Compounds for the treatment of respiratory diseases

Abstract

The present invention provides compounds of the general formula (I) and their tautomeric forms, all enantiomers and isotopic variants, and salts and solvates thereof: wherein (AA) represents a single bond or a double bond, and R 1 , R 2 , X 1 , X 2 , X 3 , X 4 , X 5 , Y and Z are as defined herein; they can be used to treat respiratory diseases and other diseases and conditions regulated by TMEM16A. #imgabs0#

Description

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

[0002] A person can inhale up to 12,000L of air per day, and with it the potential for airborne pathogens (such as bacteria, viruses, and fungal spores) to enter the airways. To protect against these airborne pathogens, the lungs have evolved innate defense mechanisms to minimize the potential for airway infection and colonization. One such mechanism is the mucus clearance system, whereby secreted mucus is pushed upward out of the airways by the coordinated beating of cilia and clearance by coughing. This continuous "cleaning" of the lungs constantly removes inhaled particles and microorganisms, thereby reducing the risk of infection.

[0003] In recent years, it has become clear that hydration of the mucus gel is critical to enable mucus clearance (Boucher 2007; Matsui et al, 1998). In normal, healthy airways, the mucus gel typically contains 97% water and 3% w / v solids, under which conditions mucus is cleared by mucociliary action. Hydration of the airway mucosa is regulated by the coordinated activity of many ion channels and transporters. Hydration of anions (Cl) is mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) and the calcium-activated chloride conductance (CaCC; TMEM16A). - / HCO3 - ) secretion balance and through epithelial Na + Na channel (ENaC) + Absorption determines the hydration state of the airway mucosa. As ions are transported across the epithelium, water is forced to follow the osmotic pressure, so fluid is either secreted or absorbed.

[0004] In respiratory diseases such as chronic bronchitis and cystic fibrosis, the solids % of the mucus gel increases with decreased hydration and decreased mucus clearance (Boucher, 2007). In cystic fibrosis, where CFTR loss-of-function mutations impair the ability of the airways to secrete fluid, the solids % can increase to 15%, which is believed to lead to small airway obstruction and mucus clearance failure. Strategies to increase airway mucus hydration include stimulating anions, thereby stimulating fluid secretion, or inhibiting Na + To this end, stimulation of TMEM16A channel activity would increase anion secretion and, therefore, fluid accumulation in the airway mucosa, hydrating mucus and enhancing mucus clearance mechanisms.

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

[0006] TMEM16A channel is expressed by epithelial cells of different organs, including lung, liver, kidney, pancreas and salivary gland. In airway epithelium, TMEM16A is expressed at high levels in goblet cells, ciliated cells and submucosal glands that produce mucus. Physiologically, TMEM16A is activated by stimulants (particularly purinergic agonists (ATP, UTP)) that activate intracellular calcium activity, and these stimulants are released by respiratory epithelial response to the periodic shear stress caused by breathing and other mechanical stimuli (such as cough). In addition to increasing anion secretion and causing airway hydration to be enhanced, the activation of TMEM16A also plays an important role in bicarbonate secretion. It is reported that bicarbonate secretion is an important regulator of mucus properties, and is an important regulator (Pezzulo et al, 2012) that controls airway lumen pH and therefore controls the activity of natural antimicrobial agents (such as defensins) .

[0007] Indirect modulation of TMEM16A through elevation of intracellular calcium has been explored clinically, such as denufosol (Kunzelmann & Mall, 2003). Although encouraging preliminary results were observed in small patient groups, this approach has not resulted in clinical benefit in larger patient groups (Accurso et al 2011; Kellerman et al 2008). This lack of clinical effect has been attributed to only transient increases in anion secretion due to the short half-life of denufosol and receptor / pathway desensitization on epithelial surfaces, as well as undesirable effects of elevated intracellular calcium, such as increased mucus release from goblet cells (Moss, 2013). Compounds that act directly on TMEM16A to enhance channel opening at low levels of elevated calcium are desired, thereby durably enhancing anion secretion and mucociliary clearance in patients and improving innate defenses. Because TMEM16A activity is independent of CFTR function, positive modulators of TMEM16A have the potential to provide clinical benefit to all patients with CF and to non-CF respiratory diseases characterized by mucus congestion, including chronic bronchitis and severe asthma.

[0008] TMEM16A modulation has been considered as a therapy for dry mouth (xerostomia) caused by salivary gland dysfunction in Sjorgen's syndrome and radiation therapy, dry eyes, cholestasis, and gastrointestinal dysmotility.

[0009] Our application PCT / GB2019 / 050209 relates to compounds that are positive modulators of TMEM16A and are therefore useful in treating diseases and conditions for which modulation of TMEM16A plays a role, particularly respiratory diseases and conditions. The inventors have developed further compounds that are positive modulators of TMEM16A.

[0010] In a first aspect of the present invention, there is provided a compound of general formula (I), including all tautomeric forms, all enantiomers and isotopic variants, and salts and solvates thereof:

[0011]

[0012] in

[0013] represents a single or double bond;

[0014] X 1 N, X 3 NH, X 2 and X 4 is C, a, c and d are single bonds, and b and e are double bonds; or

[0015] X 1 NH, X 3 N, X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds; or

[0016] X 1 N, X 2 N, X 3 CR 3 or CN(R 3a )(R 3b ), X 4 is C; b, c and e are single bonds, and a and d are double bonds;

[0017] Each R 3 , R 3a and R 3b are independently H or methyl; or

[0018] X 1 N, X 3 O, X 2 and X 4is C, a, c and d are single bonds, and b and e are double bonds;

[0019] X 1 and X 4 N, X 2 is C, and X 3 is CH; a and c are double bonds, and b, d and e are single bonds;

[0020] X 1 O, X 3 N, X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds;

[0021] X 5 is CH or N;

[0022] R 1 for

[0023] i.-OR 5 , provided that X 2 Not for N;

[0024] Where R 5 is a 5- or 6-membered carbocyclyl or heterocyclyl group optionally substituted by OH;

[0025] or

[0026] ii.CH(R 7 )-N(R 8 )-C(O)OR 9

[0027] R 7 is H, phenyl or optionally substituted by one or more selected from OH and O(C 1-4 Alkyl) substituted C 1-3 alkyl;

[0028] R 8 is H, methyl or C optionally substituted by one or more substituents selected from OH and methoxy 2-3 alkyl;

[0029] R 9 is C optionally substituted by one or more substituents selected from halo, OH and methoxy 1-4 Alkyl; or

[0030] R 7 and R 8 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic ring, which optionally contains additional heteroatoms selected from N, O and S and is optionally replaced by C 1-3 Alkyl substitution; or

[0031] iii.CH(R 7 )-N(R 8 )-C(O)N(R 9 )(R 10 );

[0032] R 7 , R 8 and R 9 As defined above, and R 10 is H or methyl; or

[0033] iv.CH(R 11 )(R 12 );

[0034] R 11 H, methyl, CH2OR 13 , OR 13 or N(R 13 )(R 14 );

[0035] Each R 13 and R 14 are independently H or methyl; and

[0036] R 12 Selected from:

[0037] a 5- or 6-membered carbocyclyl or oxygen-containing heterocyclyl ring, wherein the carbocyclyl or heterocyclyl ring is optionally substituted with OH; and

[0038] A 6-membered aryl or 6-membered heteroaryl ring, wherein the aryl or heteroaryl ring is optionally substituted with one or more substituents selected from the group consisting of OH, methoxy, chloro, fluoro; C optionally substituted with one or more substituents selected from the group consisting of halo, OH and CN 1-6 alkyl; a 3 to 6 membered cycloalkyl or heterocyclyl group, wherein the cycloalkyl or heterocyclyl group is 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 Alkyl; and optionally one or more selected from C 1-4 a 5-membered heteroaryl group substituted with an alkyl and a halo substituent; or

[0039] When R 12 When it is a 6-membered aryl or heteroaryl ring, R 12 The substituents on R 11 and, together with the atoms to which they are attached, form a 6-membered aryl or heteroaryl ring R 12 A fused 5- or 6-membered ring, wherein the 5- or 6-membered ring is optionally C 1-3 Alkyl substitution; or

[0040] v 2-6 Alkyl, which is optionally substituted by one or more selected from phenyl, OR 15 and N(R 15 )(R 16 ) is substituted by a substituent;

[0041] Each R 15 and R 16 Independently selected from H or C 1-3 Alkyl; or

[0042] vi. a 3- to 8-membered cycloalkyl ring, which is optionally substituted with one or more substituents selected from OH, CN, halo, and C optionally substituted with one or more substituents selected from halo, OH, and CN. 1-4 alkyl;

[0043] Z is a linker selected from -NH-C(O)- and -C(O)-NH-;

[0044] Y is -CH2- or -CH(CH3)-;

[0045] 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 the aryl, heteroaryl, or carbocyclic ring system is optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, CN, nitro, OH, C optionally substituted with one or more substituents selected from the group consisting of halo, OH, and CN 1-6 alkyl, optionally substituted with one or more substituents selected from halo, OH and CN 1-6 alkyl), and NH—C(O)OC optionally substituted by one or more substituents selected from halo and OH 1-6 Alkyl; or

[0046] Y and R 2 Together they form the group -CH2-C(R 17 )(R 18 )-CH2-N(R 19 )-C(O)OR 20 ;

[0047] Where R 17 , R 18 and R 19 Each of the 1-4 Alkyl, or R 18 and R 19 Combined with the atoms to which they are attached, they form optionally C 1-3 an alkyl-substituted 5- or 6-membered heterocyclyl ring; and

[0048] R 20is C optionally substituted by one or more halo substituents 1-6 Alkyl; or

[0049] Y and R 2 together to form C substituted with one or more substituents selected from halo, OH and CN 3-10 an alkyl group; or

[0050] Y and R 2 Together they form a 3- to 8-membered carbocyclic ring, which is optionally substituted by one or more substituents selected from halo, OH, CN and C optionally substituted by one or more substituents selected from halo, OH and CN. 1-6 alkyl;

[0051] The premise is:

[0052] I. When X 1 N, X 3 NH, X 2 and X 4 is C, a, c and d are single bonds, and b and

[0053] When e is a double bond:

[0054] A. When R 1 CH(R 11 )(R 12 );where R 11 is H or methyl, and R 12 is unsubstituted or substituted phenyl with 1 or 2 substituents, wherein the substituents are selected from halo and methoxy:

[0055] i 2 is not phenyl or heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by 1 or 2 groups selected from halo, C 1-4 Alkyl, C 1-4 substituted with substituents of the alkoxy and 5-membered heteroaryl rings; and

[0056] ii.Y and R 2 Not combined to form a 3- to 8-membered cycloalkyl ring optionally substituted with methyl; or a C optionally substituted with CN 3-10 Alkyl Group

[0057] B. When R 1 CH(R 11 )(R 12 );where R 12 is phenyl, R 11 and R 12 The substituents on the benzene ring are combined with the atoms to which they are attached to form 12 A fused 5- or 6-membered ring, wherein the 5- or 6-membered ring is optionally C 1-3When alkyl is substituted:

[0058] i 2 is not phenyl or heteroaryl, wherein the phenyl or heteroaryl is optionally substituted with 1, 2 or 3 substituents, wherein the substituents are selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 alkoxy; and

[0059] ii.Y and R 2 Does not combine to form C substituted by CN 3-10 alkyl;

[0060] C. When R 1 CH(R 11 )(R 12 );where R 11 is H, and R 12 When it is cyclohexyl:

[0061] R 2 is not phenyl optionally substituted by 1, 2 or 3 substituents, wherein the substituents are selected from halo, methyl, methoxy; unsubstituted 5 to 8 membered heteroaryl;

[0062] D. When R 1 is C optionally substituted by a single substituent selected from OH and phenyl 2-6 When alkyl:

[0063] R 2 is not phenyl or 5- to 10-membered heteroaryl, any of which is optionally substituted with one or two substituents, wherein the substituents are selected from halo, methyl, trifluoromethyl, O(C 1-4 alkyl) or a 5-membered heteroaryl ring;

[0064] E. When R 1 When it is an unsubstituted 3- to 8-membered cycloalkyl ring:

[0065] R 2 is not optionally substituted with one selected from halo, OH, methyl, trifluoromethyl, O(C 1-4 alkyl) or a phenyl substituted with a substituent of a 5-membered heteroaryl ring;

[0066] II. When X 1 N, X 2 N, X 3 CR 3 or CN(R 3a )(R 3b ), X 4 is C; b, c and e are single bonds, and a and d are double bonds; each R 3 , R 3a and R3b When independently H or methyl:

[0067] A. When R 1 CH(R 11 )(R 12 ); and R 11 is H, and R 12 When it is unsubstituted or substituted by 1 or 2 substituents selected from halo and methoxy phenyl:

[0068] R 2 is not phenyl optionally substituted with one halo substituent;

[0069] B. When R 1 is C optionally substituted by phenyl 2-6 When alkyl:

[0070] R 2 is not phenyl or naphthyl optionally substituted by one or two substituents selected from halo, methoxy and 5-membered heteroaryl groups;

[0071] III. When X 1 N, X 3 O, X 2 and X 4 When C, a, c and d are single bonds, and b and e are double bonds:

[0072] A. When R 1 CH(R 11 )(R 12 ); and R 11 is H, and R 12 When it is unsubstituted or substituted by 1 or 2 substituents selected from halo and methoxy phenyl:

[0073] i 2 is not phenyl or heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by one or two substituted or substituted groups selected from halo, C 1-4 Alkyl, C 1-4 substituted with substituents of the alkoxy and 5-membered heteroaryl groups; and

[0074] ii.Y and R 2 Not combined to form a C substituted with one or more substituents selected from halo and OH 3-10 Alkyl Group

[0075] B. When R 1 CH(R 11 )(R 12 ); and R 12 is phenyl, and R 12 The substituents on R 11and the atoms to which they are attached form a 6-membered aryl or heteroaryl ring R 12 A fused 5- or 6-membered ring, wherein the 5- or 6-membered ring is optionally C 1-3 When alkyl is substituted:

[0076] Y and R 2 Does not combine to form a C substituted with one or more halo substituents 3-10 alkyl;

[0077] IV. When X 1 O, X 3 N, X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds; R 1 CH(R 11 )(R 12 ); and R 11 H and R 12 When it is unsubstituted or substituted by 1 or 2 substituents selected from halo and methoxy phenyl:

[0078] i 2 is not phenyl or heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by one, two or three selected from halo, C 1-4 Alkyl, C 1-4 substituted with substituents of the alkoxy and 5-membered heteroaryl groups; and

[0079] ii.Y and R 2 not combined to form an unsubstituted 3 to 8-membered cycloalkyl ring; or C optionally substituted by one or more substituents selected from halo and OH 3-10 Alkyl group.

[0080] Among some suitable compounds of general formula (I):

[0081] When X 1 N, X 2 N, X 3 CR 3 or CN(R 3a )(R 3b ), 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 When independently H or methyl:

[0082] A. When R 1 CH(R 11 )(R 12 ); and R 11 is H, and R 12When it is unsubstituted or substituted by 1 or 2 substituents selected from halo and methoxy phenyl:

[0083] R 2 is not phenyl optionally substituted with one halo substituent;

[0084] B. When R 1 is C optionally substituted by phenyl 2-6 When alkyl:

[0085] R 2 is not phenyl, thienyl or naphthyl optionally substituted by one or two substituents selected from halo, methoxy and 5-membered heteroaryl groups.

[0086] The compounds of general formula (I) are modulators of TMEM 16A and are therefore useful in treating or preventing diseases and disorders affected by the modulation of TMEM16A.

[0087] Throughout the specification and following claims, unless the context requires otherwise, the word "comprise" and variations such as "comprising" and "containing", will be understood to imply the inclusion of stated integers, steps, groups of integers or groups of steps but not the exclusion of any other integers, steps, groups of integers or groups of steps.

