable substituents for the group include OH, fluoro, 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, for example, OH, methyl, methoxy and NHC(O)OC 1~4 Alkyl.

[0075] Appropriately, R 2 When is a carbocyclic ring system as defined above, it is unsubstituted or substituted with a single substituent as defined above, the substituent being suitably located at the carbon atom attached to the moiety Y.

[0076] More appropriately, R 2 is an unsubstituted cyclopentyl, cyclohexyl or cycloheptyl ring, especially unsubstituted cycloheptyl.

[0077] In an alternative, more suitable compound, R 2 Ha, Halo, C 1~4 Alkyl and C 1~4 haloalkyl. Even more suitably, in this case, R 2 is C 1~2 Cyclopropyl substituted with haloalkyl, particularly cyclopropyl substituted with a single trifluoromethyl substituent, in which case the trifluoromethyl can be attached to position 1 of the cyclopropyl ring, i.e., the atom at which the cyclopropyl group is attached to the rest of the molecule.

[0078] In other compounds of the invention, R 2 is a 6-10 membered aryl or 5-10 membered heteroaryl ring system, optionally substituted as defined above. In this case, more suitably, R 2 is phenyl, or fluoro, chloro, OH, C 1~6 alkyl (optionally substituted with one or more substituents selected from OH and halo), O(C 1~6 alkyl), and O(C 1~6 haloalkyl), even more suitably fluoro, chloro, OH, C 1~4 Alkyl, C substituted with OH 1~4 Alkyl, and O(C 1~4 alkyl); especially fluoro, chloro, OH, C 1~4 C substituted with alkyl, OH and methoxy 1~4and alkyl, aryl, arylsulfonyl ...

[0079] In still other compounds of the invention, Y and R 2 are both replaced by C as defined above. 3~10 Forms an alkyl group. In some cases, this is a branched C 5~10 It may be an alkyl group, more suitably a branched alkyl group of the form: CH2C(R 21 )(R 22 )(R 23 ), CH(CH3)C(R 21 )(R 22 )(R 23 ) or C(CH3)2C(R 21 )(R 22 )(R 23 )(In the formula, each R 21 , R 22 and R 23 is C 1~4 Alkyl, except for YR 2 The total number of carbon atoms in the moiety is less than 10, and at least one carbon atom is substituted with one or more substituents selected from halo, OH, and CN.

[0080] In other more suitable compounds of the invention, Y and R 2 and C substituted with one or more substituents as described above. 2~6 Forms an alkyl group. More suitably, C 2~6 The alkyl group is substituted with one or more halo substituents. Even more suitably in this type of compound, Y and R 2 and C substituted with one or more of the above substituents. 3~4 The YR groups form an alkyl group, but are more suitably substituted with one or more halo substituents, particularly one or more fluoro substituents. 2 An example of the group is -CH2-CH2-CF3.

[0081] In even more suitable compounds of the present invention, Y and R 2together form a 3-6 membered carbocyclic ring optionally substituted with one or more substituents as described above. More suitably, Y and R 2 are both optionally substituted as above, more suitably halo, C 1~4 Alkyl, and C 1~4 one or more substituents selected from haloalkyl, particularly a single C 1~2 Form a cyclopropyl or cyclobutyl ring substituted with a haloalkyl substituent (such as trifluoromethyl), in which case the trifluoromethyl can be attached to position 1 of the cyclopropyl ring, i.e., the atom where the cyclopropyl group is attached to the rest of the molecule.

[0082] In still other compounds of the invention, Y and R 2 are both groups -CH2-C(R 17 )(R 18 )-CH2-N(R 19 )-C(O)OR 20 Form each R 17 , R 18 , R 19 and R 20 is as defined above.

[0083] In this case, more appropriately, each R 18 and R 19 are independently H or methyl, especially methyl, or R 18 and R 19 combine with the atoms to which they are attached to form a six-membered heterocyclic ring; R 20 is C 1~6 Alkyl, for example i-propyl, s-butyl or t-butyl.

[0084] Where compatible, the embodiments and preferences described above for compounds of formula (I) also extend to compounds of formula (Ix).

[0085] Specific examples of novel compounds of general formula (I) include: 2-(1-Adamantyl)-N-[2-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide (Compound 1); 2-(1-adamantyl)-N-[2-(tetrahydropyran-2-ylmethyl)-1H-benzimidazol-5-yl]acetamide (compound 1.1); 2-(2-adamantyl)-N-(2-benzyl-1H-benzimidazol-5-yl) (compound 2); 2-(2-adamantyl)-N-[2-(2-phenylethyl)-1H-benzimidazol-5-yl]acetamide (compound 2.1); 2-(2-adamantyl)-N-[2-[methoxy(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 2.2); 2-(2-adamantyl)-N-[2-[(2-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 2.3); 2-(2-adamantyl)-N-[2-[(R)-methylamino(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 3); 2-(1-Adamantyl)-N-[2-[(2-chloro-3-pyridyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 4); 2-(2-adamantyl)-N-[2-[(2-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 5); 2-(2-adamantyl)-N-[2-[(4-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 5.1); 2-(2-adamantyl)-N-[2-[(5-chloro-2-hydroxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 5.2); 2,2,2-trifluoroethyl N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate (compound 6); 2-(1-Adamantyl)-N-[2-[[3-(3,5-dimethylisoxazol-4-yl)phenyl]methyl]-3H-benzimidazol-5-yl]acetamide (compound 7); tert-Butyl N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate (compound 8); 2-(2-adamantyl)-N-(2-tetrahydrofuran-3-yloxy-1H-benzimidazol-5-yl)acetamide (compound 9); N-(cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide (compound 10); 2-(1-adamantyl)-N-[3-amino-2-[(2-hydroxyphenyl)methyl]indazol-6-yl]acetamide (compound 11); 2-Cyclohexyl-N-(2-isopropyl-1,3-benzoxazol-5-yl)acetamide (compound 12); N-(cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]indazole-6-carboxamide (compound 13); 2-(1-Adamantyl)-N-(2-benzyl-3H-imidazo[4,5-c]pyridin-6-yl)acetamide (compound 14); 2-benzyl-N-(cycloheptylmethyl)imidazo[1,2-a]pyridine-7-carboxamide (compound 15); 2-(1-adamantyl)-N-(2-benzylindazol-6-yl)acetamide (compound 16); 2-(1-adamantyl)-N-(2-benzyl-3-methyl-indazol-6-yl)acetamide (compound 17); N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide (compound 18); tert-Butyl N-[3-[(2-benzyl-1H-benzimidazole-5-carbonyl)amino]-2,2-dimethyl-propyl]carbamate (compound 19); 2-tert-butyl-N-(cycloheptylmethyl)-3H-benzimidazole-5-carboxamide (compound 20); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (compound 21); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (compound 21.1); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (compound 21.2); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide (compound 21.3); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1,3-benzoxazole-5-carboxamide (compound 21.4); 2-[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide (compound 22); 2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide (compound 23); 2-benzyl-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (compound 24); 2-benzyl-N-(cyclopentylmethyl)-1H-benzimidazole-5-carboxamide (compound 24.1); 2-benzyl-N-(cycloheptylmethyl)-1H-benzimidazole-5-carboxamide (compound 24.2); N-(cycloheptylmethyl)-2-[(2-fluoro-6-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25); N-(cycloheptylmethyl)-2-[(5-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25.1); N-(cycloheptylmethyl)-2-[(3-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25.2); N-(cycloheptylmethyl)-2-[(2-hydroxy phenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25.3); N-(cycloheptylmethyl)-2-[(4-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25.4); N-(cycloheptylmethyl)-2-[(3-hydroxy phenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25.5); 2-(5-chloro-2-hydroxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide (compound 26); N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide (compound 27); N-(cycloheptylmethyl)-2-(1-methylcyclobutyl)-3H-benzimidazole-5-carboxamide (compound 28); 2-[[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (compound 29); 2-[[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (compound 29.1); N-[[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (compound 30); 2-[[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (compound 31); 2-[[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (compound 31.1); 2-[[5-fluoro-2-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (compound 32); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyridine-7-carboxamide (compound 33); and salts and solvates of the above.

[0086] The compound of general formula (IA) is a compound of general formula (II): TIFF0007797206000007.tif18170 (in the formula, R 1 is as defined for general formula (I), and R 31 is OH or halo, for example chloro), General formula (III) TIFF0007797206000008.tif22170(in the formula, 5 , Z, Y and R 2 can be prepared by reacting with a compound of general formula (I)

[0087] Suitably, the reaction is carried out in the presence of a coupling reagent under basic conditions, for example in the presence of an amine such as diisopropylethylamine (DIPEA) or triethylamine (TEA), and in an organic solvent such as DMF.

[0088] Suitable coupling reagents include 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 Examples of suitable benzotriazoles include tetrafluoroborate (TATU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), carbodiimides such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and triazoles such as 1-hydroxy-7-azabenzotriazole (HOAt) or hydroxybenzotriazole (HOBt). Suitably, the reaction is carried out under basic conditions, for example, in the presence of an amine such as diisopropylethylamine (DIPEA), and in an organic solvent such as DMF.

[0089] The reaction between compounds of general formula (II) and (III) can be carried out in a single step or alternatively in two steps. In a two-step reaction, in the first step, a compound of general formula (IV) TIFF0007797206000009.tif33170 (in the formula, R 1 , X 5 , Z, Y and R 2 is as defined for general formula (I),

[0090] The intermediate of general formula (IV) can be isolated and then further reacted to produce the required product of general formula (I). The reagents are as described above for the single step reaction, except that in the compound of general formula (II), R 31 is preferably halo, especially chloro.

[0091] Compounds of general formula (II) are readily available or can be synthesized by known methods. For example, R 1 is CH(R 11 )(R 12 ), then R 11 is as defined above, and R 12 (R 30 ) m and each R is a 6-membered aryl or heteroaryl ring substituted with 30 is optionally substituted with one or more substituents independently selected from OH, methoxy, chloro, fluoro, halo, and O 1~6 alkyl or C 1~4 is a 5-membered heteroaryl group optionally substituted with one or more substituents selected from alkyl and halo; m is 0, 1, 2, 3, 4, or 5. Compounds of general formula (II) can be converted to other compounds of general formula (II). For example, compounds of general formula (II) having fluoro and methoxy substituents can be alkylated as shown in Example 21 below.

[0092] In some cases, R of the compound of general formula (II) 1 The R group can be protected and the protecting group removed after reaction with the compound of general formula (III). 1 Protection may be required if the group contains an aromatic ring substituted with OH or alkyl substituted with OH. The use of protecting groups in such cases is illustrated in the examples below, where R 1 The group is CH(R 11 )(R 12 ) and R 11 is H and R 12is a phenyl substituted with OH and -C(CH)-CHOH. In this case, in the compound of general formula (II), the OH group is protected as a lactone, and the ring is opened by treatment with a reducing agent such as sodium borohydride or boron hydride, to give the required R 12 The base can be obtained.

[0093] R 31 The compound of general formula (II) in which is OH can be represented by general formula (V) TIFF0007797206000010.tif19170 (in the formula, R 1 is as defined above, and R 32 is C 1~6 alkyl or benzyl) can be prepared by hydrolysis of the compound of formula (I).

[0094] The hydrolysis may be, for example, a base hydrolysis using an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide, in a mixture of water and a polar solvent, typically an alcoholic solvent such as methanol or ethanol.

[0095] R 1 R 30 Compounds of general formula (V) benzyl substituted with R 30 is C 1~4 Compounds that are 5-membered heteroaryl groups optionally substituted with one or more substituents selected from alkyl and halo have the general formula (VI): TIFF0007797206000011.tif29170 (in the formula, R 30 is C 1~4 is a 5-membered heteroaryl group optionally substituted with one or more substituents selected from alkyl and halo, General formula (VII): TIFF0007797206000012.tif27170 (in the formula, R 32 is as defined for general formula (V), and R 55 can be prepared by reacting with a halophenylacetic acid ester of (wherein is halo, especially bromo).

[0096] Typically, the reaction is carried out in the presence of tripotassium phosphate and a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)2Cl2), in a solvent such as dioxane, and under an inert atmosphere, usually nitrogen. The reaction temperature is suitably about 80-120°C, for example about 100°C.

[0097] The compound of general formula (III) may be represented by general formula (VIII): TIFF0007797206000013.tif23170(in the formula, 5 , Z, Y and R 2 is as defined for general formula (I) It can be synthesized by reducing the compound

[0098] Suitable reduction methods include, for example, catalytic hydrogenation over a palladium / carbon catalyst. Alternatively, the reducing agent can be a transition metal, such as zinc, under acidic conditions.

[0099] Compounds of general formula (VIII) in which Z is -NHC(O)- (i.e., NH is bonded to a phenyl group) can be prepared by the reaction of general formula (IX): TIFF0007797206000014.tif20170 (in the formula, R 2 is as defined for general formula (I)) with a compound of general formula (X): TIFF0007797206000015.tif21170(in the formula, 5 can be prepared by reacting a compound of general formula (I) with a compound of formula (I)

[0100] The reaction can be carried out in the presence of an amine and a coupling reagent, such as DIPEA. Suitable coupling reagents are as discussed above for the reaction of compounds of general formulas (II) and (III). N,N-dimethylformamide is a suitable solvent.

[0101] In some cases, R of the compound of general formula (IX) 2 Substituents on the group may require protection. For example, as shown in Example 29 below, R 2 When is phenyl substituted at adjacent positions with OH and 2-hydroxy-1,1-dimethylethyl, it can be protected as a lactone. The synthesis of lactone-protected compounds of general formula (IX) (intermediate B) is described below.

[0102] Compounds of general formula (IX) and (X) are readily available or can be prepared by methods known to those skilled in the art.

[0103] X 5 A variant of the above process that is particularly suitable for preparing compounds where N and Z is -NHC(O)- comprises reacting a compound of general formula (IX) with a halogenating agent such as thionyl chloride followed by the use of ammonium hydroxide to form a compound of general formula (XI): TIFF0007797206000016.tif21170 (in the formula, R 2 is as defined for general formula (I).

[0104] The compound of general formula (XI) is reacted with a compound of general formula (XII): TIFF0007797206000017.tif31170(in the formula, 5 is as defined for general formula (I), and R 33 is C 1~6 alkyl or benzyl, and R 34 is halo, especially bromo); General formula (VIIIa): TIFF0007797206000018.tif32170(in the formula, 5 Y and R 2 is as defined for general formula (I), and R 33 is as defined in general formula (XII), and Z is -NHC(O)- (i.e., NH is bonded to a phenyl group). to give a protected compound of formula:

[0105] Suitably the reaction is carried out in the presence of an amine such as (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine and a copper catalyst such as copper iodide.

[0106] The compound of general formula (VIIIa) can be deprotected to give the compound of general formula (VIII) as defined above. Deprotection of the compound of general formula (VIIIa) can be achieved by treatment with an acid such as hydrochloric acid.

[0107] The protected compound of general formula (XII) can be prepared by the method of general formula (XIII): TIFF0007797206000019.tif21170(in the formula, 5 is as defined for general formula (I), and R 34 is as defined for general formula (XII), General formula (XIV): TIFF0007797206000020.tif17170 (in the formula, R 33 is as defined for general formula (XII)) and It can be prepared by reacting in the presence of a base, for example, sodium hydride.

[0108] Compounds of general formula (VIIIa) can be reduced as described above for compounds of general formula (VIII) to give compounds of general formula (IIIa): TIFF0007797206000021.tif34170(in the formula, 5 , Z, Y and R 2 is as defined for general formula (I), and R 33 is C 1~6 alkyl or benzyl) The compound of formula (I) can be obtained.

[0109] Compounds of general formula (IIIa) can be reacted with compounds of general formula (II) using the reaction conditions described above to give compounds of general formula (IVa): TIFF0007797206000022.tif46170 (in the formula, R1 , X 5 , Z, Y and R 2 is as defined for general formula (I), and R 33 is as defined for general formula (IIIa) A protected compound of formula (I) can be obtained.

[0110] Compounds of general formula (IVa) can be treated with an acid, for example HCl in dioxane, to remove the protecting group to yield compounds of general formula (IV), which can be reacted as described above to give compounds of general formula (I).

[0111] Compounds of general formula (III) where Z is -C(O)NH- (i.e., C(O) is attached to a phenyl group) can be prepared by the general formula (XV): TIFF0007797206000023.tif30170(in the formula, 5 is as defined for general formula (I), General formula (XVI): R 2 -Y-NH2(XVI) (In the formula, R 2 and Y are as defined for general formula (I)) with a compound of formula (I).

[0112] The reaction can be carried out in the presence of an amine and a coupling reagent, such as DIPEA or TEA. Suitable coupling reagents are as discussed above for the reaction of compounds of general formula (II) and (III). N,N-dimethylformamide is a suitable solvent.

[0113] Compounds of general formula (XV) and (XVI) are known, readily available or can be prepared by known methods.

[0114] Compounds of formula (IA) in which Z is -NHC(O)- (i.e., NH is attached to the benzimidazole) can be prepared by reacting compounds of general formula (IX) defined above with the general formula (XVII): TIFF0007797206000024.tif25170 (in the formula, R 1 and X 5 can also be prepared by reacting a compound of general formula (I) with a compound of general formula (I).

[0115] The reaction can be carried out in the presence of an amine and a coupling reagent, such as DIPEA. Suitable coupling reagents are as discussed above for the reaction of compounds of general formulas (II) and (III). N,N-dimethylformamide is a suitable solvent.

[0116] The compound of general formula (XVII) can be represented by general formula (XVIII): TIFF0007797206000025.tif26170 (in the formula, R 1 and X 5 can be prepared by reduction of a compound of general formula (I)

[0117] Suitably the reduction is carried out by catalytic hydrogenation over a palladium or platinum catalyst, for example a Pd / C catalyst.

[0118] Compounds of general formula (XVIII) can be prepared by reacting compounds of general formula (II) defined above with compounds of general formula (XIX): TIFF0007797206000026.tif23170(in the formula, 5 can be prepared by reacting a compound of general formula (I) with a compound of formula (I)

[0119] The reaction can be carried out in the presence of an amine and a coupling reagent, such as DIPEA. Suitable coupling reagents are as discussed above for the reaction of compounds of general formula (II) and (III). N,N-dimethylformamide is a suitable solvent. HATU can be used as a coupling agent for the reaction between compounds of general formula (II) and (XIX).

[0120] R 1 OR 5The compound of general formula (I), which is a compound of general formula (IA), is a compound of general formula (XX): TIFF0007797206000027.tif29170 (in the formula, R 5 , X 5 , Z, Y and R 2 is as defined for general formula (I), and R 35 is a protecting group, suitably CH2O(CH2)2Si(R 36 ) 3, and each R 36 independently C 1~6 The compound (wherein the aryl group is alkyl or phenyl) can be prepared by deprotection, for example, by reaction with either a strong acid such as trifluoroacetic acid or a fluoride source such as tetrabutylammonium fluoride.

[0121] The compound of general formula (XX) is represented by general formula (XXI): TIFF0007797206000028.tif31170(in the formula, 5 , Z, Y and R 2 is as defined for general formula (I), and R 35 is as defined for general formula (XX), and R 37 is halo, especially chloro) Compounds of general formula (XXII): R 5 -OH (XXII) (In the formula, R 5 is as defined for general formula (I), It can be prepared by reacting in the presence of a strong base, for example, a metal hydride such as sodium hydride.

[0122] Suitably, the reaction of compounds of general formula (XXI) and (XXII) and deprotection to give compounds of general formula (I) is carried out in a single step.

[0123] Compounds of general formula (XXII) are known, readily available, or can be prepared by known methods.

[0124] The compound of general formula (XXI) can be represented by general formula (XXIII): TIFF0007797206000029.tif26170(in the formula, 5 , Z, Y and R 2 is as defined for general formula (I), and R 37 is as defined for general formula (XXI); General formula (XXIV): R 35 -R 38 (XXIV) (In the formula, R 35 is as defined for general formula (XX), and R 38 is halo, especially chloro or bromo

[0125] Compounds of general formula (XXIV) are known, readily available or can be prepared by known methods.

[0126] Compounds of general formula (XXIII) in which Z is -NHC(O)- (i.e., NH is bonded to a phenyl group) can be prepared by the reaction of compounds of general formula (XXV): TIFF0007797206000030.tif25170(in the formula, 5 is as defined for general formula (I), and R 37 is as defined for general formula (XXI), General formula (XXVI): TIFF0007797206000031.tif21170 (in the formula, R 2 is as defined for general formula (I), and R 39 is halo, especially chloro).

[0127] Suitably the reaction is carried out in the presence of a base such as N,N-diisopropylethylamine (DIPEA) in a polar organic solvent such as dichloromethane.

[0128] Compounds of general formula (XXVI) can be prepared from compounds of general formula (IX) defined above by reaction with a halogenating agent such as thionyl chloride.

[0129] The compound of general formula (XXV) can be represented by general formula (XXVII): TIFF0007797206000032.tif26170(in the formula, 5 is as defined for general formula (I), and R 37 is as defined for general formula (XXI), Typically, it can be prepared by reduction using iron and ammonium chloride.

[0130] Compounds of general formula (XXVII) are known and readily available or can be prepared by methods known to those skilled in the art.

[0131] Compounds of general formula (XXIII) where Z is -C(O)NH- (i.e., C(O) is attached to a phenyl group) can be prepared using a combination of the methods described above for compounds of general formula (XXIII) where Z is -NHC(O)- (i.e., NH is attached to a benzimidazole group) and the method for compounds of general formula (III) where Z is -C(O)NH- (preparation from compounds of general formula (XV)).

[0132] An alternative method for preparing compounds of general formula (IA) in which Z is -NHC(O)- (i.e., NH is attached to a phenyl group) is by reaction of a compound of general formula (XVII) as defined above with a compound of general formula (XXVI) as defined above.

[0133] Suitably, the reaction is carried out in the presence of an amine and a coupling reagent such as DIPEA. Suitable coupling agents are as discussed above for the reaction of compounds of general formula (II) and general formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0134] The compound of general formula (XXX) has the general formula (XXXI): TIFF0007797206000033.tif23170 (in the formula, R 1 and X 5 can be prepared by reducing a compound of general formula (I)

[0135] Suitable reduction methods include catalytic hydrogenation, typically using a palladium / carbon catalyst, and the reaction is carried out in a polar organic solvent, typically an alcoholic solvent such as ethanol.

[0136] Compounds of general formula (XXXI) can be prepared from compounds of general formula (II) as defined above, in particular R 31 can be prepared by reacting a compound of general formula (II) in which is OH with a compound of general formula (XIX) as defined above.

[0137] Suitably, the reaction is carried out in the presence of an amine and a coupling reagent such as DIPEA. Suitable coupling agents are as discussed above for the reaction of compounds of general formula (II) and general formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0138] An alternative method for preparing compounds of general formula (IA) where Z is -C(O)NH- (i.e., -C(O) is attached to the benzimidazole group) is to prepare compounds of general formula (XXXIII): TIFF0007797206000034.tif30170 (in the formula, R 1 and X 5 is as defined for general formula (I), By reacting with a compound of general formula (XVI) as defined above.

[0139] The reaction can be carried out in the presence of an amine and a coupling reagent, such as DIPEA. Suitable coupling reagents are as discussed above for the reaction of compounds of general formulas (II) and (III). For example, HATU can be used. N,N-dimethylformamide is a suitable solvent.

[0140] The carboxylic acid of general formula (XXXIII) is represented by the general formula (XXXIIIa): TIFF0007797206000035.tif30170 (in the formula, R 1 and X 5 is as defined for general formula (I), and R 40 is C 1~6 alkyl or benzyl) It can be prepared by hydrolysis of the ester of

[0141] Typically, the hydrolysis is alkaline hydrolysis and is carried out using a base such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide, in an aqueous solvent, suitably a solvent comprising a mixture of water and an alcohol or THF and an alcohol, suitable alcohols including methanol and ethanol.

[0142] Compounds of general formula (XXXIIIa) can be prepared by reacting compounds of general formula (II) defined above with compounds of general formula (XXXIV): TIFF0007797206000036.tif27170(in the formula, 5 is as defined for general formula (I), and R 40 can be prepared by reacting a compound of general formula (XXXIIIa) with a compound of general formula (XXXIIIb)

[0143] The reaction can be carried out in the presence of an amine and a coupling reagent, such as DIPEA. Suitable coupling reagents are as discussed above for the reaction of compounds of general formulas (II) and (III). For example, HATU can be used. N,N-dimethylformamide is a suitable solvent.

[0144] Compounds of general formula (XXXIV) are known and commercially available or can be prepared by methods well known to those skilled in the art, for example by hydrolysis of compounds of general formula (XV).

[0145] Compounds of general formula (IC) where Z is -C(O)NH- (i.e., C(O) attached to the central ring system) can be prepared by the general formula (XXXV): TIFF0007797206000037.tif28170 (in the formula, R 1 and X 5 is as defined for general formula (I), It can be prepared by reacting with a compound of general formula (XVI) as defined above.

[0146] Suitably, the reaction is carried out in the presence of an amine and a coupling reagent such as DIPEA. Suitable coupling agents are as discussed above for the reaction of compounds of general formula (II) and general formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0147] The compound of general formula (XXXV) can be represented by general formula (XXXVI): TIFF0007797206000038.tif28170 (in the formula, R 1 and X 5 is as defined for general formula (I), and R 40 can be prepared by hydrolysis of a compound of general formula (XXXIIIa) (which is as defined for general formula (XXXIIIa)).

[0148] Typically, the hydrolysis is alkaline hydrolysis, carried out using a base such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide, in an aqueous solvent, suitably a solvent comprising a mixture of water and an alcohol (such as methanol or ethanol).

[0149] Compounds of general formula (XXXVI) can be prepared by reacting a compound of general formula (II) defined above with a compound of general formula (XXXVII): TIFF0007797206000039.tif28170 (in the formula, R 1 and X 5 is as defined for general formula (I), and R 40 can be prepared by reacting a compound of general formula (XXXIIIa) with a compound of general formula (XXXIIIb)

[0150] Suitably, the reaction is carried out in the presence of an amine and a coupling reagent such as DIPEA. Suitable coupling agents are as discussed above for the reaction of compounds of general formula (II) and general formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0151] Compounds of general formula (XXXVII) are known, readily available, or can be prepared by known methods.

[0152] Compounds of general formula (IC) where Z is -NHC(O)- (i.e., NH attached to the central ring system) can be prepared by the general formula (XXXVIII): TIFF0007797206000040.tif21170 (in the formula, R 1 and X 5 is as defined for general formula (I), It can be prepared by reacting with a compound of general formula (XXVI) as defined above.

[0153] Suitably, the reaction is carried out in the presence of an amine and a coupling reagent such as DIPEA. Suitable coupling agents are as discussed above for the reaction of compounds of general formula (II) and general formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0154] Compounds of general formula (XXXVIII) are known, readily available, or can be prepared by known methods.

[0155] Compounds of general formula (IB) where Z is -NHC(O)- (i.e., NH attached to the central ring system) can be prepared by converting compounds of general formula (IX) defined above into compounds of general formula (XL): TIFF0007797206000041.tif28170 (in the formula, R 1 , R 3 and X 5 can be prepared by reacting a compound of general formula (I) with a compound of general formula (I)

[0156] Suitably, the reaction is carried out in the presence of an amine and a coupling reagent such as DIPEA. Suitable coupling agents are as discussed above for the reaction of compounds of general formula (II) and general formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0157] The compound of general formula (XL) has the general formula (XLI): TIFF0007797206000042.tif29170 (in the formula, R 1 , R 3 and X 5 can be prepared by reducing a compound of general formula (I) (as defined above).

[0158] The reduction can be carried out by catalytic hydrogenation using, for example, a palladium / carbon catalyst.

[0159] CR 3 The compound of general formula (XLI) in which is replaced by C—NH2 can be represented by general formula (XLII): TIFF0007797206000043.tif20170(in the formula, 5 is as defined for general formula (I), and R 42 is halo, especially fluoro) General formula (XLIII): TIFF0007797206000044.tif14170 (in the formula, R 1can be prepared by reacting a compound of general formula (I) with a compound of formula (I)

[0160] Suitably the reaction is carried out under basic conditions, for example using DIPEA, in an alcoholic solvent such as t-butanol.

[0161] Compounds of general formula (XLII) and (XLIII) are known, readily available or can be prepared by known methods.

[0162] Alternatively, compounds of general formula (IB) where Z is -NHC(O)- (i.e., NH attached to the central ring system) can be prepared by the compound of general formula (XLV): TIFF0007797206000045.tif30170 (in the formula, R 2 , R 3 , X 5 and Y is as defined for general formula (I), General formula (XLVIII): R 1 -R 43 (XLVIII) (In the formula, R 1 is as defined for general formula (I), and R 43 is halo, in particular chloro or bromo), It can be prepared by reaction under mildly basic conditions, for example in the presence of potassium carbonate.

[0163] Compounds of general formula (XLVIII) are known, readily available or can be prepared by known methods.

[0164] Compounds of general formula (XLV) can be prepared by reacting compounds of general formula (IX) defined above with compounds of general formula (XLVI): TIFF0007797206000046.tif31170 (in the formula, R 3 and X 5 can be prepared by reacting a compound of formula (I) with a compound of formula (I)

[0165] Suitably, the reaction is carried out in the presence of an amine and a coupling reagent such as DIPEA. Suitable coupling agents are as discussed above for the reaction of compounds of general formula (II) and general formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0166] Compounds of general formula (XLVI) are known and readily available or can be synthesized by methods known to those skilled in the art.

[0167] Compounds of general formula (IB) where Z is -C(O)NH- (i.e., C(O) attached to the central ring system) can be represented by general formula (XLVII): TIFF0007797206000047.tif37170(in the formula, Y, R 2 , R 3 and X 5 is as defined above for general formula (I), It can be prepared by reacting with a compound of general formula (XLVIII) as defined above.

[0168] The compound of general formula (XLVII) can be represented by general formula (XLIX): TIFF0007797206000048.tif37170 (in the formula, R 3 and X 5 is as defined above for general formula (I), It can be prepared by reacting with a compound of general formula (XVI) as defined above.

[0169] Suitably, the reaction is carried out in the presence of an amine and a coupling reagent such as DIPEA. Suitable coupling agents are as discussed above for the reaction of compounds of general formula (II) and general formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0170] Compounds of general formula (XLIX) are known, readily available or can be prepared by known methods.

[0171] The compound of formula (IB) is R 3a and R 3b R where either or both are H 3 Substituent N(R 3a )(R 3b ), it may be necessary to protect the amine group during synthesis. For example, R 3 The compound of general formula (XLI) above, wherein is NH, can be protected by reacting with a compound of general formula (XIV) above to protect the free amine group. The following steps are carried out as described above, and following reaction of a protected compound of general formula (XL) with a compound of general formula (IX), a protected compound of formula (ID) is obtained, which can be deprotected by treatment with an acid such as trifluoroacetic acid.

[0172] Similarly, R 3 Compounds of general formula (XLIX) where is NH can be protected by reaction with compounds of general formula (XIV) as described above. The protecting group can be removed before or after the next step. The compound of general formula (ID) may be a compound of general formula (L): TIFF0007797206000049.tif22170 (in the formula, R 1 and X 5 is as defined in general formula (I), and R 45 is halo, for example bromo), It can be prepared by reacting formic acid, methanesulfonyl chloride, triethylamine, and a compound of general formula (XVI) as defined above in the presence of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and a Pd catalyst (Xantphos Pd-G3 (third generation (G3) Buchwald precatalyst)), and a base (such as sodium carbonate).

[0173] Suitably the reaction is carried out in an organic solvent such as toluene.

[0174] The compound of general formula (L) has the general formula (LI): TIFF0007797206000050.tif23170(in the formula, 5 is as defined in general formula (I), and R 45 is as defined for general formula (L), General formula (LII): TIFF0007797206000051.tif19170 (in the formula, R 1 is as defined for general formula (I), and R 46 is halo, for example bromo).

[0175] Suitably the reaction is carried out under basic conditions, for example in the presence of sodium bicarbonate in an alcoholic solvent such as ethanol.

[0176] Compounds of general formula (LI) and (LII) are known and readily available or can be prepared by methods known to those skilled in the art.

[0177] Compounds of general formula (I) can also be prepared from other compounds of general formula (I). For example, R 1 and R 2 If either or both of the groups contain an alkoxy-substituted phenyl group, this can be converted to an OH-substituted phenyl by treatment with boron tribromide.

[0178] R 1 is CH(R 7 )-N(R 8 )-C(O)OR 9a The first compound of general formula (I) is 1 is CH(R 7 )-N(R 8 )-C(O)OR 9b and a second compound of general formula (I) wherein R 9a and R 9b are different from each other, but both are the same as the above R 9As defined in

[0179] In the first step, R 1 is CH(R 7 )-N(R 8 )-C(O)OR 9a A compound of general formula (I), where R is a hydroxy group, is treated with an acid, for example HCl in a solvent such as dioxane. This produces a compound similar to general formula (I), but where R 1 Substituent is CH(R 7 )-NH(R 8 ) is replaced by the general formula (LV): TIFF0007797206000052.tif20170 (in the formula, R 9b is as defined above, and R 50 is halo, especially chloro), Reach the product you need.

[0180] R 1 is CH(R 7 )-N(R 8 )-C(O)OR 9 Compounds of general formula (I) of formula HN(R 9 )(R 10 )(wherein, R 9 and R 10 is as described above for general formula (I) to give R 1 is CH(R 7 )-N(R 8 )-C(O)N(R 9 )(R 10 ) can be converted into a compound of general formula (I).

[0181] Other interconversions of various substituents can be carried out by methods well known to those skilled in the art.

[0182] Compounds of formula (Ix) can be prepared in a similar manner to compounds of formula (I).

[0183] Compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) and (IE) are modulators of TMEM16A and therefore, in a further aspect of the present invention, there are provided compounds of general formula (I) as defined above, including all tautomeric forms, all enantiomers and isotopic variants, and salts and solvates thereof, for use in medicine, in particular in the treatment or prevention of diseases and conditions affected by modulation of TMEM16A.

[0184] More suitable compounds for use in the treatment or prevention of diseases and conditions affected by modulation of TMEM16A are as defined above.

[0185] There is also provided the use of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in the manufacture of a medicament for the treatment or prevention of a respiratory disease or condition affected by modulation of TMEM16A.

[0186] Also provided are methods for the treatment or prevention of diseases and conditions affected by modulation of TMEM16A, comprising administering to a patient in need of such treatment an effective amount of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE).

[0187] Diseases and conditions affected by modulation of TMEM16A include respiratory diseases and conditions, dry mouth (xerostomia), hyperkinesia, cholestasis, and ocular conditions.

[0188] Also provided are: A compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in the treatment or prevention of a respiratory disease or condition. A compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in the treatment or prevention of dry mouth (xerostomia). A compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in the treatment or prevention of hyperkinesia. A compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in the treatment or prevention of cholestasis. A compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in the treatment or prevention of ocular conditions.

[0189] The present invention also provides the following: Use of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in the manufacture of a medicament for the treatment or prevention of a respiratory disease or condition. Use of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in the manufacture of a medicament for the treatment or prevention of dry mouth (xerostomia). Use of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in the manufacture of a medicament for the treatment or prevention of hyperkinesia. Use of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in the manufacture of a medicament for the treatment or prevention of cholestasis. Use of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in the manufacture of a medicament for the treatment or prevention of an ophthalmic condition.

[0190] It further provides: A method for the treatment or prevention of a respiratory disease or condition, which method comprises administering to a patient in need of such treatment an effective amount of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE). A method for the treatment or prevention of dry mouth (xerostomia), which method comprises administering to a patient in need of such treatment an effective amount of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE). A method for the treatment or prevention of intestinal hypermotility, which method comprises administering to a patient in need of such treatment an effective amount of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE). A method for the treatment or prevention of cholestasis, which method comprises administering to a patient in need of such treatment an effective amount of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE). A method for the treatment or prevention of an ocular condition, which method comprises administering to a patient in need of such treatment an effective amount of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE).

[0191] Respiratory diseases and conditions that may be treated or prevented by the compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) include cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis including non-cystic fibrosis, asthma and primary ciliary dyskinesia.

[0192] Dry mouth (xerostomia) which may be treated or prevented by the compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) may result from Sjögren's syndrome, radiation therapy, and xerogenic drugs.

[0193] The hypermotility that may be treated or prevented by the compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) may be associated with a condition selected from gastric dyspepsia, gastroparesis, chronic constipation and irritable bowel syndrome.

[0194] Ocular conditions that may be treated or prevented by the compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) include dry eye disease.

[0195] The compounds of the invention are generally administered as part of a pharmaceutical composition and therefore the invention further provides a pharmaceutical composition comprising a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) and a pharmaceutically acceptable excipient.

[0196] More suitable compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in pharmaceutical compositions are as described above, in particular the novel compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE).

[0197] The pharmaceutical compositions may be formulated for oral, rectal, nasal, bronchial (inhalation), topical (including dermal, transdermal, ophthalmic, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and prepared by any of the methods well known in the art of pharmacy.

[0198] The composition can be prepared by associating the active agent defined above with an excipient. Generally, the formulation is prepared by uniformly and intimately associating the active agent with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product. The present invention also extends to a method for preparing a pharmaceutical composition, which comprises combining or associating a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) with a pharmaceutically acceptable carrier or vehicle.

[0199] Formulations for oral administration herein may be presented as discrete units such as capsules, sachets or tablets, each containing a predetermined amount of active agent; as a powder or granules; as a solution or suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as a bolus, etc.

[0200] For compositions for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes vehicles such as common additives, e.g., binders, e.g., syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose, and starch; fillers and carriers, e.g., corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid; and lubricants, e.g., magnesium stearate, sodium stearate, and other metallic stearates, glycerol stearate, stearic acid, silicone fluid, talc wax, oils, and colloidal silica. Flavorings, e.g., peppermint, wintergreen oil, cherry flavor, and the like, can also be used. It may be desirable to add a coloring agent to facilitate easy identification of the dosage form. Tablets can also be coated by methods well known in the art.

[0201] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active agent in a free-flowing form as a powder or granules, optionally mixed with binders, lubricants, inert diluents, preservatives, surface-active agents, or dispersing agents, etc. Molded tablets can be made by molding in a suitable machine a mixture of moistened powdered compound and an inert liquid diluent. Tablets can optionally be coated or grooved and can be formulated to provide a slow or controlled release of the active agent therefrom.

[0202] Other formulations suitable for buccal administration include lozenges which comprise the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles which comprise the active agent in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes which comprise the active agent in a suitable liquid carrier.

[0203] For topical application to the skin, the compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) may be made up into creams, ointments, jellies, solutions or suspensions, etc. Cream or ointment formulations that may be used for drugs are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.

[0204] Local administration to the lung can be achieved by using aerosol formulations. Aerosol formulations typically contain the 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 comprises 40% to 99.5% by weight, e.g., 40% to 90% by weight, of the total inhalation composition. The formulation may contain additives, including cosolvents (e.g., ethanol) and surfactants (e.g., lecithin, sorbitan trioleate, etc.). Other possible additives include polyethylene glycol, polyvinylpyrrolidone, glycerin, etc. Aerosol formulations are packaged in canisters from which the appropriate dose is delivered by a metered valve (eg, as supplied by Bespak, Valois, or 3M, or by Aptar, Coster, or Vari).

[0205] Topical administration to the lung can also be achieved by the use of non-pressurized formulations, such as aqueous solutions or suspensions. These can be administered using a nebulizer, which can be, for example, handheld and portable, or for home or hospital use (i.e., non-portable). The formulation can contain additives such as water, buffers, tonicity adjusters, pH adjusters, surfactants, and co-solvents. Suspension and aerosol formulations (whether pressurized or not) typically contain the compounds of the invention in finely divided form, for example, 0.5-10 μm, e.g., about 1-5 μm D. 50 The particle size distribution is D 10 , D 50 , and D 90 The particle size distribution can be expressed using the value of D 50 The median is defined as the particle size in microns that divides the distribution in half. Measurements obtained from laser diffraction are more accurately described as a volume distribution, so the D obtained using this procedure 50 The value is a more meaningful Dv 50 As used herein, the Dv value refers to the particle size distribution measured using laser diffraction. Similarly, the Dv value used in the context of laser diffraction is referred to as the median of the volume distribution. 10 and D 90 The value is Dv 10 and Dv 90 Each value indicates that 10% of the distribution is D 10 Below the value, 90% of the distribution is D 90 This refers to the particle size in the value.

[0206] Local administration to the lung can also be achieved by the use of dry powder formulations. Dry powder formulations typically have a mass mean diameter (MMAD) of 1 to 10 μm or a D of 0.5 to 10 μm, for example about 1 to 5 μm. 50The compound of the present disclosure is included in a micronized form having a particle size of 100 μm or more. 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 can be carried out using a jet mill such as that manufactured by Hosokawa Alpine. The resulting particle size distribution can be measured using laser diffraction (e.g., using a Malvern Mastersizer 2000S instrument). Formulations typically contain a topically acceptable diluent such as lactose, glucose, or mannitol (preferably lactose), and usually produce particles with a relatively large particle size, e.g., a mass mean diameter (MMAD) of 50 μm or more, e.g., 100 μm or more, or a D of 40 to 150 μm. 50 As used herein, the term "lactose" refers to lactose-containing components, including α-lactose monohydrate, β-lactose monohydrate, α-lactose anhydrous, β-lactose anhydrous, and amorphous lactose. The lactose component can be processed by micronization, sieving, milling, compaction, agglomeration, or spray drying. Also encompassed are various commercially available forms of lactose, such as Lactohale® (inhalation-grade lactose; DFE Pharma), InhaLac® 70 (sieved lactose for dry powder inhalers; Meggle), Pharmatose® (DFE Pharma), and Respitose® (sieved) inhalation-grade lactose; DFE Pharma). 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.

[0207] The dry powder formulation may also include other additives. Thus, in one embodiment, a dry powder formulation according to the present disclosure includes magnesium or calcium stearate. Such formulations may have excellent chemical and / or physical stability, especially if such formulations also include lactose.

[0208] Dry powder formulations are typically delivered using dry powder inhaler (DPI) devices. Examples of dry powder delivery systems include SPINHALER®, DISKHALER®, TURBOHALER®, DISKUS®, SKYEHALER®, ACCUHALER®, and CLICKHALER®. Further examples of dry powder delivery systems include 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.

[0209] In one embodiment, a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) is provided as a micronized dry powder formulation, for example comprising a suitable grade of lactose.

[0210] Thus, in one aspect of the present invention there is provided a pharmaceutical composition comprising a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in particulate form in combination with particulate lactose, the composition optionally comprising magnesium stearate.

[0211] In one embodiment, a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) is provided as a micronized dry powder formulation packed into a device such as a DISKUS, comprising a suitable grade of lactose and magnesium stearate. Suitably, such a device is a multi-dose device, for example, the formulation is packed into blisters for use in a multi-unit dose device such as a DISKUS.

[0212] In another embodiment, the compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) is provided as a micronized dry powder formulation, for example comprising a suitable grade of lactose, filled into a hard shell capsule for use in a single dose device such as an AEROLISER.

[0213] In another embodiment, the compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) is provided as a micronized dry powder formulation comprising a suitable grade of lactose and magnesium stearate filled into a hard shell capsule for use in a single dose device such as an AEROLISER.

[0214] In another embodiment, the compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) is provided as a fine powder for use in an inhalation dosage form, the powder comprising: 50 The microparticles are 0.5-10 μm, e.g., approximately 1-5 μm, and have been produced by a size reduction process other than jet mill micronization (e.g., spray drying, spray freezing, microfluidization, high-pressure homogenization, supercritical fluid crystallization, supercritical crystallization, or a combination of these methods), or other suitable particle formation methods known in the art used to produce microparticles with an aerodynamic diameter of 0.5-10 μm. The resulting particle size distribution can be measured using laser diffraction (e.g., using a Malvern Mastersizer 2000S instrument). The particles can contain the compound alone or in combination with other suitable additives that can aid processing. The resulting microparticles can form the final formulation for delivery to humans, or, optionally, can be further formulated with other suitable additives to facilitate delivery in an acceptable dosage form.

[0215] The compound of the present invention can also be administered rectally in the form of suppositories or enemas, including aqueous or oily solutions, as well as 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 active ingredients with conventional suppository bases 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 melts in the rectum to release the drug.Such materials are cocoa butter and polyethylene glycol.

[0216] Generally, for compositions intended for topical administration to the eye in the form of eye drops or eye ointment, the total amount of compounds of general formula (I) is about 0.0001 to less than 4.0% (w / w).

[0217] Preferably, for topical ocular administration, compositions administered according to general formula (I), (Ix), (IA), (IB), (IC), (ID), or (IE) will be formulated as solutions, suspensions, emulsions, and other dosage forms. Aqueous solutions are generally preferred based on ease of formulation and the patient's ability to easily administer such compositions by instilling one to two drops of the solution into the affected eye. However, the compositions can also be suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions. Suspensions may be preferred for compounds that are poorly soluble in water.

[0218] An alternative to ocular administration is intravitreal injection of a solution or suspension of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE). Additionally, a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) may also be introduced by means of an ocular implant or insert.

[0219] Compositions administered according to general formula (I), (Ix), (IA), (IB), (IC), (ID), or (IE) may also contain various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymers, preservatives, cosolvents, and viscosity enhancers. Suitable pharmaceutical compositions of general formula (I), (Ix), (IA), (IB), (IC), (ID), or (IE) comprise a compound of the present invention formulated with a tonicity agent and a buffer. Pharmaceutical compositions of general formula (I), (Ix), (IA), (IB), (IC), (ID), or (IE) may further optionally contain surfactants and / or emollients and / or stabilizing polymers.

[0220] Various tonicity adjusting agents can be used to adjust the tonicity of the composition, preferably to that of natural tears, for ophthalmic compositions. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, monosaccharides and / or sugar alcohols such as dextrose, fructose, and galactose, simple polyols such as mannitol, sorbitol, xylitol, lactitol, isomaltitol, and maltitol, and hydrogenated starch hydrolysates can be added to the composition to approximate physiological osmolality. The amount of such tonicity adjusting agents will vary depending on the specific agent added. However, generally, the composition will contain a sufficient amount of tonicity adjusting agent to provide the final composition with an ophthalmologically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm, and most preferably about 290 mOsm). Generally, the tonicity adjusting agent of the present invention will be present in a range of 2-4% w / w. Preferred tonicity adjusting agents of the present invention include monosaccharides or sugar alcohols such as D-mannitol.

[0221] An appropriate 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. Preferably, however, the buffer is selected to maintain a target pH within the range of pH 5-8, more preferably a target pH of pH 5-7.

[0222] Surfactants may optionally be used to deliver higher concentrations of compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID), or (IE). Surfactants function to solubilize compounds and stabilize colloidal dispersions, such as micellar solutions, microemulsions, emulsions, and suspensions. Examples of surfactants that may be optionally used include polysorbates, poloxamers, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate. Preferred surfactants for use in the present invention have a hydrophilic / lipophilic balance (HLB) in the range of 12.4 to 13.2 and are acceptable for ophthalmic use (e.g., Triton X114 and tyloxapol).

[0223] An additional agent that may be added to ophthalmic compositions of compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID), or (IE) is a emollient that functions as a stabilizing polymer. The stabilizing polymer must be ionic / charge-eligible for topical ocular use, more specifically, exhibit a zeta potential of (-)10 to 50 mV for physical stability, and be water-dispersible (i.e., water-soluble). Preferred stabilizing polymers of the present invention are polyelectrolytes, or polyelectrolytes from the family of crosslinked polyacrylates, such as Carbopol and Pemulen®, specifically Carbomer 974p (polyacrylic acid), in multiples of 0.1 to 0.5% w / w.

[0224] Other compounds may also be added to the ophthalmic compositions of compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID), or (IE) to increase the viscosity of the carrier. Examples of viscosity-increasing agents include, but are not limited to, polysaccharides such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, and various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers.

[0225] Topical ophthalmic products are typically packaged in multi-dose form. Therefore, preservatives are required to prevent microbial contamination during use. Suitable preservatives include benzalkonium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propylparaben, phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are typically used at levels of 0.001-1.0% w / v. Unit-dose compositions of general formula (I), (Ix), (IA), (IB), (IC), (ID), or (IE) are sterile but typically not preserved. Therefore, such compositions generally will not contain preservatives.

[0226] Parenteral formulations are generally sterile.

[0227] A medical practitioner or other skilled artisan will be able to determine the appropriate dosage of a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE), and therefore the amount of a compound of the invention that should be included in any particular formulation (whether in unit dosage form or not).

[0228] The compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) may be used in combination with one or more other active agents useful in the treatment or prevention of a disease or condition affected by modulation of TMEM16A, particularly a respiratory disease or condition, such as one of the diseases and conditions mentioned above.

[0229] Additional active agents of this type may be included in the pharmaceutical compositions described above, or may be administered separately, either simultaneously with, or at an earlier or later time than, a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID), or (IE).

[0230] Thus, in a further aspect of the present invention, there is also provided a product comprising a compound of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) and an additional agent useful for the treatment or prophylaxis of respiratory diseases or conditions affected by modulation of TMEM16A, in particular respiratory diseases or conditions, such as one of the diseases and conditions mentioned above, as a combined preparation for simultaneous, sequential or separate use in treating such diseases or conditions.

[0231] Also provided are compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in combination with an additional agent useful in the treatment or prophylaxis of respiratory diseases or conditions, particularly respiratory diseases or conditions, affected by modulation of TMEM16A, such as one of the diseases and conditions mentioned above, for simultaneous, sequential or separate use in the treatment of such diseases or conditions.

[0232] Suitable additional active agents that may be included in pharmaceutical compositions or combination formulations with compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) include: Beta-2 adrenergic receptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, olodaterol, vilanterol and abesiterol; antihistamines, for example, histamine H1 receptor antagonists or H4 receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine; dornase alfa; Corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, and fluticasone furoate; Leukotriene antagonists such as montelukast and zafirlukast; anticholinergic compounds, particularly muscarinic antagonists such as ipratropium, tiotropium, glycopyrrolate, aclidinium and umeclidinium; CFTR repair therapies (e.g., CFTR potentiators, correctors, or amplifiers) such as ivacaftor, QBW251, bamacaftor (VX659), elexacaftor (VX445), VX561 / CPT-656, VX152, VX440, GLP2737, GLP2222, GLP2451, PTI438, PTI801, PTI808, FDL-169, and FDL-176, and CFTR correctors such as lumacaftor and tezacaftor, or combinations thereof (e.g., a combination of ivacaftor, tezacaftor, and elexacaftor); ENaC modulators, especially ENaC inhibitors; antibiotics; antivirals such as ribavirin and neuraminidase inhibitors such as zanamivir; antifungal agents such as PUR1900; Airway hydration agents (osmolytes) such as hypertonic saline and mannitol (Bronchytol®); and Mucolytic agents such as N-acetylcysteine.

[0233] When the additional active agent 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 our applications WO 2017 / 221008, WO 2018 / 096325, WO 2019 / 077340, and WO 2019 / 220147, any of the exemplary compounds for use therein may be used in combination with general formula (I), (Ix), (IA), (IB), (IC), (ID), or (IE). Compounds particularly suitable for use in combination with compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) include compounds having a cation selected from: 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)ethyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-{[2-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidin-1-yl)ethyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)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-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)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-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)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-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)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-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)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-benzodiazol-3-ium; Suitable anions include, for example, halides, sulfates, nitrates, phosphates, formates, acetates, trifluoroacetates, fumarates, citrates, tartrates, oxalates, succinates, mandelates, methanesulfonates, or p-toluenesulfonates.

[0234] The invention is illustrated by the following non-limiting examples and the following figures. [Brief explanation of the drawings]

[0235] [Figure 1] FIG. 1 is an example trace from a whole-cell patch clamp (Qpatch) TMEM16A potentiator assay used in the biological examples, illustrating the method used in the assay. [Example]

[0236] The invention is illustrated by the following non-limiting examples.

[0237] Example General conditions: Mass spectra were performed on an LC-MS system using electrospray ionization. They were performed using either a Waters Acquity uPLC system or a Shimadzu LCMS-2010EV system equipped with a Waters PDA and ELS detector. [M+H]+ refers to the monoisotopic molecular weight.

[0238] NMR spectra were recorded on a Bruker Avance III HD 500 MHz equipped with a 5 mm broadband inversion probe, a Bruker Avance III HD 250 MHz equipped with a 5 mm broadband observation SmartProbe, or a 400 MHz Avance III HD Nanobay using the solvent as an internal deuterium lock. Unless otherwise stated, spectra were recorded at room temperature and referenced using the solvent peak.

[0239] With reference to the following examples, compounds of preferred embodiments were synthesized using methods described herein or other methods known in the art.

[0240] The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified, if necessary, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. 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.

[0241] Compounds were purified by flash column chromatography on normal-phase silica on a Biotage® Isolera system using the appropriate SNAP or Sfar cartridge and gradient. Alternatively, compounds were purified on reverse-phase silica using either a Biotage® Isolera or Biotage® Selekt system with the appropriate SNAP C18 or Sfar C18 cartridge and reverse-phase eluent, or by preparative HPLC (unless otherwise specified).

[0242] Preparative HPLC using acidic pH, early elution method Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: RT) and a gradient of 10 to 95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) in 14.44 min, followed by 95% B in 2.11 min, with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0243] Preparative HPLC using acidic pH, standard elution method Purification by preparative HPLC (acidic pH, standard elution) was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: RT) and a gradient of 30 to 95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) in 11 min, followed by 95% B in 2.11 min, with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0244] Preparative HPLC using basic pH, early elution method Purification by preparative HPLC (basic pH, fast elution) was performed on a Gilson LC system using a Waters Xbridge C18 column (30 mm x 100 mm, 10 μM; temperature: RT) and a gradient of 10 to 95% (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) in 14.44 min, followed by 95% B in 2.11 min, with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0245] Preparative HPLC using basic pH, standard elution method Purification by preparative HPLC (basic pH, standard elution) was performed on a Gilson LC system using a Waters Xbridge C18 column (30 mm x 100 mm, 10 μM; temperature: RT) and a gradient of 30 to 95% (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) in 11 min, followed by 95% B in 2.11 min, with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0246] Unless otherwise stated, analytical HPLC conditions were as follows:

[0247] Method A Column: Phenomenex Kinetix-XB C18 2.1 x 100 mm, 1.7 μm Column temperature: 40℃ Eluent: 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

[0248] Method B Column: Kinetex Core-Shell C18 2.1 x 50 mm, 5 μm Column temperature: 40℃ Eluent: 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

[0249] Method C Column: Phenomenex Gemini-NX C18 2.0 x 50 mm, 3 μm Column temperature: 40℃ Eluent: 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

[0250] Method D Column: Waters UPLC® BEH™ C18, 2.1 x 50 mm, 1.7 μm Column temperature: 40℃ Eluent: A: H2O + 0.1% formic acid, B: Acetonitrile + 0.1% formic acid Flow rate: 0.9mL / min Gradient: 0-1.10 min, 5-100% B, 1.10-1.35 min, 100% B, 1.35-1.40 min, 100-5% B, 1.40-1.50 min, 5% B

[0251] Method E Column: Kinetex Core-Shell C18 2.1 x 50 mm, 5 μm Column temperature: 40℃ Eluent: A: H2O + 0.1% formic acid, B: Acetonitrile + 0.1% formic acid Flow rate: 1.2mL / min Gradient: 0-1.83 min, 5-100% B, 1.83-2.25 min, 100% B, 2.25-2.26 min, 100-5% B, 2.26-2.8 min, 5% B

[0252] Method F Column: Waters UPLC® BEH™ C18, 2.1 x 100 mm, 1.7 μm Column temperature: 40℃ Eluent: 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

[0253] Method G Column: Waters UPLC® BEH™ C18, 2.1 x 30 mm, 1.7 μm Column temperature: 40℃ Eluent: A: 2 mM ammonium bicarbonate, buffered to pH 10, B: acetonitrile Flow rate: 1.0mL / min Gradient: 0-0.75 min, 5-100% B, 0.75-0.85 min, 100% B, 0.85-0.9 min, 100-5% B, 0.9-1.0 min, 5% B

[0254] The following examples are intended to illustrate the present invention and should not be construed as limitations thereon. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporations are carried out in vacuo, preferably between about 15 mmHg and 100 mmHg (= 20-133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, and NMR. Abbreviations used are conventional in the art. Unless defined, terms have their generally accepted meanings.

[0255] Abbreviation AcOH acetic acid aq.Aqueous solution BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) br Wide d doublet dd Doublet of Doublets DCC N,N'-dicyclohexylcarbodiimide DCE Dichloroethane DCM dichloromethane DIPEA Diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc 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 multiplet min mL milliliter m / z mass-to-charge ratio NMR nuclear magnetic resonance Q Quartet Rt retention time s singlet t triplet TBME Methyl tert-butyl ether TBTU N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran VT Variable Temperature

[0256] Preparation example Example 1 2-(1-Adamantyl)-N-[2-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide TIFF0007797206000053.tif28170Step 1: 2-(1-Adamantyl)-N-(4-amino-3-nitro-phenyl)acetamide TIFF0007797206000054.tif28170 2-Nitrobenzene-1,4-diamine (3.15 g, 20.59 mmol) was added to 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 h, the reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). A black precipitate formed in the biphasic mixture. The solid was filtered off and discarded. The phases were separated, and the organic layer was washed with water (100 mL) and brine (2 × 50 mL), dried over MgSO4, and concentrated in vacuo to give a brown / black oil. The oil was triturated in DCM (ca. 40 mL) and the resulting suspension filtered to give the title compound as a red / black solid. LC-MS (Method B): Rt 1.24 min; MS m / z 330.2=[M+H]+ (99% at 215 nm) 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 2: 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide A suspension of 2-(1-adamantyl)-N-(4-amino-3-nitro-phenyl)acetamide (Step 1) (4.82 g, 14.63 mmol) and Pd / C (10%, 1.24 g, 1.17 mmol) in EtOH (50 mL) was placed under a hydrogen atmosphere and stirred for 18 hours. The resulting mixture was filtered through Celite® (filter material) and the solid was washed with EtOH (3 × 10 mL). The filtrate was concentrated in vacuo to provide the title compound as a purple solid. LC-MS (Method B): Rt 0.93 min; MS m / z 300.3=[M+H]+(98% at 215 nm) 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). Step 3: 2-(1-adamantyl)-N-[2-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide 2-Cyclohexylacetic acid (0.06 g, 0.4 mmol), HATU (0.17 g, 0.44 mmol), and DIPEA (0.21 mL, 1.2 mmol) were dissolved in DMF (2.5 mL) and stirred at room temperature for 1 hour. 2-(1-Adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 2) (0.12 g, 0.4 mmol) was added, and the mixture was stirred at room temperature overnight. Water (8 mL) was added, followed by EtOAc (8 mL), and the resulting suspension was collected by filtration and washed with EtOAc to give a pale purple solid. The solid was sonicated with MeCN, filtered, dried under vacuum, and suspended in acetic acid (2 mL). The suspension was stirred overnight at 60 °C in a sealed vessel. The resulting mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (5 mL) and saturated aqueous sodium bicarbonate solution (5 mL). The layers were separated and the organic portion was washed with saturated aqueous sodium bicarbonate (5 mL) and concentrated in vacuo before being passed through a phase-separating Isolute® cartridge. The resulting residue was purified by C18 reverse-phase chromatography eluting with 10-100% MeCN (+0.2% ammonium hydroxide) in water to afford the title compound as a light brown solid. LC-MS (method A): Rt 2.87 min; MS m / z 406.4=[M+H]+ (99% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.07-11.89(m,1H),9.73-9.53(m,1H),8.03-7.74(m,1H),7.46-7.00(m,2H),2.67-2.59(m,2H),2.08-2. 01(m,2H),1.98-1.89(m,3H),1.86-1.75(m,1H),1.71-1.55(m,17H),1.28-1.08(m,3H),1.05-0.92(m,2H).