[0088] In this specification, reference to "pharmaceutical use" refers to use for administration to humans or animals, particularly humans or mammals, such as domestic or livestock mammals, to treat or prevent diseases or medical conditions. The term "pharmaceutical composition" refers to a composition suitable for pharmaceutical use, and "pharmaceutical" refers to a medicament suitable for use in a pharmaceutical composition. Other similar terms should be interpreted accordingly.

[0089] In this specification, the term "C 1-6 "Alkyl" refers to a straight or branched chain fully saturated hydrocarbon group having 1 to 6 carbon atoms. The term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. Other alkyl groups, such as C 1-10 Alkyl groups are as defined above but contain varying numbers of carbon atoms.

[0090] Unless otherwise indicated, the terms "carbocycle" and "carbocyclyl" refer to non-aromatic hydrocarbon ring systems containing 3 to 10 ring carbon atoms and optionally one or more double bonds. The carbocyclic group can be a monocyclic ring or can contain two or three rings that can be fused or bridged, wherein the carbon atoms in the bridge are included in the number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl and bridged systems, such as bicyclo [1.1.1] pentyl, bicyclo - [2.2.1] heptyl, bicyclo - [2.2.2] octyl and adamantyl.

[0091] In the context of this specification, unless otherwise indicated, the terms "heterocycle" and "heterocyclyl" refer to non-aromatic ring systems containing 3 to 10 ring atoms, including at least one heteroatom selected from N, O and S. The heterocyclic group can be a monocyclic ring or can contain two or three rings that can be fused or bridged, wherein the bridge atom is included in the number of ring atoms. Examples include tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and thiomorpholinyl, and fused systems such as cyclopropyl-fused pyrrolidine. Mention of oxygen-containing heterocycles includes rings in which the only heteroatom is oxygen, such as tetrahydrofuran and tetrahydropyran, and rings in which there are other heteroatoms selected from N and S, such as morpholine.

[0092] Unless otherwise stated, the terms "aryl" and "aromatic" in the context of this specification refer to a ring system having an aromatic character of 5 to 14 ring carbon atoms and containing up to three rings. When an aryl group contains more than one ring, not all rings must be fully aromatic. Examples of aromatic moieties are benzene, naphthalene, fluorene, tetralin, indane and indene.

[0093] Unless otherwise indicated, the terms "heteroaryl" and "heteroaromatic" in the context of this specification refer to a ring system having an aromatic character of 5 to 14 ring atoms, at least one of which is a heteroatom selected from N, O and S, and containing up to three rings. When a heteroaryl group contains more than one ring, not all rings must be aromatic. Examples of heteroaryl groups include pyridine, pyrimidine, indole, indazole, thiophene, benzothiophene, benzoxazole, benzofuran, dihydrobenzofuran, tetrahydrobenzofuran, benzimidazole, benzimidazolinone, quinoline and indole.

[0094] The term "oxy" refers to a C=O substituent wherein the carbon atom is a ring atom of a carbocyclyl, heterocyclyl group, or a non-aromatic aryl or heteroaryl group.

[0095] The term "halogen" refers to fluorine, chlorine, bromine or iodine, while the term "halo" refers to a fluoro, chloro, bromo or iodo group. Similarly, "halide" refers to fluoride, chloride, bromide or iodide.

[0096] As used herein, the term “C 1-6 "Haloalkyl" refers to a C group as defined above in which one or more hydrogen atoms are replaced by a halo group. 1-6 Alkyl groups. Any number of hydrogen atoms may be replaced up to full halogen substitution. Examples include trifluoromethyl, chloroethyl and 1,1-difluoroethyl. Fluoroalkyl groups are haloalkyl groups where halo is fluoro.

[0097] The term "isotopic variant" refers to an isotopically labeled compound that is identical to those described in formula (I), but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature, or in which the proportion of atoms having an atomic mass or mass number less common 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.

[0098] In an alternative aspect of the invention, there is provided a compound of general formula (Ix), including all tautomeric forms, all enantiomeric and isotopic variations and salts and solvates thereof:

[0099]

[0100] in

[0101] represents a single bond or a double bond;

[0102] X 1 N, X 3 NH, X 2 and X 4 is C, a, c and d are single bonds, and b and e are double bonds; or

[0103] X 1 NH, X 3 N, X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds; or

[0104] X 1 N, X 2 N, X 3 CR 3 or CN(R 3a )(R 3b ), X 4 is C; b, c and e are single bonds, and a and d are double bonds;

[0105] Each R 3 , R 3a and R 3b are independently H or methyl; or

[0106] X 1 N, X 3 O, X 2 and X4 is C, a, c and d are single bonds, and b and e are double bonds;

[0107] X 1 and X 4 N, X 2 is C, and X 3 is CH; a and c are double bonds, and b, d and e are single bonds;

[0108] X 1 O, X 3 N, X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds;

[0109] X 5 is CH or N;

[0110] R 1 for

[0111] i.-OR 5 or N(R 5 )(R 6 ), provided that X 2 Not for N;

[0112] Where R 5 is a 5- or 6-membered carbocyclyl or heterocyclyl group optionally substituted by OH;

[0113] R 6 is H, methyl or ethyl; or

[0114] ii.CH(R 7 )-N(R 8 )-C(O)OR 9

[0115] R 7 is H, phenyl or optionally substituted by one or more selected from OH and O(C 1-4 Alkyl) substituted C 1-3 alkyl;

[0116] R 8 is H, methyl or C optionally substituted by one or more substituents selected from OH and methoxy 2-3 alkyl;

[0117] R 9 is C optionally substituted by one or more substituents selected from halo, OH and methoxy 1-4 Alkyl; or

[0118] R 7 and R 8Together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic ring, which optionally contains additional heteroatoms selected from N, O and S and is optionally replaced by C 1-3 Alkyl substitution; or

[0119] iii.CH(R 7 )-N(R 8 )-C(O)N(R 9 )(R 10 );

[0120] R 7 , R 8 and R 9 As defined above, and R 10 is H or methyl; or

[0121] iv.CH(R 11 )(R 12 );

[0122] R 11 H, methyl, CH2OR 13 , OR 13 or N(R 13 )(R 14 );

[0123] Each R 13 and R 14 are independently H or methyl;

[0124] R 12 is a 5- or 6-membered carbocyclyl or heterocyclyl ring, which is optionally substituted with OH; or a 6-membered aryl or heteroaryl ring, any of which is optionally substituted with one or more selected from OH, methoxy, chlorine, fluorine and C 1-3 or a 5-membered heteroaryl group, which is optionally substituted by one or more selected from C 1-4 Alkyl and halo substituents; or

[0125] When R 12 When it is a 6-membered aryl or heteroaryl ring, R 12 The substituents on R 11 and, together with the atoms to which they are attached, form a 6-membered aryl or heteroaryl ring R 12 A fused 5- or 6-membered ring, wherein the 5- or 6-membered ring is optionally C 1-3 Alkyl substitution; or

[0126] v 2-4 Alkyl, which is optionally substituted by one or more selected from phenyl, OR 15 and N(R 15 )(R 16 ) is substituted by a substituent;

[0127] Each R 15 and R 16 Independently selected from H or C 1-3 alkyl;

[0128] Z is a linker selected from -NH-C(O)- and -C(O)-NH-;

[0129] Y is -CH2- or -CH(CH3)-;

[0130] R 2 is a 6- to 10-membered aryl, 5- to 10-membered heteroaryl or 5- to 10-membered carbocyclic ring system, any of which is optionally substituted by one or more selected from fluorine, chlorine, 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)OC 1-6 The alkyl group is substituted by a substituent; or

[0131] Y and R 2 Together they form the group -CH2-C(R 17 )(R 18 )-CH2-N(R 19 )-C(O)OR 20 ;

[0132] Where R 17 , R 18 and R 19 Each of the 1-4 Alkyl, or R 18 and R 19 Combined with the atoms to which they are attached, they form optionally C 1-3 an alkyl-substituted 5- or 6-membered heterocyclyl ring; and

[0133] R 20 is C optionally substituted by one or more halo substituents 1-6 Alkyl; or Y and R 2 Together they form unsubstituted C 5-10 Alkyl groups; provided that:

[0134] (i) When R 1 is an optionally substituted C as defined above 2-4 Alkyl, R 2 is not an optionally substituted aryl or heteroaryl as defined above; and

[0135] (ii) When R 1 CH(R 11 )(R 12), where R 11 is H or methyl, and R 12 is phenyl or cyclohexyl, either of which is optionally substituted as defined above;

[0136] R 2 is not optionally substituted aryl or heteroaryl as defined above; and

[0137] Y and R 2 Does not combine to form C 5-10 Alkyl group.

[0138] More suitably, there is provided a compound of formula (I) or (Ix) as defined above, provided that:

[0139] When R 1 C 2-6 Alkyl, R 2 is not an optionally substituted aryl or heteroaryl as defined above; and

[0140] When R 1 CH(R 11 )(R 12 ), where R 11 When it is H or methyl;

[0141] R 2 is not an optionally substituted aryl or heteroaryl as defined above; and / or

[0142] Y and R 2 does not combine to form a substituted C as defined above 5-10 Alkyl group.

[0143] Suitably, there is provided a compound of formula (I) or (Ix) as defined above, provided that:

[0144] When R 1 C 2-6 Alkyl, R 2 is not an optionally substituted aryl or heteroaryl as defined above; and

[0145] When R 1 CH(R 11 )(R 12 ), where R 11 When it is H or methyl;

[0146] R 2 is not an optionally substituted aryl or heteroaryl as defined above; and / or

[0147] Y and R 2 does not combine to form a substituted C as defined above 5-10 Alkyl group.

[0148] Alternatively, there is provided a compound of formula (I) or (Ix) as defined above, provided that:

[0149] When R 1 C 2-4 Alkyl, R 2 is not an optionally substituted aryl or heteroaryl as defined above; and

[0150] When R 1 CH(R 11 )(R 12 ), where R 11 When it is H or methyl;

[0151] R 2 is not an optionally substituted aryl or heteroaryl as defined above; and / or

[0152] Y and R 2 does not combine to form a substituted C as defined above 5-10 Alkyl group.

[0153] Among some suitable compounds of general formula (I) and (Ix):

[0154] X 1 N, X 3 NH, X 2 and X 4 is C, a, c and d are single bonds, and b and e are double bonds; or

[0155] X 1 NH, X 3 N, X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds; or

[0156] X 1 N, X 2 N, X 3 CR 3 or CN(R 3a )(R 3b ), X 4 is C; b, c and e are single bonds, and a and d are double bonds;

[0157] Each R 3 , R 3a and R 3b are independently H or methyl; or

[0158] X 1 N, X 3 O, X 2 and X 4is C, a, c and d are single bonds, and b and e are double bonds;

[0159] X 1 and X 4 N, X 2 is C, and X 3 is CH; a and c are double bonds, and b, d and e are single bonds.

[0160] More appropriately

[0161] X 1 N, X 3 NH, X 2 and X 4 is C, a, c and d are single bonds, and b and e are double bonds; or

[0162] X 1 NH, X 3 N, X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds; or

[0163] X 1 N, X 2 N, X 3 CR 3 or CN(R 3a )(R 3b ), X 4 is C; b, c and e are single bonds, and a and d are double bonds;

[0164] Each R 3 , R 3a and R 3b is independently H or methyl.

[0165] Particularly suitable compounds of the general formula (I) are those in which:

[0166] X 1 N, X 3 NH, X 2 and X 4 is C, a, c and d are single bonds, and b and e are double bonds;

[0167] or a tautomer thereof, wherein

[0168] X 1 NH, X 3 N, X 2 and X 4 is C, a, b and d are single bonds, and c and e are double bonds.

[0169] In some compounds of formula (I):

[0170] When R 1 is an optionally substituted C as defined above 2-4 Alkyl, R 2 is not an optionally substituted aryl or heteroaryl as defined above; and

[0171] When R 1 CH(R 11 )(R 12 ), where R 11 is H or methyl, and R 12 is phenyl or cyclohexyl, either of which is optionally substituted as defined above;

[0172] R 2 is not an optionally substituted aryl or heteroaryl as defined above; and / or

[0173] Y and R 2 does not combine to form a substituted C as defined above 5-10 Alkyl group.

[0174] In other compounds of general formula (I):

[0175] When R 1 C 2-4 Alkyl, R 2 is not an optionally substituted aryl or heteroaryl as defined above; and

[0176] When R 1 CH(R 11 )(R 12 ), where R 11 When it is H or methyl;

[0177] R 2 is not optionally substituted aryl or heteroaryl as defined above; and

[0178] Y and R 2 Does not combine to form C 5-10 Alkyl group.

[0179] The compound of general formula (I) may be a compound of general formula (IA), (IB), (IC), (ID) or (IE):

[0180]

[0181] Where R 1 , X 5 , Z, Y and R 2 As defined for formula (I) or for formula (Ix).

[0182] The compounds of general formula (IA) may also be in tautomeric form:

[0183]

[0184] In some cases, the compound of formula (I) is a compound of formula (IA).

[0185] In some cases, the compound of formula (I) is a compound of formula (IB).

[0186] In some cases, the compound of formula (I) is a compound of formula (IC).

[0187] In some cases, the compound of formula (I) is a compound of formula (ID).

[0188] In some cases, the compound of formula (I) is a compound of formula (IE).

[0189] The present invention also provides:

[0190] A compound of general formula (IA), wherein R 1 , X 5 , Z, Y and R 2 As defined for formula (I) or for formula (Ix), provided that:

[0191] A. When R 1 CH(R 11 )(R 12 );where R 11 is H or methyl, and R 12 is unsubstituted or substituted phenyl with 1 or 2 substituents, wherein the substituents are selected from halo and methoxy:

[0192] i 2 is not phenyl or heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by 1 or 2 groups selected from halo, C 1-4 Alkyl, C 1-4 substituted with substituents of the alkoxy and 5-membered heteroaryl rings; and

[0193] ii.Y and R 2 Not combined to form a 3- to 8-membered cycloalkyl ring optionally substituted with methyl; or a C 3-10 Alkyl Group

[0194] B. When R 1 CH(R 11 )(R 12 );where R 11 is H, and R 12 is phenyl and R 12 The substituents on R 11and the atoms to which they are attached form a 6-membered aryl or heteroaryl ring R 12 A fused 5- or 6-membered ring, wherein the 5- or 6-membered ring is optionally C 1-3 When alkyl is substituted:

[0195] i 2 is not phenyl or heteroaryl, wherein the phenyl or heteroaryl is optionally substituted with 1, 2 or 3 substituents, wherein the substituents are selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 alkoxy; and

[0196] ii.Y and R 2 Does not combine to form C substituted by CN 3-10 alkyl;

[0197] C. When R 1 CH(R 11 )(R 12 );where R 11 is H, and R 12 When it is cyclohexyl:

[0198] R 2 is not phenyl optionally substituted by 1, 2 or 3 substituents, wherein the substituents are selected from halo, methyl, methoxy; unsubstituted 5 to 8 membered heteroaryl;

[0199] D. When R 1 is C optionally substituted by a single substituent selected from OH and phenyl 2-6 When alkyl:

[0200] R 2 is not phenyl or 5- to 10-membered heteroaryl, any of which is optionally substituted with one or two substituents, wherein the substituents are selected from halo, methyl, trifluoromethyl, O(C 1-4 alkyl) or a 5-membered heteroaryl ring;

[0201] E. When R 1 When it is an unsubstituted 3- to 8-membered cycloalkyl ring:

[0202] R 2 is not optionally substituted with one selected from halo, OH, methyl, trifluoromethyl, O(C 1-4 alkyl) or a phenyl substituted with a substituent of a 5-membered heteroaryl ring; and

[0203] A compound of formula (IB), wherein R 1 , X 5 , Z, Y and R 2 As defined for formula (I) or for formula (Ix), provided that:

[0204] A. When R 1 CH(R 11 )(R 12 ); and R 11 is H, and R 12 When it is unsubstituted or substituted by 1 or 2 substituents selected from halo and methoxy phenyl:

[0205] R 2 is not phenyl optionally substituted with one halo substituent;

[0206] B. When R 1 is C optionally substituted by phenyl 2-6 When alkyl:

[0207] R 2 is not phenyl, thienyl or naphthyl optionally substituted with one or two substituents selected from halo, methoxy and 5-membered heteroaryl groups; and

[0208] A compound of general formula (IC), wherein R 1 , X 5 , Z, Y and R 2 As defined for formula (I) or for formula (Ix), provided that:

[0209] When R 1 CH(R 11 )(R 12 ), where R 11 is H or methyl, and R 12 is an optionally substituted phenyl group as defined above:

[0210] R 2 is not optionally substituted aryl or heteroaryl as defined above; and

[0211] A compound of general formula (IC), wherein R 1 , X 5 , Z, Y and R 2 As defined for formula (I) or for formula (Ix), provided that:

[0212] A. When R 1 CH(R 11 )(R 12 ); and R 11 is H, and R 12 When it is unsubstituted or substituted by 1 or 2 substituents selected from halo and methoxy phenyl:

[0213] i 2 is not phenyl or heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by one or two substituted or substituted groups selected from halo, C 1-4Alkyl, C 1-4 substituted with substituents of the alkoxy and 5-membered heteroaryl groups; and

[0214] ii.Y and R 2 Not combined to form a C substituted with one or more substituents selected from halo and OH 3-10 Alkyl Group

[0215] B. When R 1 CH(R 11 )(R 12 ); and R 11 is H, and R 12 is phenyl, and R 12 The substituents on R 11 and the atoms to which they are attached form a 6-membered aryl or heteroaryl ring R 12 A fused 5- or 6-membered ring, wherein the 5- or 6-membered ring is optionally C 1-3 When alkyl is substituted:

[0216] Y and R 2 Does not combine to form a C substituted with one or more halo substituents 3-10 alkyl;

[0217] A compound of formula (ID); and

[0218] A compound of general formula (IE), wherein R 1 , X 5 , Z, Y and R 2 As defined for formula (I) or for formula (Ix), provided that:

[0219] i 2 is not phenyl or heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by one, two or three selected from halo, C 1-4 Alkyl, C 1-4 substituted with substituents of the alkoxy and 5-membered heteroaryl groups; and

[0220] ii.Y and R 2 not combined to form an unsubstituted 3- to 8-membered cycloalkyl ring; or C substituted by one or more substituents selected from halo and OH 3-10 Alkyl group.

[0221] Compounds of the general formulae (IA), (IB), (IC) and (ID) are more suitable, especially compounds of the general formulae (IA), (IB) and (IC), more especially compounds of the general formulae (IA) and (IB).

[0222] Compounds of the general formula (IA) are particularly suitable.

[0223] Suitably in the compounds of formula (I), (Ix), (IA), (IB), (IC), (ID) and (IE), X 5 For CH.

[0224] In some compounds of the invention, Z is -NHC(O)-, such that the nitrogen atom is attached to the central ring and C(O) is attached to Y.

[0225] In other compounds of the invention, Z is -C(O)NH-, such that the -C(O) is attached to the central ring and the nitrogen atom is attached to Y.

[0226] In some more suitable compounds of the present invention, Y is -CH2-.

[0227] In some suitable compounds of the present invention, particularly compounds of Formula (IA), (IC), (ID) and (IE), R 1 OR 5 In these compounds, R 5 Suitably it is an unsubstituted 5 or 6 membered heterocyclyl group, especially an oxygen-containing heterocyclyl group, and suitably it is a tetrahydrofuranyl or tetrahydropyranyl group, especially tetrahydrofuranyl, for example tetrahydrofuran-3-yl.

[0228] In other suitable compounds of the present invention, R 1 CH(R 7 )-N(R 8 )-C(O)OR 9 In this type of compound, a more suitable group R 7 Including H, phenyl and C substituted by methoxy 1-3 Alkyl, in particular H, phenyl or CH2OCH3.

[0229] R 8 Suitably H, methyl or ethyl optionally substituted by OH or OCH3. 8 Specific examples include H, methyl, ethyl, CH2CH2OCH3 and CH2CH2OH.

[0230] R 9 Suitably C optionally substituted by one or more halo substituents 2-4 More preferably, R 9 C 2-4 A branched alkyl group (such as isopropyl or tert-butyl) or a C 2-4 A haloalkyl group (such as 2,2,2-trifluoroethyl).

[0231] Alternatively, as described above, R 7 and R 8Together with the atoms to which they are attached, they may combine to form a 5- or 6-membered heterocyclic ring optionally containing additional heteroatoms. In this case, the 5- or 6-membered heterocyclic ring may be a ring containing only R 8 The heterocyclic ring connected to the nitrogen atom or containing R 8 The ring thus formed may be C 1-3 The alkyl group (particularly methyl or ethyl) is substituted, but more suitably is unsubstituted. Examples of such rings include pyrrolidine, piperidine, piperazine and morpholine, especially pyrrolidine and morpholine.

[0232] In other suitable compounds of the present invention, R 1 CH(R 7 )-N(R 8 )-C(O)N(R 9 )(R 10 Among these compounds, more suitable R 7 , R 8 and R 9 Part as above for R 1 CH(R 7 )-N(R 8 )-C(O)OR 9 As described above, R 10 It is H or methyl.

[0233] In other compounds of the present invention, R 1 CH(R 11 )(R 12 ).

[0234] In some of these compounds, R 12 is a 5- or 6-membered carbocyclic ring or an oxygen-containing heterocyclic ring which is optionally substituted by OH.

[0235] In these compounds, R 11 Suitably it is H or methyl, more suitably it is H.

[0236] R 12 More suitably, R is cyclopentyl or cyclohexyl or an oxygen-containing 5 or 6-membered heterocyclic ring, optionally containing further heteroatoms, such as tetrahydrofuranyl, tetrahydropyranyl or morpholinyl. More suitably, R 12 It is cyclopentyl, cyclohexyltetrahydrofuranyl or tetrahydropyranyl.

[0237] As mentioned above, R 12 Optionally substituted with OH. Typically, R 12 is unsubstituted or has a single OH substituent. 12 With a single OH substituent, it may be located adjacent to CH(R 11) is attached to a ring atom.

[0238] In which R 1 CH(R 11 )(R 12 ), R 12 In other compounds wherein the aryl or heteroaryl ring is a 6-membered aryl or heteroaryl ring, wherein the aryl or heteroaryl ring is optionally substituted with one or more substituents selected from the group consisting of OH, methoxy, chlorine, fluorine, C optionally substituted with halo or OH 1-6 Alkyl and optionally one or more selected from C 1-4 A 5-membered heteroaryl group substituted with alkyl and halo substituents.

[0239] More preferably, in these compounds, R 11 is H, methyl or methoxy, especially H.

[0240] More appropriately, R 12 is selected from phenyl or pyridinyl, for example pyridin-3-yl, and is suitably unsubstituted or selected from OH, methoxy, fluorine, chlorine and C optionally substituted by OH 1-4 Alkyl is substituted with one or more substituents (suitably one, two or three substituents); more suitably the phenyl or pyridyl R 12 is unsubstituted or substituted by one, two or three selected from OH, methoxy, fluorine, chlorine and C optionally substituted by OH 3-4 The alkyl group is substituted with a substituent.

[0241] In some of these compounds, R 12 is unsubstituted phenyl. Alternatively, R 12 is a phenyl group having a single OH or methoxy substituent at position 2, 3 or 4 of the phenyl ring. As a further alternative, R 12 It may be phenyl having a first substituent selected from OH and methoxy (especially OH) and one or two C substituents selected from halogen, CN or optionally substituted by halogen, OH or CN. 1-4 Additional substituents for the alkyl group.

[0242] In some particularly suitable compounds, R 12 is phenyl, which is substituted by a first substituent selected from OH and methoxy (especially OH) and a second substituent selected from fluorine and chlorine. 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. More preferably, R 12 is a phenyl group having an OH substituent at the 2-position and a fluorine group at the 3-, 4-, 5- or 6-position.

[0243] In particularly suitable compounds of the alternative, R 12is phenyl having a first substituent selected from OH and methoxy (especially OH), a second substituent selected from fluorine and chlorine, and a C optionally substituted with OH or CN 1-4 Alkyl but especially C with a single OH substituent 3-4 The third substituent of the alkyl group. More suitably, R 12 is phenyl, the phenyl having a first substituent OH, a second substituent fluorine and a third substituent selected from tert-butyl, -C(CH3)2OH and -C(CH3)2CH2OH. In some examples, the third substituent is at the 4-position, the fluorine substituent is at the 2-position, and the OH is at the 5-position.

[0244] Among other alternative compounds, R 12 is phenyl, which is substituted with a first substituent selected from OH and methoxy (especially OH) and a second substituent selected from:

[0245] C 1-6 alkyl, optionally substituted with one or more substituents selected from halo, OH and CN; and

[0246] 3 to 6 membered cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl group is optionally substituted by one or more substituents selected from halo, OH, CN and C optionally substituted by one or more substituents selected from halo, OH and CN. 1-6 alkyl.

[0247] In this case, more suitably, the phenyl group R 12 It is also substituted with a third substituent selected from chlorine and fluorine (especially fluorine).

[0248] In other compounds of this type, R 12 is phenyl, the phenyl being substituted by a 5-membered heteroaryl ring, the 5-membered heteroaryl ring being optionally substituted by one or more C 1-4 Alkyl groups (especially one or two such groups) are substituted (suitably with one or two methyl groups). Suitable 5-membered heteroaryl groups include nitrogen-containing heteroaryl groups such as pyrrole, oxazole, thiazole and imidazole.

[0249] In other compounds of this type, R 12 is an unsubstituted pyridyl group, typically an unsubstituted pyridin-3-yl group. 12 For the CH(R 11 ) is a pyridyl radical having a single substituent selected from OH, methoxy, fluorine and chlorine at adjacent ring positions to the atoms to which it is attached. 12 In the case of pyridin-3-yl, the substituent may be at the 2-position. Alternatively, R 2 is a C having one to three groups selected from halo, OH and optionally substituted by OH 1-4A pyridyl group substituted with an alkyl group, for example having a C 3-4 An alkyl group and one or two further substituents selected from OH and halo-substituted pyridyl.

[0250] When R 1 CH(R 11 )(R 12 ), where R 12 is a 6-membered aryl or heteroaryl ring and R 12 The substituents on R 11 Combined with a 6-membered aryl or heteroaryl ring R 12 When the fused 5- or 6-membered ring is fused, the fused 5- or 6-membered ring is suitably saturated so that the group CH(R 11 )(R 12 ) is, for example, benzofuran, indoline or indane, in particular dihydrobenzofuran.

[0251] As mentioned above, R 1 Can be C 2-6 Alkyl, which is optionally substituted by one or more selected from phenyl, OR 15 and N(R 15 )(R 16 ) is substituted with a substituent. In more suitable compounds of this type, R 1 C 2-3 Alkyl, which is optionally substituted by one or more selected from phenyl, OR 15 and N(R 15 )(R 16 ) is substituted by a substituent, wherein R 15 and R 16 Each of is independently as defined above but is especially H or methyl.

[0252] Suitably, the alkyl group R 1 is unsubstituted or substituted by one or more selected from phenyl and OR 15 Substituents (usually a single substituent) substituted, where R 15 As defined above but more suitably H or methyl.

[0253] Alternatively, R 1 It may be a 3- to 8-membered cycloalkyl ring, which is optionally substituted by one or more substituents selected from OH, CN, halo, and C optionally substituted by one or more substituents selected from halo and OH. 1-4 In this case, more suitably, R 1 is a 3 to 6 membered ring or more suitably a 3 to 4 membered ring, which is optionally substituted by one or more substituents, for example one or two substituents (especially one substituent), as described above. 12When the cycloalkyl group is present, particularly suitable substituents include C 1-4 Alkyl and C 1-4 Haloalkyl, more preferably including C 1-2 Alkyl and C 1-2 Haloalkyl, such as methyl and trifluoromethyl.

[0254] In some suitable compounds of the present invention, R 2 is an optionally substituted 3- to 10-membered carbocyclic ring system as defined above.

[0255] 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, especially bicyclo-[2.2.1]heptanyl or adamantyl. 2 Compounds where R is adamantyl are particularly suitable. 2 In the case of a bridged carbocyclic ring system, it is unsubstituted.

[0256] 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, fluorine, C 1-6 Alkyl, O(C 1-6 Alkyl) and NH-C(O)OC 1-6 Alkyl groups, especially OH, C 1-4 Alkyl, O(C 1-4 Alkyl) and NH-C(O)OC 1-4 Alkyl groups, such as OH, methyl, methoxy, and NHC(O)OC 1-4 alkyl.

[0257] Suitably, when R 2 When a carbocyclic ring system is as described above, it is unsubstituted or substituted by a single substituent as defined above. The substituent is suitably located on the carbon atom to which the moiety Y is attached.

[0258] More appropriately, R 2 is an unsubstituted cyclopentyl, cyclohexyl or cycloheptyl ring, especially unsubstituted cycloheptyl.

[0259] In the alternative more suitable compounds, R 2 is substituted with one or more selected from halogen, C 1-4 Alkyl and C 1-4A cyclopropyl or cyclobutyl ring substituted with a haloalkyl substituent. More preferably, in this case, R 2 To be C 1-2 Cyclopropyl substituted with haloalkyl, in particular cyclopropyl substituted with a single trifluoromethyl substituent. In this case, the trifluoromethyl group may be attached to the 1-position of the cyclopropyl ring, i.e. the atom via which the cyclopropyl group is attached to the rest of the molecule.

[0260] In other compounds of the present invention, R 2 is an optionally substituted 6 to 10 membered aryl or 5 to 10 membered heteroaryl ring system as defined above. In this case, more suitably, R 2 is phenyl or a 5- or 6-membered heteroaryl ring optionally substituted by one or more substituents selected from the group consisting of fluorine, chlorine, OH, C optionally substituted by one or more substituents selected from the group consisting of OH and halo 1-6 Alkyl, O(C 1-6 alkyl) and O(C 1-6 haloalkyl), more preferably fluorine, chlorine, OH, C 1-4 Alkyl, C substituted by OH 1-4 Alkyl and O(C 1-4 alkyl); especially fluorine, chlorine, OH, C 1-4 Alkyl, C substituted with OH and methoxy 1-4 alkyl.

[0261] In other compounds of the present invention, Y and R 2 together to form a substituted C as defined above 3-10 An alkyl group. In some cases, this can be a branched C 5-10 An alkyl group, and more preferably a branched alkyl group of the form:

[0262] 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 ), where R 21 , R 22 and R 23 Each of the C 1-4 Alkyl, provided that 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.

[0263] In other more suitable compounds of the present invention, Y and R 2 together to form C substituted with one or more substituents as described above 2-6 More preferably, C 2-6 The alkyl group is substituted with one or more halo substituents. In this type of compound, more preferably, Y and R 2 Together they form C 3-4 An alkyl group substituted by one or more substituents as described above but more suitably substituted by one or more halo substituents and especially substituted by one or more fluoro substituents. 2 An example of a group is -CH2-CH2-CF3.

[0264] In further more suitable compounds of the present invention, Y and R 2 Together they form a 3 to 6 membered carbocyclic ring which is optionally substituted by one or more substituents as described above. 2 together to form a cyclopropyl or cyclobutyl ring, which is optionally substituted as described above, but more suitably by one or more selected from halo, C 1-4 Alkyl and C 1-4 Substitution of a haloalkyl group, especially by a single C 1-2 The haloalkyl group may be substituted with a trifluoromethyl group, for example. In this case, the trifluoromethyl group may be attached to the 1 position of the cyclopropyl ring, i.e. the atom through which the cyclopropyl group is attached to the rest of the molecule.

[0265] In other compounds of the present invention, Y and R 2 Together they form the group -CH2-C(R 17 )(R 18 )-CH2-N(R 19 )-C(O)OR 20 , where R 17 , R 18 , R 19 and R 20 Each of is as defined above.