[0257] Example 1.1 2-(1-Adamantyl)-N-[2-(tetrahydropyran-2-ylmethyl)-1H-benzimidazol-5-yl]acetamide TIFF0007797206000056.tif30170 The title compound was prepared analogously to Step 3 of Example 1 from 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 2 of Example 1) and 2-tetrahydropyran-2-ylacetic acid. LC-MS (method A): Rt 2.34 min; MS m / z 408.3=[M+H]+(100% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.10-11.83(m,1H),9.75-9.50(m,1H),8.05-7.71(m,1H),7.45-7.00(m,2H),3.90-3.78(m,1H),3.78-3.61(m,1H),3.41-3. 31(m,1H),2.94-2.79(m,2H),2.07-2.02(m,2H),1.97-1.89(m,3H),1.83-1.54(m,14H),1.52-1.37(m,3H),1.31-1.19(m,1H).

[0258] Example 2 2-(2-adamantyl)-N-(2-benzyl-1H-benzimidazol-5-yl) TIFF0007797206000057.tif39170Step 1: Ethyl 2-(2-adamantylidene)acetate Ethyl 2-diethoxyphosphorylacetate (7.26 mL, 36.61 mmol) was added dropwise to a cooled (0 °C) suspension of NaHCO₂, a 60% dispersion in mineral oil (1.86 g, 46.6 mmol) in THF (100 mL). After stirring at 0 °C for 30 min, adamantan-2-one (5.0 g, 33.28 mmol) was added, and the mixture was warmed to room temperature and stirred for 2 h. The resulting mixture was diluted with DCM (100 mL) and washed with brine (100 mL). The aqueous portion was extracted with DCM (100 mL), and the combined organic extracts were dried over MgSO₄ and concentrated in vacuo to give a colorless oil. The oil was purified by chromatography on silica eluting with 0–20% EtOAc in heptane to give the title compound as a colorless oil. LC-MS (Method B): Rt 1.43 min; MS m / z 221.3=[M+H]+ (97% at 215 nm) 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: Ethyl 2-(2-adamantyl)acetate A suspension of ethyl 2-(2-adamantylidene)acetate (Step 1) (95%, 14.0 g, 60.37 mmol) and Pd / C (10%, 6.42 g, 6.04 mmol) in 125 mL of EtOH was 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 in vacuo to give the title compound as a colorless oil. LC-MS (Method B): Rt 1.47 min; MS m / z 223.0=[M+H]+(100% at 215 nm) 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 ethyl 2-(2-adamantyl)acetate (Step 2) (100%, 18.3 g, 82.31 mmol) and 2 M aqueous sodium hydroxide (82.31 mL, 164.63 mmol) in MeOH (200 mL) was stirred at 70 °C for 2 h. The mixture was cooled to room temperature and concentrated in vacuo. The resulting solution was diluted with water (200 mL) and 6 M aqueous HCl (ca. 30 mL) was added, resulting in the formation of a white precipitate. EtOAc (300 mL) was added and the phases were separated. The aqueous portion was extracted with more EtOAc (200 mL), and the combined organic extracts were washed with brine (200 mL), dried over MgSO4, and concentrated in vacuo to give the title compound as a white solid. LC-MS (Method B): Rt 1.15 min; MS m / z 193.4=[M+H]+(100% at 215 nm) 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). Step 4: 2-(2-adamantyl)-N-(4-amino-3-nitro-phenyl)acetamide TIFF0007797206000061.tif32170HATU (13.66 g, 35.91 mmol) was added to a cooled (0 °C) solution of 2-(2-adamantyl)acetic acid (Step 3) (6.34 g, 32.65 mmol) in DMF (60 mL). DIPEA (8.53 mL, 48.97 mmol) 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 cooled to 0 °C, and 2-nitrobenzene-1,4-diamine (5.0 g, 32.65 mmol) was added. The resulting solution was stirred at 0 °C for 1 hour, warmed to room temperature, and then diluted with water (60 mL). EtOAc (100 mL) and additional water (40 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL) and the combined organic extracts were washed with saturated aqueous sodium bicarbonate (2 x 100 mL), 10% potassium carbonate solution (2 x 100 mL) and filtered under vacuum. The biphasic filtrate was placed in a separatory funnel and the layers separated. The organic layer was passed through a phase-separating Isolute® cartridge and concentrated in vacuo to give a dark / brown / red gum. DCM (approximately 80 mL) was added and the suspension was stirred. Further DCM was added and the suspension was filtered under vacuum, washed with DCM and dried under vacuum to give the title compound as a red / brown solid. LC-MS (Method B): Rt 1.22 min; MS m / z 330.2=[M+H]+(100% at 215 nm) 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 5: 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide A solution of 2-(2-adamantyl)-N-(4-amino-3-nitro-phenyl)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 at room temperature overnight. The resulting mixture was filtered through Celite® (filter material), washed with EtOAc, and concentrated in vacuo to provide the title compound as a brown foam. LC-MS (Method B): Rt 0.97 min; MS m / z 300.2=[M+H]+(100% at 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). Step 6: 2-(2-adamantyl)-N-(2-benzyl-1H-benzimidazol-5-yl)acetamide DIPEA (4.20 mL, 24.05 mmol) was added to a mixture of 2-phenylacetic acid (1.64 g, 12.02 mmol) and HATU (5.03 g, 13.23 mmol) in DMF (30 mL), and the mixture was stirred at room temperature for 10 min. The resulting mixture was added to a solution of 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 5) (3.60 g, 12.02 mmol) in DMF (30 mL) and stirred at room temperature overnight. The mixture was partitioned between water (100 mL) and EtOAc (100 mL), and the phases were separated. The organic extract was washed with water (100 mL), resulting in the formation of a solid precipitate in the organic and aqueous layers. The aqueous portion was back-extracted with EtOAc (80 mL), and the combined organic suspension was filtered and dried in a vacuum oven to give the desired amide intermediate as a pale purple solid. The solid was suspended in acetic acid (20 mL) and stirred at 60°C for 1 hour, then at 66°C for 4 hours. The resulting mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (2 x 50 mL) and water (2 x 30 mL). The organic phase was passed through a phase-separating Isolute® cartridge and concentrated in vacuo to give the crude product as a brown, oily solid. The solid was suspended in MeCN and filtered under vacuum to give a pale pink solid. Purification of the solid by C18 reverse-phase chromatography, eluting with 10–100% MeCN in water (+0.1% ammonium hydroxide modifier), gave a pale yellow solid. The solid was dissolved in boiling MeOH (40 mL), and the mixture was cooled to room temperature overnight and then further cooled to 0°C for 30 minutes. The resulting precipitate was filtered and dried in a vacuum oven to give the title product. LC-MS (method A): Rt 2.72 min; MS m / z 400.3=[M+H]+(100% at 215 nm) 1H NMR(250 MHz,DMSO-d6,VT at 353K)δ 11.86(br.s,1H),9.52(br.s,1H),7.85(br.s,1H),7.48-7.08(m,7H),4.14(s,2) H),2.48-2.40(m,2H),2.34-2.20(m,1H),2.07-1.66(m,12H),1.61-1.48(m,2H).

[0259] Example 2.1 2-(2-Adamantyl)-N-[2-(2-phenylethyl)-1H-benzimidazol-5-yl]acetamide The title compound was prepared from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 5 of Example 2) and 3-phenylpropanoic acid in a manner analogous to Step 6 of Example 2. LC-MS (method A): Rt 2.84 min; MS m / z 414.3=[M+H]+ (99% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.10(br.s,1H),9.81(br.s,1H),7.92(br.s,1H),7.45-7.05(m,7H),3.14-3.01(m,4H),2.45(d,J=7.6 Hz, 2H), 2.27-2.20 (m, 1H), 1.98-1.91 (m, 2H), 1.89-1.65 (m, 10H), 1.56-1.48 (m, 2H).

[0260] Example 2.2 2-(2-Adamantyl)-N-[2-[methoxy(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide TIFF0007797206000064.tif40170 The title compound was prepared analogously to Step 6 of Example 2 from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 5 of Example 2) and 2-methoxy-2-phenyl-acetic acid. LC-MS (method A): Rt 2.88 min; MS m / z 430.3=[M+H]+ (99% at 215 nm) Variable temperature 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),3.39-3. 34(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).

[0261] Example 2.3 2-(2-Adamantyl)-N-[2-[(2-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide TIFF0007797206000065.tif41170 The title compound was prepared analogously to Step 6 of Example 2 from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 5 of Example 2) and 2-(2-methoxyphenyl)acetic acid. LC-MS (method A): Rt 2.85 min; MS m / z 430.4=[M+H]+ (97% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 11.95(br.s,1H),9.87-9.72(m,1H),7.91(s,1H),7.42-7.29(m,1H),7.28-7.08(m,3H),7.00(d,J=8.3 Hz,1H),6.88(td,J=7.4,1.0 Hz,1H),4.08(s,2H),3.79(s,3H),2.46-2.42(m,2H),2.27-2.20(m,1H),1.99-1.90(m,2H),1.89-1.64(m,10H),1.56-1.47(m,2H).

[0262] Example 3 2-(2-Adamantyl)-N-[2-[(R)-methylamino(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide TIFF0007797206000066.tif30170 Step 1: N-[(R)-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]-phenyl-methyl]-N-methyl-carbamate tert-butyl The title compound was prepared from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 5 of Example 2) and (2R)-2-[tert-butoxycarbonyl(methyl)amino]-2-phenylacetic acid in analogy to Step 6 of Example 2. LC-MS (method A): Rt 3.52 min; MS m / z 529.4=[M+H]+ (99% at 215 nm) Variable temperature 1H NMR(250 MHz,DMSO-d6,353K)δ 12.10(br.s,1H),9.57(s,1H),7.92(s,1H),7.54-7.13(m,7H),6.62(s,1H),2.81(s,3H), 2.49-2.45(m,2H),2.34-2.24(m,1H),2.05-1.70(m,12H),1.63-1.50(m,2H),1.42(s,9H). Step 2: 2-(2-adamantyl)-N-[2-[(R)-methylamino(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide To a solution of tert-butyl N-[(R)-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]-phenyl-methyl]-N-methyl-carbamate (Step 1) (40 mg, 0.08 mmol) in DCM (2 mL) was added TFA (0.12 mL, 1.51 mmol). The resulting solution was stirred at room temperature for 5.5 hours and then concentrated in vacuo. The crude residue was dissolved in MeOH (0.5 mL) and passed through a 1 g Isolute® SCX cartridge, eluting with MeOH (10 mL) followed by 3.5 N NH3 in MeOH (10 mL). The methanolic ammonia eluent was concentrated in vacuo to give the title compound as an off-white solid. LC-MS (method A): Rt 2.38 min; MS m / z 429.4=[M+H]+(100% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.18(s,1H),9.91-9.69(m,1H),8.04-7.77(m,1H),7.54-7.04(m,7H),4.99-4.81(m,1H), 2.47-2.41(m,2H),2.28(s,3H),2.26-2.19(m,1H),1.98-1.64(m,12H),1.55-1.46(m,2H).

[0263] Example 4 2-(1-Adamantyl)-N-[2-[(2-chloro-3-pyridyl)methyl]-1H-benzimidazol-5-yl]acetamide TIFF0007797206000067.tif28170Step 1: N-[4-[[2-(1-adamantyl)acetyl]amino]-2-amino-phenyl]-2-(2-chloro-3-pyridyl)acetamide To a solution of 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 2 of Example 1) (192 mg, 0.64 mmol), 2-(2-chloro-3-pyridyl)acetic acid (100 mg, 0.58 mmol), and DIPEA (214 μL, 1.22 mmol) in DCM (3 mL) was added HATU (244 mg, 0.64 mmol), and the mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with DCM and washed with water (10 mL) and brine (10 mL). The organic extract was separated, dried over NaSO, and concentrated in vacuo. The crude residue was purified by chromatography on silica eluting with 0-10% MeOH in DCM. Further purification by C18 reverse phase chromatography eluting with 10-100% MeCN+0.1% formic acid in H2O gave the title compound as a pale orange powder. LC-MS (Method B): Rt 1.11 min; MS m / z 453.1 / 455.2=[M+H]+(77% at 215 nm) Step 2: 2-(1-adamantyl)-N-[2-[(2-chloro-3-pyridyl)methyl]-1H-benzimidazol-5-yl]acetamide N-[4-[[2-(1-adamantyl)acetyl]amino]-2-amino-phenyl]-2-(2-chloro-3-pyridyl)acetamide (Step 1) (80%, 32 mg, 0.06 mmol) was dissolved in acetic acid (0.5 mL) and heated at 60 °C. After 1 h, excess acetic acid was removed in vacuo and the residue was dissolved in EtOAc. The mixture was washed with saturated aqueous sodium bicarbonate, brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by chromatography on silica eluting with 0-10% MeOH in DCM. Further purification by preparative HPLC (basic pH, fast elution method) afforded the title compound. LC-MS (method A): Rt 2.38 min; MS m / z 435.3 / 437.3=[M+H]+(98% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.21(br.s,1H),9.71(br.s,1H),8.34(dd,J=4.7,1.8 Hz,1H),8.00(s,1H),7.84(dd,J=7.6,1.7 Hz,1H),7.43(dd,J=7.5,4.7 Hz,1H),7.40-7.06(m,2H),4.29(s,2H),2.05(s,2H),1.93(s,3H),1.68-1.57(m,12H).

[0264] Example 5 2-(2-Adamantyl)-N-[2-[(2-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide TIFF0007797206000069.tif41170 1M BBr3 in DCM (0.28 mL, 0.28 mmol) was added dropwise to an ice-cold solution of 2-(2-adamantyl)-N-[2-[(2-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Example 2.3) (61 mg, 0.14 mmol) in DCM (3 mL). The mixture was stirred in an ice bath for 5 minutes and then at room temperature overnight. The mixture was cooled in an ice bath and treated with an additional portion of 1M BBr3 in DCM (0.14 mL, 0.14 mmol). The reaction mixture was stirred at room temperature for 90 minutes, and then water (5 mL) was added. Most of the aqueous phase was removed with a pipette, and the remaining suspension was collected by filtration. The solid was dissolved in MeOH and purified by acidic C18 reverse phase chromatography eluting with 10-100% MeCN in water (+0.1% formic acid) to give the title compound as a white solid. LC-MS (method A): Rt 2.65 min; MS m / z 416.3=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.03(br.s,1H),9.82(br.s,2H),8.08-7.72(m,1H),7.51-7.09(m,2H),7.09-7.03(m,2H),6.83(dd,J=7.1,0.9 Hz,1H),6.73(td,J=7.4,1.1 Hz,1H),4.05(s,2H),2.44(d,J=7.6 Hz,2H),2.29-2.17(m,1H),2.00-1.89(m,2H),1.89-1.63(m,10H),1.60-1.43(m,2H).

[0265] Example 5.1 2-(2-Adamantyl)-N-[2-[(4-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide TIFF0007797206000070.tif47170Step 1: 2-(2-Adamantyl)-N-[2-[(4-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide TIFF0007797206000071.tif48170 The title compound was prepared analogously to Step 6 of Example 2 from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 5 of Example 2) and 2-(4-methoxyphenyl)acetic acid. LC-MS (method A): Rt 2.78 min; MS m / z 430.4=[M+H]+ (98% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.06(s,1H),9.81(s,1H),8.04-7.75(m,1H),7.45-6.99(m,4H),6.95-6.80(m,2H),4.05(s,2H),3.71(s,3H),2.44(d,J=7.7 Hz, 2H), 2.26-2.19 (m, 1H), 1.98-1.89 (m, 2H), 1.89-1.63 (m, 10H), 1.56-1.47 (m, 2H). Step 2: 2-(2-adamantyl)-N-[2-[(4-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide The title compound was prepared analogously to Example 5 from 2-(2-adamantyl)-N-[2-[(4-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Step 1). LC-MS (method A): Rt 2.48 min; MS m / z 416.3=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.07(s,1H),9.81(s,1H),9.26(s,1H),7.91(s,1H),7.36(d,J=8.0 Hz,1H),7.26-7.15(m,1H),7.14-7.01(m,2H),6.76-6.62(m,2H),4.01(s,2H),2.45(d,J=7.5 Hz, 2H), 2.27-2.20 (m, 1H), 1.99-1.91 (m, 2H), 1.90-1.66 (m, 10H), 1.57-1.48 (m, 2H).

[0266] Example 5.2 2-(2-Adamantyl)-N-[2-[(5-chloro-2-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide TIFF0007797206000072.tif39170Step 1: 2-(2-Adamantyl)-N-[2-[(5-chloro-2-methoxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide TIFF0007797206000073.tif42170 The title compound was prepared analogously to Step 6 of Example 2 from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 5 of Example 2) and 2-(5-chloro-2-methoxy-phenyl)acetic acid. LC-MS (method A): Rt 3.01 min; MS m / z 464.3 / 466.3=[M+H]+(99% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 10.04(s,1H),8.13(d,J=1.5 Hz,1H),7.51(d,J=8.7 Hz,1H),7.41-7.30(m,3H),7.10-7.05(m,1H),4.26(s,2H),3.76(s,3H),2.49(d,J=7.7 Hz, 2H), 2.29-2.20 (m, 1H), 1.99-1.92 (m, 2H), 1.90-1.65 (m, 10H), 1.59-1.48 (m, 2H). Step 2: 2-(2-adamantyl)-N-[2-[(5-chloro-2-hydroxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide The title compound was prepared analogously to Example 5 from 2-(2-adamantyl)-N-[2-[(5-chloro-2-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Step 1). LC-MS (method A): Rt 2.56 min; MS m / z 450.3 / 452.3=[M+H]+(100% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.24(br.s,1H),10.04(br.s,1H),9.85(s,1H),7.95(s,1H),7.38(d,1H),7.29-7.05(m,3H),6.92-6.72(m,1H),4.07(s,2H),2.45(d,J=7.7 Hz, 2H), 2.27-2.20 (m, 1H), 1.99-1.90 (m, 2H), 1.89-1.65 (m, 10H), 1.57-1.47 (m, 2H).

[0267] Example 6 2,2,2-Trifluoroethyl N-[[5-[[2-(1-Adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate TIFF0007797206000074.tif30170Step 1: tert-butyl N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate TIFF0007797206000075.tif29170 The title compound was prepared analogously to Step 3 of Example 1 from 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 2 of Example 1) and 2-(tert-butoxycarbonylamino)acetic acid. LC-MS (Method B): Rt 1.11 min; MS m / z 439.2=[M+H]+(100% at 215 nm) 1H NMR(250 MHz,DMSO-d6)δ 12.03(s,1H),9.67(s,1H),7.94(s,1H),7.44-7.30(m,2H),7.31-7.10(m,1H),4.31(d,J=5.9 Hz, 2H), 2.05 (s, 2H), 1.97-1.89 (m, 3H), 1.74-1.54 (m, 12H), 1.41 (s, 9H). Step 2: 2-(1-adamantyl)-N-[2-(aminomethyl)-1H-benzimidazol-5-yl]acetamide TIFF0007797206000076.tif31170 tert-Butyl N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate (Step 1) (0.79 g, 1.8 mmol) was dissolved in 1,4-dioxane (10 mL) and treated with 4 M HCl in dioxane (635 μL, 18 mmol). After stirring at room temperature under an inert atmosphere for 3 days, an additional portion of 4 M HCl in dioxane (635 μL, 18 mmol) was added and stirring continued for 24 h. The resulting mixture was concentrated in vacuo, and the crude residue was dissolved in MeOH (approximately 10 mL). The mixture was passed through a 5 g Isolute® SCX column eluting with MeOH (20 mL) followed by 7 M NH3 in MeOH (20 mL). The methanolic ammonia eluent was concentrated in vacuo to give the title compound as a reddish-brown solid. LC-MS (method A): Rt 1.89 min; MS m / z 339.2=[M+H]+ (99% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.00(br.s,1H),9.65(s,1H),7.93(br.s,1H),7.44-7.30(m,1H),7.17(br.s,1H) ,3.88(s,2H),2.34(br.s,2H),2.05(s,2H),1.99-1.89(m,3H),1.69-1.57(m,12H). Step 3: 2,2,2-trifluoroethyl N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate A solution of 2,2,2-trifluoroethyl chloroformate (24 mg, 0.14 mmol) in DMF (0.2 mL) was added to a solution of 2-(1-adamantyl)-N-[2-(aminomethyl)-1H-benzimidazol-5-yl]acetamide (Step 2) (50 mg, 0.15 mmol) and DIPEA (0.031 mL, 0.18 mmol) in DMF (1 mL). The resulting mixture was stirred at room temperature for 90 minutes. Water (4 mL) was added, followed by EtOAc (4 mL), and the layers were separated. The organic portion was washed with water (2 × 4 mL), passed through an Isolute® cartridge, and concentrated in vacuo to give a brown oil. The oil was purified by preparative HPLC (acidic pH, standard elution) to give the title compound as an off-white powder. LC-MS (method A): Rt 2.50 min; MS m / z 465.3=[M+H]+ (97% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.15(br.s,1H),9.69(s,1H),8.29(t,J=5.8 Hz,1H),8.07-7.78(m,1H),7.51-7.05(m,2H),4.68(q,J=9.1 Hz,2H),4.41(d,J=6.0 Hz,2H),2.05(s,2H),1.98-1.86(m,3H),1.75-1.50(m,12H).

[0268] Example 7 2-(1-Adamantyl)-N-[2-[[3-(3,5-dimethylisoxazol-4-yl)phenyl]methyl]-3H-benzimidazol-5-yl]acetamide TIFF0007797206000077.tif43170Step 1: 2-[3-(3,5-dimethylisoxazol-4-yl)phenyl]acetic acid ethyl ester A solution of ethyl 2-(3-bromophenyl)acetate (360 μL, 2.06 mmol), potassium phosphate tripotassium (1310 mg, 6.17 mmol), and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (505 mg, 2.26 mmol) in 1,4-dioxane (10 mL) was degassed under a stream of N for 10 minutes, and then Pd(dppf)Cl.DCM (168 mg, 0.21 mmol) was added. The mixture was heated at 100° C. for 1 hour and then cooled to room temperature. The mixture was diluted with EtOAc and filtered through Celite® (filter material). The filtrate was absorbed onto silica and purified by chromatography on silica eluting with 0-50% EtOAc in heptane to give the title compound as a colorless viscous oil. LC-MS (Method B): Rt 1.13 min; MS m / z 260.1=[M+H]+ (99% at 215 nm) 1H NMR (250 MHz, chloroform-d) δ 7.44-7.36 (m, 1H), 7.29 (s, 1H), 7.22-7.12 (m, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.65 (s, 2H), 2.41 (s, 3H), 2.28 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). Step 2: 2-[3-(3,5-dimethylisoxazol-4-yl)phenyl]acetic acid To a solution of ethyl 2-[3-(3,5-dimethylisoxazol-4-yl)phenyl]acetate (Step 1) (231 mg, 0.89 mmol) in THF (1.5 mL), MeOH (1.5 mL), and water (1.5 mL) was added LiOH (26 mg, 1.07 mmol), and the mixture was stirred at room temperature for 2 h. Additional LiOH (11 mg, 0.45 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The resulting mixture was acidified to pH 1 using 1 M HCl and diluted with EtOAc (10 mL). The organic phase was separated, washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give the title compound as a pale yellow oil, which crystallized upon standing at room temperature. LC-MS (Method B): Rt 0.97 min; MS m / z 232.2=[M+H]+ (99% at 215 nm) 1H NMR (500 MHz, chloroform-d) δ 7.41 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.21-7.16 (m, 2H), 3.70 (s, 2H), 2.40 (s, 3H), 2.27 (s, 3H). Step 3: 2-(1-adamantyl)-N-[2-[[3-(3,5-dimethylisoxazol-4-yl)phenyl]methyl]-3H-benzimidazol-5-yl]acetamide To a solution of 2-[3-(3,5-dimethylisoxazol-4-yl)phenyl]acetic acid (Step 2) (100 mg, 0.43 mmol), DIPEA (159 μL, 0.91 mmol), and 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide (Step 2 of Example 1) (117 mg, 0.39 mmol) in DMF (2 mL) was added HATU (148 mg, 0.39 mmol), and the mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with EtOAc (20 mL), washed with water (2 × 10 mL), brine (10 mL), dried over NaSO, and concentrated in vacuo to give a dark red oil. The oil was dissolved in 4 M HCl in dioxane (2 mL) and stirred at 80 °C in a sealed tube for 1 h. After cooling to room temperature, the mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc (10 mL) and saturated aqueous sodium bicarbonate (10 mL). The phases were separated and the organic extract was washed with brine (5 mL), dried over Na2SO4, and concentrated in vacuo to give a yellow oil. The crude product was purified by preparative HPLC (basic pH, fast elution method) to give the title compound as a yellow powder. LC-MS (method A): Rt 2.68 min; MS m / z 495.3=[M+H]+(100% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.24-12.15(m,1H),9.73-9.61(m,1H),7.98-7.83(m,1H),7.43-7.10(m,6H),4.2 0(s,2H),2.39(s,3H),2.21(s,3H),2.05(s,2H),1.93(s,3H),1.67-1.58(m,12H).

[0269] Example 8 tert-Butyl N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate TIFF0007797206000080.tif37170Step 1: tert-Butyl N-[(5-nitro-1H-benzimidazol-2-yl)methyl]carbamate To a solution of 2-(tert-butoxycarbonylamino)acetic acid (2 g, 11.42 mmol) in DMF (50 mL) was added HATU (4.78 g, 12.56 mmol), followed by DIPEA (3.99 mL, 22.83 mmol). The resulting mixture was stirred under an inert atmosphere for 1 h, and 4-nitrobenzene-1,2-diamine (1.75 g, 11.42 mmol) was added. After stirring overnight at room temperature, the mixture was poured into saturated aqueous sodium bicarbonate (100 mL) and diluted with EtOAc (100 mL). The layers were separated, and the aqueous portion was back-extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with water (3 × 25 mL), brine (3 × 25 mL), dried over NaSO, and concentrated in vacuo. The residue was dissolved in acetic acid (40 mL) and stirred at 70° C. for 1 h. The resulting mixture was concentrated in vacuo, redissolved in EtOAc, and washed with saturated aqueous sodium bicarbonate (50 mL), water (3×50 mL), and brine (50 mL). The organic extract was dried over MgSO and concentrated in vacuo. The resulting crude black oil was purified by chromatography on silica eluting with 0-100% EtOAc in heptane to provide the title compound. LC-MS (Method B): Rt 0.99 min; MS m / z 293.1=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.88(s,1H),8.40(s,1H),8.09(d,J=8.9 Hz,1H),7.68(d,J=6.3 Hz,1H),7.53(s,1H),4.42(d,J=5.8 Hz, 2H), 1.41(s, 9H). Step 2: tert-butyl N-[(5-amino-1H-benzimidazol-2-yl)methyl]carbamate A solution of tert-butyl N-[(5-nitro-1H-benzimidazol-2-yl)methyl]carbamate (Step 1) (100%, 1.5 g, 5.13 mmol) in EtOH (50 mL) was degassed with nitrogen and charged with Pd / C (10%, 163.19 mg, 0.15 mmol). The mixture was placed under an atmosphere of hydrogen and stirred at room temperature overnight. The resulting mixture was filtered through Celite® (filter material) and washed with EtOH (20 mL). The filtrate was concentrated in vacuo to provide the title compound as a beige solid. LC-MS (Method B): Rt 0.46-0.63 min; MS m / z 263.1=[M+H]+(99% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 11.73-11.45(m,1H),7.28(s,1H),7.20-7.09(m,1H),6.74-6.57(m,1H),6.50-6.36(m,1H),4.85-4.58(m,2H),4.25(d,J=5.8 Hz, 2H), 1.41(s, 9H). Step 3: tert-butyl N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate A mixture of 2-(2-adamantyl)acetic acid (Step 3 of Example 2) (74 mg, 0.38 mmol), HOAt (62 mg, 0.46 mmol), and EDCI (88 mg, 0.46 mmol) in DCM (0.5 mL) was stirred for 15 min, and tert-butyl N-[(5-amino-1H-benzimidazol-2-yl)methyl]carbamate (100 mg, 0.38 mmol) was added, followed by DIPEA (0.13 mL, 0.76 mmol). The resulting mixture was stirred at room temperature for 48 h and then diluted with water (2 mL). The organic portion was separated, and the aqueous solution was further extracted with DCM (3 mL). The combined organic extracts were diluted with water (5 mL), and the resulting suspension was collected by filtration. Purification of the solid by preparative HPLC (acidic pH, fast elution method) afforded the title compound as an off-white solid. LC-MS (method A): Rt 2.77 min; MS m / z 439.4=[M+H]+ (97% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.07-12.00(m,1H),9.87-9.75(m,1H),8.00-7.85(m,1H),7.43-7.11(m,3H),4.34-4.27(m,2H),2.47- 2.43(m,2H),2.27-2.21(m,1H),1.99-1.91(m,2H),1.89-1.66(m,10H),1.57-1.49(m,2H),1.41(s,9H).