[0266] In this case, more appropriately, each R 18 and R 19 is independently H or methyl, especially methyl, or R 18 and R 19 Combined with the atoms to which they are attached, they form a 6-membered heterocyclic ring; and R 20 C 1-6 Alkyl, for example isopropyl, sec-butyl or tert-butyl.

[0267] Where compatible, the above embodiments and preferred ranges for compounds of formula (I) also include compounds of formula (Ix).

[0268] Specific examples of the novel compounds of general formula (I) include the following:

[0269] 2-(1-adamantyl)-N-[2-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide (Compound 1);

[0270] 2-(1-adamantyl)-N-[2-(tetrahydropyran-2-ylmethyl)-1H-benzimidazol-5-yl]acetamide (Compound 1.1);

[0271] 2-(2-adamantyl)-N-(2-benzyl-1H-benzimidazol-5-yl) (Compound 2);

[0272] 2-(2-adamantyl)-N-[2-(2-phenylethyl)-1H-benzimidazol-5-yl]acetamide (Compound 2.1);

[0273] 2-(2-adamantyl)-N-[2-[methoxy(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 2.2);

[0274] 2-(2-adamantyl)-N-[2-[(2-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 2.3);

[0275] 2-(2-adamantyl)-N-[2-[(R)-methylamino(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 3);

[0276] 2-(1-adamantyl)-N-[2-[(2-chloro-3-pyridyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 4);

[0277] 2-(2-adamantyl)-N-[2-[(2-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 5);

[0278] 2-(2-adamantyl)-N-[2-[(4-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 5.1);

[0279] 2-(2-adamantyl)-N-[2-[(5-chloro-2-hydroxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Compound 5.2);

[0280] 2,2,2-trifluoroethyl N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate (Compound 6);

[0281] 2-(1-adamantyl)-N-[2-[[3-(3,5-dimethylisoxazol-4-yl)phenyl]methyl]-3H-benzimidazol-5-yl]acetamide (Compound 7);

[0282] tert-Butyl N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate (Compound 8);

[0283] 2-(2-adamantyl)-N-(2-tetrahydrofuran-3-yloxy-1H-benzimidazol-5-yl)acetamide (Compound 9);

[0284] N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide (Compound 10);

[0285] 2-(1-adamantyl)-N-[3-amino-2-[(2-hydroxyphenyl)methyl]indazol-6-yl]acetamide (Compound 11);

[0286] 2-Cyclohexyl-N-(2-isopropyl-1,3-benzoxazol-5-yl)acetamide (Compound 12);

[0287] N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]indazole-6-carboxamide (Compound 13);

[0288] 2-(1-adamantyl)-N-(2-benzyl-3H-imidazo[4,5-c]pyridin-6-yl)acetamide (Compound 14);

[0289] 2-Benzyl-N-(cycloheptylmethyl)imidazo[1,2-a]pyridine-7-carboxamide (Compound 15);

[0290] 2-(1-adamantyl)-N-(2-benzylindazol-6-yl)acetamide (Compound 16);

[0291] 2-(1-adamantyl)-N-(2-benzyl-3-methyl-indazol-6-yl)acetamide (Compound 17);

[0292] N-(2-tert-Butyl-1H-benzoimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide (Compound 18);

[0293] N-[3-[(2-Benzyl-1H-benzimidazole-5-carbonyl)amino]-2,2-dimethyl-propyl]carbamic acid tert-butyl ester (Compound 19);

[0294] 2-tert-Butyl-N-(cycloheptylmethyl)-3H-benzimidazole-5-carboxamide (Compound 20);

[0295] 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Compound 21);

[0296] 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (Compound 21.1);

[0297] 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (Compound 21.2);

[0298] 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide (Compound 21.3);

[0299] 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1,3-benzoxazole-5-carboxamide (Compound 21.4);

[0300] 2-[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide (Compound 22);

[0301] 2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide (Compound 23);

[0302] 2-Benzyl-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (Compound 24);

[0303] 2-Benzyl-N-(cyclopentylmethyl)-1H-benzimidazole-5-carboxamide (Compound 24.1);

[0304] 2-Benzyl-N-(cycloheptylmethyl)-1H-benzimidazole-5-carboxamide (Compound 24.2);

[0305] N-(Cycloheptylmethyl)-2-[(2-fluoro-6-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25);

[0306] N-(Cycloheptylmethyl)-2-[(5-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25.1);

[0307] N-(Cycloheptylmethyl)-2-[(3-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25.2);

[0308] N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25.3);

[0309] N-(Cycloheptylmethyl)-2-[(4-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25.4);

[0310] N-(Cycloheptylmethyl)-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide (Compound 25.5);

[0311] 2-(5-Chloro-2-hydroxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide (Compound 26);

[0312] N-(2-tert-Butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide (Compound 27);

[0313] N-(Cycloheptylmethyl)-2-(1-methylcyclobutyl)-3H-benzimidazole-5-carboxamide (Compound 28);

[0314] 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);

[0315] 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);

[0316] N-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Compound 30);

[0317] 2-[[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (Compound 31);

[0318] 2-[[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Compound 31.1);

[0319] 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);

[0320] 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyridine-7-carboxamide (Compound 33);

[0321] and salts and solvates thereof.

[0322] The compound of general formula (IA) can be prepared by the following method: making a compound of general formula (II):

[0323]

[0324] Where R 1 As defined for formula (I), and R 31 is OH or halogenated, such as chlorine;

[0325] Reaction with a compound of general formula (III):

[0326]

[0327] Where X 5 , Z, Y and R 2 As defined for general formula (I).

[0328] Suitably, the reaction is carried out in the presence of a coupling agent and 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.

[0329] Suitable coupling agents include known peptide coupling agents such as O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N, N', N'-tetramethyluronium tetrafluoroborate (TATU), (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy) tripyrrolidinylphosphonium hexafluorophosphate (PyBOP); carbodiimide, such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI); and triazole, 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.

[0330] The reaction between the compounds of formula (II) and (III) can be carried out in one step or in two steps. In the two-step reaction, the first step produces an intermediate of formula (IV):

[0331]

[0332] Where R 1 , X 5 , Z, Y and R 2 As defined for general formula (I).

[0333] The intermediate of general formula (IV) can be isolated and then further reacted to produce the desired product of general formula (I). The reagents are as described above for the single step reaction, but preferably, in the compound of general formula (II), R 31 is halogenated, especially chlorine.

[0334] The compounds of general formula (II) are readily available or can be synthesized by known methods. 1 CH(R 11 )(R 12 ), where R 11 As defined above and R 12 For (R 30 ) m A substituted 6-membered aryl or heteroaryl ring, wherein each R 30 are independently OH, methoxy, chlorine, fluorine, C optionally substituted with one or more substituents selected from halo and O 1-6 Alkyl, or optionally one or more selected from C 1-4alkyl and halogenated substituents; and m is 0, 1, 2, 3, 4 or 5. Compounds of formula (II) can be converted into other compounds of formula (II). For example, compounds of formula (II) with fluorine and methoxy substituents can be alkylated as shown in Example 21 below.

[0335] In some cases, R of the compound of formula (II) 1 The group may be protected and the protecting group may be removed after reacting with the compound of formula (III). 1 If the group contains an aromatic ring substituted with OH or an alkyl group substituted with OH, protection may be required. Examples of the use of protecting groups in this case are given in the following examples, where R 1 The group is CH(R 11 )(R 12 ), where R 11 is H, and R 12 is a phenyl group substituted by OH and -C(CH2)2-CH2OH. In this case, in the compound of general formula (II), the OH group is protected as a lactone, which can be opened by treatment with a reducing agent such as sodium borohydride or lithium borohydride to give the desired R 12 Group.

[0336] Where R 31 Compounds of general formula (II) where OH is OH can be prepared by hydrolysis of compounds of general formula (V):

[0337]

[0338] Where R 1 As defined above; and R 32 C 1-6 Alkyl or benzyl.

[0339] The hydrolysis may be a base hydrolysis, for example using an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide in a polar solvent, typically an alcoholic solvent such as a mixture of methanol or ethanol and water.

[0340] The compound of general formula (V) (wherein R 1 For R 30 Substituted benzyl, wherein R 30 is optionally one or more selected from C 1-4 A 5-membered heteroaryl group substituted with an alkyl or halogenated substituent) can be prepared by the following method: a compound of the general formula (VI):

[0341]

[0342] Where R 30is optionally one or more selected from C 1-4 a 5-membered heteroaryl group substituted with an alkyl or halogenated substituent;

[0343] Reaction with a halophenyl acetate of general formula (VII):

[0344]

[0345] Where R 32 As defined for formula (V), and R 55 is halogenated, especially bromine.

[0346] 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 a nitrogen atmosphere). The reaction temperature is suitably about 80 to 120°C, for example about 100°C.

[0347] The compound of general formula (III) can be synthesized by reducing the compound of general formula (VIII):

[0348]

[0349] Where X 5 , Z, Y and R 2 As defined for general formula (I).

[0350] Suitable reduction methods include catalytic hydrogenation, for example over a palladium on carbon catalyst. Alternatively, the reducing agent may be a transition metal, such as zinc, for example under acidic conditions.

[0351] The compound of formula (VIII) wherein Z is -NHC(O)- (i.e. NH is linked to a phenyl group) can be prepared by the following method: a compound of formula (IX):

[0352]

[0353] Where R 2 As defined for formula (I), react with a compound of formula (X):

[0354]

[0355] Where X 5 As defined for general formula (I).

[0356] The reaction may be carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and (III). N,N-dimethylformamide is a suitable solvent.

[0357] In some cases, in the compound of formula (IX), R 2 Substituents on the group may need to be protected. For example, as shown in Example 29 below, when R 2 When is a phenyl group substituted with OH and 2-hydroxy-1,1-dimethylethyl at adjacent positions, it can be protected as a lactone. The synthesis of lactone-protected compounds of general formula (IX) (intermediate B) is described below.

[0358] Compounds of general formula (IX) and (X) are readily available or can be prepared by methods known to those skilled in the art.

[0359] In a variation of the above method, it is particularly suitable for preparing a compound wherein X 5 Wherein N is N and Z is -NHC(O)-, the compound of general formula (IX) can be reacted with a halogenating agent such as thionyl chloride and then with ammonium hydroxide to form a compound of general formula (XI):

[0360]

[0361] Where R 2 As defined for general formula (I).

[0362] Compounds of general formula (XI) can be reacted with protected compounds of general formula (XII):

[0363]

[0364] Where X 5 As defined for the general formula (I), R 33 C 1-6 alkyl or benzyl, and R 34 is halogenated, especially bromine;

[0365] Obtain the protected compound of general formula (VIIIa):

[0366]

[0367] Where X 5 , Y and R 2 As defined for the general formula (I), R 33 As defined for formula (XII), and Z is -NHC(O)- (ie NH is attached to a phenyl group).

[0368] 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.

[0369] Compounds of general formula (VIIIa) may be deprotected to give compounds of general formula (VIII) as defined above. Deprotection of compounds of general formula (VIIIa) may be achieved by treatment with an acid such as hydrochloric acid.

[0370] The protected compound of general formula (XII) can be prepared by the following method: making a compound of general formula (XIII):

[0371]

[0372] Where X 5 As defined for formula (I), and R 34 As defined for formula (XII);

[0373] With formic anhydride of general formula (XIV):

[0374]

[0375] Where R 33 As defined for formula (XII);

[0376] The reaction is carried out in the presence of a base such as sodium hydride.

[0377] Compounds of general formula (VIIIa) can be reduced as described above for compounds of general formula (VIII) to give compounds of general formula (IIIa):

[0378]

[0379] Where X 5 , Z, Y and R 2 As defined for formula (I), and R 33 C 1-6 Alkyl or benzyl.

[0380] The compound of general formula (IIIa) can be reacted with the compound of general formula (II) using the above reaction conditions to obtain the protected compound of general formula (IVa):

[0381]

[0382] Where R 1 , X 5 , Z, Y and R 2 As defined for formula (I), and R 33 As defined for formula (IIIa).

[0383] Compounds of general formula (IVa) may be treated with an acid, such as HCl in dioxane, to remove the protecting groups and produce compounds of general formula (IV), which may be reacted as described above to give compounds of general formula (I).

[0384] The compound of formula (III) wherein Z is -C(O)NH- (i.e. C(O) is linked to a phenyl group) can be prepared by the following method: a compound of formula (XV):

[0385]

[0386] Where X 5 As defined for formula (I);

[0387] Reaction with a compound of general formula (XVI):

[0388] R 2 -Y-NH2

[0389] (XVI)

[0390] Where R 2 and Y are as defined for general formula (I).

[0391] The reaction may be carried out in the presence of an amine such as DIPEA or TEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and (III). N,N-dimethylformamide is a suitable solvent.

[0392] Compounds of the general formulae (XV) and (XVI) are known and readily available or can be prepared by known methods.

[0393] Compounds of formula (IA) wherein Z is -NHC(O)- (ie NH is attached to the benzimidazole) may also be prepared by reacting a compound of formula (IX) as defined above with a compound of formula (XVII):

[0394]

[0395] Where R 1 and X 5 As defined for general formula (I).

[0396] The reaction may be carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and (III). N,N-dimethylformamide is a suitable solvent.

[0397] Compounds of general formula (XVII) can be prepared by reducing compounds of general formula (XVIII):

[0398]

[0399] Where R 1 and X 5 As defined for general formula (I).

[0400] Suitably, the reduction is carried out by catalytic hydrogenation over a palladium or platinum catalyst, such as a Pd / C catalyst.

[0401] Compounds of general formula (XVIII) may be prepared by reacting a compound of general formula (II) as defined above with a compound of general formula (XIX):

[0402]

[0403] Where X 5 As defined for general formula (I).

[0404] The reaction can be carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of 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 formula (II) and (XIX).

[0405] A compound of formula (I) (a compound of formula (IA) wherein R 1 OR 5 ) can be prepared by deprotecting a compound of the general formula (XX):

[0406]

[0407] Where R 5 , X 5 , Z, Y and R 2 As defined for formula (I), and R 35 is a protecting group, suitably a silyl protecting group, such as CH2O(CH2)2Si(R 36 )3, where each R 36 Independently for C 1-6 Alkyl or phenyl groups, for example by reaction with a strong acid such as trifluoroacetic acid or a fluoride source such as tetrabutylammonium fluoride.

[0408] The compound of general formula (XX) can be prepared by the following method: making a compound of general formula (XXI):

[0409]

[0410] Where X 5 , Z, Y and R 2 As defined for the general formula (I), R 35As defined for formula (XX), and R 37 is halogenated, especially chlorine;

[0411] Reaction with a compound of general formula (XXII):

[0412] R 5 -OH (XXII)

[0413] Where R 5 As defined for formula (I);

[0414] The reaction is carried out in the presence of a strong base, for example a metal hydride such as sodium hydride.

[0415] 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.

[0416] Compounds of general formula (XXII) are known and readily available or can be prepared by known methods.

[0417] The compound of general formula (XXI) can be prepared from the compound of general formula (XXIII):

[0418]

[0419] Where X 5 , Z, Y and R 2 As defined for formula (I), and R 37 As defined for formula (XXI);

[0420] Prepared by reaction with a compound of general formula (XXIV):

[0421] R 35 -R 38

[0422] (XXIV)

[0423] Where R 35 As defined for formula (XX), and R 38 is halogenated, especially chlorine or bromine.

[0424] Compounds of general formula (XXIV) are known and readily available or can be prepared by known methods.

[0425] The compound of general formula (XXIII) wherein Z is -NHC(O)- (i.e. NH is linked to a phenyl group) can be prepared by the following method: a compound of general formula (XXV):

[0426]

[0427] Where X 5 As defined for formula (I), and R 37 As defined for formula (XXI);

[0428] Reaction with a compound of general formula (XXVI):

[0429]

[0430] Where R 2 As defined for formula (I), and R 39 is halogenated, especially chlorine.

[0431] 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.

[0432] Compounds of general formula (XXVI) may be prepared from compounds of general formula (IX) as defined above by reaction with a halogenating agent such as thionyl chloride.

[0433] Compounds of general formula (XXV) can be prepared by reducing compounds of general formula (XXVII):

[0434]

[0435] Where X 5 As defined for formula (I), and R 37 As defined for formula (XXI);

[0436] Reduction is usually performed using iron and ammonium chloride.

[0437] Compounds of general formula (XXVII) are known and readily available or can be prepared by methods known to those skilled in the art.

[0438] Compounds of general formula (XXIII) wherein Z is -C(O)NH- (i.e., C(O) is linked to a phenyl group) can be prepared using a combination of the above-mentioned methods for compounds of general formula (XXIII) wherein Z is -NHC(O)- (i.e., NH is linked to a benzimidazole group) and methods for compounds of general formula (III) wherein Z is -C(O)NH- (prepared from compounds of general formula (XV)).

[0439] An alternative method for preparing compounds of formula (IA) wherein Z is -NHC(O)- (ie NH is attached to a phenyl group) is to react a compound of formula (XVII) as defined above with a compound of formula (XXVI) as defined above.

[0440] Suitably, the reaction is carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0441] Compounds of general formula (XXX) can be prepared by reducing compounds of general formula (XXXI):

[0442]

[0443] Where R 1 and X 5 As defined for general formula (I).

[0444] Suitable reduction methods include catalytic hydrogenation, typically using a palladium on carbon catalyst, and the reaction is carried out in a polar organic solvent, typically an alcoholic solvent such as ethanol.

[0445] Compounds of general formula (XXXI) can be prepared by treating a compound of general formula (II) as defined above (especially wherein R 31 The method may be carried out by reacting a compound of formula (II) wherein OH is OH) with a compound of formula (XIX) as defined above.

[0446] Suitably, the reaction is carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0447] An alternative method of preparing compounds of general formula (IA) wherein Z is -C(O)NH- (ie -C(O) is attached to the benzimidazole group) is by reacting compounds of general formula (XXXIII):

[0448]

[0449] Where R 1 and X 5 As defined for formula (I);

[0450] Reaction with a compound of formula (XVI) as defined above.

[0451] The reaction may be carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and (III). For example HATU may be used. N,N-dimethylformamide is a suitable solvent.

[0452] Formic acid of general formula (XXXIII) can be prepared by hydrolysis of ester of general formula (XXXIIIa):

[0453]

[0454] Where R 1 and X 5 As defined for formula (I), and R 40 C 1-6 Alkyl or benzyl.

[0455] Typically, the hydrolysis is a basic hydrolysis and is carried out using a base such as an alkali metal hydroxide (eg lithium hydroxide or sodium hydroxide) in an aqueous solvent, suitable solvents include water and an alcohol or a mixture of THF and an alcohol, where suitable alcohols include methanol and ethanol.

[0456] Compounds of general formula (XXXIIIa) can be prepared by reacting a compound of general formula (II) as defined above with a compound of general formula (XXXIV):

[0457]

[0458] Where X 5 As defined for formula (I), and R 40 As defined for formula (XXXIIIa).

[0459] The reaction can be carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and (III). For example, HATU can be used. N,N-dimethylformamide is a suitable solvent.

[0460] Compounds of the general formula (XXXIV) are known and commercially available or can be prepared by methods familiar to those skilled in the art, for example by hydrolysis of compounds of the general formula (XV).

[0461] Compounds of formula (IC) wherein Z is -C(O)NH- (i.e. C(O) is attached to the central ring system) can be prepared by the following method: Compounds of formula (XXXV):

[0462]

[0463] Where R 1 and X 5 As defined for formula (I);

[0464] Reaction with a compound of formula (XVI) as defined above.

[0465] Suitably, the reaction is carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0466] Compounds of general formula (XXXV) can be prepared by hydrolyzing compounds of general formula (XXXVI):

[0467]

[0468] Where R 1 and X 5 As defined for formula (I), and R 40 For example, for the general formula (XXXIIIa)

[0469] defined.

[0470] Typically, the hydrolysis is a basic hydrolysis and is carried out using a base such as an alkali metal hydroxide (eg lithium hydroxide or sodium hydroxide) in an aqueous solvent, suitable solvents include mixtures of water and alcohols such as methanol and ethanol.

[0471] Compounds of general formula (XXXVI) can be prepared by reacting a compound of general formula (II) as defined above with a compound of general formula (XXXVII):

[0472]

[0473] Where R 1 and X 5 As defined for formula (I), and R 40

[0474] As defined for formula (XXXIIIa).

[0475] Suitably, the reaction is carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0476] Compounds of the general formula (XXXVII) are known and readily available or can be prepared by known methods.

[0477] Compounds of general formula (IC) wherein Z is -NHC(O)- (i.e. NH is attached to the central ring system) can be prepared by the following method: Compounds of general formula (XXXVIII):

[0478]

[0479] Where R 1 and X 5 As defined for formula (I);

[0480] Reaction with a compound of formula (XXVI) as defined above.

[0481] Suitably, the reaction is carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0482] Compounds of the general formula (XXXVIII) are known and readily available or can be prepared by known methods.

[0483] Compounds of general formula (IB) wherein Z is -NHC(O)- (ie NH is attached to the central ring system) can be prepared by reacting a compound of general formula (IX) as defined above with a compound of general formula (XL):

[0484]

[0485] Where R 1 , R 3 and X 5 As defined above for general formula (I).

[0486] Suitably, the reaction is carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0487] Compounds of general formula (XL) can be prepared by reducing compounds of general formula (XLI):

[0488]

[0489] Where R 1 , R 3 and X 5 As defined above for general formula (I).

[0490] The reduction can be carried out by catalytic hydrogenation, for example using a palladium on carbon catalyst.

[0491] CR 3 The compound of the general formula (XLI) substituted with C-NH2 can be prepared by the following method:

[0492]

[0493] Where X 5 As defined for formula (I), and R 42 is halogenated, especially fluorine;

[0494] Reaction with a compound of formula (XLIII)

[0495]

[0496] Where R 1 As defined for general formula (I).

[0497] Suitably, the reaction is carried out under basic conditions, for example using DIPEA and in an alcoholic solvent such as tert-butanol.

[0498] Compounds of the general formulae (XLII) and (XLIII) are known and readily available or can be prepared by known methods.

[0499] Alternatively, compounds of formula (IB) wherein Z is -NHC(O)- (ie NH is attached to the central ring system) can be prepared by the following method: Compounds of formula (XLV):

[0500]

[0501] Where R 2 , R 3 , X 5 and Y are as defined for formula (I);

[0502] Reaction with a compound of general formula (XLVIII):

[0503] R 1 -R 43

[0504] (XLVIII)

[0505] Where R 1 As defined for formula (I), and R 43 is halogenated, especially chlorine or bromine;

[0506] The reaction is carried out under mild alkaline conditions (eg in the presence of potassium carbonate).

[0507] Compounds of general formula (XLVIII) are known and readily available or can be prepared by known methods.

[0508] Compounds of general formula (XLV) may be prepared by reacting a compound of general formula (IX) as defined above with a compound of general formula (XLVI):

[0509]

[0510] Where R 3 and X 5 As defined for general formula (I).

[0511] Suitably, the reaction is carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0512] Compounds of general formula (XLVI) are known and readily available or can be synthesized by methods known to those skilled in the art.

[0513] Compounds of formula (IB) wherein Z is -C(O)NH- (i.e. C(O) is attached to the central ring system) can be prepared by the following method: Compounds of formula (XLVII):

[0514]

[0515] Among them, Y, R 2 , R 3 and X 5 As defined above for formula (I);

[0516] Reacting with a compound of general formula (XLVIII) as defined above.

[0517] The compound of general formula (XLVII) can be prepared by the following method: making the compound of general formula (XLIX):

[0518]

[0519] Where R 3 and X 5 As defined above for formula (I);

[0520] Reaction with a compound of general formula (XVI) as defined above.

[0521] Suitably, the reaction is carried out in the presence of an amine such as DIPEA and a coupling agent. Suitable coupling agents are as discussed above for the reaction of compounds of formula (II) and formula (III). Suitable solvents include polar organic solvents such as N,N-dimethylformamide.

[0522] Compounds of the general formula (XLIX) are known and readily available or can be prepared by known methods.

[0523] When the compound of formula (IB) has R 3 Substituent N(R 3a )(R 3b ), where R 3aand R 3b One or both of them are H, and the amine group may need to be protected during the synthesis. 3 The compound of the above-mentioned general formula (XLI) being NH2 can be protected by reacting with the compound of the above-mentioned general formula (XIV) to protect the free amine group. The following steps are carried out as described above and after the protected compound of the general formula (XL) reacts with the compound of the general formula (IX) to obtain the protected compound of the formula (ID), the protecting group can be removed by treating with an acid such as trifluoroacetic acid.

[0524] Similarly, where R 3 The compound of general formula (XLIX) which is NH2 can be protected by reacting with the compound of general formula (XIV) described above. The protecting group can be removed before or after the subsequent step.

[0525] The compound of general formula (ID) can be prepared by the following method: making a compound of general formula (L):

[0526]

[0527] Where R 1 and X 5 As defined in general formula (I), and R 45 is halogenated, such as bromine;

[0528] with formic acid, methanesulfonyl chloride, triethylamine and a compound of the general formula (XVI) as defined above in the presence of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and a Pd catalyst such as XantPhos Pd-G3 (third generation (G3) Buchwald precatalyst) and a base such as sodium carbonate.

[0529] Suitably, the reaction is carried out in an organic solvent such as toluene.

[0530] The compound of general formula (L) can be prepared by the following method: making the compound of general formula (LI):

[0531]

[0532] Where X 5 As defined in general formula (I), and R 45 As defined for formula (L);

[0533] Reaction with a compound of general formula (LII):

[0534]

[0535] Where R 1As defined for formula (I), and R 46 is halogenated, for example bromine.

[0536] Suitably, the reaction is carried out under basic conditions (for example in the presence of sodium bicarbonate) and in an alcoholic solvent such as ethanol.

[0537] Compounds of the general formula (LI) and (LII) are known and readily available or can be prepared by methods known to those skilled in the art.

[0538] Compounds of general formula (I) can also be prepared from other compounds of general formula (I). 1 and R 2 When one or both of the moieties contain a phenyl group substituted with an alkoxy group, they can be converted to a phenyl group substituted with an OH group by treatment with boron tribromide.

[0539] R 1 CH(R 7 )-N(R 8 )-C(O)OR 9a The first compound of the general formula (I) is converted into a compound wherein R 1 CH(R 7 )-N(R 8 )-C(O)OR 9b The second compound of the general formula (I) wherein R 9a and R 9b Different from each other, but both are as described above for R 9 As defined above, the conversion is performed by a method comprising:

[0540] In the first step, R 1 CH(R 7 )-N(R 8 )-C(O)OR 9a The compound of general formula (I) is treated with an acid such as HCl in a solvent such as dioxane. This produces a compound similar to general formula (I) but wherein R 1 The substituent is CH(R 7 )-NH(R 8 ) is replaced. The compound is then treated with a compound of formula (LV):

[0541]

[0542] Where R 9b As defined above, and R 50 is halogenated, especially chlorine;

[0543] The desired product is obtained.

[0544] Where R1 CH(R 7 )-N(R 8 )-C(O)OR 9 The compound of general formula (I) can be hydrolyzed (usually alkaline hydrolysis) using a metal hydroxide such as sodium hydroxide or lithium hydroxide and then reacted with a compound of formula HN(R 9 )(R 10 ) is reacted with an amine to convert it into 1 CH(R 7 )-N(R 8 )-C(O)N(R 9 )(R 10 ) of the general formula (I), wherein R 9 and R 10 As described above for general formula (I).

[0545] Other interconversions of various substituent groups can be carried out by methods familiar to those skilled in the art.

[0546] Compounds of formula (Ix) can be prepared in a similar manner to compounds of formula (I).

[0547] Compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) and (IE) are modulators of TMEM16A. Therefore, in another aspect of the present invention, there is provided a compound of general formula (I) as defined above (including all tautomeric forms, all enantiomers and isotopic variants thereof, as well as salts and solvates thereof) for use in medicine, in particular for the treatment or prevention of diseases and disorders affected by the modulation of TMEM16A.

[0548] Further suitable compounds for use in the treatment or prevention of diseases and disorders affected by the modulation of TMEM16A are as defined above.

[0549] Also provided is the use of a compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in the preparation of a medicament for treating or preventing diseases and disorders affected by the modulation of TMEM16A.

[0550] Also provided is a method for treating or preventing diseases and conditions affected by the modulation of TMEM16A, the method comprising administering to a patient in need of such treatment an effective amount of a compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE).

[0551] Diseases and disorders affected by modulation of TMEM16A include respiratory diseases and disorders, dry mouth (xerostomia), overactive bowel, cholestasis, and ocular disorders.

[0552] Also provided:

[0553] A compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in the treatment or prevention of respiratory diseases and disorders.

[0554] - A compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in the treatment or prevention of dry mouth (xerostomia).

[0555] - A compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in the treatment or prevention of intestinal overactivity.

[0556] - A compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in the treatment or prevention of cholestasis.

[0557] - A compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in the treatment or prevention of an eye disorder.

[0558] The present invention also provides:

[0559] Use of a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for the preparation of a medicament for the treatment or prevention of respiratory diseases and disorders.

[0560] Use of a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for the preparation of a medicament for the treatment or prevention of dry mouth (xerostomia).

[0561] Use of a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for the preparation of a medicament for treating or preventing intestinal overactivity.

[0562] Use of a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in the preparation of a medicament for treating or preventing cholestasis.

[0563] Use of a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in the preparation of a medicament for treating or preventing an eye disorder.

[0564] Further provided:

[0565] A method for treating or preventing diseases and disorders of the respiratory system, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE).

[0566] A method for treating or preventing dry mouth (xerostomia), which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE).

[0567] A method for treating or preventing intestinal overactivity, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE).

[0568] A method for treating or preventing cholestasis, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE).

[0569] A method for treating or preventing an ocular disorder, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE).

[0570] Respiratory diseases and conditions that can be treated or prevented using compounds of 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 bronchiectasis, asthma and primary ciliary dyskinesia.

[0571] Dry mouth (xerostomia) that may be treated or prevented with compounds of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) may be caused by Sjogren's syndrome, radiation therapy and xenobiotic drugs.

[0572] Intestinal overactivity that may be treated or prevented using compounds of 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.

[0573] Ocular disorders that may be treated or prevented using compounds of Formula (I), (Ix), (IA), (IB), (IC), (ID), or (IE) include dry eye.

[0574] The compounds of the invention will generally be administered as part of a pharmaceutical composition and the invention therefore further provides a pharmaceutical composition comprising a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) and a pharmaceutically acceptable excipient.

[0575] More suitable compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) for use in pharmaceutical compositions are as discussed above, especially novel compounds of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE).

[0576] 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 may be prepared by any methods well known in the art of pharmacy.

[0577] The composition can be prepared by combining the active agent defined above with an excipient. In general, the preparation method of the preparation is to make the active agent and a liquid carrier or a finely divided solid carrier or both uniformly and tightly combined, and then, if necessary, the product is formed. The present invention relates to a method for preparing a pharmaceutical composition, which method comprises combining or associating a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) with a pharmaceutical carrier or vehicle.

[0578] The preparations for oral administration in the present invention can be expressed as: discrete units, such as capsules, sachets or tablets, each discrete unit containing a predetermined amount of active agent; powder or granules; a solution or suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or an oil-in-water liquid emulsion or an oil-in-water liquid emulsion; or a pill, etc.

[0579] For compositions (e.g., tablets and capsules) for oral administration, the term "acceptable carrier" includes vehicles such as commonly used excipients, e.g., binders, such as syrup, gum arabic, gelatin, sorbitol, gum tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants, such as magnesium stearate, sodium stearate and other metal stearates, stearyl glyceride, stearic acid, silicone oil, talcum wax, oil and colloidal silicon dioxide. Flavoring agents such as peppermint, wintergreen oil, cherry flavoring, etc. may also be used. It may be necessary to add a colorant to make the dosage form easy to identify. Tablets may also be coated by methods well known in the art.