[0270] Example 9 2-(2-Adamantyl)-N-(2-tetrahydrofuran-3-yloxy-1H-benzimidazol-5-yl)acetamide TIFF0007797206000083.tif28170Step 1a: 2-Chloro-1H-benzimidazol-5-amine Iron (2.83 g, 50.61 mmol) was added to a suspension of 2-chloro-5-nitro-1H-benzimidazole (2 g, 10.12 mmol) and ammonium chloride (2.71 g, 50.61 mmol) in EtOH (60 mL) and water (20 mL), and the reaction mixture was heated at 80° C. for 1 h. After cooling to room temperature, the mixture was filtered through Celite® (filter material), and the filtrate was partitioned between EtOAc (100 mL) and saturated NH 4 Cl (100 mL). The phases were separated, and the organic portion was washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4 , and concentrated in vacuo to give the title compound as a beige foam. LC-MS (Method B): Rt 0.15 min; MS m / z 168.0 / 170.0=[M+H]+(100%ELS) 1H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 7.16 (d, J = 8.5 Hz, 1H), 6.58 (s, 1H), 6.51 (dd, J = 8.5, 1.9 Hz, 1H), 4.93 (s, 2H). Step 1b: 2-(2-adamantyl)acetyl chloride A suspension of 2-(2-adamantyl)acetic acid (Example 2, Step 3) (600 mg, 3.09 mmol) in thionyl chloride (10 mL, 137.85 mmol) was heated to reflux for 30 min. After cooling to room temperature, the solvent was removed in vacuo and the residue was azeotroped with DCM (3 × 10 mL) to give the title compound as a yellow oil. Step 2: 2-(2-adamantyl)-N-(2-chloro-1H-benzimidazol-5-yl)acetamide A solution of 2-(2-adamantyl)acetyl chloride (Step 1b) (100%, 657 mg, 3.09 mmol) in DCM (15 mL) was added dropwise over 5 min to a suspension of 2-chloro-1H-benzimidazol-5-amine (Step 1a) (518 mg, 3.09 mmol) and DIPEA (807 μL, 4.63 mmol) in DCM (15 mL). After standing at room temperature for 16 h, the mixture was diluted with water (30 mL). The phases were separated, and the aqueous portion was extracted with DCM (4 × 5 mL) and EtOAc (5 mL). The combined organic portions were concentrated in vacuo, and the resulting residue was suspended in DCM (10 mL). The solid was collected by filtration, washed with DCM, and dried under vacuum to give the title compound as a cream solid. LC-MS (Method B): Rt 1.18 min; MS m / z 344.1 / 346.1=[M+H]+(97% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 13.08(s,1H),9.93(s,1H),8.01(s,1H),7.50-7.11(m,2H),2.46(d,J=7.7 Hz, 2H), 2.28-2.20 (m, 1H), 1.97-1.90 (m, 2H), 1.87-1.66 (m, 10H), 1.57-1.45 (m, 2H). Step 3: 1:1 mixture of 2-(adamantan-2-yl)-N-(2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-5-yl)acetamide and 2-(adamantan-2-yl)-N-(2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-6-yl)acetamide TIFF0007797206000087.tif59170 2-(Chloromethoxy)ethyl-trimethylsilane (39 μL, 0.22 mmol) was added to an ice-cold suspension of 2-(2-adamantyl)-N-(2-chloro-1H-benzimidazol-5-yl)acetamide (Step 2) (50 mg, 0.15 mmol) and potassium carbonate (60 mg, 0.44 mmol) in DMF (2 mL). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. An additional portion of 2-(chloromethoxy)ethyl-trimethylsilane (39 μL, 0.22 mmol) was added, and stirring was continued overnight at room temperature. The resulting mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (5 mL), passed through a phase-separating Isolute® cartridge, and concentrated in vacuo to give an orange oil. The oil was purified by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in heptane to give the title compound. LC-MS (Method B): Rt 1.54 and 1.57 min; MS m / z 474.2 / 476.2 = [M+H]+ (89% at 215 nm) Step 4: 2-(2-adamantyl)-N-(2-tetrahydrofuran-3-yloxy-1H-benzimidazol-5-yl)acetamide A 1:1 mixture of 2-(adamantan-2-yl)-N-(2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-5-yl)acetamide and 2-(adamantan-2-yl)-N-(2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-6-yl)acetamide (Step 3) (50 mg, 0.11 mmol) and tetrahydrofuran-3-ol (0.085 mL, 0.11 mmol) were dissolved in DMF (1 mL). NaH, 60% dispersion in mineral oil (6 mg, 0.16 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h and then at 55 °C for 3 h. An additional portion of NaH-pretreated tetrahydrofuran-3-ol (0.085 mL, 0.11 mmol), a 60% dispersion of mineral oil (6 mg, 0.16 mmol) in DMF (1 mL) was added, and the mixture was stirred at 55° C. for 24 hours. After cooling to room temperature, the reaction was quenched with water, and the mixture was partitioned between EtOAc (20 mL) and water (20 mL). The layers were separated, and the organic portion was washed with brine (20 mL), dried over NaSO, and concentrated in vacuo. The crude residue was dissolved in DCM (10 mL) and treated with TFA (1 mL). After stirring for 24 hours, the mixture was concentrated in vacuo. The crude residue was dissolved in MeOH (1 mL) and passed through a 1 g Isolute® SCX column, eluting with MeOH (10 mL) followed by 7N NH in MeOH (10 mL). The methanolic ammonia eluent was concentrated in vacuo and the residue was further purified by preparative HPLC under the following conditions to give the title compound as a white solid. A Gilson LC system was used with a Waters CSH column (19 mm x 100 mm, 5 μM, room temperature) and a gradient of 5-25% over 2 min (A = 0.2% ammonium hydroxide in water, B = 0.2% ammonium hydroxide in acetonitrile), followed by 25-40% for 14 min, then 95% B for 2 min, with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector. LC-MS (method A): Rt 3.07 min; MS m / z 396.3=[M+H]+ (97% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 9.72(s,1H),7.73(s,1H),7.17(d,J=8.5 Hz,1H),7.07(d,J=8.3 Hz,1H),5.55-5.49(m,1H),3.89(d,J=3.0 Hz,2H),3.88-3.83(m,1H),3.78(td,J=8.4,4.5 Hz,1H),2.43(d,J=7.6 Hz,2H),2.31-2.19(m,2H),2.13-2.06(m,1H),1.98-1.91(m,2H),1.88 -1.84(m,1H),1.83-1.78(m,3H),1.77-1.66(m,6H),1.55-1.47(m,2H).

[0271] Example 10 N-(cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide TIFF0007797206000088.tif29170Step 1: 2-[(2-methoxyphenyl)methyl]-1,3-benzoxazole-5-carboxylate methyl ester To a solution of 2-(2-methoxyphenyl)acetic acid (239 mg, 1.44 mmol) in DMF (6 mL), DIPEA (0.25 mL, 1.44 mmol), HATU (546 mg, 1.44 mmol), followed by methyl 3-amino-4-hydroxybenzoate (200 mg, 1.2 mmol) were added, and the mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (2 × 10 mL). The organic extract was washed with brine, dried over NaSO, and concentrated in vacuo. The crude residue was dissolved in acetic acid (6 mL) and heated at 120 °C overnight. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was dissolved in EtOAc and washed with saturated aqueous sodium bicarbonate (10 mL), brine (10 mL), dried over NaSO, and concentrated in vacuo. The crude residue was absorbed onto silica and purified by chromatography on silica eluting with 0-50% EtOAc in heptane to afford the title compound. LC-MS (Method B): Rt 1.20 min; MS m / z 298.0=[M+H]+(93% at 215 nm) 1H NMR(250 MHz,chloroform-d)δ 8.36(d,J=1.6 Hz,1H),8.04(dd,J=8.5,1.6 Hz,1H),7.48(d,J=8.6 Hz,1H),7.32-7.25(m,2H),7.00-6.88(m,2H),4.31(s,2H),3.94(s,3H),3.81(s,3H). Step 2: 2-[(2-methoxyphenyl)methyl]-1,3-benzoxazole-5-carboxylic acid To a solution of methyl 2-[(2-methoxyphenyl)methyl]-1,3-benzoxazole-5-carboxylate (Step 1) (95%, 73 mg, 0.23 mmol) in THF (0.33 mL) / MeOH (0.33 mL) / water (0.33 mL) was added LiOH (8 mg, 0.35 mmol), and the mixture was heated at 50 °C for 1 h. After cooling to room temperature, the mixture was acidified to pH 2 using 1 M HCl solution. The resulting mixture was diluted with water (5 mL) and extracted with IPA / CHCl (1:1, 2 × 5 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo to give the title compound as a pale yellow solid. LC-MS (Method B): Rt 1.09 min; MS m / z 284.0=[M+H]+ (92% at 215 nm) Step 3: N-(cycloheptylmethyl)-2-[(2-methoxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide To a solution of 2-[(2-methoxyphenyl)methyl]-1,3-benzoxazole-5-carboxylic acid (Step 2) (96%, 48 mg, 0.16 mmol) in DMF (1 mL) was added DIPEA (34 μL, 0.2 mmol), HATU (74 mg, 0.2 mmol), and cycloheptylmethanamine (28 μL, 0.2 mmol), and the mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with EtOAc and washed with water (5 mL) and brine (5 mL). The organic portion was separated, dried over NaSO, and concentrated in vacuo. The crude residue was absorbed onto silica and purified by chromatography on silica eluting with 0–50% EtOAc in heptane to afford the title compound as a colorless glass. LC-MS (Method B): Rt 1.31 min; MS m / z 393.1=[M+H]+ (99% at 215 nm) 1H NMR(500 MHz,chloroform-d)δ 8.01(d,J=1.5 Hz,1H),7.78(dd,J=8.5,1.8 Hz,1H),7.48(d,J=8.5 Hz,1H),7.32-7.27(m,2H),6.95(td,J=7.5,1.0 Hz,1H),6.91(d,J=8.2 Hz,1H),6.16(br.s,1H),4.30(s,2H),3.81(s,3H),3.32(t,J=6.2 Hz,2H),1.82-1.75(m,3H),1.72-1.65(m,2H),1.61-1.56(m,2H),1.53-1.42(m,4H),1.29-1.22(m,2H). Step 4: N-(cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide The title compound was prepared from N-(cycloheptylmethyl)-2-[(2-methoxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide (Step 3) and 1 M BBr3 in DCM in analogy to Example 5. LC-MS (method A): Rt 3.61 min; MS m / z 379.3=[M+H]+ (99% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 9.59(s,1H),8.50(t,J=5.8 Hz,1H),8.13(d,J=1.4 Hz,1H),7.85(dd,J=8.5,1.7 Hz,1H),7.70(d,J=8.4 Hz,1H),7.20(dd,J=7.5,1.5 Hz,1H),7.12(td,J=7.9,1.7 Hz,1H),6.83(dd,J=8.1,1.0 Hz,1H),6.78(td,J=7.4,1.1 Hz,1H),4.24(s,2H),3.11(t,J=6.3 Hz,2H),1.80-1.69(m,3H),1.66-1.60(m,2H),1.57-1.51(m,2H),1.50-1.44(m,2H),1.42-1.34(m,2H),1.21-1.13(m,2H).

[0272] Example 11 2-(1-Adamantyl)-N-[3-amino-2-[(2-hydroxyphenyl)methyl]indazol-6-yl]acetamide TIFF0007797206000092.tif33170Step 1: 2-[(2-methoxyphenyl)methyl]-6-nitro-indazol-3-amine TIFF0007797206000093.tif34170 DIPEA (1.51 mL, 8.67 mmol) was added to a mixture of 2-fluoro-4-nitro-benzonitrile (240 mg, 1.44 mmol) and (2-methoxyphenyl)methylhydrazine hydrochloride (545 mg, 2.89 mmol) in tert-butanol (5 mL). The resulting mixture was stirred at room temperature for 1 h and then heated to 140 °C overnight. After cooling to room temperature and standing for 3 days, the mixture was diluted with saturated aqueous sodium bicarbonate (20 mL) and EtOAc (20 mL). The phases were separated, and the organic portion was washed with saturated aqueous sodium bicarbonate (20 mL), brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative HPLC (acidic pH, standard method) to give the title compound as a bright red solid. LC-MS (Method B): Rt 1.10 min; MS m / z 299.0=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.17(d,J=1.7 Hz,1H),7.89(d,J=9.0 Hz,1H),7.41(dd,J=9.1,2.0 Hz,1H),7.27(td,J=8.2,1.6 Hz,1H),7.05(d,J=7.8 Hz,1H),6.84(td,J=6.7,0.9 Hz,1H),6.61(s,2H),6.54(dd,J=7.5,1.4 Hz,1H),5.40(s,2H),3.85(s,3H). Step 2: tert-butyl N-tert-butoxycarbonyl-N-[2-[(2-methoxyphenyl)methyl]-6-nitro-indazol-3-yl]carbamate TIFF0007797206000094.tif53170A solution of 2-[(2-methoxyphenyl)methyl]-6-nitro-indazol-3-amine (Step 1) (90%, 67 mg, 0.2 mmol) in DCM (5 mL) was treated with Boc anhydride (97 mg, 0.45 mmol) followed by DMAP (5 mg, 0.04 mmol) and stirred at room temperature for 18 h. Additional Boc anhydride (40 mg) was added and the reaction mixture was stirred for an additional 3 h. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc (15 mL) and 1:1 water:brine (15 mL). The phases were separated and the aqueous portion was back-extracted with EtOAc (15 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-80% EtOAc in heptane afforded the title compound as a yellow / orange solid. LC-MS (Method B): Rt 1.42 min; MS m / z 499.1=[M+H]+ (99% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.69-8.67(m,1H),7.86(dd,J=9.1,1.9 Hz,1H),7.80(d,J=9.2 Hz,1H),7.35-7.29(m,1H),7.12(dd,J=7.6,1.5 Hz,1H),7.07(d,J=8.1 Hz,1H),6.90(t,J=7.3 Hz,1H),5.56(s,2H),3.81(s,3H),1.21(s,18H). Step 3: tert-butyl N-[6-amino-2-[(2-methoxyphenyl)methyl]indazol-3-yl]-N-tert-butoxycarbonyl-carbamate A mixture of tert-butyl N-tert-butoxycarbonyl-N-[2-[(2-methoxyphenyl)methyl]-6-nitro-indazol-3-yl]carbamate (Step 2) (85%, 135 mg, 0.23 mmol) and EtOH (8 mL) was placed under a nitrogen atmosphere. Pd / C (10%, 24.41 mg, 0.02 mmol) was added, and the resulting mixture was placed under a hydrogen atmosphere and stirred at room temperature for 4 hours. The resulting mixture was filtered through Celite® (filter material), washed with EtOAc, and the filtrate was concentrated in vacuo to give the title compound as a pale orange foam. LC-MS (Method B): Rt 1.19 min; MS m / z 469.3=[M+H]+(90% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 7.28-7.23(m,1H),7.11(d,J=8.8 Hz,1H),7.02(dd,J=7.8,0.7 Hz,1H),6.93(dd,J=5.9,1.8 Hz,1H),6.84(td,J=7.4,0.9 Hz,1H),6.57(dd,J=8.9,1.8 Hz,1H),6.45(d,J=1.1 Hz,1H),5.25(s,2H),5.12(s,2H),3.81(s,3H),1.23(s,18H). Step 4: tert-butyl N-[6-[[2-(1-adamantyl)acetyl]amino]-2-[(2-methoxyphenyl)methyl]indazol-3-yl]-N-tert-butoxycarbonyl-carbamate TIFF0007797206000096.tif54170 The title compound was prepared from tert-butyl N-[6-amino-2-[(2-methoxyphenyl)methyl]indazol-3-yl]-N-tert-butoxycarbonyl-carbamate (Step 3) and 2-(1-adamantyl)acetic acid in analogy to Step 1 of Example 1. LC-MS (Method B): Rt 1.51 min; MS m / z 645.4=[M+H]+(95% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 9.78(s,1H),8.05(s,1H),7.37(dd,J=8.9,0.4 Hz,1H),7.30-7.25(m,1H),7.12(dd,J=9.0,1.6 Hz,1H),7.04(d,J=7.9 Hz,1H),6.99(dd,J=7.6,1.6 Hz,1H),6.85(td,J=7.5,1.0 Hz, 1H), 5.38 (s, 2H), 3.82 (s, 3H), 2.09 (s, 2H), 1.96-1.92 (m, 3H), 1.70-1.57 (m, 12H), 1.21 (s, 18H). Step 5: 2-(1-adamantyl)-N-[3-amino-2-[(2-methoxyphenyl)methyl]indazol-6-yl]acetamide TIFF0007797206000097.tif35170 The title compound was prepared from tert-butyl N-[6-[[2-(1-adamantyl)acetyl]amino]-2-[(2-methoxyphenyl)methyl]indazol-3-yl]-N-tert-butoxycarbonyl-carbamate (Step 4) and TFA in analogy to Step 2 of Example 3. LC-MS (method A): Rt 2.79 min; MS m / z 445.3=[M+H]+ (91% at 215 nm) 1H NMR(500 MHz,MeOH-d4)δ 7.54-7.52(m,1H),7.46-7.43(m,1H),7.16(td,J=8.2,1.7 Hz,1H),6.90(d,J=7.9 Hz,1H),6.79-6.73(m,2H),6.67(dd,J=7.6,1.5 Hz,1H),5.23(s,2H),3.80(s,3H),2.01(s,2H),1.87(br.s,3H),1.67-1.58(m,12H). Step 6: 2-(1-adamantyl)-N-[3-amino-2-[(2-hydroxyphenyl)methyl]indazol-6-yl]acetamide The title compound was prepared from 2-(1-adamantyl)-N-[3-amino-2-[(2-methoxyphenyl)methyl]indazol-6-yl]acetamide (Step 5) and 1 M BBr3 in DCM in analogy to Example 5. LC-MS (method A): Rt 2.60 min; MS m / z 431.3=[M+H]+ (95% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 9.56(s,1H),7.66(d,J=1.0 Hz,1H),7.51(d,J=8.8 Hz,1H),7.13-7.08(m,1H),6.88(dd,J=7.6,1.5 Hz,1H),6.82(dd,J=8.0,0.7 Hz,1H),6.73-6.69(m,2H),6.28(br.s,1H),5.23(s,2H),4.02(br.s,2H),2.05(s,2H),1.93(s,3H),1.68-1.58(m,12H).

[0273] Example 12 2-Cyclohexyl-N-(2-isopropyl-1,3-benzoxazol-5-yl)acetamide A solution of 2-isopropyl-1,3-benzoxazol-5-amine (50 mg, 0.28 mmol) in DCM (2 mL) was treated with DIPEA (0.1 mL, 0.57 mmol) and the mixture was stirred at room temperature. To this mixture was added 2-cyclohexylacetyl chloride (55 mg, 0.34 mmol) dropwise and stirring was continued at room temperature for 1 hour. The resulting mixture was diluted with DCM and washed with Na2CO3 (3 x 5 mL). The organic portion was dried (hydrophobic frit) and concentrated in vacuo. Purification of the crude product by preparative HPLC (basic pH, fast elution method) gave the title compound as an off-white solid. LC-MS (method A): Rt 3.56 min; MS m / z 301.1=[M+H]+ (94% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 9.95(s,1H),8.00(d,J=1.9 Hz,1H),7.56(d,J=8.7 Hz,1H),7.45(dd,J=8.8,2.0 Hz,1H),3.27-3.18(m,1H),2.19(d,J=7.1 Hz,2H),1.83-1.73(m,1H),1.73-1.57(m,5H),1.36(d,J=6.9 Hz,6H),1.30-1.08(m,3H),1.03-0.93(m,2H).

[0274] Example 13 N-(cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]indazole-6-carboxamide TIFF0007797206000099.tif36170Step 1: N-(cycloheptylmethyl)-1H-indazole-6-carboxamide A solution of 1H-indazole-6-carboxylic acid (200 mg, 1.23 mmol) in DMF (4 mL) was treated with cycloheptylmethanamine (0.2 mL, 1.36 mmol), DIPEA (0.26 mL, 1.48 mmol), followed by HATU (563 mg, 1.48 mmol), and the resulting mixture was stirred at room temperature for 30 min. The mixture was diluted with EtOAc (30 mL) and water (30 mL), and the phases were separated. The organic portion was washed with water (2 × 30 mL), brine (30 mL), dried over NaSO, and concentrated in vacuo. Purification of the crude product by C18 reverse-phase chromatography, eluting with 10–100% MeCN in water (0.1% formic acid modifier), afforded the title compound as a pale orange solid. LC-MS (method B): Rt 1.12 min; MS m / z 272.2=[M+H]+(100% at 215 nm) 1H NMR(250 MHz,DMSO-d6)δ 13.31(s,1H),8.55(t,J=5.7 Hz,1H),8.13(s,1H),8.05-7.97(m,1H),7.80(dd,J=8.5,0.6 Hz,1H),7.57(dd,J=8.5,1.4 Hz, 1H), 3.12 (t, J=6.3 Hz, 2H), 1.86-1.30 (m, 11H), 1.27-1.07 (m, 2H). Step 2: N-(cycloheptylmethyl)-2-[(2-methoxyphenyl)methyl]indazole-6-carboxamide TIFF0007797206000101.tif38170 N-(cycloheptylmethyl)-1H-indazole-6-carboxamide (Step 1) (100 mg, 0.37 mmol), 1-(chloromethyl)-2-methoxy-benzene (154 μL, 1.11 mmol), sodium iodide (166 mg, 1.11 mmol), and potassium carbonate (255 mg, 1.84 mmol) in 1,4-dioxane (3 mL) in a sealed tube were heated to 110° C. overnight. The resulting mixture was diluted with EtOAc (15 mL) and water (15 mL). The phases were separated, and the organic portion was washed with water (15 mL), brine (15 mL), and concentrated in vacuo to give a yellow oil. Purification of the crude product by C18 reverse phase chromatography eluting with 10-100% MeCN in water (0.1% formic acid modifier) ​​afforded the title compound as a white solid. LC-MS (method A): Rt 3.90 min; MS m / z 392.3=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.44(t,J=5.7 Hz,1H),8.39(d,J=0.7 Hz,1H),8.14-8.10(m,1H),7.73(dd,J=8.8,0.7 Hz,1H),7.47(dd,J=8.7,1.4 Hz,1H),7.33(td,J=8.3,1.8 Hz,1H),7.06(d,J=7.7 Hz,1H),7.00(dd,J=7.5,1.7 Hz,1H),6.91(td,J=7.5,0.9 Hz,1H),5.63(s,2H),3.83(s,3H),3.11(t,J=6.3 Hz, 2H), 1.81-1.68 (m, 3H), 1.67-1.59 (m, 2H), 1.58-1.33 (m, 6H), 1.24-1.12 (m, 2H). Step 3: N-(cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]indazole-6-carboxamide The title compound was prepared from N-(cycloheptylmethyl)-2-[(2-methoxyphenyl)methyl]indazole-6-carboxamide (Step 2) and 1 M BBr3 in DCM in analogy to Example 5. LC-MS (method A): Rt 3.54 min; MS m / z 378.2=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 9.86(s,1H),8.44(t,J=5.8 Hz,1H),8.37(d,J=0.7 Hz,1H),8.15-8.10(m,1H),7.73(dd,J=8.8,0.8 Hz,1H),7.47(dd,J=8.7,1.4 Hz,1H),7.15(td,J=8.0,1.7 Hz,1H),7.00(dd,J=7.6,1.6 Hz,1H),6.87(dd,J=8.1,1.0 Hz,1H),6.76(td,J=7.5,1.1 Hz,1H),5.59(s,2H),3.11(t,J=6.3 Hz,2H),1.82-1.68(m,3H),1.68-1.59(m,2H),1.58-1.44(m,4H),1.44-1.34(m,2H),1.22-1.14(m,2H).

[0275] Example 14 2-(1-Adamantyl)-N-(2-benzyl-3H-imidazo[4,5-c]pyridin-6-yl)acetamide TIFF0007797206000102.tif34170Step 1a: 2-(1-adamantyl)acetamide TIFF0007797206000103.tif21170 2-(1-Adamantyl)acetic acid (2.5 g, 12.87 mmol) was dissolved in thionyl chloride (10.21 mL, 140.70 mmol) and heated at 50 °C for 30 min. The resulting mixture was concentrated in vacuo and azeotroped with DCM to remove the thionyl chloride. The residue was cooled in an ice bath and treated dropwise with concentrated ammonium hydroxide (12 mL, 12.87 mmol) with stirring for 2 h. The resulting solid was sonicated, collected by filtration, and washed with excess water. The gummy solid was dried under vacuum overnight to give a white solid. The solid was suspended in EtOAc (200 mL) and sonicated until dissolved. The organic mixture was washed with 2M sodium carbonate solution (2×50 mL), water (2×50 mL), brine (10 mL), filtered through a hydrophobic frit and concentrated in vacuo to give the title compound as a white solid. LC-MS (Method B): Rt 1.01 min; MS m / z 194.1=[M+H]+ (88% at 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 7.12 (s, 1H), 6.62 (s, 1H), 1.95-1.88 (m, 3H), 1.78 (s, 2H), 1.70-1.49 (m, 12H). Step 1b: tert-butyl N-(2-bromo-5-methyl-4-pyridyl)carbamate To a solution of 2-bromo-5-nitro-pyridin-4-amine (0.9 g, 4.13 mmol) in DMF (8 mL) was added a 60% dispersion of NaH in mineral oil (182 mg, 4.54 mmol) at 0 °C, and the mixture was stirred for 15 min. A solution of Boc anhydride (1.08 g, 4.95 mmol) in DMF (8 mL) was added dropwise, and the mixture was allowed to warm to room temperature and stirred for 3 h. An additional portion of Boc anhydride (0.54 g, 2.48 mmol) in DMF (1 mL) was added, and stirring was continued overnight at room temperature. The mixture was re-treated portionwise with solid Boc anhydride (0.54 g, 2.48 mmol) and stirred overnight at room temperature. Water (30 mL) and EtOAc (30 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (30 mL), and the combined organic extracts were washed with water (3 × 20 mL), saturated aqueous sodium bicarbonate (3 × 20 mL), brine (20 mL), dried over NaSO, and concentrated in vacuo. Purification by chromatography on silica eluting with 0–100% EtOAc in heptane gave a white gummy solid. The solid was dissolved in MeOH and purified by C18 reverse-phase chromatography eluting with 10–100% MeCN in water containing 0.1% formic acid to give the title compound as a white solid. LC-MS (Method B): Rt 1.32 min; MS m / z 318.0 / 320.0=[M+H]+(100% at 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.92 (s, 1H), 8.15 (s, 1H), 1.48 (s, 9H). Step 2: tert-butyl N-[2-[[2-(1-adamantyl)acetyl]amino]-5-nitro-4-pyridyl]carbamate TIFF0007797206000105.tif36170 tert-Butyl N-(2-bromo-5-nitro-4-pyridyl)carbamate (Step 1b) (526 mg, 1.65 mmol), 2-(1-adamantyl)acetamide (Step 1a) (640 mg, 3.31 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (71 mg, 0.5 mmol), and potassium phosphate (702 mg, 3.31 mmol) were suspended in dioxane (18 mL). The mixture was placed under a nitrogen atmosphere, treated with copper iodide (94 mg, 0.5 mmol), and heated at 110 °C for 1 hour using microwave radiation. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (10 mL) and water (10 mL), the organic layer separated, washed with water (10 mL), passed through a hydrophobic frit and concentrated in vacuo. The resulting solid was purified by chromatography on silica eluting with 0-100% EtOAc in heptane, followed by trituration with diethyl ether to give the title compound as a pale yellow solid. LC-MS (Method B): Rt 1.57 min; MS m / z 431.2=[M+H]+(100% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 10.91-10.74(m,1H),9.97-9.82(m,1H),9.01-8.86(m,2H),2.25-2.13(m,2H),1.98-1.86(m,3H),1.72-1.54(m,12H),1.52-1.43(m,9H). Step 3: tert-butyl N-[2-[[2-(1-adamantyl)acetyl]amino]-5-amino-4-pyridyl]carbamate TIFF0007797206000106.tif33170 The title compound was prepared analogously to Example 11, Step 3 from tert-butyl N-[2-[[2-(1-adamantyl)acetyl]amino]-5-nitro-4-pyridyl]carbamate (Step 2) and 10% Pd / C. LC-MS (Method B): Rt 1.09 min; MS m / z 401.7=[M+H]+ (97% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 9.73(s,1H),8.54(s,1H),8.34(s,1H),7.67(s,1H),4.83(s,2H),2.05(s,2H),1.95-1.87(m,3H),1.70-1.54(m,12H),1.49(s,9H). Step 4: tert-butyl N-[2-[[2-(1-adamantyl)acetyl]amino]-5-[(2-phenylacetyl)amino]-4-pyridyl]carbamate 2-Phenylacetic acid (0.07 g, 0.5 mmol), HATU (0.21 g, 0.55 mmol), and DIPEA (0.26 mL, 1.5 mmol) were dissolved in DMF (1 mL) and stirred at room temperature for 10 minutes. To this mixture was added a solution of tert-butyl N-[2-[[2-(1-adamantyl)acetyl]amino]-5-amino-4-pyridyl]carbamate (Step 3) (0.2 g, 0.5 mmol) in DMF (2 mL), and stirring was continued at room temperature overnight. An additional portion of a solution containing 2-phenylacetic acid (0.035 g, 0.25 mmol), HATU (0.11 g, 0.28 mmol), and DIPEA (0.13 mL, 0.75 mmol) in DMF (0.5 mL) pre-stirred for 10 min was added to the main reaction mixture, and stirring was continued for 2 h. The resulting mixture was partitioned between water (8 mL) and EtOAc (8 mL). The organic layer was separated, washed with 10% potassium carbonate solution (2 × 10 mL), water (2 × 10 mL), and passed through a hydrophobic frit. The filtrate was concentrated in vacuo, and the crude material was purified by chromatography on silica, eluting with 0–100% EtOAc in heptane, to give a brown oil. The oil was purified by C18 reverse-phase chromatography, eluting with 10–100% MeCN in water containing 0.2% ammonium hydroxide, to give the title compound as a white solid. LC-MS (Method B): Rt 1.37 min; MS m / z 519.8=[M+H]+ (97% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 10.18(s,1H),9.56(s,1H),8.74-8.53(m,2H),8.14-8.02(m,1H),7.39-7.19(m,5H),3.77- 3.56 (m, 2H), 2.18-2.08 (m, 2H), 1.98-1.84 (m, 3H), 1.72-1.54 (m, 12H), 1.54-1.44 (m, 9H). Step 5: N-[6-[[2-(1-adamantyl)acetyl]amino]-4-amino-3-pyridyl]-2-phenyl-acetamide TIFF0007797206000108.tif43170 The title compound was prepared analogously to Step 2 of Example 6 from tert-butyl N-[2-[[2-(1-adamantyl)acetyl]amino]-5-[(2-phenylacetyl)amino]-4-pyridyl]carbamate (Step 5) and 4M HCl. LC-MS (Method B): Rt 1.03 min; MS m / z 419.7=[M+H]+ (99% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 9.81(s,1H),9.23(s,1H),7.77(s,1H),7.50(s,1H),7.37-7.20(m,5H),5.83-5.77( m,2H),3.66-3.60(m,2H),2.12-2.03(m,2H),1.95-1.87(m,3H),1.70-1.52(m,12H). Step 6: 2-(1-adamantyl)-N-(2-benzyl-3H-imidazo[4,5-c]pyridin-6-yl)acetamide A solution of N-[6-[[2-(1-adamantyl)acetyl]amino]-4-amino-3-pyridyl]-2-phenyl-acetamide (Step 5) (68 mg, 0.16 mmol) in acetic acid (1 mL) was placed under a nitrogen atmosphere in a sealed vessel and heated at 120° C. for 2 days. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (5 mL) and washed with saturated aqueous sodium bicarbonate (5 mL). The layers were separated and the organic portion was passed through a phase-separating Isolute® cartridge and concentrated in vacuo. Purification of the resulting oil by C18 reverse-phase chromatography, eluting with 10-100% MeCN (+0.2% ammonium hydroxide) in water, afforded the title compound as a white solid. LC-MS (method A): Rt 2.86 min; MS m / z 401.3=[M+H]+ (98% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.51(br.s,1H),10.23-10.00(m,1H),8.54-8.45(m,1H),8.24-8.11(m,1H),7.40-7.1 8(m,5H),4.23-4.13(m,2H),2.19-2.10(m,2H),1.97-1.86(m,3H),1.72-1.50(m,12H).

[0276] Example 15 2-Benzyl-N-(cycloheptylmethyl)imidazo[1,2-a]pyridine-7-carboxamide TIFF0007797206000109.tif32170Step 1: 2-Benzyl-7-bromo-imidazo[1,2-a]pyridine To a solution of 4-bromopyridin-2-amine (150 mg, 0.87 mmol) in EtOH (2 mL) was added 1-bromo-3-phenyl-propan-2-one (203 mg, 0.95 mmol), followed by NaHCO (219 mg, 2.6 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The crude residue was partitioned between EtOAc (20 mL) and water (20 mL), and the organic portion was separated, washed with brine (20 mL), dried over NaSO, and concentrated in vacuo. Purification of the crude product by C reverse-phase chromatography eluting with 0–100% MeCN in water (0.1% formic acid modifier) ​​afforded the title compound as an off-white solid. LC-MS (Method B): Rt 0.85 min; MS m / z 287.0 / 289.0=[M+H]+(100% at 215 nm) 1H NMR(250 MHz,DMSO-d6)δ 8.43(dd,J=7.2,0.7 Hz,1H),7.82-7.72(m,1H),7.67-7.65(m,1H),7.33-7.15(m,5H),6.99(dd,J=7.2,2.0 Hz,1H),4.02(s,2H). Step 2: 2-benzyl-N-(cycloheptylmethyl)imidazo[1,2-a]pyridine-7-carboxamide All reagents were placed in the COware apparatus (carbon monoxide generating system) according to the following procedure; Chamber A was charged with 2-benzyl-7-bromo-imidazo[1,2-a]pyridine (Step 1) (110 mg, 0.38 mmol), sodium carbonate (122 mg, 1.15 mmol), and XantPhos Pd-G3 (3rd generation G3 Buchwald precatalyst) (36 mg, 0.04 mmol). Toluene (4 mL) was added, followed by cycloheptylmethanamine (73 mg, 0.57 mmol). The reaction mixture was degassed with nitrogen for 5 minutes. To chamber B, formic acid (43 μL, 1.15 mmol) in toluene (5 mL) was added, followed by mesyl chloride (89 μL, 1.15 mmol). Both chambers were degassed with nitrogen, sealed, and TEA (320 μL, 2.3 mmol) was added to chamber B to generate carbon monoxide. The COware apparatus was heated at 100 °C overnight. The resulting mixture was concentrated in vacuo, dissolved in 20:1 EtOAc:THF solution (25 mL), and washed with water (2 x 25 mL). The organic portion was concentrated in vacuo and purified by preparative HPLC (basic pH, fast elution method) to give the title compound as a white solid. LC-MS (method A): Rt 2.40 min; MS m / z 362.2=[M+H]+ (99% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.57(t,J=5.7 Hz,1H),8.49(dd,J=7.1,0.8 Hz,1H),8.01-7.99(m,1H),7.72(s,1H),7.33-7.27(m,4H),7.24(dd,J=7.1,1.7 Hz,1H),7.22-7.17(m,1H),4.07(s,2H),3.11(t,J=6.3 Hz,2H),1.80-1.67(m,3H),1.67-1.58(m,2H),1.58-1.32(m,6H),1.21-1.12(m,2H).

[0277] Example 16 2-(1-Adamantyl)-N-(2-benzylindazol-6-yl)acetamide TIFF0007797206000111.tif33170Step 1: 2-(1-Adamantyl)-N-(1H-indazol-6-yl)acetamide A solution of 1H-indazol-6-amine (250 mg, 1.88 mmol), HATU (785 mg, 2.07 mmol), DIPEA (0.49 mL, 2.82 mmol), and 2-(1-adamantyl)acetic acid (365 mg, 1.88 mmol) in DMF (2 mL) was stirred for 2 h. The resulting mixture was partitioned between EtOAc (25 mL) and water (25 mL). The organic layer was separated, washed with water (25 mL), brine (2 × 25 mL), dried over MgSO, and concentrated in vacuo to give a brown solid. The solid was purified by chromatography on silica eluting with 0–100% EtOAc in heptane to give the title compound as an off-white solid. LC-MS (Method B): Rt 1.21 min; MS m / z 311.0=[M+H]+(85% at 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 12.84 (s, 1H), 9.87 (s, 1H), 8.16 (s, 1H), 7.94 (s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.06 (dd, J = 8.7, 1.7 Hz, 1H), 2.09 (s, 2H), 1.96-1.90 (m, 3H), 1.70-1.57 (m, 12H). Step 2: 2-(1-Adamantyl)-N-(2-benzylindazol-6-yl)acetamide Bromomethylbenzene (0.04 mL, 0.36 mmol) was added to an ice-cold suspension of 2-(1-adamantyl)-N-(1H-indazol-6-yl)acetamide (Step 1) (100 mg, 0.32 mmol) and potassium carbonate (134 mg, 0.97 mmol) in 1,4-dioxane (2 mL) and heated at 110 °C for 20 h. The resulting mixture was cooled to room temperature and partitioned between DCM (10 mL) and water (10 mL). The organic layer was passed through a hydrophobic frit and concentrated in vacuo. The resulting red oil was purified by preparative HPLC (acidic pH, fast elution method) to give the title compound as an off-white solid. LC-MS (method A): Rt 4.09 min; MS m / z 400.3=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 9.72(s,1H),8.39-8.31(m,1H),8.05(s,1H),7.59(d,J=8.8 Hz,1H),7.37-7.31(m,2H),7.31-7.27(m,3H),7.06(dd,J=9.0,1.7 Hz,1H),5.58(s,2H),2.07(s,2H),1.93(s,3H),1.70-1.56(m,12H).

[0278] Example 17 2-(1-Adamantyl)-N-(2-benzyl-3-methyl-indazol-6-yl)acetamide TIFF0007797206000113.tif33170Step 1: 2-(1-Adamantyl)-N-(3-methyl-1H-indazol-6-yl)acetamide TIFF0007797206000114.tif32170 The title compound was prepared from 2-(1-adamantyl)acetic acid and 3-methyl-1H-indazol-6-amine in a manner analogous to Step 1 of Example 16. LC-MS (Method B): Rt 1.23 min; MS m / z 325.0=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.38(s,1H),9.82(s,1H),8.06-8.04(m,1H),7.55(d,J=8.6 Hz,1H),7.03(dd,J=8.6,1.6 Hz, 1H), 2.42 (s, 3H), 2.08 (s, 2H), 1.97-1.90 (m, 3H), 1.70-1.57 (m, 12H). Step 2: 2-(1-adamantyl)-N-(2-benzyl-3-methyl-indazol-6-yl)acetamide The title compound was prepared from 2-(1-adamantyl)-N-(3-methyl-1H-indazol-6-yl)acetamide (Step 1) and bromomethylbenzene in analogy to Step 2 of Example 16. LC-MS (C method): Rt 5.30 min; MS m / z 414.2=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 9.69(s,1H),7.99(s,1H),7.55(d,J=8.9 Hz,1H),7.34-7.29(m,2H),7.29-7.24(m,1H),7.16-7.12(m,2H),7.01(dd,J=9.0,1.6 Hz, 1H), 5.56 (s, 2H), 2.53 (s, 3H), 2.07 (s, 2H), 1.96-1.91 (m, 3H), 1.68-1.57 (m, 12H).

[0279] Example 18 N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide TIFF0007797206000115.tif25170Step 1: 2-tert-butyl-5-nitro-1H-benzimidazole TIFF0007797206000116.tif27170 The title compound was prepared from 4-nitrobenzene-1,2-diamine and 2,2-dimethylpropanoic acid in a manner similar to Step 1 of Example 8. LC-MS (Method B): Rt 0.87 min; MS m / z 220.0=[M+H]+(100% at 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 12.80(br.s,1H),8.38(br.s,1H),8.07(dd,J=8.8,2.2 Hz,1H),7.65(d,J=8.5 Hz,1H),1.43(s,9H). Step 2: 2-tert-butyl-1H-benzimidazol-5-amine TIFF0007797206000117.tif21170 The title compound was prepared from 2-tert-butyl-5-nitro-1H-benzimidazole (Step 1) and 10% Pd / C in analogy to Step 2 of Example 8. 1H NMR (500 MHz, MeOH-d4) δ 7.28 (d, J = 6.9 Hz, 1H), 6.87 (s, 1H), 6.69 (dd, J = 8.5, 2.0 Hz, 1H), 1.43 (s, 9H). Step 3: N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-methoxy-phenyl)acetamide To a solution of 2-(5-chloro-2-methoxy-phenyl)acetic acid (70 mg, 0.35 mmol) in DMF (1 mL) was added DIPEA (0.06 mL, 0.35 mmol), HATU (133 mg, 0.35 mmol), followed by a solution of 2-tert-butyl-1H-benzimidazol-5-amine (Step 2) (80%, 69 mg, 0.29 mmol) in DMF (0.5 mL). The mixture was stirred at room temperature for 2 h, then diluted with EtOAc and washed with water (5 mL) and brine (5 mL). The organic portion was dried over NaSO and concentrated in vacuo. The crude residue was purified by chromatography on silica eluting with 50–100% EtOAc in heptane to give the title compound as a colorless powder. LC-MS (Method B): Rt 1.04 min; MS m / z 372.0 / 374.1=[M+H]+(88% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 11.94(br.s,1H),10.02(br.s,1H),7.95(br.s,1H),7.41(br.s,1H),7.31-7.28(m,2H),7.15(br.s,1H),7.01(d,J=8.4 Hz, 1H), 3.77 (s, 3H), 3.65 (s, 2H), 1.38 (s, 9H). Step 4: N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide The title compound was prepared analogously to Example 5 from N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-methoxy-phenyl)acetamide (Step 3) and 1M BBr3 in DCM. LC-MS (method A): Rt 1.76 min; MS m / z 358.2 / 359.2=[M+H]+(99% at 215 nm) 1H NMR(500 MHz,MeOH-d4)δ 7.93(br.s,1H),7.44(br.s,1H),7.33-7.12(m,2H),7.09(dd,J=8.6,2.6 Hz,1H),6.80(d,J=8.6 Hz, 1H), 3.69 (s, 2H), 1.45 (s, 9H).

[0280] Example 19 tert-Butyl N-[3-[(2-benzyl-1H-benzimidazole-5-carbonyl)amino]-2,2-dimethylpropyl]carbamate TIFF0007797206000119.tif38170 The title compound was prepared analogously to Step 3 of Example 10 from 2-benzyl-1H-benzimidazole-5-carboxylic acid and tert-butyl N-(3-amino-2,2-dimethyl-propyl)carbamate. LC-MS (method A): Rt 2.35 min; MS m / z 437.3=[M+H]+(97% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.31(t,J=6.3 Hz,1H),8.00(s,1H),7.66(dd,J=8.4,1.4 Hz,1H),7.51(d,J=8.3 Hz,1H),7.34-7.30(m,4H),7.28-7.20(m,1H),6.88(t,J=6.6 Hz,1H),4.20(s,2H),3.09(d,J=6.4 Hz,2H),2.79(d,J=6.6 Hz, 2H), 1.40 (s, 9H), 0.81 (s, 6H).

[0281] Example 20 2-tert-butyl-N-(cycloheptylmethyl)-3H-benzimidazole-5-carboxamide TIFF0007797206000120.tif26170Step 1: 3,4-Diamino-N-(cycloheptylmethyl)benzamide To a solution of cycloheptylmethanamine (2.27 mL, 15.77 mmol) and 3,4-diaminobenzoic acid (2 g, 13.14 mmol) in THF (50 mL) and DMF (20 mL) was added TBTU (5.06 g, 15.77 mmol) and TEA (5.5 mL, 39.43 mmol). The reaction mixture was stirred at room temperature for 19 hours and then concentrated in vacuo. The crude product was dissolved in EtOAc (50 mL) and washed with water (2 × 25 mL). The aqueous portion was back-extracted with EtOAc (3 × 50 mL), and the organic extracts were combined, washed with brine (2 × 25 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by C18 reverse phase chromatography eluting with 0-100% MeCN in water to give the title compound as a light brown solid. LC-MS (Method B): Rt 0.96 min; MS m / z 262.1=[M+H]+(95% at 215 nm) 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: 2-tert-Butyl-N-(cycloheptylmethyl)-3H-benzimidazole-5-carboxamide A mixture of 2,2-dimethylpropanoic acid (23 mg, 0.23 mmol), HATU (87 mg, 0.23 mmol), and TEA (67 μL, 0.38 mmol) in DMF (1.91 mL) was stirred at room temperature. After 1 h, 3,4-diamino-N-(cycloheptylmethyl)benzamide (Step 1) (50 mg, 0.19 mmol) in DMF (1 mL) was added, and stirring was continued for 18 h. The resulting mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous sodium bicarbonate (2 × 10 mL). The organic portion was dried over Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in acetic acid (1.91 mL) and stirred at 60 °C for 3 h. The mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous sodium bicarbonate (3 × 20 mL). The organic portion was dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-100% EtOAc in heptane followed by 0-100% MeOH in EtOAc to give the title compound as a colorless solid. LC-MS (method A): Rt 2.12 min; MS m / z 328.2=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.34-12.17(m,1H),8.42-8.25(m,1H),8.14-7.84(m,1H),7.71-7.60(m,1H),7.57-7.39(m,1H),3.11(t,J=6.3 Hz,2H),1.81-1.68(m,3H),1.69-1.60(m,2H),1.59-1.51(m,2H),1.50-1.43(m,2H),1.43-1.35(m,11H),1.23-1.12(m,2H).

[0282] Example 21 2-[(4-tert-butyl-2-fluoro-5-hydroxyphenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000122.tif49170Step 1: 2-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)acetic acid A solution of 2-(2-fluoro-5-methoxy-phenyl)acetic acid (5.0 g, 27.15 mmol) in DCE (181 mL) was treated with tert-butanol (31.16 mL, 325.8 mmol) and concentrated sulfuric acid (17.37 mL, 325.8 mmol). After 1 h, additional tert-butanol (10.0 mL, 105 mmol) and concentrated sulfuric acid (5.8 mL, 109 mmol) were added, and the reaction was stirred overnight. The resulting mixture was diluted with water (150 mL), and the phases were separated. The aqueous layer was extracted with DCM (3 × 150 mL). The combined organic extracts were washed with brine, dried over NaSO, and concentrated in vacuo. The crude residue was diluted with MeOH (100 mL) and treated with 2 M HCl in MeOH (100 mL, freshly prepared from thionyl chloride). The reaction mixture was stirred at reflux for 40 h. The resulting mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (150 mL) and washed with saturated aqueous sodium bicarbonate (150 mL). The organic layer was separated, and the aqueous portion was further extracted with DCM (3 × 100 mL). The organic extracts were combined, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography on silica eluting with 0–10% EtOAc in heptane afforded the methyl ester of the desired product. The material was dissolved in a mixture of 1 M aqueous LiOH (80 mL) and THF (80 mL) and stirred for 1 h. The volatiles were then removed in vacuo, and the aqueous solution was acidified with 1 M HCl, which precipitated the desired product. The solid was collected by filtration, washed with excess water and dried to give 2-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)acetic acid (5.22 g, 21.3 mmol, 78% yield) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 6.93 (d, J = 6.1 Hz, 1H), 6.92 (s, 1H), 3.77 (s, 3H), 3.54 (s, 2H), 1.31 (s, 9H). Step 2: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylate methyl TIFF0007797206000124.tif53170 To a stirred solution of 2-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)acetic acid (Step 1) (289 mg, 1.2 mmol), methyl 3,4-diaminobenzoate (200 mg, 1.2 mmol), and DIPEA (0.24 mL, 1.35 mmol) in DMF (4 mL) was added HATU (458 mg, 1.2 mmol), and the reaction mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo, and the residue was diluted with saturated NaHCO (10 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine (2 × 10 mL), dried over NaSO, and concentrated in vacuo. The crude material was dissolved in acetic acid (4 mL) and stirred at 80 °C for 1 h. The resulting mixture was concentrated in vacuo and the residue was partitioned between saturated NaHCO3 (10 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine (2 x 10 mL), dried over Na2SO4, and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in heptane gave the title compound as a viscous brown oil. LC-MS (Method B): Rt 1.20 min; MS m / z 371.1=[M+H]+(87% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.66-12.56(m,1H),8.16-8.02(m,1H),7.83-7.73(m,1H),7.62-7.49(m,1H),7.08-7. 03(m,1H),7.00-6.95(m,1H),4.24-4.17(m,2H),3.85(s,3H),3.78(s,3H),1.31(s,9H). Step 3: 2-[(4-tertbutyl-2-fluoro-5-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid A solution of methyl 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylate (Step 2) (87%, 282 mg, 0.66 mmol) in THF (1 mL) and MeOH (1 mL) was treated with 1 M LiOH (1.0 mL, 2.0 mmol), and the reaction mixture was stirred at room temperature for 1.5 h. Additional 1 M LiOH (1.0 mL, 2.0 mmol) was added, and the reaction was stirred overnight. Solid LiOH (16 mg, 0.66 mmol) was added, and stirring was continued for 1 h. Additional solid LiOH (32 mg, 1.32 mmol) was added, and stirring was continued for an additional 3 h. The resulting mixture was diluted with EtOAc (5 mL) and HO (5 mL). The pH was adjusted to 4 using 2 M KHSO. The layers were separated and the aqueous portion was extracted with EtOAc (5 mL). The organic extracts were combined, dried over Na2SO4, concentrated in vacuo, and azeotroped with EtOAc / heptane to give the title compound as a beige solid. LC-MS (Method B): Rt 1.06 min; MS m / z 357.3=[M+H]+ (93% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.75-12.25(m,2H),8.17-7.96(m,1H),7.81-7.70(m,1H),7.61-7.44(m,1H),7.05(d,J=6.7 Hz, 1H), 6.97 (d, J=11.8 Hz, 1H), 4.20 (s, 2H), 3.78 (s, 3H), 1.31 (s, 9H). Step 4: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide To a stirred solution of HATU (73 mg, 0.19 mmol), 2-[(4-tert-butyl-2-fluoro-5-methoxyphenyl)methyl]-1H-benzimidazole-5-carboxylic acid (85%, 80 mg, 0.19 mmol), and 1-(trifluoromethyl)cyclopropanamine hydrochloride (34 mg, 0.21 mmol) in DMF (1 mL) was added DIPEA (70 μL, 0.4 mmol), and the reaction mixture was stirred at room temperature for 4 h. Additional 1-(trifluoromethyl)cyclopropanamine hydrochloride (34 mg, 0.21 mmol) and DIPEA (70 μL, 0.4 mmol) were added, and the mixture was allowed to stand overnight. The resulting mixture was diluted with saturated aqueous NaHCO (4 mL) and EtOAc (4 mL). The organic layer was separated, washed with brine (2 x 4 mL), dried over Na2SO4, and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 0-100% EtOAc in heptane gave the title compound as an orange solid. LC-MS (D method): Rt 0.97 min; MS m / z 464.2=[M+H]+(86% at 215 nm) 1H NMR (400 MHz, methanol-d4)δ 8.15-7.91(m,1H),7.75-7.68(m,1H),7.64-7.45(m,1H),7.01(d,J=11.9 Hz,1H),6.92(d,J=6.6 Hz, 1H), 4.26 (s, 2H), 3.80 (s, 3H), 1.40-1.36 (m, 2H), 1.34 (s, 9H), 1.26-1.18 (m, 2H). Step 5: 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000127.tif50170 1M BBr3 in DCM (441 μL, 0.44 mmol) was added dropwise to a stirred solution of 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Step 4) (70%, 79 mg, 0.12 mmol) in DCM (790 μL), and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo (at 20 °C). The residue was extracted with saturated aqueous NaHCO3 (2 mL) and EtOAc (2 × 2 mL). The combined organic extracts were washed with brine (2 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC (acidic pH, standard elution method). The product fractions were combined, the pH adjusted to 7-8 using NaHCO3, and extracted with EtOAc (x2). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound as an off-white powder. LC-MS (method A): Rt 2.74 min; MS m / z 450.3=[M+H]+(100% at 215 nm) 1H NMR (500 MHz, methanol-d4) δ 8.04(br.s,1H),7.74-7.69(m,1H),7.60-7.48(m,1H),6.94(d,J=12.0 Hz,1H),6.58(d,J=6.8 Hz, 1H), 4.19 (s, 2H), 1.40-1.37 (m, 2H), 1.35 (s, 9H), 1.24-1.20 (m, 2H).

[0283] Example 21.1 2-[(4-tert-butyl-2-fluoro-5-hydroxyphenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000128.tif50170Step 1: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000129.tif48170 The title compound was prepared from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid (Step 3 of Example 21) and [1-(trifluoromethyl)cyclopropyl]methanamine hydrochloride in analogy to Step 4 of Example 21. LC-MS (D method): Rt 1.00 min; MS m / z 478.2=[M+H]+ (99% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.70-12.29(m,1H),8.58-8.43(m,1H),8.10-7.78(m,1H),7.70-7.60(m,1H),7.50(br.s,1H),7.04(d,J=6.7 Hz,1H),6.97(d,J=11.8 Hz,1H),4.19(s,2H),3.77(s,3H),3.61(d,J=6.1 Hz,2H),1.31(s,9H),0.97-0.92(m,2H),0.92-0.87(m,2H). Step 2: 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide The title compound was prepared from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (Step 1) and BBr3 in analogy to Step 5 of Example 21. LC-MS (method A): Rt 2.82 min; MS m / z 464.3=[M+H]+ (89% at 215 nm) 1H NMR (500 MHz, methanol-d4)δ 8.03(s,1H),7.71(dd,J=8.5,1.6 Hz,1H),7.57(d,J=7.9 Hz,1H),6.96(d,J=12.0 Hz,1H),6.60(d,J=6.8 Hz,1H),4.21(s,2H),3.73(s,2H),1.37(s,9H),1.03-0.95(m,4H)

[0284] Example 21.2 2-[(4-tert-butyl-2-fluoro-5-hydroxyphenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide TIFF0007797206000130.tif51170Step 1: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide TIFF0007797206000131.tif50170 The title compound was prepared from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid (Step 3 of Example 21) and 3,3,3-trifluoropropan-1-amine hydrochloride in analogy to Step 4 of Example 21. LC-MS (Method B): Rt 1.13 min; MS m / z 452.7=[M+H]+ (89% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.61-12.37(m,1H),8.65-8.53(m,1H),8.12-7.86(m,1H),7.71-7.42(m,2H),7.04(d,J=6.7 Hz,1H),6.97(d,J=11.8 Hz,1H),4.19(s,2H),3.77(s,3H),3.54-3.47(m,2H),2.61-2.52(m,2H),1.31(s,9H). Step 2: 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide The title compound was prepared analogously to Step 5 of Example 21 from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (Step 1) and BBr3. LC-MS (method A): Rt 2.61 min; MS m / z 438.5=[M+H]+ (97% at 215 nm) 1H NMR (500 MHz, methanol-d4) δ 8.02(br.s,1H),7.70(d,J=8.3 Hz,1H),7.55(br.s,1H),6.94(d,J=12.0 Hz,1H),6.58(d,J=6.8 Hz,1H),4.19(s,2H),3.64(t,J=7.0 Hz,2H),2.54(qt,J=11.0,7.1 Hz,2H),1.35(s,9H).

[0285] Example 21.3 2-[(4-tert-butyl-2-fluoro-5-hydroxyphenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide TIFF0007797206000132.tif41170Step 1: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1,3-benzoxazole-5-carboxylate methyl TIFF0007797206000133.tif39170 The title compound was prepared analogously to Step 2 of Example 21 from 2-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)acetic acid (Step 1 of Example 21) and methyl 3-amino-4-hydroxy-benzoate. LC-MS (D method): Rt 1.21 min; MS m / z 372.3=[M+H]+ (98% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.25-8.21(m,1H),8.00(dd,J=8.6,1.7 Hz,1H),7.82(dd,J=8.6,0.5 Hz,1H),7.10(d,J=6.7 Hz,1H),7.01(d,J=11.8 Hz, 1H), 4.37 (s, 2H), 3.88 (s, 3H), 3.79 (s, 3H), 1.32 (s, 9H). Step 2: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1,3-benzoxazole-5-carboxylic acid TIFF0007797206000134.tif44170 The title compound was prepared analogously to Step 3 of Example 21 from methyl 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1,3-benzoxazole-5-carboxylate (Step 1) and 2M lithium hydroxide. LC-MS (D method): Rt 1.07 min; MS m / z 358.2=[M+H]+ (86% at 215 nm) 1H NMR(400 MHz,DMSO-d6)δ 13.03(br.s,1H),8.20(s,1H),7.98(d,J=8.5 Hz,1H),7.78(d,J=8.5 Hz,1H),7.10(d,J=6.6 Hz,1H),7.01(d,J=11.8 Hz, 1H), 4.36 (s, 2H), 3.79 (s, 3H), 1.32 (s, 9H). Step 3: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide The title compound was prepared in analogy to Step 4 of Example 21 from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1,3-benzoxazole-5-carboxylic acid (Step 2) and [1-(trifluoromethyl)cyclopropanamine; hydrochloride]. LC-MS (D method): Rt 1.13 min; MS m / z 465.3=[M+H]+(79% at 215 nm) 1H NMR(400 MHz,DMSO-d6)δ 9.22(s,1H),8.18(d,J=1.4 Hz,1H),7.89(dd,J=8.6,1.8 Hz,1H),7.76(d,J=8.5 Hz,1H),7.09(d,J=6.7 Hz,1H),7.01(d,J=11.8 Hz,1H),4.36(s,2H),3.79(s,3H),1.34-1.30(m,11H),1.20-1.16(m,2H). Step 4: 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide The title compound was prepared from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide (Step 3) and 1M BBr in analogy to Step 5 of Example 21. LC-MS (method A): Rt 3.87 min; MS m / z 451.2=[M+H]+ (96% at 215 nm) 1H NMR(400 MHz,DMSO-d6)δ 9.39(s,1H),9.23(s,1H),8.19(d,J=1.3 Hz,1H),7.90(dd,J=8.6,1.8 Hz,1H),7.76(d,J=8.9 Hz,1H),6.92(d,J=12.0 Hz,1H),6.75(d,J=6.9 Hz,1H),4.27(s,2H),1.35-1.30(m,11H),1.21-1.15(m,2H).

[0286] Example 21.4 2-[(4-tert-butyl-2-fluoro-5-hydroxyphenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1,3-benzoxazole-5-carboxamide TIFF0007797206000136.tif41170Step 1: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1,3-benzoxazole-5-carboxamide TIFF0007797206000137.tif43170 The title compound was prepared from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1,3-benzoxazole-5-carboxylic acid (Step 2 of Example 21.3) and [1-(trifluoromethyl)cyclopropyl]methanamine; hydrochloride in analogy to Step 4 of Example 21. LC-MS (D method): Rt 1.15 min; MS m / z 479.3=[M+H]+(48% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.66(t,J=6.1 Hz,1H),8.14(d,J=1.4 Hz,1H),7.86(dd,J=8.6,1.7 Hz,1H),7.76(d,J=8.5 Hz,1H),7.10(d,J=6.7 Hz,1H),7.01(d,J=11.8 Hz,1H),4.36(s,2H),3.79(s,3H),3.61(d,J=6.1 Hz,2H),1.32(s,9H),0.97-0.89(m,4H). Step 2: 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1,3-benzoxazole-5-carboxamide The title compound was prepared from 2-[(4-tert-butyl-2-fluoro-5-methoxyphenyl)methyl]-N-{[1-(trifluoromethyl)cyclopropyl]methyl}-1,3-benzoxazole-5-carboxamide (Step 1) and 1 M BBr in analogy to Step 5 of Example 21. LC-MS (method A): Rt 4.03 min; MS m / z 465.2=[M+H]+(95% at 215 nm) 1H NMR(400 MHz,DMSO-d6)δ 9.38(s,1H),8.67(t,J=6.0 Hz,1H),8.16(d,J=1.3 Hz,1H),7.87(dd,J=8.5,1.7 Hz,1H),7.76(d,J=8.6 Hz,1H),6.92(d,J=12.0 Hz,1H),6.75(d,J=6.9 Hz,1H),4.27(s,2H),3.62(d,J=6.1 Hz,2H),1.32(s,9H),0.98-0.89(m,4H).