[0580] Tablets can be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing an active agent in a free-flowing form (such as a powder or granules) optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant in a suitable machine. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and can be formulated to allow for sustained or controlled release of the active agent.

[0581] Other formulations suitable for oral administration include lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; lozenges comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.

[0582] For topical application to the skin, the compounds of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) can be formulated into creams, ointments, jellies, solutions or suspensions, etc. Cream or ointment formulations useful for the drug are conventional formulations well known in the art, for example, as described in standard textbooks of pharmacology such as the British Pharmacopoeia.

[0583] Local application to the lung can be achieved by using an aerosol formulation. Aerosol formulations generally include active ingredients suspended or dissolved in suitable aerosol propellants, such as chlorofluorocarbons (CFCs) or hydrofluorocarbons (HFCs). 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). Propellant generally accounts for 40% to 99.5% by weight of the total inhalation composition, for example 40% to 90% by weight. The preparation may include excipients, including cosolvents (e.g., ethanol) and surfactants (e.g., lecithin, sorbitan trioleate, etc.). Other possible excipients include polyethylene glycol, polyvinyl pyrrolidone, glycerol, etc. Aerosol formulations are packaged in canisters and delivered with a metering valve (eg supplied by Bespak, Valois or 3M or alternatively by Aptar, Coster or Vari) for a suitable dose.

[0584] Topical administration to the lungs can also be achieved by using non-pressurized formulations such as aqueous solutions or suspensions. These can be administered by a nebulizer, which can be, for example, hand-held and portable or for home or hospital use (i.e., non-portable). The formulation can contain excipients such as water, buffers, tonicity regulators, pH regulators, surfactants, and cosolvents. Suspensions and aerosol formulations (whether pressurized or not) will generally contain the compound of the invention in finely divided form, such as D 50 The particle size distribution can be calculated using D 10 , D 50 and D 90 The value indicates the particle size distribution D 50 The median is defined as the particle size in micrometers that bisects the distribution. Measurements obtained from laser diffraction are more accurately described as volume distributions, so the D obtained using this procedure is 50 The value is more meaningfully called 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 10 and D 90 The value is the average Dv 10 and Dv 90 The values ​​are respectively those where 10% of the distribution is below D 10 value and 90% of the distribution is below D 90 The granularity of the value.

[0585] Topical administration to the lungs can also be achieved by using a dry powder formulation. A dry powder formulation will contain a compound of the disclosure in finely divided form, typically having a mass mean diameter (MMAD) of 1-10 μm or a D of 0.5-10 μm (e.g., about 1-5 μm). 50 . Powders of the compounds of the invention in finely divided form may be prepared by micronization or similar size reduction methods. Micronization may be performed using a jet mill such as that manufactured by Hosokawa Alpine. The resulting particle size distribution may be measured using laser diffraction (e.g. using a Malvern Mastersizer 2000S instrument). The formulation will typically contain a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose), typically having a larger particle size, e.g. a mass mean diameter (MMAD) of 50 μm or greater (e.g. 100 μm or greater), or a D of 40-150 μm. 50As used herein, the term "lactose" refers to lactose-containing components, including α-lactose monohydrate, β-lactose monohydrate, anhydrous α-lactose, anhydrous β-lactose and amorphous lactose. The lactose component can be processed by micronization, sieving, grinding, compression, agglomeration or spray drying. It also includes various forms of commercially available lactose, such as (inhalation grade lactose; DFE Pharma), 70 (sieved lactose for dry powder inhalers; Meggle), (DFE Pharma) and (Sieve Inhalation Grade Lactose; DFE Pharma) product. In one embodiment, the lactose component is selected from the group consisting of α-lactose monohydrate, anhydrous α-lactose and amorphous lactose. Preferably, the lactose is α-lactose monohydrate.

[0586] The dry powder formulation may also contain other excipients. Thus, in one embodiment, the dry powder formulation according to the present disclosure comprises magnesium stearate or calcium stearate. Such formulations may have excellent chemical stability and / or physical stability, especially when such formulations also comprise lactose.

[0587] Dry powder formulations are typically delivered using a dry powder inhaler (DPI) device. Exemplary dry powder delivery systems include Other examples of dry powder delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER / NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X-CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR, and PROHALER.

[0588] In one embodiment, the compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) is provided as a micronized dry powder formulation, for example containing a suitable grade of lactose.

[0589] Therefore, as one aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) in granular form and granular lactose, optionally comprising magnesium stearate.

[0590] In one embodiment, the compound of 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 device such as a DISKUS. Suitably, such a device is a multi-dose device, for example the formulation is filled into blisters for use in a multiple unit dose device such as a DISKUS.

[0591] In another embodiment, a compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) is provided as a micronized dry powder formulation, e.g., containing a suitable grade of lactose, filled into a hard shell capsule for use in a single dose device such as an AEROLISER.

[0592] In another embodiment, the compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) is provided as a micronized dry powder formulation, containing 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.

[0593] In another embodiment, the compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) is provided as a fine powder for inhalation dosage form, wherein the powder is D 50 The invention relates to fine particles of 0.5-10 μm (e.g., about 1-5 μm), which are prepared by a size reduction method other than jet mill micronization, such as spray drying, spray freezing, microfluidization, high pressure homogenization, supercritical fluid crystallization, ultrasonic crystallization, or a combination of these methods thereof, or other suitable particle formation methods known in the art for preparing fine particles with an aerodynamic particle size 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 include a single compound or a combination of a compound and other suitable excipients that can contribute to processing. The resulting fine particles can be formed into a final formulation for delivery to a person or can be optionally further formulated with other suitable excipients to promote acceptable dosage form delivery.

[0594] The compounds of the present invention can also be administered rectally, for example in the form of suppositories or enemas, including aqueous or oily solutions and suspensions, emulsions and foams. Such compositions are prepared according to standard procedures well known to those skilled in the art. For example, suppositories can be prepared by mixing the active ingredient with conventional suppository bases such as cocoa butter or other glycerides. In this case, the drug is mixed with a suitable non-irritating excipient, which 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.

[0595] Typically, for compositions intended for topical application to the eye in the form of eye drops or eye ointment, the total amount of compounds of general formula (I) will be from about 0.0001% (w / w) to less than 4.0%.

[0596] Preferably, for topical ocular administration, the compositions administered according to 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 ability of the patient to easily administer such compositions by instilling one to two drops of solution into the affected eye. However, the composition may also be a suspension, a viscous or semi-viscous gel, or other type of solid or semi-solid composition. For compounds that are sparingly soluble in water, suspensions may be preferred.

[0597] An alternative method of administration to the eye is intravitreal injection of a solution or suspension of a compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE). In addition, the compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) may also be introduced via an ocular implant or insert.

[0598] Compositions administered according to formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) may also contain a variety of other ingredients, including but not limited to tonicity agents, buffers, surfactants, stabilizing polymers, preservatives, co-solvents and viscosity increasing agents. Suitable pharmaceutical compositions of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) include a compound of the invention formulated with a tonicity agent and a buffer. Pharmaceutical compositions of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) may further optionally contain a surfactant and / or a demulcent and / or a stabilizing polymer.

[0599] Various tonicity agents can be used to adjust the tonicity of the composition, preferably to the tonicity of the natural tears of the ophthalmic composition. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, monosaccharides such as dextrose, fructose, galactose and / or simple polyols such as sugar alcohols, mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol and hydrogenated starch hydrolysates can be added to the composition to approach physiological tonicity. This amount of tonicity agent will vary depending on the specific agent to be added. However, in general, the composition will have a tonicity agent in an amount sufficient to make the final composition have an ophthalmologically acceptable osmotic pressure (usually about 150-450mOsm, preferably 250-350mOsm, most preferably about 290mOsm). In general, the tonicity agent of the present invention will be present in the range of 2% to 4% w / w. Preferred tonicity agents of the present invention include monosaccharides or sugar alcohols, such as D-mannitol.

[0600] A suitable buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) may be added to the composition to prevent pH drift under storage conditions. The specific concentration will vary depending on the reagent used. However, preferably, the buffer is selected to maintain the target pH in the range of pH 5 to 8, and more preferably to maintain a target pH of pH 5 to 7.

[0601] Surfactants may optionally be used to deliver higher concentrations of the compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE). Surfactants serve to solubilize the compound and stabilize colloidal dispersions such as micellar solutions, microemulsions, emulsions and suspensions. Examples of surfactants that may optionally be used include polysorbates, poloxamers, polyethylene glycol 40 stearate, polyethylene glycol 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, such as Triton X114 and tyloxapol.

[0602] Another agent that may be added to the ophthalmic composition of the compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) is a demulcent which acts as a stabilizing polymer. The stabilizing polymer should be an ionic / charged example preferably for topical ocular use, more specifically a polymer that has a negative charge on its surface, can exhibit a zeta potential of (-) 10-50 mV for physical stability, and is capable of being dispersed in water (i.e., water soluble). Preferred stabilizing polymers of the present invention are polyelectrolytes, or if more than one, polyelectrolytes from the family of cross-linked polyacrylates, such as 0.1%-0.5% w / w of Carbomer and Pemulen(R), particularly Carbomer 974p (polyacrylic acid).

[0603] Other compounds may also be added to the ophthalmic composition of the compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) to increase the viscosity of the carrier. Examples of viscosity enhancers include, but are not limited to: polysaccharides such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, various polymers of the cellulose family; vinyl polymers; and acrylic polymers.

[0604] Topical ophthalmic products are usually packaged in multiple doses. Therefore, preservatives are needed to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzalkonium bromide, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are usually used at a level of 0.001% to 1.0% w / v. The unit dose composition of general formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) will be sterile, but usually unpreserved. Therefore, such compositions will usually not contain preservatives.

[0605] Parenteral formulations will generally be sterile.

[0606] A physician or other skilled person will be able to determine appropriate dosages of a compound of 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 pharmaceutical formulation, whether in unit dosage form or otherwise.

[0607] The compounds of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) can be used in combination with one or more other active agents that are useful for treating or preventing diseases or conditions affected by the modulation of TMEM16A, in particular respiratory diseases or conditions, such as one of the above-mentioned diseases and conditions.

[0608] This type of additional active agent may be included in the above-described pharmaceutical compositions, but alternatively it may be administered separately, either simultaneously with the compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE), or at an earlier or later time.

[0609] Therefore, in another aspect of the present invention, a product is provided, which comprises a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) and an additional agent for the treatment or prevention of respiratory diseases, as a combined preparation for simultaneous, sequential or separate use in the treatment of diseases or disorders affected by the modulation of TMEM16A, in particular respiratory diseases or disorders (e.g. one of the above-mentioned diseases and disorders).

[0610] Also provided are combinations of compounds of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) with additional agents useful for treating or preventing respiratory disorders as combined preparations for simultaneous, sequential or separate use in the treatment of diseases or disorders affected by the modulation of TMEM16A, in particular respiratory diseases or disorders (e.g., one of the above-mentioned diseases and disorders).

[0611] Suitable additional active agents that may be included in the pharmaceutical composition or combined preparation with a compound of Formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) include:

[0612] beta2 adrenergic receptor agonists such as metaproterenol, isoproterenol, pantothecin, albuterol, formoterol, salmeterol, indacaterol, terbutaline, metaproterenol, bitolterol mesylate, pirbuterol, olodaterol, vilanterol, and abediterol;

[0613] antihistamines, for example histamine H1 receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine or H4 receptor antagonists;

[0614] dornase alfa;

[0615] corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, and fluticasone furoate;

[0616] Leukotriene antagonists, such as montelukast and zafirlukast;

[0617] anticholinergic compounds, particularly muscarinic antagonists such as ipratropium, tiotropium, glycopyrrolate, aclidinium and umeclidinium;

[0618] 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);

[0619] ENaC modulators, particularly ENaC inhibitors;

[0620] antibiotic;

[0621] antiviral agents, such as ribavirin and neuraminidase inhibitors, such as zanamivir;

[0622] Antifungal drugs, such as PUR1900;

[0623] Airway moisturizers (osmolytes), such as hypertonic saline and mannitol and

[0624] Mucolytics, such as N-acetylcysteine.

[0625] 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, and any of the exemplary compounds of these applications may be used in combination with a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE). Particularly suitable compounds for use in combination with a compound of formula (I), (Ix), (IA), (IB), (IC), (ID) or (IE) include compounds having a cation and a suitable anion, the cation being selected from:

[0626] 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,

[0627] 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,

[0628] 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,

[0629] 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,

[0630] 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,

[0631] 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}carboxamido)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,

[0632] 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,

[0633] Suitable anions are, for example, halides, sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate or p-toluenesulfonate.

[0634] The present invention is illustrated by the following non-limiting examples and accompanying drawings, in which:

[0635] Figure 1 is an exemplary trace of a whole-cell patch clamp (Qpatch) TMEM16A potentiator assay used in the biological examples and illustrates the methods used in the assay.

[0636] Examples

[0637] The invention is illustrated by the following non-limiting examples.

[0638] Examples

[0639] General conditions:

[0640] Mass spectra were run on LC-MS systems using electrospray ionization. These were run using a Waters Acquity uPLC system or a Shimadzu LCMS-2010EV system equipped with a Waters PDA and ELS detector. [M+H]+ refers to monoisotopic molecular weight.

[0641] NMR spectra were recorded on a Bruker Avance III HD500 MHz equipped with a 5 mm Broad Band Reverse Probe, a Bruker Avance III HD 250 MHz equipped with a 5 mm Broad Band Observed 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 the solvent peak was used as reference.

[0642] With reference to the following examples, compounds of the preferred embodiments were synthesized using methods described herein or other methods known in the art.

[0643] The various starting materials, intermediates and compounds of the preferred embodiments can be separated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography when appropriate. Unless otherwise specified, all starting materials are obtained from commercial suppliers and can be used without further purification. Salts can be prepared from compounds by known salt-forming procedures.

[0644] Use the appropriate SNAP cartridge or Column and gradient, in Compounds were purified by flash column chromatography on normal phase silica gel using an Isolera system. Isolera or Selekt system and appropriate SNAP C18 or Compounds were purified on reverse phase silica gel using a C18 cartridge and reverse phase eluent or by preparative HPLC where otherwise stated.