[0287] Example 22 2-[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide TIFF0007797206000138.tif35170Step 1: 5-Nitro-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole To a stirred solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (403 mg, 2.61 mmol), 4-nitrobenzene-1,2-diamine (400 mg, 2.61 mmol), and DIPEA (0.52 mL, 2.98 mmol) in DMF (8 mL) was added HATU (993 mg, 2.61 mmol), and the reaction mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, and the residue was partitioned between saturated NaHCO (15 mL) and EtOAc (15 mL). The phases were separated, and the organic layer was washed with brine (2 × 10 mL), dried over NaSO, and then concentrated in vacuo. The crude residue was dissolved in acetic acid (8 mL) and stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo, and the residue was partitioned between saturated NaHCO (25 mL) and EtOAc (25 mL). The organic layer was separated, washed with water (2 x 15 mL), dried over Na2SO4, and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 0-100% EtOAc in heptane gave the title compound as a pale yellow solid. LC-MS (method B): Rt 1.06 min; MS m / z 272.0=[M+H]+(99% at 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 13.27 (br.s, 1H), 8.45 (s, 1H), 8.13 (dd, J = 8.8, 1.8 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 1.60 (s, 4H). Step 2: 2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-amine To a solution of 5-nitro-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole (Step 1) (99%, 582 mg, 2.12 mmol) in EtOH (5.8 mL) was added Pd / C (10%, 226 mg, 0.21 mmol). The reaction mixture was placed under a hydrogen atmosphere and stirred overnight. The resulting mixture was filtered through Celite® and rinsed with EtOH (10 mL). The filtrate was concentrated in vacuo and azeotroped with DCM to give the title compound as a beige solid. 1H NMR (500 MHz, DMSO-d6) δ 12.12-11.84 (m, 1H), 7.26-7.06 (m, 1H), 6.73-6.45 (m, 2H), 4.99-4.62 (m, 2H), 1.44-1.37 (m, 4H). Step 3: 2-[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide To a stirred solution of 2-[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]acetic acid (Intermediate A) (80%, 72 mg, 0.18 mmol), 2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-amine (Step 2) (90%, 65 mg, 0.24 mmol), and DIPEA (0.05 mL, 0.27 mmol) in DMF (2 mL) was added HATU (92 mg, 0.24 mmol), and the reaction mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo, and the crude material was washed with water, brine, dried over NaSO, and concentrated in vacuo. Purification by preparative HPLC (acidic pH, fast elution method) afforded the title compound as an off-white solid. LC-MS (D method): Rt 0.88 min; MS m / z 542.2=[M+H]+ (91% at 215 nm) Step 4: 2-[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide To a solution of 2-[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide (Step 3) (90%, 44 mg, 0.07 mmol) in EtOH (5 mL) was added Pd / C (10%, 7.78 mg, 0.01 mmol). The reaction was placed under a hydrogen atmosphere and stirred for 16 h. The resulting mixture was filtered through Celite® and the filtrate was concentrated in vacuo. Purification of the crude residue by preparative HPLC (acidic pH, standard elution) afforded the title compound as an off-white solid. LC-MS (method A): Rt 2.16 min; MS m / z 452.2=[M+H]+ (95% at 215 nm) 1H NMR(400 MHz,DMSO-d6,VT at 354.7K)δ 12.23(br.s,1H),9.88(s,1H),9.44(br.s,1H),7.94(s,1H),7.49-7.39(m,1H),7.29(br.s,1H),7.05(d,J=11.4 Hz,1H),6.77(d,J=6.7 Hz, 1H), 5.55 (br.s, 1H), 3.61 (s, 2H), 1.52 (s, 6H), 1.52-1.47 (m, 4H).

[0288] Example 23 2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide TIFF0007797206000142.tif36170 Step 1: 2-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide To a stirred solution of 2-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)acetic acid (Step 1 of Example 21) (90 mg, 0.37 mmol), 2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-amine (Step 2 of Example 22) (90%, 100 mg, 0.37 mmol), and DIPEA (73 μL, 0.42 mmol) in DMF (2 mL) was added HATU (142 mg, 0.37 mmol), and the reaction mixture was stirred at room temperature for 1.5 hours. The resulting mixture was diluted with saturated aqueous NaHCO (10 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine (2 × 10 mL), dried over NaSO, and then concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 0-100% EtOAc in heptane gave the title compound as a beige solid. LC-MS (Method B): Rt 1.25 min; MS m / z 464.2=[M+H]+(97% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.45(br.s,1H),10.17(s,1H),7.98(s,1H),7.54-7.39(m,1H),7.35-7.16(m,1H),7.01(d,J=6.7 Hz, 1H), 6.95 (d, J=11.7 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 2H), 1.48 (s, 4H), 1.32 (s, 9H). Step 2: 2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide 1M BBr3 (467 μL, 0.47 mmol) was added dropwise to a cooled (0 °C) stirred solution of 2-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide (Step 1) (86%, 168 mg, 0.31 mmol) in DCM (1.5 mL). The mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for 2 h. Additional BBr3 (467 μL, 0.47 mmol) was added, and the mixture was stirred for 3 days. The resulting mixture was concentrated in vacuo, and the crude material was purified by C18 reverse-phase chromatography eluting with a gradient of 10–100% MeCN (+0.1% formic acid) in HO (+0.1% formic acid). The product fractions were combined, the pH was adjusted to 7 using NaHCO3, and the mixture was extracted with EtOAc (x2). The organic extracts were combined, dried over Na2SO4, and concentrated in vacuo to give the title compound as an off-white solid. LC-MS (method A): Rt 3.02 min; MS m / z 450.3=[M+H]+ (97% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.53-12.40(m,1H),10.23-10.09(m,1H),9.29(s,1H),8.10-7.86(m,1H),7.5 2-7.18(m,2H),6.89-6.73(m,2H),3.61-3.56(m,2H),1.48(s,4H),1.32(s,9H).

[0289] Example 24 2-Benzyl-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide To a solution of commercially available 2-benzyl-1H-benzimidazole-5-carboxylic acid (50 mg, 0.2 mmol) in DMF (2 mL) was added HATU (83 mg, 0.22 mmol), followed by DIPEA (69 μL, 0.4 mmol). The reaction mixture was stirred under nitrogen at room temperature for 10 minutes, treated with 3,3,3-trifluoropropan-1-amine (25 mg, 0.22 mmol), and then stirred at room temperature for 16 hours. The resulting mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated, washed with brine (10 mL), and concentrated in vacuo. Purification by preparative HPLC (basic pH, fast elution method) afforded the title compound as a white solid. LC-MS (method A): Rt 1.70 min; MS m / z 348.1=[M+H]+ (99% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.47(br.s,1H),8.58(t,J=5.5 Hz,1H),7.99(s,1H),7.65(dd,J=8.4,1.6 Hz,1H),7.50(d,J=8.4 Hz,1H),7.35-7.29(m,4H),7.26-7.21(m,1H),4.20(s,2H),3.50(q,J=6.9 Hz,2H),2.61-2.52(m,2H).

[0290] Example 24.1 2-Benzyl-N-(cyclopentylmethyl)-1H-benzimidazole-5-carboxamide TIFF0007797206000145.tif34170 The title compound was prepared analogously to Example 24 from commercially available 2-benzyl-1H-benzimidazole-5-carboxylic acid and cyclopentylmethanamine. LC-MS (method A): Rt 2.02 min; MS m / z 334.2=[M+H]+ (99% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.48(br.s,1H),8.37(t,J=5.7 Hz,1H),8.00(s,1H),7.66(dd,J=8.4,1.5 Hz,1H),7.49(d,J=8.2 Hz,1H),7.36-7.29(m,4H),7.26-7.21(m,1H),4.20(s,2H),3.22-3.17(m,2H) ,2.20-2.12(m,1H),1.71-1.64(m,2H),1.63-1.44(m,4H),1.30-1.22(m,2H).

[0291] Example 24.2 2-Benzyl-N-(cycloheptylmethyl)-1H-benzimidazole-5-carboxamide TIFF0007797206000146.tif35170 The title compound was prepared analogously to Example 24 from commercially available 2-benzyl-1H-benzimidazole-5-carboxylic acid and cycloheptylmethanamine. LC-MS (method A): Rt 2.43 min; MS m / z 362.2=[M+H]+ (96% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.47(br.s,1H),8.36(t,J=5.6 Hz,1H),8.00(br.s,1H),7.66(d,J=8.4 Hz,1H),7.52-7.44(m,1H),7.35-7.29(m,4H),7.26-7.21(m,1H),4.20(s,2H),3.10(t,J=6.3 Hz, 2H), 1.80-1.68 (m, 3H), 1.67-1.58 (m, 2H), 1.58-1.33 (m, 6H), 1.22-1.12 (m, 2H).

[0292] Example 25 N-(Cycloheptylmethyl)-2-[(2-fluoro-6-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000147.tif37170Step 1: 2-[(2-fluoro-6-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylate methyl ester TIFF0007797206000148.tif35170 To a stirred solution of 2-(2-fluoro-6-methoxy-phenyl)acetic acid (250 mg, 1.36 mmol), methyl 3,4-diaminobenzoate (226 mg, 1.36 mmol), and DIPEA (0.31 mL, 1.76 mmol) in DMF (6 mL) was added HATU (517 mg, 1.36 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The crude material was dissolved in acetic acid (25 mL) and stirred at 70 °C for 16 hours. The resulting mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 5-75% EtOAc in heptane afforded the title compound as an off-white solid. LC-MS (Method B): Rt 0.92 min; MS m / z 315.4=[M+H]+(94% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.43(br.s,1H),8.06(br.s,1H),7.76(br.s,1H),7.52(br.s,1H),7.37-7.30(m,1H),6.91(d,J=8.4 Hz, 1H), 6.86 (t, J=8.8 Hz, 1H), 4.19 (s, 2H), 3.85 (s, 3H), 3.79 (s, 3H). Step 2: 2-[(2-fluoro-6-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid TIFF0007797206000149.tif36170 2M aqueous LiOH (3.2 mL, 6.4 mmol) was added to a solution of 2-[(2-fluoro-6-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylate methyl (Step 1) (312 mg, 0.99 mmol) in THF (5 mL), and the mixture was stirred at 60 °C for 4 h. The resulting mixture was partially concentrated in vacuo to remove volatile solvents, and the remaining aqueous layer was acidified to pH 4 with 2 M aqueous HCl. The aqueous portion was extracted with 3:1 chloroform:IPA (3 × 30 mL), and the combined organic extracts were dried over NaSO and concentrated in vacuo to give the title compound as a pale orange powder. LC-MS (Method B): Rt 0.85 min; MS m / z 301.0=[M+H]+(94% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.19(s,1H),7.98(dd,J=8.5,1.3 Hz,1H),7.73(d,J=8.6 Hz, 1H), 7.54-7.38 (m, 1H), 6.97-6.89 (m, 2H), 4.42 (s, 2H), 3.77 (s, 3H). Step 3: N-(cycloheptylmethyl)-2-[(2-fluoro-6-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide To a stirred solution of 2-[(2-fluoro-6-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid (Step 2) (88%, 144 mg, 0.42 mmol), DIPEA (0.15 mL, 0.85 mmol), and HATU (177 mg, 0.46 mmol) in DMF (1 mL) was added cycloheptylmethanamine (59 mg, 0.46 mmol), and the mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (15 mL) and water (10 mL). The organic layer was separated, dried over NaSO, and concentrated in vacuo. Purification by preparative HPLC (basic pH, standard elution) afforded the title compound as a white powder. LC-MS (method A): Rt 2.50 min; MS m / z 410.3=[M+H]+(85% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.35-12.20(m,1H),8.40-8.26(m,1H),8.05-7.85(m,1H),7.63(dd,J=24.2,7.9 Hz,1H),7.44(dd,J=32.0,8.4 Hz,1H),7.36-7.28(m,1H),6.93-6.79(m,2H),4.16(s,2H),3.78(s,3H),3.13-3.06 (m,2H),1.80-1.67(m,3H),1.66-1.43(m,6H),1.41-1.31(m,2H),1.22-1.09(m,2H). Step 4: N-(cycloheptylmethyl)-2-[(2-fluoro-6-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide To a cooled (0 °C) solution of N-(cycloheptylmethyl)-2-[(2-fluoro-6-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (Step 3) (85%, 124 mg, 0.26 mmol) in DCM (0.5 mL) was added 1 M BBr3 in DCM (0.77 mL, 0.77 mmol), and the mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with MeOH (ca. 5 mL) and concentrated in vacuo. Purification by preparative HPLC (basic pH, fast elution method) afforded the title compound as a white powder. LC-MS (method A): Rt 2.32 min; MS m / z 396.2=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.36-8.30(m,1H),7.96(s,1H),7.64(dd,J=8.4,1.3 Hz,1H),7.45(d,J=8.3 Hz,1H),7.17-7.10(m,1H),6.71(d,J=8.3 Hz,1H),6.66(t,J=8.7 Hz,1H),4.14(s,2H),3.10(t,J=6.3 Hz,2H),1.80-1.68(m,3H),1.68-1.59(m,2H),1.58-1.42(m,4H),1.42-1.32(m,2H),1.21-1.11(m,2H).

[0293] The compounds of the tabulated examples below (Table 1) were prepared analogously to steps 1-4 of Example 25 by replacing 2-(2-fluoro-6-methoxy-phenyl)acetic acid (step 1) with the appropriate commercially available phenylacetic acid. TIFF0007797206000151.tif237170TIFF0007797206000152.tif237170

[0294] Example 25.5 N-(Cycloheptylmethyl)-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000153.tif36170Step 1; 2-[(3-benzyloxyphenyl)methyl]-1H-benzimidazole-5-carboxylate methyl ester 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 min, followed by the addition of methyl 3,4-diaminobenzoate (1.38 g, 8.3 mmol). After stirring at room temperature for 18 h, the resulting mixture was concentrated in vacuo, and the residue was partitioned between saturated NaHCO (100 mL) and EtOAc (125 mL). The organic layer was separated, washed with water (2 × 75 mL) and brine (2 × 75 mL), dried over NaSO, and then concentrated in vacuo. The resulting material was triturated with MeOH (40 mL), and the off-white solid was filtered and dried in a vacuum oven at 40 °C for 3 h. The solid was then suspended in AcOH (25 mL) and stirred at 70 °C for 6 h. The resulting mixture was concentrated in vacuo, and the residue was diluted with saturated NaHCO (100 mL) and EtOAc (125 mL). The organic layer was separated, washed with water (2 × 75 mL), brine (2 × 75 mL), dried over NaSO, and concentrated in vacuo to provide the title compound as an off-white powder. LC-MS (Method B): Rt 1.05 min; MS m / z 373.0=[M+H]+(98% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.20-7.99(m,1H),7.79(dd,J=8.4,1.6 Hz,1H),7.56(d,J=8.4 Hz,1H),7.48-7.39(m,2H),7.39-7.33(m,2H),7.33-7.27(m,1H),7.24(t,J=7.9 Hz, 1H), 7.06-6.98 (m, 1H), 6.97-6.83 (m, 2H), 5.07 (s, 2H), 4.19 (s, 2H), 3.85 (s, 3H). Step 2: 2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxylate methyl TIFF0007797206000155.tif43170 To a suspension of methyl 2-[(3-benzyloxyphenyl)methyl]-1H-benzimidazole-5-carboxylate (Step 1) (95%, 700 mg, 1.79 mmol) in EtOH (20 mL) was added 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 Celite® and rinsed with EtOH (45 mL). The filtrate was concentrated in vacuo to afford the title compound as a pale orange / brown solid. LC-MS (Method B): Rt 0.83 min; MS m / z 283.1=[M+H]+ (98% at 215 nm) 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 TIFF0007797206000156.tif44170 2M saturated aqueous LiOH (2.53 mL, 5.06 mmol) was added to a solution of methyl 2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxylate (Step 2) (95%, 501 mg, 1.69 mmol) in THF (8 mL), and the reaction mixture was stirred at 50 °C for 4 h. The resulting mixture was partially concentrated (to remove THF), and the remaining aqueous layer was acidified to pH 4 and extracted with 3:1 chloroform:IPA (3 × 30 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo to give the title compound as a pale orange powder. LC-MS (Method B): Rt 0.73 min; MS m / z 269.1=[M+H]+(95% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 13.48-11.55(m,2H),9.37(s,1H),8.10(s,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-(cycloheptylmethyl)-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide The title compound was prepared from 2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxylic acid (Step 3) and cycloheptylmethanamine in analogy to Step 3 of Example 25. LC-MS (method A): Rt 2.18 min; MS m / z 378.3=[M+H]+(100% at 215 nm) 1H NMR (500 MHz, methanol-d4)δ 8.53-8.42(m,1H),8.04(d,J=1.2 Hz,1H),7.73(dd,J=8.5,1.6 Hz,1H),7.57(d,J=8.5 Hz,1H),7.16(t,J=7.9 Hz,1H),6.80(d,J=7.7 Hz,1H),6.78-6.74(m,1H),6.70(dd,J=8.1,2.0 Hz,1H),4.21(s,2H),3.26(t,J=6.4 Hz,2H),1.94-1.79(m,3H),1.79-1.69(m,2H),1.69-1.61(m,2H),1.61-1.44(m,4H),1.35-1.25(m,2H).

[0295] Example 26 2-(5-chloro-2-hydroxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide TIFF0007797206000157.tif32170 Step 1: N-(4-amino-3-nitro-phenyl)-2-(5-chloro-2-methoxy-phenyl)acetamide To a solution of 2-(5-chloro-2-methoxyphenyl)acetic acid (2.88 g, 14.37 mmol) in DMF (65 mL) was added DIPEA (2.74 mL, 15.67 mmol) and HATU (5.96 g, 15.67 mmol), followed by 2-nitrobenzene-1,4-diamine (2 g, 13.06 mmol), and the mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, and the residue was dissolved in EtOAc and washed with water (30 mL). A precipitate formed that was filtered from the biphasic mixture, and the layers were separated. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 10–70% EtOAc in heptane afforded the title compound as a yellow powder. LC-MS (Method B): Rt 1.10 min; MS m / z 336.0 / 338.0=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,chloroform-d)δ 7.93(d,J=1.8 Hz,1H),7.71(d,J=9.0 Hz,1H),7.46(br.s,1H),7.29-7.26(m,2H),6.89(d,J=8.4 Hz,1H),6.77(d,J=9.0 Hz, 1H), 5.97 (s, 2H), 3.92 (s, 3H), 3.65 (s, 2H). Step 2: 2-(5-chloro-2-methoxy-phenyl)-N-(3,4-diaminophenyl)acetamide To a cooled (0 °C) solution of N-(4-amino-3-nitro-phenyl)-2-(5-chloro-2-methoxy-phenyl)acetamide (Step 1) (100%, 200 mg, 0.6 mmol) in MeOH (4.5 mL) / acetic acid (1.5 mL) was added zinc (195 mg, 2.98 mmol), and the mixture was allowed to warm to room temperature with stirring for 45 minutes. The resulting mixture was filtered through Celite®, the filtrate rinsed with MeOH was concentrated in vacuo, and the crude residue was dissolved in EtOAc and washed with saturated NaHCO3 solution. The organic portion was separated, washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give the title compound as a red / brown solid. LC-MS (Method B): Rt 0.91 min; MS m / z 306.0 / 308.0=[M+H]+(98% at 215 nm) 1H NMR(500 MHz,chloroform-d)δ 7.33(br.s,1H),7.28(d,J=2.6 Hz,1H),7.24(dd,J=8.7,2.6 Hz,1H),7.07(d,J=2.3 Hz,1H),6.85(d,J=8.7 Hz,1H),6.59(d,J=8.2 Hz,1H),6.52(dd,J=8.2,2.3 Hz,1H),3.88(s,3H),3.62(s,2H). Step 3: 2-(5-chloro-2-methoxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide To a solution of 3,3-dimethylbutanoic acid (66 μL, 0.52 mmol) in DMF (2.5 mL) was added TEA (0.09 mL, 0.52 mmol) and HATU (198 mg, 0.52 mmol), followed by 2-(5-chloro-2-methoxy-phenyl)-N-(3,4-diaminophenyl)acetamide (Step 2) (98%, 140 mg, 0.43 mmol), and the mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with EtOAc and washed with 1 M aqueous HCl. The combined organic layer was separated, washed with brine, dried over NaSO, and concentrated in vacuo. The crude residue was dissolved in acetic acid (2.5 mL) and heated at 60° C. for 2 h, followed by 80° C. for 4 h. After standing at room temperature for 3 days, the mixture was concentrated in vacuo, the residue was dissolved in EtOAc, and washed successively with saturated NaHCO3 solution and brine. The organic portion was separated, dried over Na2SO4, and concentrated in vacuo. The crude residue was absorbed onto silica and purified by chromatography eluting with 50-100% EtOAc in heptane, followed by preparative HPLC (acidic pH, standard elution) to afford the title compound as a colorless solid. LC-MS (Method B): Rt 1.04 min; MS m / z 386.1 / 388.1=[M+H]+(98% at 215 nm) 1H NMR (500 MHz, chloroform-d) δ 7.84-7.80 (m, 1H), 7.42-7.37 (m, 1H), 7.24-7.22 (m, 1H), 7.20-7.16 (m, 1H), 6.98-6.92 (m, 1H), 6.83-6.78 (m, 1H), 3.84-3.80 (m, 3H), 3.63-3.60 (m, 2H), 2.67-2.63 (m, 2H), 0.96-0.93 (m, 9H). Step 4: 2-(5-chloro-2-hydroxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide To a cooled (0 °C) solution of 2-(5-chloro-2-methoxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide (Step 3) (98%, 14 mg, 0.04 mmol) in DCM (1 mL) was added 1 M BBr in DCM (54 μL, 0.05 mmol), and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of saturated NaHCO (5 drops), and the resulting mixture was concentrated by removing the DCM under a stream of nitrogen. The residue was dissolved in EtOAc (3 mL) and washed with saturated NaHCO solution (1 mL). The organic layer was separated and dried over NaSO. The solution was filtered, concentrated under a stream of nitrogen, and dried in a vacuum oven to give the title compound as a colorless glass. LC-MS (method A): Rt 1.95 min; MS m / z 372.2 / 374.3=[M+H]+(100% at 215 nm) 1H NMR (500 MHz, methanol-d4) δ 7.92(d,J=1.4 Hz,1H),7.44(d,J=8.6 Hz,1H),7.24-7.20(m,2H),7.09(dd,J=8.6,2.6 Hz,1H),6.80(d,J=8.6 Hz, 1H), 3.69 (s, 2H), 2.73 (s, 2H), 1.03 (s, 9H).

[0296] Example 27 N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide TIFF0007797206000161.tif26170Step 1: 2-tert-butyl-5-nitro-1H-benzimidazole TIFF0007797206000162.tif28170To a solution of 4-nitrobenzene-1,2-diamine (200 mg, 1.31 mmol), 2,2-dimethylpropanoic acid (160 mg, 1.57 mmol) and DIPEA (274 μL, 1.57 mmol) in DMF (7 mL) was added HATU (546 mg, 1.44 mmol), and the mixture was stirred at room temperature for 1 h. Another 1 equivalent of 2,2-dimethylpropanoic acid, DIPEA, and HATU were added, and stirring was continued overnight. The reaction mixture was diluted with EtOAc and water (10 mL) and brine (10 mL). The organic extract was dried over Na2SO4 and concentrated in vacuo. The crude residue was dissolved in acetic acid (7 mL) and heated at 60°C for 2 hours, then at 70°C for an additional 2 hours. After cooling to room temperature, the reaction mixture was left stirring for 3 days. The acetic acid was removed in vacuo, and the residue was dissolved in EtOAc and then washed with saturated NaHCO3 solution. The combined organic layers were separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification of the crude material by chromatography on silica, eluting with 30-100% EtOAc in heptane, afforded the title compound. LC-MS (Method B): Rt 0.87 min; MS m / z 220.0=[M+H]+(100% at 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 12.80(br.s,1H),8.38(br.s,1H),8.07(dd,J=8.8,2.2 Hz,1H),7.65(d,J=8.5 Hz,1H),1.43(s,9H). Step 2: 2-tert-butyl-1H-benzimidazol-5-amine To a solution of 2-tert-butyl-5-nitro-1H-benzimidazole (Step 1) (70 mg, 0.32 mmol) in EtOH (4 mL) under a N atmosphere was added Pd / C (10%, 15 mg, 0.14 mmol). The nitrogen atmosphere was replaced with a hydrogen atmosphere, and the mixture was stirred at room temperature overnight. The resulting mixture was filtered through Celite® and washed with MeOH. The filtrate was concentrated in vacuo to afford the title compound as a pale pink glass. 1H NMR (500 MHz, methanol-d4) δ 7.28 (d, J = 6.9 Hz, 1H), 6.87 (s, 1H), 6.69 (dd, J = 8.5, 2.0 Hz, 1H), 1.43 (s, 9H). Step 3: N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-methoxy-phenyl)acetamide To a solution of 2-(5-chloro-2-methoxy-phenyl)acetic acid (70 mg, 0.35 mmol) in DMF (1 mL) was added DIPEA (0.06 mL, 0.35 mmol) and HATU (133.08 mg, 0.35 mmol), followed by a solution of 2-tert-butyl-1H-benzimidazol-5-amine (Step 2) (80%, 69 mg, 0.29 mmol) in DMF (0.5 mL), and the mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with EtOAc and washed with water (5 mL) and brine (5 mL). The organics were separated, dried over Na2SO4, and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 50–100% EtOAc in heptane afforded the title compound as a colorless powder. LC-MS (Method B): Rt 1.04 min; MS m / z 372.0 / 374.1=[M+H]+(88% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 11.94(br.s,1H),10.06-9.92(m,1H),7.98-7.73(m,1H),7.47-7.38(m,1H),7.31-7.28(m,2H),7.19-7.10(m,1H),7.01(d,J=8.4 Hz, 1H), 3.77 (s, 3H), 3.67-3.61 (m, 2H), 1.38 (s, 9H). Step 4: N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide To a cooled (0 °C) solution of N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-methoxy-phenyl)acetamide (Step 3) (88%, 103 mg, 0.25 mmol) in DCM (1 mL) was added 1 M BBr in DCM (0.39 mL, 0.39 mmol). The mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the dropwise addition of saturated NaHCO solution (5 mL). The resulting mixture was diluted with EtOAc and washed with saturated NaHCO solution. The organic portion was separated, washed with brine, dried over NaSO, and concentrated in vacuo to give a pale pink powder. The powder was triturated with MeCN / water (1:1, 1 mL) and filtered. The filter cake was washed with ether and dried in a vacuum oven to give the title compound as a colorless powder. LC-MS (method A): Rt 1.76 min; MS m / z 358.2 / 360.2=[M+H]+(99% at 215 nm) 1H NMR (500 MHz, methanol-d4)δ 7.93(br.s,1H),7.44(br.s,1H),7.33-7.12(m,2H),7.09(dd,J=8.6,2.6 Hz,1H),6.80(d,J=8.6 Hz,1H),3.71-3.65 m,2H),1.45(s,9H).

[0297] Example 28 N-(cycloheptylmethyl)-2-(1-methylcyclobutyl)-3H-benzimidazole-5-carboxamide TIFF0007797206000165.tif29170Step 1: 3,4-Diamino-N-(cycloheptylmethyl)benzamide A solution of cycloheptylmethanamine (209 mg, 1.64 mmol), 3,4-diaminobenzoic acid (250 mg, 1.64 mmol), DCC (373 mg, 1.81 mmol), and DMAP (221 mg, 1.81 mmol) in DCM (30 mL) was stirred at room temperature for 18 h. The resulting mixture was concentrated in vacuo, and the crude material was purified by chromatography on silica eluting with 10–100% EtOAc in heptane. The resulting yellow solid was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was washed with water (2 × 30 mL), brine (30 mL), dried over NaSO, and concentrated in vacuo to give the title compound as a pale yellow solid. LC-MS (Method B): Rt 0.95 min; MS m / z 262.1=[M+H]+ (96% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 7.85(t,J=5.8 Hz,1H),7.06(d,J=1.4 Hz,1H),6.98(dd,J=8.0,1.4 Hz,1H),6.49(d,J=8.1 Hz,1H),4.93(br.s,4H),3.01(t,J=6.3 Hz,2H),1.72-1.60(m,5H),1.57-1.44(m,4H),1.41-1.30(m,2H),1.16-1.06(m,2H). Step 2: N-(cycloheptylmethyl)-2-(1-methylcyclobutyl)-3H-benzimidazole-5-carboxamide A mixture of 1-methylcyclobutanecarboxylic acid (26 mg, 0.23 mmol), HATU (87 mg, 0.23 mmol), and TEA (67 μL, 0.38 mmol) in DMF (2 mL) was stirred at room temperature for 1 h and then treated with 3,4-diamino-N-(cycloheptylmethyl)benzamide (Step 1) (50 mg, 0.19 mmol) in DMF (1 mL), and the mixture was stirred for 18 h. The resulting mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous sodium bicarbonate (2 × 10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in acetic acid (2 mL) and stirred at 60 °C for 3 h. The mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous sodium bicarbonate (3 × 20 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 0-100% EtOAc in heptane followed by 0-100% MeOH in EtOAc afforded the title compound as a colorless solid. LC-MS (method A): Rt 2.17 min; MS m / z 340.3=[M+H]+ (99% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.41-12.22(m,1H),8.48-8.25(m,1H),8.20-7.88(m,1H),7.72-7.61(m,1H),7.60-7.40(m,1H),3.12(t,J=6.3 Hz,2H),2.67-2.59(m,2H),2.14-2.00(m,3H),1.97-1.86(m,1H),1.83-1.69(m,3H),1.69-1.62( m,2H),1.60(s,3H),1.58-1.52(m,2H),1.52-1.45(m,2H),1.45-1.34(m,2H),1.23-1.12(m,2H).