[0645] Preparative HPLC using acidic pH, early elution method

[0646] Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: RT) with a gradient of 10%-95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 14.44 min, then 95% B for 2.11 min, injection volume 1500 μL, flow rate 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0647] Preparative HPLC using acidic pH, standard elution method

[0648] Purification was performed by preparative HPLC (acidic pH, standard elution method) on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: RT) with a gradient of 30%-95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) for 11 min, then 95% B for 2.11 min, injection volume of 1500 μL, flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0649] Preparative HPLC using basic pH, early elution method

[0650] Purification was performed by preparative HPLC (basic pH, early elution method) on a Gilson LC system using a Waters Xbridge C18 column (30 mm x 100 mm, 10 μM; temperature: RT) with a gradient of 10%-95% (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) for 14.44 min, then 95% B for 2.11 min, injection volume of 1500 μL, flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0651] Preparative HPLC using basic pH, standard elution method

[0652] Purification was performed by preparative HPLC (basic pH, standard elution method) on a Gilson LC system using a Waters Xbridge C18 column (30 mm x 100 mm, 10 μM; temperature: RT) with a gradient of 30%-95% (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) for 11 min, then 95% B for 2.11 min, injection volume of 1500 μL, flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0653] If not stated otherwise, analytical HPLC conditions were as follows:

[0654] Method A

[0655] Column: Phenomenex Kinetix-XB C18 2.1x100mm, 1.7μm

[0656] Column temperature 40℃

[0657] Eluent: A: H2O + 0.1% formic acid, B: acetonitrile + 0.1% formic acid

[0658] Flow rate: 0.6mL / min

[0659] Gradient: 0-5.3min 5-100% B, 5.3-5.8min 100% B, 5.8-5.82min 100-5% B, 5.82-7.00min 5% B

[0660] Method B

[0661] Column: Kinetex Core-Shell C18 2.1x50mm, 5μm

[0662] Column temperature 40℃

[0663] Eluent: A: H2O + 0.1% formic acid, B: acetonitrile + 0.1% formic acid

[0664] Flow rate: 1.2mL / min

[0665] Gradient: 0-1.20min 5-100% B, 1.20-1.30min 100% B, 1.30-1.31min 100-5% B, 1.31-1.7min 5% B

[0666] Method C

[0667] Column: Phenomenex Gemini-NX C18 2.0x50mm, 3μm

[0668] Column temperature 40℃

[0669] Eluent: A: 2 mM ammonium bicarbonate, buffered to pH 10, B: acetonitrile

[0670] Flow rate: 1mL / min

[0671] Gradient: 0-1.80min 1-100% B, 1.80-2.10min 100% B, 2.10-2.30min 100-1% B, 2.30-3.50min 1% B

[0672] Method D

[0673] Column: Waters BEH TM C18, 2.1x50mm, 1.7μm

[0674] Column temperature 40℃

[0675] Eluent: A: H2O + 0.1% formic acid, B: acetonitrile + 0.1% formic acid

[0676] Flow rate: 0.9mL / min

[0677] Gradient: 0-1.10min 5-100% B, 1.10-1.35min 100% B, 1.35-1.40min 100-5% B, 1.40-1.50min 5% B

[0678] Method E

[0679] Column: Kinetex Core-Shell C18 2.1x50mm, 5μm

[0680] Column temperature 40℃

[0681] Eluent: A: H2O + 0.1% formic acid, B: acetonitrile + 0.1% formic acid

[0682] Flow rate: 1.2mL / min

[0683] Gradient: 0-1.83min 5-100% B, 1.83-2.25min 100% B, 2.25-2.26min 100-5% B, 2.26-2.8min 5% B

[0684] Method F

[0685] Column: Waters BEH TM C18 2.1x100mm, 1.7μm

[0686] Column temperature 40℃

[0687] Eluent: A: 2 mM ammonium bicarbonate, buffered to pH 10, B: acetonitrile

[0688] Flow rate: 0.6mL / min

[0689] Gradient: 0-5.3min 5-100% B, 5.3-5.8min 100% B, 5.8-5.82min 100-5% B, 5.82-7.00min 5% B

[0690] Method G

[0691] Column: Waters BEH TM C18 2.1x30mm, 1.7μm

[0692] Column temperature: 40℃

[0693] Eluent: A: 2 mM ammonium bicarbonate, buffered to pH 10, B: acetonitrile

[0694] Flow rate: 1.0mL / min

[0695] Gradient: 0-0.75min 5-100% B, 0.75-0.85min 100% B, 0.85-0.9min 100-5% B, 0.9-1.0min 5% B

[0696] The following examples are intended to illustrate the present invention and should not be construed as limiting it. Temperatures are expressed in degrees Celsius. If not otherwise mentioned, all evaporations are performed in a vacuum, preferably between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods, such as microanalysis and spectral characteristics, such as MS, IR, and NMR. The abbreviations used are conventional abbreviations in the art. If undefined, these terms have their generally accepted meanings.

[0697] abbreviation

[0698] AcOH Acetic acid

[0699] aq. water-based

[0700] BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

[0701] br Broad Peak

[0702] d Twin Peaks

[0703] dd double peaks

[0704] DCC N,N'-Dicyclohexylcarbodiimide

[0705] DCE Dichloroethane

[0706] DCM Dichloromethane

[0707] DIPEA Diisopropylethylamine

[0708] DMAP 4-dimethylaminopyridine

[0709] DMF N,N-Dimethylformamide

[0710] EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0711] EtOAc Ethyl acetate

[0712] EtOH

[0713] HOAt 1-Hydroxy-7-azabenzotriazole

[0714] HATU 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0715] HPLC High Pressure Liquid Chromatography

[0716] IPA Isopropyl Alcohol

[0717] MeCN Acetonitrile

[0718] MeOH MeOH

[0719] MS

[0720] m multiplet

[0721] min

[0722] mL milliliters

[0723] m / z mass-to-charge ratio

[0724] NMR Nuclear Magnetic Resonance

[0725] q quartet

[0726] Rt retention time

[0727] s Single peak

[0728] t Triple Peak

[0729] TBME tert-butyl methyl ether

[0730] TBTU N,N,N',N'-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate

[0731] TEA Triethylamine

[0732] TFA Trifluoroacetic acid

[0733] THF Tetrahydrofuran

[0734] VT variable temperature

[0735] Preparation of Examples

[0736] Example 1

[0737] 2-(1-adamantyl)-N-[2-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide

[0738]

[0739] Step 1: 2-(1-adamantyl)-N-(4-amino-3-nitro-phenyl)acetamide

[0740]

[0741] 2-Nitrobenzene-1,4-diamine (3.15g, 20.59mmol) is added to a solution of 2-(1-adamantyl)acetic acid (4.0g, 20.59mmol), HATU (8.61g, 22.65mmol) and DIPEA (5.38mL, 30.88mmol) in DMF (20mL). After stirring at room temperature for 18 hours, the reaction mixture is distributed between EtOAc (100mL) and water (100mL). A black precipitate is formed in a biphasic mixture. The solid is filtered out and discarded. The phases are separated, and the organic layer is washed with water (100mL) and brine (2x50mL), dried over MgSO4, and concentrated in vacuo to give a brown / black oil. The oil is ground in DCM (~40mL), and the resulting suspension is filtered to give the title compound as a red / black solid.

[0742] LC-MS (Method B): Rt 1.24 min; MS m / z 330.2 = [M+H]+ (99% @ 215 nm)

[0743] 1H NMR(500MHz,DMSO-d6)δ9.73(s,1H),8.39(d,J=2.5Hz,1H),7.50(dd,J=9.1,2.5Hz,1H),7.29( s,2H),6.96(d,J=9.1Hz,1H),2.00(s,2H),1.93(s,3H),1.69–1.63(m,3H),1.63–1.54(m,9H).

[0744] Step 2: 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide

[0745]

[0746] 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 h. The resulting mixture was purified by (filter material) and wash the solid with EtOH (3 x 10 mL).The filtrate was concentrated in vacuo to give the title compound as a purple solid.

[0747] LC-MS (Method B): Rt 0.93 min; MS m / z 300.3 = [M+H]+ (98% @ 215 nm)

[0748] 1H NMR(500MHz,DMSO-d6)δ9.12(s,1H),6.83(d,J=2.3Hz,1H),6.52(dd,J=8.2,2.3Hz,1 H), 6.38 (d, J = 8.2Hz, 1H), 4.54–4.22 (m, 4H), 1.96–1.88 (m, 5H), 1.70–1.54 (m, 12H).

[0749] Step 3: 2-(1-adamantyl)-N-[2-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide

[0750] 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 lavender solid. The solid was sonicated in MeCN, filtered, dried in vacuo and suspended in acetic acid (2 mL). The suspension was stirred in a sealed container at 60 ° C overnight. The resulting mixture was concentrated in vacuo, and the residue was distributed 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 then separated by phase separation. The resulting residue was purified by C18 reverse phase chromatography eluting with 10%-100% MeCN in water (+0.2% ammonium hydroxide) to afford the title compound as a light brown solid.

[0751] LC-MS (Method A): Rt 2.87 min; MS m / z 406.4 = [M+H]+ (99% @ 215 nm)

[0752] 1H NMR(500MHz,DMSO-d6)δ12.07–11.89(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,2 H),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).

[0753] Example 1.1

[0754] 2-(1-adamantyl)-N-[2-(tetrahydropyran-2-ylmethyl)-1H-benzimidazol-5-yl]acetamide

[0755]

[0756] The title compound was prepared in analogy to Example 1, Step 3, from 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide (Example 1, Step 2) and 2-tetrahydropyran-2-ylacetic acid.

[0757] LC-MS (Method A): Rt 2.34 min; MS m / z 408.3 = [M+H]+ (100% @ 215 nm)

[0758] 1H NMR (500MHz, DMSO-d6) δ12.10–11.83(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,1 H),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).

[0759] Example 2

[0760] 2-(2-adamantyl)-N-(2-benzyl-1H-benzimidazol-5-yl)

[0761]

[0762] Step 1: 2-(2-adamantanylidene)acetic acid ethyl ester

[0763]

[0764] Ethyl 2-diethoxyphosphoryl acetate (7.26 mL, 36.61 mmol) was added dropwise to a suspension of cooled (0°C) NaH, 60% dispersed in a THF (100 mL) solution of mineral oil (1.86 g, 46.6 mmol). After stirring at 0°C for 30 min, adamantane-2-one (5.0 g, 33.28 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting mixture was diluted with DCM (100 mL) and washed with water (100 mL). The aqueous portion was extracted with DCM (100 mL), and the combined organic extracts were dried over MgSO4 and concentrated in vacuo to give a colorless oil. The oil was purified by silica gel chromatography, eluted with a heptane solution of 0-20% EtOAc to give the title compound as a colorless oil.

[0765] LC-MS (Method B): Rt 1.43 min; MS m / z 221.3 = [M+H]+ (97% @ 215 nm)

[0766] 1H NMR (500 MHz, CHLOROFORM-d) δ5.58 (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).

[0767] Step 2: 2-(2-Adamantyl)acetic acid ethyl ester

[0768]

[0769] A suspension of ethyl 2-(2-adamantanylidene)acetate (step 1) (95%, 14.0 g, 60.37 mmol) and Pd / C (10%, 6.42 g, 6.04 mmol) in EtOH (125 mL) 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 (2x10 mL). The filtrate was concentrated in vacuo to give the title compound as a colorless oil.

[0770] LC-MS (Method B): Rt 1.47 min; MS m / z 223.0 = [M+H]+ (100% @ 215 nm)

[0771] 1H NMR (500MHz, chloroform-d) δ4.12(q,J=7.1Hz,2H),2.44(d,J=7.6Hz,2H),2.23(t,J=7.6Hz,1H ),1.91–1.75(m,8H),1.71(d,J=10.9Hz,4H),1.62–1.50(m,3H),1.25(t,J=7.1Hz,3H).

[0772] Step 3: 2-(2-Adamantyl)acetic acid

[0773]

[0774] A solution of ethyl 2-(2-adamantyl)acetate (step 2) (100%, 18.3 g, 82.31 mmol) in MeOH (200 mL) and 2M aqueous sodium hydroxide solution (82.31 mL, 164.63 mmol) was stirred at 70 °C for 2 hours. The mixture was cooled to room temperature and concentrated in vacuo. The resulting solution was diluted with water (200 mL) and 6M aqueous HCl solution (~30 mL) was added to form a white precipitate. EtOAc (300 mL) was added and the phases were separated. The aqueous portion was further extracted with 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.

[0775] LC-MS (Method B): Rt 1.15 min; MS m / z 193.4 = [M+H]+ (100% @ 215 nm)

[0776] 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).

[0777] Step 4: 2-(2-Adamantyl)-N-(4-amino-3-nitro-phenyl)acetamide

[0778]

[0779] HATU (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 min and the resulting solution was stirred at 0 °C for 5 min and at room temperature for 10 min. The solution was cooled back 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 and after warming to room temperature, diluted with water (60 mL). EtOAc (100 mL) and more 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 solution (2 x 100 mL), 10% potassium carbonate solution (2 x 100 mL) and vacuum filtered. The biphasic filtrate was placed in a separatory funnel and the layers were separated. The organic layer was separated by phase separation. The mixture was stirred for 2-3 hr at 4 0 ℃ for 1 hr. The mixture was stirred for 2-3 ...

[0780] LC-MS (Method B): Rt 1.22 min; MS m / z 330.2 = [M+H]+ (100% @ 215 nm)

[0781] 1H NMR(500MHz,DMSO-d6)δ9.88(s,1H),8.40(d,J=2.5Hz,1H),7.52(dd,J=9.1,2.5Hz,1H),7.31(s,2H),7 .03–6.90(m,1H),2.41(d,J=7.6Hz,2H),2.21(t,J=7.5Hz,1H),1.95–1.60(m,12H),1.56–1.46(m,2H).

[0782] Step 5: 2-(2-Adamantyl)-N-(3,4-diaminophenyl)acetamide

[0783]

[0784] 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 purified by (filter material), washing with EtOAc, and concentrated in vacuo to afford the title compound as a brown foam.

[0785] LC-MS (Method B): Rt 0.97 min; MS m / z 300.2 = [M+H]+ (100% @ 215 nm)

[0786] 1H NMR (500MHz, DMSO-d6) δ9.27(s,1H),6.81(d,J=2.3Hz,1H),6.53(dd,J=2.3,6.5Hz,1H),6.38(d,J=6.4Hz ,1H),4.60–4.07(m,4H),2.33(d,J=7.6Hz,2H),2.20–2.13(m,1H),1.95–1.62(m,12H),1.55–1.42(m,2H).

[0787] Step 6: 2-(2-Adamantyl)-N-(2-benzyl-1H-benzimidazol-5-yl)acetamide

[0788] DIPEA (4.20mL, 24.05mmol) is added to a mixture of 2-phenylacetic acid (1.64g, 12.02mmol) and HATU (5.03g, 13.23mmol) in DMF (30mL), and the mixture is stirred at room temperature for 10 minutes. The resulting mixture is added to a solution of 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (step 5) (3.60g, 12.02mmol) in DMF (30mL) and stirred at room temperature overnight. The mixture is distributed between water (100mL) and EtOAc (100mL), and each phase is separated. The organic extract is washed with water (100mL) so that a solid precipitate is formed in the organic layer and the aqueous layer. The aqueous portion is stripped with EtOAc (80mL), and the combined organic suspension is filtered and dried in a vacuum oven to obtain the desired amide intermediate as a lavender 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 distributed between EtOAc (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The phases were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (2x50 mL) and water (2x30 mL). The organic phase was separated by phase separation. The 1-hydroxy-2-nitropropene (2-nitropropene) of 4-nitropropene (2-nitropropene) (4-nitropropene) ...

[0789] LC-MS (Method A): Rt 2.72 min; MS m / z 400.3 = [M+H]+ (100% @ 215 nm)

[0790] 1H NMR (250MHz, DMSO-d6, VT at 353K) δ11.86(br.s,1H),9.52(br.s,1H),7.85(br.s,1H),7.48–7.08( m,7H),4.14(s,2H),2.48–2.40(m,2H),2.34–2.20(m,1H),2.07–1.66(m,12H),1.61–1.48(m,2H).

[0791] Example 2.1

[0792] 2-(2-Adamantyl)-N-[2-(2-phenylethyl)-1H-benzimidazol-5-yl]acetamide

[0793]

[0794] The title compound was prepared in analogy to Example 2, Step 6, from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Example 2, Step 5) and 3-phenylpropionic acid.

[0795] LC-MS (Method A): Rt 2.84 min; MS m / z 414.3 = [M+H]+ (99% @ 215 nm)

[0796] 1H NMR(500MHz,DMSO-d6)δ12.10(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=7.6Hz,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).

[0797] Example 2.2

[0798] 2-(2-Adamantyl)-N-[2-[methoxy(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0799]

[0800] The title compound was prepared in analogy to Example 2, Step 6, from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Example 2, Step 5) and 2-methoxy-2-phenyl-acetic acid.

[0801] LC-MS (Method A): Rt 2.88 min; MS m / z 430.3 = [M+H]+ (99% @ 215 nm)

[0802] 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).

[0803] Example 2.3

[0804] 2-(2-adamantyl)-N-[2-[(2-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0805]

[0806] The title compound was prepared in analogy to Example 2, Step 6, from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Example 2, Step 5) and 2-(2-methoxyphenyl)acetic acid.