[0298] Example 29 2-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000167.tif42170Step 1: 3,4-Diamino-N-[[1-(trifluoromethyl)cyclopropyl]methyl]benzamide 3,4-Diaminobenzoic acid (150 mg, 0.99 mmol), [1-(trifluoromethyl)cyclopropyl]methanamine hydrochloride (173 mg, 0.99 mmol), EDCI (208 mg, 1.08 mmol), and DMAP (132 mg, 1.08 mmol) in DCM (10 mL) were stirred at room temperature. DIPEA (344 μL, 1.97 mmol) was added, and the reaction mixture was stirred under an inert atmosphere for 3 days. The resulting mixture was diluted with EtOAc (20 mL), washed with water (2 × 20 mL), dried over NaSO, and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 0–100% MeOH in EtOAc afforded the title compound as a tan residue. 1H NMR(500 MHz,DMSO-d6)δ 7.96(t,J=6.2 Hz,1H),7.02(d,J=2.0 Hz,1H),6.95(dd,J=8.1,2.0 Hz,1H),6.48(d,J=8.1 Hz,1H),4.96(s,2H),4.55(s,2H),3.54(d,J=6.2 Hz,2H),0.92-0.81(m,4H). Step 2: 2-[(5-fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000169.tif42170 The title compound was prepared from 3,4-diamino-N-[[1-(trifluoromethyl)cyclopropyl]methyl]benzamide (Step 1) and 2-(5-fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)acetic acid (Intermediate B) in a similar manner to Step 1 of Example 25. LC-MS (D method): Rt 0.80 min; MS m / z 476.2=[M+H]+(53% at 215 nm) Step 3: 2-[[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide 2-[(5-Fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (Step 2) (53%, 146 mg, 0.16 mmol) was dissolved in THF (500 μL) and treated with LiBH (4 M in THF) (154 μL, 0.61 mmol), and the reaction mixture was stirred for 18 h. Additional THF (1 mL) and LiBH (4 M in THF) (154 μL, 0.61 mmol) were added, and the mixture was stirred for an additional 2 h. One drop of MeOH was added, and stirring was continued for an additional 2 h. The resulting mixture was purified by C18 reverse-phase chromatography eluting with 5–100% MeCN in water. The product fractions were combined, concentrated in vacuo, and further purified by chromatography on silica eluting with 0-100% EtOAc in heptane, followed by 0-100% MeOH in EtOAc. The product fractions were combined, concentrated in vacuo, and further purified by preparative HPLC (acidic pH, standard elution method). The product fractions were combined and concentrated in vacuo to remove most of the organics. The aqueous portion was treated with NaHCO (sat. aq.) (7.5 mL) and EtOAc (20 mL), and the organic layer was separated, dried over NaSO, filtered, and concentrated in vacuo to provide the title compound. LC-MS (method A): Rt 2.13 min; MS m / z 480.3=[M+H]+(100% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 9.46(s,1H),8.67(s,1H),8.09(s,1H),7.81(d,J=8.7 Hz,1H),7.67(d,J=8.2 Hz,1H),6.95(d,J=12.2 Hz,1H),6.67(d,J=6.9 Hz,1H),4.27(s,2H),3.62(d,J=6.1 Hz,2H),3.59(s,2H),1.24(s,6H),0.99-0.94(m,2H),0.94-0.89(m,2H).

[0299] Example 29.1 2-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide TIFF0007797206000170.tif43170Step 1: 3,4-Diamino-N-(3,3,3-trifluoropropyl)benzamide TIFF0007797206000171.tif271703,3,3-Trifluoropropan-1-amine hydrochloride (108 mg, 0.72 mmol) and 3,4-diaminobenzoic acid (100 mg, 0.66 mmol) were suspended in 1,4-dioxane (2 mL) and treated with DIPEA (241 μL, 1.38 mmol), TBTU (211 mg, 0.66 mmol), and DCM (0.5 mL). The reaction mixture was stirred for 1 h and then concentrated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in heptane, followed by a gradient of 0 to 100% MeOH in EtOAc, to give the title compound as a purple residue. LC-MS (C method): Rt 1.16 min; MS m / z 248.3=[M+H]+ (41% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.05(t,J=5.6 Hz,1H),7.02(d,J=2.0 Hz,1H),6.92(dd,J=8.1,2.0 Hz,1H),6.46(d,J=8.1 Hz, 1H), 4.95 (s, 2H), 4.54 (s, 2H), 3.42-3.35 (m, 2H), 2.65-2.57 (m, 2H). Step 2: 2-[(5-fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide TIFF0007797206000172.tif41170 The title compound was prepared analogously to Step 1 of Example 25 from 3,4-diamino-N-(3,3,3-trifluoropropyl)benzamide (Step 1) and 2-(5-fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)acetic acid (Intermediate B). LC-MS (D method): Rt 0.75 min; MS m / z 450.2=[M+H]+(54% at 215 nm) Step 3: 2-[[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide The title compound was prepared from 2-[(5-fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (Step 2) and 4M LiBH4 in analogy to Step 3 of Example 29. LC-MS (method A): Rt 1.90 min; MS m / z 454.3=[M+H]+ (95% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.58(br.s,1H),9.34(br.s,1H),8.60(t,J=5.1 Hz,1H),8.01(s,1H),7.66(d,J=8.2 Hz,1H),7.51(s,1H),6.91(d,J=12.1 Hz,1H),6.62(d,J=7.0 Hz,1H),4.73(br.s,1H),4.10(s,2H),3.58(s,2H),3.51(q,J=6.9 Hz, 2H), 2.63-2.51 (m, 2H), 1.24 (s, 6H).

[0300] Example 30 N-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000173.tif36170Step 1: Methyl 2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxylate To a stirred solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (371 mg, 2.41 mmol), methyl 3,4-diaminobenzoate (400 mg, 2.41 mmol), and DIPEA (0.47 mL, 2.66 mmol) in DMF (8 mL) was added HATU (915 mg, 2.41 mmol), and the mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo, and the residue was partitioned between saturated NaHCO (25 mL) and EtOAc (25 mL). The organic layer was separated, washed with brine (2 × 25 mL), dried over NaSO, and concentrated in vacuo. The resulting crude product was dissolved in acetic acid (8 mL) and stirred at 80 °C for 1 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between saturated NaHCO (25 mL) and EtOAc (25 mL). The organic layer was washed with brine (25 mL), dried over Na2SO4, and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 0-100% EtOAc in heptane gave the title compound as a brown viscous oil. LC-MS (Method B): Rt 1.04 min; MS m / z 285.1=[M+H]+ (93% at 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 12.93(br.s,1H),8.15(s,1H),7.84(d,J=8.4 Hz,1H),7.68-7.54(m,1H),3.86(s,3H),1.60-1.53(s,4H). Step 2: 2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxylic acid A solution of methyl 2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxylate (Step 1) (93%, 630 mg, 2.06 mmol) in THF (3 mL) and MeOH (3 mL) was treated with 1 M lithium hydroxide hydrate (3.09 mL, 6.18 mmol) and stirred at room temperature for 1.5 h. Additional 1 M lithium hydroxide hydrate (3.09 mL, 6.18 mmol) was added, and the mixture was stirred overnight. Solid lithium hydroxide hydrate (260 mg, 6.18 mmol) was added, and stirring was continued for 5 h. The resulting mixture was diluted with EtOAc (15 mL) and HO (15 mL). The pH was adjusted to 4 using 2 M KHSO, the layers were separated, and the aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound as a beige sticky / gummy solid. LC-MS (Method B): Rt 0.89 min; MS m / z 270.9=[M+H]+ (98% at 215 nm) 1H NMR(500MHz,DMSO-d6)δ 12.95-12.83(m,1H),12.72(br.s,1H),8.24-8.00(m,1H),7.88-7.76(m,1H),7.69-7.51(m,1H),1.59-1.52(m,4H).NMR purity 80% Step 3: N-[(2-fluoro-5-methoxy-phenyl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide To a stirred solution of HATU (507 mg, 1.33 mmol), 2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxylic acid (Step 2) (80%, 450 mg, 1.33 mmol), and (2-fluoro-5-methoxy-phenyl)methanamine (207 mg, 1.33 mmol) in DMF (5 mL) was added DIPEA (256 μL, 1.47 mmol), and the mixture was stirred at room temperature for 1 h and allowed to stand overnight. The resulting mixture was diluted with saturated aqueous NaHCO (10 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine (2 × 10 mL), dried over NaSO, and then concentrated in vacuo. Purification by chromatography on silica eluting with 0-100% EtOAc in heptane gave the title compound as a viscous brown oil. LC-MS (D method): Rt 0.80 min; MS m / z 408.2=[M+H]+(82% at 215 nm) 1H NMR (500 MHz, methanol-d4) δ 8.12(br.s,1H),7.83-7.78(m,1H),7.66-7.58(m,1H),7.01(t,J=9.3 Hz,1H),6.95(dd,J=6.0,3.2 NMR purity 69% Step 4: N-[(4-bromo-2-fluoro-5-methoxy-phenyl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide Bromine (122 μL, 2.13 mmol, 2.4 equiv.) was added to a solution of N-[(2-fluoro-5-methoxy-phenyl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Step 3) (69%, 524 mg, 0.89 mmol) in anhydrous MeCN (10 mL), and the mixture was stirred overnight at room temperature. The reaction was carefully quenched with 10% aqueous sodium sulfite (10 mL) and then diluted with saturated aqueous NaHCO (10 mL) and EtOAc (10 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (10 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with a gradient of 0-75% EtOAc in heptane followed by C18 reverse phase chromatography eluting with 10-100% MeCN in water with 0.1% formic acid modifier afforded the title compound as a yellow viscous oil. LC-MS (D method): Rt 0.89 min; MS m / z 486.1 / 488.1=[M+H]+(84% at 215 nm) 1H NMR (500 MHz, methanol-d4)δ 8.12(s,1H),7.80(dd,J=8.5,1.5 Hz,1H),7.62(d,J=8.5 Hz,1H),7.35(d,J=9.1 Hz,1H),7.10(d,J=6.5 Hz, 1H), 4.61 (s, 2H), 3.83 (s, 3H), 1.61-1.56 (m, 2H), 1.55-1.50 (m, 2H). Step 5: N-[(4-bromo-2-fluoro-5-methoxy-phenyl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1-(2-trimethylsilylethoxymethyl)benzimidazole-5-carboxamide TIFF0007797206000178.tif61170 The title compound was prepared from N-[(4-bromo-2-fluoro-5-methoxy-phenyl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Step 4) and 2-(chloromethoxy)ethyl-trimethylsilane in analogy to Step 3 of Example 9. LC-MS (D method): Rt 1.21 min; MS m / z 616.2 / 618.2=[M+H]+(86% at 215 nm) 1H NMR (500 MHz, methanol-d4) δ 8.29-8.20 (m, 1H), 7.95-7.84 (m, 1H), 7.78-7.72 (m, 1H), 7.37-6.98 (m, 2H), 5.97-5.78 (m, 2H), 4.65-4.60 (m, 2H), 3.85-3.59 (m, 5H), 1.69-1.64 (m, 3H), 1.58-1.53 ​​(m, 2H), 0.97-0.84 (m, 2H), 0.02-0.09 (m, 9H) [2:1 mixture of regioisomers not separated but used as a mixture in the next step]. Step 6: 2-[5-fluoro-2-methoxy-4-[[[2-[1-(trifluoromethyl)cyclopropyl]-1-(2-trimethylsilylethoxymethyl)benzimidazole-5-carbonyl]amino]methyl]phenyl]-2-methyl-propionic acid methyl ester TIFF0007797206000179.tif63170 The title compound was prepared from N-[(4-bromo-2-fluoro-5-methoxy-phenyl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1-(2-trimethylsilylethoxymethyl)benzimidazole-5-carboxamide (Step 5) and (1-methoxy-2-methyl-prop-1-enoxy)-trimethyl-silane in analogy to Step 4 of Intermediate B. LC-MS (E method): Rt 1.80 min; MS m / z 638.4=[M+H]+ (87% at 215 nm) 1H NMR (500 MHz, methanol-d4)δ 8.24-8.21(m,1H),7.94-7.84(m,1H),7.78-7.72(m,1H),7.09-7.05(m,1H),7.02-6.99(m,1H),5.82-5.77(m,2H),4.66-4.62(m,2H),3 .73(s,3H),3.72-3.69(m,2H),3.60(s,3H),1.69-1.65(m,2H),1.58-1.54(m,2H),1.46(s,6H),0.96-0.92(m,2H),-0.02--0.06(m,9H). Step 7: N-[(5-fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide To a cooled (0 °C) stirred solution of methyl 2-[5-fluoro-2-methoxy-4-[[[2-[1-(trifluoromethyl)cyclopropyl]-1-(2-trimethylsilylethoxymethyl)benzimidazole-5-carbonyl]amino]methyl]phenyl]-2-methyl-propanoate (Step 6) (87%, 73 mg, 0.1 mmol) in DCM (300 µL) was added BBr3 (299 µL, 0.3 mmol) under N2, and the mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo (at 30 °C). The residue was quenched with acetonitrile in MeCN:HO (1:1). Purification by C18 reverse phase chromatography eluting with 10-100% MeCN in water with 0.1% formic acid modifier gave the title compound as an orange viscous oil. LC-MS (D method): Rt 0.86 min; MS m / z 462.2=[M+H]+ (73% at 215 nm) Step 8: N-[[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide The title compound was prepared from N-[(5-fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Step 7) in analogy to Step 3 of Example 29. LC-MS (method A): Rt 2.50 min; MS m / z 466.1=[M+H]+ (96% at 215 nm) 1H NMR (500 MHz, methanol-d4)δ 8.15(br.s,1H),7.83(dd,J=8.5,1.5 Hz,1H),7.64(d,J=7.8 Hz,1H),6.96(d,J=12.3 Hz,1H),6.80(d,J=6.8 Hz, 1H), 4.69-4.53 (m, 3H), 3.80 (s, 2H), 1.62-1.57 (m, 2H), 1.57-1.52 (m, 2H), 1.35 (s, 6H).

[0301] Example 31 2-[[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide TIFF0007797206000181.tif48170Step 1: 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-1H-benzimidazole-5-carboxylate methyl ester TIFF0007797206000182.tif51170 The title compound was prepared analogously to Step 1 of Example 22 from 2-[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]acetic acid (Intermediate A) and methyl 3,4-diaminobenzoate. LC-MS (C method): Rt 1.63 min; MS m / z 449.3=[M+H]+(86% at 215 nm) Step 2: 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-1H-benzimidazole-5-carboxylic acid To a solution of methyl 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-1H-benzimidazole-5-carboxylate (Step 1) (86%, 415 mg, 0.79 mmol) in THF (1.2 mL) was added 2 M LiOH (1.2 mL, 2.4 mmol), and the resulting mixture was vigorously stirred at room temperature for 6 h. Additional 2 M LiOH (0.6 mL, 1.2 mmol) was added, and the mixture was heated at 50 °C for 1 h and then allowed to stand at room temperature for 3 days. Volatile solvents were removed in vacuo (30 °C), and the pH of the resulting aqueous mixture was adjusted to 4 by dropwise addition of saturated aqueous NH4Cl and 1 M HCl. The mixture was extracted with EtOAc (3 x 25 mL) and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound as a brown viscous oil. LC-MS (C method): Rt 1.12 min; MS m / z 435.3=[M+H]+ (97% at 215 nm) 1H NMR (500 MHz, methanol-d4)δ 8.31-8.29(m,1H),8.09(dd,J=8.6,1.5 Hz,1H),7.69-7.66(m,1H),7.41(d,J=11.5 Hz,1H),7.39-7.35(m,2H),7.31-7.23(m,3H),7.02(d,J=6.2 Hz,1H),5.12(s,2H),4.42(s,2H),1.57(s,6H). Step 3: 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide To a stirred solution of HATU (91 mg, 0.24 mmol), 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-1H-benzimidazole-5-carboxylic acid (Step 2) (83%, 114 mg, 0.22 mmol), and 3,3,3-trifluoropropan-1-amine hydrochloride (72 mg, 0.48 mmol) in DMF (1.5 mL) was added DIPEA (133 μL, 0.76 mmol), and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with saturated aqueous NaHCO (4 mL) and EtOAc (4 mL). The organic layer was separated, washed with brine (2 × 4 mL), dried over NaSO, and concentrated in vacuo. Purification by chromatography on NH-silica eluting with 0-100% EtOAc in heptane gave the title compound as a yellow viscous oil. LC-MS (C method): Rt 1.60 min; MS m / z 530.5=[M+H]+ (98% at 215 nm) 1H NMR (400 MHz, methanol-d4)δ 8.03(br.s,1H),7.73(dd,J=8.4,1.4 Hz,1H),7.60-7.50(m,1H),7.37-7.30(m,3H),7.28-7.20(m,3H),6.94(d,J=6.3 Hz,1H),5.07(s,2H),4.25(s,2H),3.66(t,J=7.0 Hz,2H),2.55(qt,J=11.0,7.0 Hz,2H),1.56(s,6H). Contains 25% w / w EtOAc by NMR. Step 4: 2-[[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide To a solution of 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (Step 3) (73%, 107 mg, 0.15 mmol) in EtOH (2 mL) was added 10% Pd / C [50% in HO] (5%, 31 mg, 0.015 mmol). The reaction was placed under an atmosphere of H and stirred for 2 h. The resulting mixture was filtered through a pad of Celite® and rinsed with EtOH (10 mL). The filtrate was concentrated in vacuo and purified by chromatography on C18-silica eluting with 10–100% MeCN (0.2% ammonium hydroxide) in HO (0.2% ammonium hydroxide). The product fractions were combined, the pH adjusted to 7 using 1M HCl, and then extracted with EtOAc (x2). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the title compound as a beige solid. LC-MS (method A): Rt 1.78 min; MS m / z 440.2=[M+H]+ (98% at 215 nm) 1H NMR (500 MHz, methanol-d4) δ 8.03(br.s,1H),7.73-7.67(m,1H),7.61-7.48(m,1H),7.03(d,J=11.2 Hz,1H),6.66(d,J=6.6 Hz, 1H), 4.21 (s, 2H), 3.64 (t, J=7.1 Hz, 2H), 2.59-2.49 (m, 2H), 1.56 (s, 6H).

[0302] Example 31.1 2-[[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000185.tif50170Step 1: 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000186.tif53170 The title compound was prepared from 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-1H-benzimidazole-5-carboxylic acid (Step 2 of Example 31) and 1-(trifluoromethyl)cyclopropanamine hydrochloride in analogy to Step 3 of Example 31. LC-MS (C method): Rt 1.61 min; MS m / z 542.4=[M+H]+(100% at 215 nm) 1H NMR (400 MHz, methanol-d4) δ 8.04(br.s,1H),7.77-7.70(m,1H),7.61-7.49(m,1H),7.38-7.30(m,3H),7.29-7.19(m,3H),6.95(d,J=6.3 Hz, 1H), 5.07 (s, 2H), 4.25 (s, 2H), 1.56 (s, 6H), 1.41-1.36 (m, 2H), 1.27-1.20 (m, 2H). Step 2: 2-[[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide The title compound was prepared from 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Step 1) in analogy to Step 4 of Example 31. LC-MS (method A): Rt 1.86 min; MS m / z 452.2=[M+H]+ (98% at 215 nm) 1H NMR (500 MHz, methanol-d4) δ 8.04(br.s,1H),7.74-7.69(m,1H),7.61-7.49(m,1H),7.03(d,J=11.2 Hz,1H),6.66(d,J=6.6 Hz, 1H), 4.20 (s, 2H), 1.56 (s, 6H), 1.40-1.36 (m, 2H), 1.24-1.20 (m, 2H).

[0303] Example 32 2-[[5-Fluoro-2-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide TIFF0007797206000187.tif37170 Step 1: Methyl 2-[5-fluoro-2-methoxy-3-[[5-[[1-(trifluoromethyl)cyclopropyl]methylcarbamoyl]-1H-benzimidazol-2-yl]methyl]phenyl]-2-methyl-propanoate To a solution of 2-[5-fluoro-2-methoxy-3-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)phenyl]acetic acid (Intermediate C) (88%, 156 mg, 0.48 mmol) in DMF (5 mL) was added HATU (230 mg, 0.6 mmol), followed by DIPEA (0.21 mL, 1.21 mmol). After stirring for 5 minutes, ammonium [2-amino-4-[[1-(trifluoromethyl)cyclopropyl]methylcarbamoyl]phenyl]formate (formate salt from Step 1 of Example 29) (88%, 175 mg, 0.48 mmol) was added, and the reaction mixture was stirred at room temperature under an inert atmosphere for 4 hours. The resulting mixture was diluted with EtOAc (40 mL), washed with water (2 × 25 mL), brine (25 mL), dried over NaSO, and concentrated in vacuo. The crude material was dissolved in acetic acid (5 mL) and stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (25 mL) and NaHCO (25 mL). The layers were separated, and the aqueous portion was back-extracted with EtOAc (25 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo. Purification of the crude material by C18 reverse-phase chromatography, eluting with a gradient of 10–100% MeCN (+0.1% formic acid) in HO (+0.1% formic acid), afforded the title compound as a pale yellow solid. LC-MS (Method B): Rt 1.09 min; MS m / z 522.3=[M+H]+(100% at 215 nm) H NMR (400 MHz, methanol-d) δ 8.57 (t, J = 6.0 Hz, 1H), 8.11 (br.s, 1H), 8.04-8.00 (m, 1H), 7.71 (dd, J = 8.5, 1.4 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 9.8, 3.1 Hz, 1H), 6.91-6.85 (m, 1H), 4.35-4.29 (m, 2H), 3.73-3.68 (m, 5H), 3.57 (s, 3H), 1.50 (s, 6H), 1.05-0.89 (m, 4H). NH protons were partially exchanged. Step 2: 2-[(5-fluoro-3,3-dimethyl-2-oxo-benzofuran-7-yl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide To a solution of methyl 2-[5-fluoro-2-methoxy-3-[[5-[[1-(trifluoromethyl)cyclopropyl]methylcarbamoyl]-1H-benzimidazol-2-yl]methyl]phenyl]-2-methylpropanoate (Step 1) (100%, 78 mg, 0.15 mmol) in DCM (2.5 mL) under an inert atmosphere, 1 M BBr3 in DCM (0.45 mL, 0.45 mmol) was added, resulting in the formation of a gum. The gum was scratched to a solid, sonicated for 5 minutes, and stirring was continued at room temperature for 2 hours. An additional portion of 1 M BBr3 in DCM (0.45 mL, 0.45 mmol) was added, the resulting solid was scratched and sonicated, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was taken up in MeCN:HO and stirred for 1 h. Purification of the mixture by C18 reverse-phase chromatography eluting with a gradient of 10 to 100% MeCN (+0.1% formic acid) in HO (+0.1% formic acid) afforded the title compound as a colorless oil. LC-MS (D method): Rt 0.91 min; MS m / z 476.2=[M+H]+(99% at 215 nm) 1H NMR (400 MHz, methanol-d4)δ 8.09(s,1H),8.02(d,J=1.3 Hz,1H),7.71(dd,J=8.5,1.6 Hz,1H),7.57(d,J=8.5 Hz,1H),7.11(dd,J=7.6,2.7 Hz,1H),7.03(dd,J=9.8,2.6 Hz,1H),4.35(s,2H),3.70(s,2H),1.49(s,6H),1.03-0.92(m,4H). Step 3: 2-[[5-fluoro-2-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide The title compound was prepared from 2-[(5-fluoro-3,3-dimethyl-2-oxo-benzofuran-7-yl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (Step 2) and 4M LiBH in THF in analogy to Step 3 of Example 29. LC-MS (method A): Rt 2.25 min; MS m / z 480.3=[M+H]+(95% at 215 nm) H NMR (500 MHz, methanol-d) δ 8.31 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.68 (dd, J = 8.5, 1.7 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 11.1, 3.1 Hz, 1H), 6.81 (dd, J = 8.2, 3.1 Hz, 1H), 4.25-4.20 (m, 2H), 3.73-3.67 (m, 4H), 1.36 (s, 6H), 1.02-0.93 (m, 4H). Singlet at 8.31 partially exchanged with D.

[0304] Example 33 2-[(4-tert-butyl-2-fluoro-5-hydroxyphenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyridine-7-carboxamide TIFF0007797206000190.tif48170Step 1: 1-Bromo-3-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)propan-2-one Two drops of DMF were added to a solution of 2-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)acetic acid (Example 21, Step 1) (300 mg, 1.25 mmol) in DCM (10 mL), followed by thionyl chloride (453 μL, 6.24 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo, azeotroped with dry MeCN, and the residue was dissolved in dry MeCN (20 mL). The mixture was cooled to 0° C. and treated dropwise with 2 M trimethylsilyldiazomethane in ether (0.94 mL, 1.87 mmol), and the resulting mixture was allowed to warm to room temperature with stirring for 2 hours. The mixture was recooled to 0° C. and treated dropwise with a solution of HBr in acetic acid (33%, 1.08 mL, 6.24 mmol) and stirred while warming to room temperature for 1 hour. The reaction was diluted with acetic acid (5 mL), water (80 mL), and EtOAc (80 mL). The organics were separated and further washed with water (2 x 40 mL) and brine (40 mL). The combined aqueous layers were back-extracted with EtOAc, and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 0-100% EtOAc in heptane to give the title compound as a yellow oil. LC-MS (Method D): Rt 1.11 min (59% at 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 6.97-6.93 (m, 1H), 6.87-6.84 (m, 1H), 4.48 (s, 2H), 3.95 (s, 2H), 3.77 (s, 3H), 1.31 (s, 9H). Step 2: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]imidazo[1,2-a]pyridine-7-carboxylate methyl To a solution of 1-bromo-3-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)propan-2-one (Step 1) (59%, 272 mg, 0.51 mmol) and methyl 2-aminopyridine-4-carboxylate (140 mg, 0.92 mmol) in TIFF0007797206000192.tif50170 DCE (10 mL) was added potassium iodide (92 mg, 0.55 mmol), and the mixture was stirred at 100 °C in a pressure tube for 4 h. The resulting mixture was cooled to room temperature, diluted with DCM (40 mL), and washed with water (2 × 25 mL). The organic portion was dried over NaSO and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 0–100% EtOAc in heptane afforded the title compound as a brown oil. LCMS (G method): Rt 0.72 min; MS m / z 371.3=[M+H]+(92% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 8.56(dd,J=7.1,0.9 Hz,1H),8.07-8.04(m,1H),7.84(s,1H),7.28(dd,J=7.1,1.7 Hz,1H),7.01(d,J=6.8 Hz, 1H), 6.96 (d, J=11.8 Hz, 1H), 4.07 (s, 2H), 3.88 (s, 3H), 3.76 (s, 3H), 1.30 (s, 9H). Step 3: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]imidazo[1,2-a]pyridine-7-carboxylic acid To a solution of methyl 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]imidazo[1,2-a]pyridine-7-carboxylate (Step 2) (92%, 100 mg, 0.25 mmol) in THF (5 mL) was added 2 M lithium hydroxide (0.37 mL, 0.75 mmol), and the reaction mixture was stirred at 40 °C for 1 h and then at 50 °C for 4 h. After cooling to room temperature, the organics were removed in vacuo, and the resulting solid was dissolved in water (10 mL). The solution was acidified to pH 4–5 using 2 M aqueous HCl (ca. 1 mL), and the resulting precipitate was extracted into EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over NaSO, and concentrated in vacuo to give the title compound as a light brown solid. LCMS (G method): Rt 0.44 min; MS m / z 357.3=[M+H]+(95% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 13.31(br.s,1H),8.52(dd,J=7.0,0.8 Hz,1H),8.01(s,1H),7.81(s,1H),7.25(dd,J=7.1,1.7 Hz,1H),7.00(d,J=6.8 Hz, 1H), 6.96 (d, J=11.8 Hz, 1H), 4.06 (s, 2H), 3.76 (s, 3H), 1.30 (s, 9H). Step 4: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyridine-7-carboxamide To a solution of 2-[(4-tert-butyl-2-fluoro-5-methoxyphenyl)methyl]imidazo[1,2-a]pyridine-7-carboxylic acid (Step 3) (87%, 100 mg, 0.24 mmol) in DMF (5 mL) was added HATU (139 mg, 0.37 mmol), followed by 1-(trifluoromethyl)cyclopropanamine hydrochloride (59 mg, 0.37 mmol) and DIPEA (0.11 mL, 0.61 mmol), and the mixture was stirred at room temperature for 2 hours under an inert atmosphere. An additional portion of 1-(trifluoromethyl)cyclopropanamine hydrochloride (59 mg, 0.37 mmol) and DIPEA (0.11 mL, 0.61 mmol) was added, and the mixture was heated at 40 ° C. for 2 hours. The resulting mixture was diluted with EtOAc (25 mL), washed with water (2 x 25 mL), brine (25 mL), dried over Na2SO4, and concentrated in vacuo. Purification by chromatography on silica eluting with 0-100% EtOAc in heptane gave the title compound as a light brown solid. LC-MS (C method): Rt 1.90 min; MS m / z 464.3=[M+H]+ (95% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 9.28(s,1H),8.51(dd,J=7.1,0.8 Hz,1H),8.04(s,1H),7.74(s,1H),7.24(dd,J=7.1,1.8 Hz,1H),7.00(d,J=6.8 Hz,1H),6.96(d,J=11.8 Hz,1H),4.05(s,2H),3.75(s,3H),1.36-1.32(m,2H),1.30(s,9H),1.20-1.14(m,2H). Step 5: 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyridine-7-carboxamide To a solution of 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyridine-7-carboxamide (Step 4) (95%, 70 mg, 0.14 mmol) in DCM (2 mL) was added 1 M BBr in DCM (430 μL, 0.43 mmol), and the reaction mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo, and the crude material was dissolved in EtOAc (15 mL). The organic mixture was washed with saturated aqueous NaHCO (10 mL), water (10 mL), dried over NaSO, and concentrated in vacuo. The crude product was purified by preparative HPLC (high pH, ​​fast elution method) to give the title compound as an off-white solid. LCMS (Method A): Rt 2.71 min; MS m / z 450.3=[M+H]+ (97% at 215 nm) 1H NMR(400 MHz,DMSO-d6)δ 9.28(s,1H),9.18(s,1H),8.53(dd,J=7.1,0.8 Hz,1H),8.05-8.01(m,1H),7.77(s,1H),7.25(dd,J=7.1,1.7 Hz,1H),6.87(d,J=12.0 Hz,1H),6.65(d,J=7.0 Hz,1H),3.96(s,2H),1.36-1.28(m,11H),1.20-1.15(m,2H).

[0305] Preparation of intermediate compounds Intermediate A 2-[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]acetic acid TIFF0007797206000195.tif59170Step 1: (3-Bromo-4-fluoro-phenyl)acetate A cooled (0 °C) solution of 3-bromo-4-fluorophenol (5 g, 26.18 mmol) and TEA (6.86 mL, 39.27 mmol) in DCM (100 mL) was treated dropwise with acetyl chloride (2.61 mL, 36.65 mmol), and the mixture was stirred at room temperature for 45 min. The resulting mixture was diluted with DCM (100 mL) and washed successively with 0.5 M HCl (120 mL), water (120 mL), saturated NaHCO (120 mL), and brine (120 mL). The organic portion was dried over NaSO and concentrated in vacuo to give the title compound as a tan solid. LC-MS (Method B): Rt 1.14 min (85% at 215 nm) 1 H NMR (500 MHz, DMSO-d6) δ 7.59 (dd, J = 6.0, 2.8 Hz, 1H), 7.43 (t, J = 8.8 Hz, 1H), 7.26-7.17 (m, 1H), 2.26 (s, 3H). Step 2: 1-(4-bromo-5-fluoro-2-hydroxy-phenyl)ethanone A mixture of (3-bromo-4-fluoro-phenyl)acetate (Step 1) (90%, 6.3 g, 24.33 mmol) and aluminum trichloride (5.84 g, 43.8 mmol) was stirred at 165 °C for 3 h. The melt was cooled to room temperature, and the resulting solid was suspended in DCM (100 mL). 2 N HCl (100 mL) was added, and the mixture was filtered through Celite® (filter material) to remove insoluble material. The layers were separated, and the aqueous portion was re-extracted with DCM (60 mL). The combined organic extracts were washed with water (140 mL), brine (140 mL), dried over NaSO, and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 0–30% EtOAc in heptane to give the title compound as an off-white solid. LC-MS (Method B): Rt 1.17 min (96% at 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.79 (d, J = 9.4 Hz, 1H), 7.33 (d, J = 5.8 Hz, 1H), 2.61 (s, 3H). Step 3: 1-(2-benzyloxy-4-bromo-5-fluoro-phenyl)ethanone TIFF0007797206000198.tif53170 Benzyl bromide (3.23 mL, 27.19 mmol) was added to a stirred mixture of 1-(4-bromo-5-fluoro-2-hydroxy-phenyl)ethanone (Step 2) (96%, 5.5 g, 22.66 mmol) and K2CO3 (7.83 g, 56.65 mmol) in DMF (25 mL), and the mixture was stirred at 80 °C for 1 h. The resulting mixture was cooled to room temperature and partitioned between EtOAc (150 mL) and water (150 mL). The aqueous layer was further extracted with EtOAc (100 mL). The combined organic extracts were washed with water (2 × 150 mL), brine (150 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 0-60% EtOAc in heptane to give the title compound as an off-white solid. LC-MS (Method B): Rt 1.35 min (87% at 215 nm) 1 H NMR(500 MHz,DMSO-d6)δ 7.65(d,J=5.5 Hz,1H),7.55-7.46(m,3H),7.44-7.40(m,2H),7.39-7.35(m,1H),5.26(s,2H),2.49(s,3H). Step 4: 2-(2-benzyloxy-4-bromo-5-fluoro-phenyl)propan-2-ol To a stirred solution of 1-(2-benzyloxy-4-bromo-5-fluoro-phenyl)ethanone (step 3) (90%, 100 mg, 0.28 mmol) in THF (1 mL) was added bromo(methyl)magnesium (3 M in EtO) (121 μL, 0.36 mmol) at −78° C. The dry ice bath was removed, and the mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with saturated aqueous NH4Cl (10 mL) and EtOAc (10 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo to give the title compound as a pale yellow solid. LC-MS (Method B): Rt 1.31 min; MS m / z 320.9 / 322.9 [M+H-H2O]+ (95% at 215 nm) 1 H NMR (400 MHz, DMSO-d6) δ 7.57-7.27 (m, 7H), 5.23 (s, 1H), 5.14 (s, 2H), 1.45 (s, 6H). Step 5: 2-[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]acetic acid To a stirred solution of potassium 3-ethoxy-3-oxopropanoate (75 mg, 0.44 mmol) and 2-(2-benzyloxy-4-bromo-5-fluoro-phenyl)propan-2-ol (Step 4) (100 mg, 0.29 mmol) in toluene (2 mL) was added DMAP (3.6 mg, 0.03 mmol). The resulting mixture was degassed with N for 5 minutes. Diallyldipalladium dichloride (2.2 mg, 0.01 mmol) and BINAP (11.0 mg, 0.02 mmol) were added, and the sealed reaction mixture was stirred at 140 °C for 3.5 hours. The resulting mixture was concentrated in vacuo, and the residue was dissolved in THF (3 mL). Insoluble material was removed by filtration, and the filtrate was diluted with MeOH (0.5 mL) and treated with 2 M aqueous LiOH (0.44 mL, 0.88 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with 2M NaOH (10 mL) and extracted with EtOAc (3 × 10 mL). The organic extracts were discarded, and the aqueous portion was acidified to pH 3 using 2M aqueous HCl. The mixture was extracted with EtOAc (3 × 10 mL), and the combined organic extracts were dried over NaSO and concentrated in vacuo to give the title compound as an off-white solid. LC-MS (Method B): Rt 1.10 min; MS m / z 301.0 [M+H-H2O]+ (93% at 215 nm) 1 H NMR(500 MHz,DMSO-d6)δ 12.40(s,1H),7.49-7.45(m,2H),7.45-7.40(m,2H),7.37-7.33(m,1H),7.31(d,J=11.5 Hz,1H),7.05(d,J=6.3 Hz, 1H), 5.08 (s, 1H), 5.06 (s, 2H), 3.57 (s, 2H), 1.46 (s, 6H).

[0306] Intermediate B 2-(5-Fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)acetic acid TIFF0007797206000200.tif41170Step 1: 2-(4-Bromo-2-fluoro-5-methoxy-phenyl)acetic acid To a cooled (0°C) solution of 2-(2-fluoro-5-methoxy-phenyl)acetic acid (45 g, 244.35 mmol) in MeCN (1200 mL) was added dropwise a solution of bromine (12.63 mL, 219.92 mmol) in MeCN (100 mL) over 10 minutes. Without removing the ice bath, the mixture was gradually warmed to room temperature (approximately 1.5 hours). A second portion of bromine (4.21 mL, 73.31 mmol) in MeCN (50 mL) was added dropwise at 0°C, and stirring was continued at room temperature for 3.5 hours. A third portion of bromine (4.21 mL, 73.31 mmol) in MeCN (50 mL) was added at room temperature, and stirring was continued for 30 minutes. The reaction was carefully quenched with saturated aqueous sodium sulfite solution (approximately 700 mL) until the bright orange color disappeared. The colorless solution was diluted with brine (200 mL) and EtOAc (200 mL) and stirred vigorously for 10 minutes, then allowed to stand at room temperature overnight. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (200 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product as a white solid. The solid was recrystallized by dissolving in AcOH (700 mL) and treating with water (4 L). The resulting mixture was stirred at room temperature for 1 hour, then at 0°C for 3 hours. The resulting solid was filtered, washed with water (200 mL), and dried under vacuum at 40°C to give the title compound as a fluffy white solid. LC-MS (Method B): Rt 1.07 min; MS m / z 523.2 / 525.1 / 527.0=[2M-H]-(99% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 12.55(br.s,1H),7.50(d,J=8.9 Hz,1H),7.13(d,J=6.6 Hz,1H),3.81(s,3H),3.61(d,J=1.3 Hz,2H). Step 2: 2-(4-Bromo-2-fluoro-5-hydroxy-phenyl)acetic acid TIFF0007797206000202.tif34170 1M BBr3 in DCM (112.9 mL, 112.9 mmol) was added dropwise over 1 h to a cooled (0 °C) stirred solution of 2-(4-bromo-2-fluoro-5-methoxy-phenyl)acetic acid (Step 1) (99%, 10 g, 37.63 mmol) in DCM (150 mL) under N2. The reaction mixture was allowed to warm to room temperature and then stirred for 1 h. The resulting mixture was concentrated in vacuo, and the residue was partitioned between water (250 mL) and EtOAc (250 mL). The organic layer was washed with water (250 mL), dried over Na2SO4, and concentrated in vacuo to provide the title compound as an off-white powder. LC-MS (Method D): Rt 0.67 min (90% at 215 nm) 1H NMR (500 MHz, methanol-d4) δ 7.23 (d, J = 9.0 Hz, 1H), 6.84 (d, J = 6.8 Hz, 1H), 3.55 (d, J = 1.2 Hz, 2H). Step 3: Benzyl 2-(5-benzyloxy-4-bromo-2-fluoro-phenyl)acetate To a solution of 2-(4-bromo-2-fluoro-5-hydroxy-phenyl)acetic acid (Step 2) (90%, 9.2 g, 33.25 mmol) in DMF (90 mL) was added K2CO3 (13.79 g, 99.75 mmol) and bromomethylbenzene (8.69 mL, 73.15 mmol), and the reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (300 mL) and water (300 mL). The aqueous layer was further extracted with EtOAc (150 mL). The combined organic extracts were washed with saturated NaHCO3 (150 mL), brine (2 x 150 mL), dried over Na2SO4, and concentrated in vacuo. Purification by chromatography on silica eluting with 0-100% TBME in heptane gave the title compound as an off-white solid. LC-MS (Method E): Rt 1.84 min (98% at 215 nm) 1H NMR(500 MHz,DMSO-d6)δ 7.56(d,J=8.9 Hz,1H),7.49-7.45(m,2H),7.43-7.32(m,8H),7.28(d,J=6.6 Hz, 1H), 5.13 (s, 2H), 5.12 (s, 2H), 3.80-3.77 (m, 2H). Step 4: 2-[2-benzyloxy-4-(2-benzyloxy-2-oxo-ethyl)-5-fluoro-phenyl]-2-methyl-propionic acid methyl ester Benzyl 2-(5-benzyloxy-4-bromo-2-fluorophenyl)acetate (Step 3) (98%, 12.5 g, 28.54 mmol), ZnF (2951 mg, 28.54 mmol), and Pd(t-BuP) (1.46 g, 2.85 mmol) in DMF (100 mL) were bubbled with N for 10 minutes at room temperature. (1-Methoxy-2-methyl-prop-1-enoxy)-trimethylsilane (11.59 mL, 57.07 mmol) was added, and the reaction mixture was heated to 80 °C overnight. The resulting mixture was filtered through a pad of Celite®, washing with EtOAc (3 × 100 mL). The filtrate was washed with brine (500 mL) and the organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 0 to 100% TBME in heptane gave the title compound as a pale yellow oil. LC-MS (Method A): Rt 4.51 min; MS m / z 449.2 = [MH] (81% at 215 nm) The sample was further purified by C18 reverse phase chromatography eluting with 10-100% MeCN in water containing 0.1% formic acid. NMR data refers to this sample. 1H NMR(500 MHz,DMSO-d6)δ 7.43-7.35(m,5H),7.38-7.29(m,5H),7.13(d,J=11.0 Hz,1H),7.11(d,J=6.5 Hz, 1H), 5.14 (s, 2H), 5.00 (s, 2H), 3.77 (s, 2H), 3.33 (s, 3H), 1.44 (s, 6H). Step 5: 2-(5-fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)acetic acid A cooled (0 °C) solution of methyl 2-[2-benzyloxy-4-(2-benzyloxy-2-oxo-ethyl)-5-fluoro-phenyl]-2-methyl-propanoate (Step 4) (70%, 10.7 g, 16.63 mmol) in DCM (250 mL) was treated with 1 M BBr3 in DCM (83.13 mL, 83.13 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was poured onto ice (500 g) and stirred for an additional 30 min. The resulting emulsion was filtered through a sintered funnel to give a clear biphasic mixture. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by C18 reverse phase chromatography eluting with 10-100% MeCN in water (0.1% formic acid modifier) ​​afforded the title compound as an off-white solid. LC-MS (Method F): Rt 1.31 min; MS m / z 237.2 = [MH] (100% at 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 12.51 (br.s, 1H), 7.41 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 5.8 Hz, 1H), 3.64 (d, J = 1.4 Hz, 2H), 1.44 (s, 6H).

[0307] Intermediate C 2-[5-Fluoro-2-methoxy-3-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)phenyl]acetic acid TIFF0007797206000205.tif37170Step 1: 2-(3-Bromo-5-fluoro-2-methoxy-phenyl)acetic acid To a stirred solution of 2-(5-fluoro-2-methoxy-phenyl)acetic acid (1.5 g, 8.15 mmol) in acetic acid (30 mL) was added bromine (3.74 mL, 65.16 mmol), and the mixture was stirred at room temperature for 1 h. The resulting mixture was cooled to 10 °C and diluted with EtOAc (100 mL). Saturated aqueous sodium thiosulfate (ca. 50 mL) was added with stirring until the dark brown color turned yellow. The mixture was diluted with water (100 mL), and the organic layer was separated. The aqueous layer was back-extracted with a 3:1 chloroform:IPA mix (3 × 50 mL), and the combined organic extracts were washed with water (2 × 50 mL), dried over Na2SO4, and concentrated in vacuo. The resulting crude material was purified by chromatography on silica eluting with 0–100% EtOAc in heptane to afford the title compound as a white solid. LC-MS (Method D): Rt 0.91 min; MS m / z 261.0 / 263.0 = [MH] (81% at 215 nm) 1H NMR (400 MHz, DMSO-d6) δ 12.52 (br.s, 1H), 7.50 (dd, J=8.0, 3.1 Hz, 1H), 7.21 (dd, J=9.0, 3.1 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 2H). Step 2: tert-butyl 2-(3-bromo-5-fluoro-2-methoxy-phenyl)acetate To a solution of 2-(3-bromo-5-fluoro-2-methoxy-phenyl)acetic acid (Step 1) (260 mg, 0.99 mmol) in tert-butanol (5 mL) was added Boc anhydride (227 mg, 1.04 mmol) and DMAP (12 mg, 0.1 mmol), and the reaction mixture was stirred at 40 °C for 5 h. The resulting mixture was concentrated in vacuo, and the residue was redissolved in EtOAc (25 mL). The organic mixture was washed with water (25 mL), saturated NaHCO (2 × 25 mL), brine (25 mL), dried over NaSO, and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 0–100% EtOAc in heptane to afford the title compound as a colorless oil. LC-MS (Method E): Rt 1.67 min (98% at 215 nm) 1H NMR (500 MHz, DMSO-d6) δ 7.51 (dd, J=8.0, 3.1 Hz, 1H), 7.20 (dd, J=9.0, 3.1 Hz, 1H), 3.71 (s, 3H), 3.64 (s, 2H), 1.41 (s, 9H). Step 3: 2-[3-(2-tertbutoxy-2-oxo-ethyl)-5-fluoro-2-methoxy-phenyl]-2-methyl-propionic acid methyl ester TIFF0007797206000208.tif35170 The title compound was prepared analogously to Step 4 of Intermediate B from tert-butyl 2-(3-bromo-5-fluoro-2-methoxy-phenyl)acetate (Step 2) and (1-methoxy-2-methyl-prop-1-enoxy)-trimethyl-silane. LC-MS (Method B): Rt 1.38 min; MS m / z 363.1=[M+Na]+ (80% at 215 nm) 1H NMR(400 MHz,DMSO-d6)δ 7.09(dd,J=10.1,3.2 Hz,1H),7.00(dd,J=8.9,3.1 Hz,1H),3.59-3.56(m,5H),3.56(s,3H),1.42(s,6H),1.39(s,9H). Step 4: 2-[5-fluoro-2-methoxy-3-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)phenyl]acetic acid To a solution of methyl 2-[3-(2-tert-butoxy-2-oxo-ethyl)-5-fluoro-2-methoxy-phenyl]-2-methyl-propanoate (Step 3) (80%, 215 mg, 0.51 mmol) in DCM (10 mL) was added TFA (387 μL, 5.05 mmol) and the mixture was stirred at room temperature for 2 hours. An additional portion of TFA (387 μL, 5.05 mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The resulting mixture was concentrated in vacuo and azeotroped twice with DCM to give the title compound as a brown oil. LC-MS (Method B): Rt 1.07 min; MS m / z 283.0 = [MH] (88% at 215 nm) 1H NMR(400 MHz,DMSO-d6)δ 7.11-7.05(m,1H),7.02(dd,J=8.9,3.1 Hz,1H),3.60(s,2H),3.58(s,3H),3.57-3.55(m,3H),1.42(s,6H).

[0308] Biological Examples An automated whole-cell patch clamp assay for detecting TMEM16A activity in recombinant cells Cell culture and preparation Fischer rat thyroid (FRT) cells stably expressing human TMEM16A (TMEM16Aabc mutant; Dr. Luis Galietta, Insituto Giannina, Italy) were cultured in T-75 flasks in Coon's modified Hams 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). Cells were harvested at approximately 90% confluence for experiments by detachment with a 2:1 (v / v) mixture of Detachin (BMS Biotechnology) and 0.25% (w / v) trypsin-EDTA. Cells were cultured at 3.5–4.5 × 10 in a medium consisting of CHO-S-SFM II (Sigma), 25 mM HEPES (Sigma), and soybean trypsin inhibitor (Sigma). 6 Diluted to a density of 100 cells / mL.

[0309] Whole-cell patch-clamp recording FRT-TMEM16A cells were whole-cell patch-clamped using an automated planar patch-clamp system (Qpatch, Sophion). Briefly, once a high-resistance (Gohm) seal was established between the cell 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. The following solutions (all Sigma reagents) were used in the assay: 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 at 325 mOsm. Extracellular solution (mM): N-methyl-D-glucamine 130, CaCl2 2, MgCl2 1, HEPES 10, pH 7.3, sucrose at 320 mOsm.

[0310] The intracellular solution is designed to generate the maximum TMEM16A-mediated current (EC for calcium ions). 20 Intracellular calcium was buffered at a level required to give approximately 20% activation of TMEM16A. Cells were voltage-clamped at a holding potential of -70 mV, and combined voltage step (to +70 mV) / ramp (from -90 mV to +90 mV) combinations were applied at 0.05 Hz. After a period of current stabilization testing, the compounds were solubilized in 100% (v / v) DMSO and subsequently diluted into extracellular solution to generate cumulative concentration-response curves. Each concentration of test compound was incubated for 5 min before the next concentration was added. After the final concentration tested, the highest concentration of either a known active positive modulator or the TMEM16A inhibitor CaCCinhA01 (Del La Fuente et al., 2008) was added to define the upper and lower limits of the assay.

[0311] Compound activity was quantified by measuring the increase in current upon compound addition and expressing this as a percentage increase over baseline TMEM16A current levels. The percentage increase in current was determined for each concentration, and the data were plotted as a function of concentration using either Qpatch software or Graphpad Prism v6.05 to determine the maximum effect (EC 50 ) and the concentration giving 50% of maximum efficacy (percentage of baseline increase).

[0312] The calculation of the results is shown in Figure 1, which shows an example trace of the Qpatch TMEM16A assay. BL is equal to the baseline current, and I [#1]is equal to the peak current during the incubation period for test compound concentration 1.

[0313] Peak TMEM16A current at +70 mV was plotted as a function of time during the assay. Baseline current (I BL ) was measured after a period of stabilization. The increase in current for each compound addition was determined by taking 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, this is: (I [#1] -I BL / I BL ) x 100

[0314] For each additional concentration tested, the increase in current was determined by subtracting the current from the previous incubation period and normalizing to the baseline value - for test concentration 2 in Figure 1, this is: (I [#2] -I [#1} / I BL ) x 100

[0315] The value for each test concentration is plotted as a cumulative function of concentration, and for test concentration 2 this is the sum of the peak changes measured between concentration 1 and concentration 2.

[0316] The results obtained for exemplary compounds are shown in Table 2 and show that compounds of the invention can significantly increase TMEM16A current levels.

[0317] Table 2 - 3.33 μM solutions of test compounds and calculated EC 50 Value indicates enhancement % TIFF0007797206000209.tif243170TIFF0007797206000210.tif37170

[0318] All literature and patent documents referred to herein are incorporated by reference to the maximum extent possible.

[0319] References Accurso FJ, Moss RB, Wilmott RW, Anbar RD, Schaberg AE, Durham TA, Ramsay BW; 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 (IA), (IB), (IC), (ID) or (IE), including all tautomeric forms, all enantiomeric and isotopic variants, and salts and solvates thereof: [In the formula, X ５ is CH; R １ teeth, CH (R １１ ) (R １２ ) and R １１ is H; R １２ is selected from: (ii) a 5- or 6-membered carbocyclic or oxygen-containing heterocyclic ring optionally substituted with OH; (iii) phenyl substituted with a first substituent selected from OH and methoxy; and a second substituent selected from fluoro and chloro; (iv) a first substituent selected from OH and methoxy; a second substituent selected from fluoro and chloro; and a C optionally substituted with OH or CN. １～４ phenyl substituted with a third substituent selected from alkyl; (vi) one or more C １～４ phenyl substituted with a 5-membered heteroaryl ring optionally substituted with an alkyl group; and (vii) unsubstituted pyridyl, or CH(R １１ pyridyl having a single substituent selected from OH, methoxy, fluoro, and chloro at the ring position adjacent to the atom bonded to Z is a linker selected from —NH—C(O)— and —C(O)—NH—; Y is -CH ２ - or -CH(CH ３ )-; and R ２ is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, or a 3- to 10-membered carbocycle, wherein said aryl, heteroaryl, or carbocycle is a C substituted with one or more substituents selected from fluoro; chloro; CN; nitro; OH; halo, OH, and CN. １～６ alkyl; O(C) optionally substituted with one or more substituents selected from halo, OH and CN １～６ alkyl), and NH—C(O)O—C optionally substituted with one or more substituents selected from halo and OH. １～６ optionally substituted with one or more substituents selected from alkyl; Y and R ２ together form the group -CH ２ -C(R １７ ) (R １８ )-CH ２ -N(R １９ )-C(O)OR ２０ Forming; In the formula, each R １７ , R １８ and R １９ are independently H or C １～４ alkyl or R １８ and R １９ are combined together with the atoms to which they are attached to form C １～３ forming a 5- or 6-membered heterocyclyl ring optionally substituted with alkyl; R ２０ is C optionally substituted with one or more halo １～６ is alkyl; or Y and R ２ are taken together to represent a C substituted with one or more substituents selected from halo, OH, and CN. ３～１０ forming an alkyl group; or Y and R ２ together represent halo, OH, CN, and C optionally substituted with one or more substituents selected from halo, OH, and CN. １～６ forming a 3- to 8-membered carbocyclic ring optionally substituted with one or more substituents selected from alkyl; R ３ is H or methyl. Compound.

2. General formula (IA):

2. The compound of claim 1, wherein

3. R １２ is phenyl substituted at the 2-position with OH and with a second substituent selected from fluoro and chloro; or R １２ C having a first substituent that is OH, a second substituent selected from fluoro and chloro, and a single OH substituent ３～４ 3. The compound of claim 1 or 2, which is phenyl substituted with a third substituent selected from alkyl.

4. Y is CH ２ The compound according to any one of claims 1 to 3,

5. R ２ but, an unsubstituted bridged carbocycle selected from bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo-[2.2.1]heptanyl, bicyclo-[2.2.2]octanyl or adamantyl; unsubstituted cyclopentyl, cyclohexyl or cycloheptyl; Haro, C １～４ Alkyl and C １～４ cyclopropyl or cyclobutyl substituted with one or more substituents selected from haloalkyl; and C optionally substituted with one or more substituents selected from fluoro, chloro, OH, OH and halo １～６ Alkyl, O(C １～６ alkyl) and O(C １～６ phenyl or a 5- or 6-membered heteroaryl ring optionally substituted with one or more substituents selected from: The compound according to any one of claims 1 to 4, selected from:

6. R ２ The compound of claim 5, wherein is selected from bicyclo-[2.2.1]heptanyl and adamantyl.

7. Y and R ２ Together, C substituted with one or more halo ３～４ alkyl; or Haro, C １～４ Alkyl and C １～４ a cyclopropyl or cyclobutyl ring optionally substituted with one or more substituents selected from haloalkyl; or group -CH ２ -C(R １７ ) (R １８ )-CH ２ -N(R １９ )-C(O)OR ２０ [Each R １７ , R １８ and R １９ are independently H or methyl, or R １８ and R １９ combine with the atoms to which they are attached to form a 6-membered heterocyclic ring; R ２０ is C １～６ alkyl] The compound according to any one of claims 1 to 3, 5 and 6, which forms

8. 2-(1-adamantyl)-N-[2-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide (Compound 1); 2-(1-Adamantyl)-N-[2-(tetrahydropyran-2-ylmethyl)-1H-benzimidazol-5-yl]acetamide (compound 1.1); 2-(2-adamantyl)-N-(2-benzyl-1H-benzimidazol-5-yl) (Compound 2); 2-(2-Adamantyl)-N-[2-(2-phenylethyl)-1H-benzimidazol-5-yl]acetamide (compound 2.1); 2-(2-Adamantyl)-N-[2-[methoxy(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 2.2); 2-(2-adamantyl)-N-[2-[(2-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 2.3); 2-(2-adamantyl)-N-[2-[(R)-methylamino(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 3); 2-(1-adamantyl)-N-[2-[(2-chloro-3-pyridyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 4); 2-(2-adamantyl)-N-[2-[(2-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 5); 2-(2-adamantyl)-N-[2-[(4-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 5.1); 2-(2-Adamantyl)-N-[2-[(5-chloro-2-hydroxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 5.2); 2,2,2-trifluoroethyl N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate (Compound 6); 2-(1-Adamantyl)-N-[2-[[3-(3,5-dimethylisoxazol-4-yl)phenyl]methyl]-3H-benzimidazol-5-yl]acetamide (Compound 7); tert-Butyl N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate (Compound 8); 2-(2-adamantyl)-N-(2-tetrahydrofuran-3-yloxy-1H-benzimidazol-5-yl)acetamide (compound 9); N-(cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide (compound 10); 2-(1-adamantyl)-N-[3-amino-2-[(2-hydroxyphenyl)methyl]indazol-6-yl]acetamide (Compound 11); 2-Cyclohexyl-N-(2-isopropyl-1,3-benzoxazol-5-yl)acetamide (Compound 12); N-(cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]indazole-6-carboxamide (compound 13); 2-(1-Adamantyl)-N-(2-benzyl-3H-imidazo[4,5-c]pyridin-6-yl)acetamide (compound 14); 2-benzyl-N-(cycloheptylmethyl)imidazo[1,2-a]pyridine-7-carboxamide (compound 15); 2-(1-adamantyl)-N-(2-benzylindazol-6-yl)acetamide (compound 16); 2-(1-Adamantyl)-N-(2-benzyl-3-methyl-indazol-6-yl)acetamide (compound 17); N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide (compound 18); tert-Butyl N-[3-[(2-benzyl-1H-benzimidazole-5-carbonyl)amino]-2,2-dimethyl-propyl]carbamate (Compound 19); 2-tert-butyl-N-(cycloheptylmethyl)-3H-benzimidazole-5-carboxamide (compound 20); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (compound 21); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (compound 21.1); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (compound 21.2); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide (compound 21.3); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1,3-benzoxazole-5-carboxamide (compound 21.4); 2-[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide (compound 22); 2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide (compound 23); 2-benzyl-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (compound 24); 2-benzyl-N-(cyclopentylmethyl)-1H-benzimidazole-5-carboxamide (compound 24.1); 2-benzyl-N-(cycloheptylmethyl)-1H-benzimidazole-5-carboxamide (compound 24.2); N-(cycloheptylmethyl)-2-[(2-fluoro-6-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25); N-(cycloheptylmethyl)-2-[(5-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25.1); N-(cycloheptylmethyl)-2-[(3-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25.2); N-(cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25.3); N-(cycloheptylmethyl)-2-[(4-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25.4); N-(cycloheptylmethyl)-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (compound 25.5); 2-(5-chloro-2-hydroxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide (compound 26); N-(2-tert-butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide (compound 27); N-(cycloheptylmethyl)-2-(1-methylcyclobutyl)-3H-benzimidazole-5-carboxamide (compound 28); 2-[[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (compound 29); 2-[[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (compound 29.1); N-[[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (compound 30); 2-[[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (compound 31); 2-[[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (compound 31.1); 2-[[5-fluoro-2-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (compound 32); 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyridine-7-carboxamide (compound 33); and salts and solvates thereof.

9. 9. The compound according to claim 8, which is 2-(2-adamantyl)-N-[2-[(2-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 5); or a salt thereof.

10. 9. The compound of claim 8, which is 2-(2-adamantyl)-N-[2-[(5-chloro-2-hydroxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (compound 5.2); or a salt thereof.

11. 9. The compound of claim 8, which is 2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide (compound 23); or a salt thereof.

12. 9. The compound of claim 8, which is N-(cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]indazole-6-carboxamide (compound 13); or a salt thereof.

13. 9. The compound of claim 8, which is 2-[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide (compound 22); or a salt thereof.

14. 14. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment or prevention of diseases and conditions affected by modulation of TMEM16A.

15. A medicament for the treatment or prevention of diseases and conditions affected by the modulation of TMEM16A, comprising an effective amount of a compound according to any one of claims 1 to 13.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable excipient.

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