[0807] LC-MS (Method A): Rt 2.85 min; MS m / z 430.4 = [M+H]+ (97% @ 215 nm)

[0808] 1H NMR(500MHz,DMSO-d6)δ11.95(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=8.3Hz,1H),6.88(td ,J=7.4,1.0Hz,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).

[0809] Example 3

[0810] 2-(2-Adamantyl)-N-[2-[(R)-methylamino(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0811]

[0812] Step 1: N-[(R)-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]-phenyl-methyl]-N-methyl-carbamic acid tert-butyl ester

[0813] The title compound was prepared in analogy to Example 2, Step 6, from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Example 2, Step 5) and (2R)-2-[tert-butoxycarbonyl(methyl)amino]-2-phenyl-acetic acid.

[0814] LC-MS (Method A): Rt 3.52 min; MS m / z 529.4 = [M+H]+ (99% @ 215 nm)

[0815] Variable temperature 1H NMR (250 MHz, DMSO-d6, 353 K) 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).

[0816] Step 2: 2-(2-Adamantyl)-N-[2-[(R)-methylamino(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0817] To a solution of N-[(R)-[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]-phenyl-methyl]-N-methyl-carbamic acid tert-butyl ester (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 purified by 1 g of The mixture was then purified by centrifugation on an SCX cartridge and eluted with MeOH (10 mL) followed by 3.5 N NH3 in MeOH (10 mL). The methanolic ammonia eluent was concentrated in vacuo to afford the title compound as an off-white solid.

[0818] LC-MS (Method A): Rt 2.38 min; MS m / z 429.4 = [M+H]+ (100% @ 215 nm)

[0819] 1H NMR(500MHz,DMSO-d6)δ12.18(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).

[0820] Example 4

[0821] 2-(1-adamantyl)-N-[2-[(2-chloro-3-pyridyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0822]

[0823] Step 1: N-[4-[[2-(1-adamantyl)acetyl]amino]-2-amino-phenyl]-2-(2-chloro-3-pyridyl)acetamide

[0824]

[0825] To a solution of 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide (Example 1, Step 2) (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 hour. The resulting mixture was diluted with DCM and washed with water (10 mL) and brine (10 mL). The organic extracts were separated, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by silica gel chromatography, eluting with 0-10% MeOH in DCM. Further purification by C18 reverse phase chromatography, eluting with 10%-100% MeCN in H2O + 0.1% formic acid, gave the title compound as a light orange powder.

[0826] LC-MS (Method B): Rt 1.11 min; MS m / z 453.1 / 455.2 = [M+H]+ (77% @ 215 nm)

[0827] Step 2 :2-(1-adamantyl)-N-[2-[(2-chloro-3-pyridyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0828] 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 hour, 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 silica gel chromatography eluting with 0-10% MeOH in DCM. Further purification by preparative HPLC (basic pH, early elution method) gave the title compound.

[0829] LC-MS (Method A): Rt 2.38 min; MS m / z 435.3 / 437.3 = [M+H]+ (98% @ 215 nm)

[0830] 1H NMR(500MHz,DMSO-d6)δ12.21(br.s,1H),9.71(br.s,1H),8.34(dd,J=4.7,1.8Hz,1H),8.00(s,1H),7.84(dd,J=7.6,1 .7Hz,1H),7.43(dd,J=7.5,4.7Hz,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).

[0831] Example 5

[0832] 2-(2-Adamantyl)-N-[2-[(2-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0833]

[0834] 1M BBr3 DCM (0.28mL, 0.28mmol) solution is added dropwise to an ice-cold solution of 2-(2-adamantyl)-N-[2-[(2-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (Example 2.3) (61mg, 0.14mmol) in DCM (3mL). The mixture is stirred in an ice bath for 5min, then stirred at room temperature overnight. The mixture is cooled in an ice bath and treated with another 1M BBr3 DCM (0.14mL, 0.14mmol) solution. The reaction mixture is stirred at room temperature for 90min, then water (5mL) is added. Most of the aqueous phase is removed with a pipette, and the remaining suspension is collected by filtration. The solid is dissolved in MeOH and purified by acidic C18 reverse phase chromatography, eluted with 10%-100% MeCN water (+0.1% formic acid) solution to obtain the title compound as a white solid.

[0835] LC-MS (Method A): Rt 2.65 min; MS m / z 416.3 = [M+H]+ (100% @ 215 nm)

[0836] 1H NMR(500MHz,DMSO-d6)δ12.03(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=7.1,0.9Hz,1H) ,6.73(td,J=7.4,1.1Hz,1H),4.05(s,2H),2.44(d,J=7.6Hz,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).

[0837] Example 5.1

[0838] 2-(2-Adamantyl)-N-[2-[(4-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0839]

[0840] Step 1: 2-(2-Adamantyl)-N-[2-[(4-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0841]

[0842] The title compound was prepared in analogy to Example 2, Step 6, from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Example 2, Step 5) and 2-(4-methoxyphenyl)acetic acid.

[0843] LC-MS (Method A): Rt 2.78 min; MS m / z 430.4 = [M+H]+ (98% @ 215 nm)

[0844] 1H NMR(500MHz,DMSO-d6)δ12.06(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 = 7.7Hz, 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).

[0845] Step 2: 2-(2-Adamantyl)-N-[2-[(4-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0846] The title compound was prepared in analogy to Example 5 from 2-(2-adamantyl)-N-[2-[(4-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide (step 1).

[0847] LC-MS (Method A): Rt 2.48 min; MS m / z 416.3 = [M+H]+ (100% @ 215 nm)

[0848] 1H NMR (500MHz, DMSO-d6) δ12.07(s,1H),9.81(s,1H),9.26(s,1H),7.91(s,1H),7.36(d,J=8.0Hz,1H),7.26–7.15(m,1H),7.14–7.01(m,2 H),6.76–6.62(m,2H),4.01(s,2H),2.45(d,J=7.5Hz,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).

[0849] Example 5.2

[0850] 2-(2-Adamantyl)-N-[2-[(5-chloro-2-hydroxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0851]

[0852] Step 1: 2-(2-Adamantyl)-N-[2-[(5-chloro-2-methoxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0853]

[0854] The title compound was prepared in analogy to Example 2, Step 6, from 2-(2-adamantyl)-N-(3,4-diaminophenyl)acetamide (Example 2, Step 5) and 2-(5-chloro-2-methoxy-phenyl)acetic acid.

[0855] LC-MS (Method A): Rt 3.01 min; MS m / z 464.3 / 466.3 = [M+H]+ (99% @ 215 nm)

[0856] 1H NMR (500MHz, DMSO-d6) δ10.04(s,1H),8.13(d,J=1.5Hz,1H),7.51(d,J=8.7Hz,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=7.7Hz,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).

[0857] Step 2: 2-(2-Adamantyl)-N-[2-[(5-chloro-2-hydroxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide

[0858] The title compound was prepared in analogy to Example 5 from 2-(2-adamantyl)-N-[2-[(5-chloro-2-methoxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide (step 1).

[0859] LC-MS (Method A): Rt 2.56 min; MS m / z 450.3 / 452.3 = [M+H]+ (100% @ 215 nm)

[0860] 1H NMR(500MHz,DMSO-d6)δ12.24(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=7.7Hz,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).

[0861] Example 6

[0862] 2,2,2-Trifluoroethyl N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate

[0863]

[0864] Step 1: tert-Butyl N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate

[0865]

[0866] The title compound was prepared in analogy to Example 1, Step 3, from 2-(1-adamantyl)-N-(3,4-diaminophenyl)acetamide (Example 1, Step 2) and 2-(tert-butoxycarbonylamino)acetic acid.

[0867] LC-MS (Method B): Rt 1.11 min; MS m / z 439.2 = [M+H]+ (100% @ 215 nm)

[0868] 1H NMR(250MHz,DMSO-d6)δ12.03(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=5.9Hz,2H),2.05(s,2H),1.97–1.89(m,3H),1.74–1.54(m,12H),1.41(s,9H).

[0869] Step 2: 2-(1-Adamantyl)-N-[2-(aminomethyl)-1H-benzimidazol-5-yl]acetamide

[0870]

[0871] 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 4M HCl in dioxane (635 μL, 18 mmol). After stirring at room temperature for 3 days under an inert atmosphere, another portion of 4M HCl in dioxane (635 μL, 18 mmol) was added and stirring was continued for 24 hours. The resulting mixture was concentrated in vacuo and the crude residue was dissolved in MeOH (~10 mL). The mixture was passed through 5 g of 4% HCl in dioxane (10 mL). The product was purified by chromatography on an SCX column eluting with MeOH (20 mL) and then 7M NH3 in MeOH (20 mL). The methanolic ammonia eluent was concentrated in vacuo to afford the title compound as a reddish brown solid.

[0872] LC-MS (Method A): Rt 1.89 min; MS m / z 339.2 = [M+H]+ (99% @ 215 nm)

[0873] 1H NMR(500MHz,DMSO-d6)δ12.00(br.s,1H),9.65(s,1H),7.93(br.s,1H),7.44–7.30(m,1H),7.1 7(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).

[0874] Step 3: 2,2,2-Trifluoroethyl N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate

[0875] 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 min. Water (4 mL) was added, followed by EtOAc (4 mL), and the layers were separated. The organic portion was washed with water (2 x 4 mL) and separated by phase separation. The product was purified by preparative HPLC (acidic pH, standard elution method) to afford the title compound as an off-white powder.

[0876] LC-MS (Method A): Rt 2.50 min; MS m / z 465.3 = [M+H]+ (97% @ 215 nm)

[0877] 1H NMR(500MHz,DMSO-d6)δ12.15(br.s,1H),9.69(s,1H),8.29(t,J=5.8Hz,1H),8.07–7.78(m,1H),7.51–7.0 5(m,2H),4.68(q,J=9.1Hz,2H),4.41(d,J=6.0Hz,2H),2.05(s,2H),1.98–1.86(m,3H),1.75–1.50(m,12H).

[0878] Example 7

[0879] 2-(1-adamantyl)-N-[2-[[3-(3,5-dimethylisoxazol-4-yl)phenyl]methyl]-3H-benzimidazol-5-yl]acetamide

[0880]

[0881] Step 1: Ethyl 2-[3-(3,5-dimethylisoxazol-4-yl)phenyl]acetate

[0882]

[0883] A solution of ethyl 2-(3-bromophenyl)acetate (360 μL, 2.06 mmol), tripotassium phosphate (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 N2 for 10 min, and then Pd(dppf)Cl2.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. (filter material) Filter the filtrate onto silica gel and purify by silica gel chromatography eluting with 0-50% EtOAc in heptane to give the title compound as a colorless viscous oil.

[0884] LC-MS (Method B): Rt 1.13 min; MS m / z 260.1 = [M+H]+ (99% @ 215 nm)

[0885] 1H NMR (250 MHz, CHLOROFORM-d) δ7.44–7.36 (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).

[0886] Step 2: 2-[3-(3,5-dimethylisoxazol-4-yl)phenyl]acetic acid

[0887]

[0888] To a solution of 2-[3-(3,5-dimethylisoxazol-4-yl)phenyl]ethyl 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 hours. 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 1M 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 light yellow oil, which crystallized on standing at room temperature.

[0889] LC-MS (Method B): Rt 0.97 min; MS m / z 232.2 = [M+H]+ (99% @ 215 nm)

[0890] 1H NMR (500 MHz, CHLOROFORM-d) δ7.41 (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).

[0891] Step 3: 2-(1-adamantyl)-N-[2-[[3-(3,5-dimethylisoxazol-4-yl)phenyl]methyl]-3H-benzimidazol-5-yl]acetamide

[0892] 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 (Example 1, step 2) (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 hours. The resulting mixture was diluted with EtOAc (20 mL), washed with water (2x10 mL), brine (10 mL), dried over Na2SO4 and concentrated in vacuo to give a dark red oil. The oil was dissolved in 4M HCl in dioxane (2 mL) and stirred in a sealed tube at 80°C for 1 hour. After being cooled to room temperature, the obtained mixture is concentrated in vacuo, and the obtained residue is distributed between EtOAc (10mL) and saturated sodium bicarbonate aqueous solution (10mL). Each phase is separated, and the organic extract is washed with salt water (5mL), through Na2SO4 is dried and concentrated in vacuo to obtain a yellow oil. The crude product is purified by preparative HPLC (alkaline pH, early elution method) to obtain the title compound, which is a yellow powder.

[0893] LC-MS (Method A): Rt 2.68 min; MS m / z 495.3 = [M+H]+ (100% @ 215 nm)

[0894] 1H NMR(500MHz,DMSO-d6)δ12.24–12.15(m,1H),9.73–9.61(m,1H),7.98–7.83(m,1H),7.43–7.10 (m,6H),4.20(s,2H),2.39(s,3H),2.21(s,3H),2.05(s,2H),1.93(s,3H),1.67–1.58(m,12H).

[0895] Example 8

[0896] tert-Butyl N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate

[0897]

[0898] Step 1: tert-Butyl N-[(5-nitro-1H-benzimidazol-2-yl)methyl]carbamate

[0899]

[0900] 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 hour 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 a saturated aqueous sodium bicarbonate solution (100 mL) and diluted with EtOAc (100 mL). The layers were separated and the aqueous portion was back extracted with EtOAc (3x50 mL). The combined organic extracts were washed with water (3x25 mL), brine (3x25 mL), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in acetic acid (40 mL) and stirred at 70 ° C for 1 hour. The resulting mixture was concentrated in vacuo, redissolved in EtOAc and washed with saturated aqueous sodium bicarbonate (50 mL), water (3 x 50 mL) and brine (50 mL). The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. The resulting crude black oil was purified by silica gel chromatography, eluting with 0-100% EtOAc in heptane to give the title compound.

[0901] LC-MS (Method B): Rt 0.99 min; MS m / z 293.1 = [M+H]+ (100% @ 215 nm)

[0902] 1H NMR (500MHz, DMSO-d6) δ 12.88 (s, 1H), 8.40 (s, 1H), 8.09 (d, J = 8.9Hz, 1H), 7.68 (d, J = 6.3Hz, 1H), 7.53 (s, 1H), 4.42 (d, J = 5.8Hz, 2H), 1.41 (s, 9H).

[0903] Step 2: tert-Butyl N-[(5-amino-1H-benzimidazol-2-yl)methyl]carbamate

[0904]

[0905] A solution of tert-butyl N-[(5-nitro-1H-benzoimidazol-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 a hydrogen atmosphere and stirred at room temperature overnight. The resulting mixture was purified by (filter material) and wash with EtOH (20 mL).The filtrate was concentrated in vacuo to give the title compound as a beige solid.

[0906] LC-MS (Method B): Rt 0.46-0.63 min; MS m / z 263.1 = [M+H]+ (99% @ 215 nm)

[0907] 1H NMR(500MHz,DMSO-d6)δ11.73–11.45(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=5.8Hz,2H),1.41(s,9H).

[0908] Step 3: tert-Butyl N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate

[0909] By 2-(2-adamantyl)acetic acid (example 2 step 3) (74mg, 0.38mmol), HOAt (62mg, 0.46mmol) and EDCI (88mg, 0.46mmol) mixture in DCM (0.5mL) stir 15min, and add N-[(5-amino-1H-benzoimidazol-2-yl) methyl] tert-butyl carbamate (100mg, 0.38mmol), then add DIPEA (0.13mL, 0.76mmol). Gained mixture is stirred at room temperature for 48 hours, then diluted with water (2mL). Separate organic part, and further extract aqueous phase with DCM (3mL). Dilute the organic extract merged with water (5mL), and collect gained suspension by filtration. Solid is passed through preparation HPLC (acidic pH, early elution method) purifying, obtain title compound, it is off-white solid.

[0910] LC-MS (Method A): Rt 2.77 min; MS m / z 439.4 = [M+H]+ (97% @ 215 nm)

[0911] 1H NMR(500MHz,DMSO-d6)δ12.07–12.00(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).

[0912] Example 9

[0913] 2-(2-Adamantyl)-N-(2-tetrahydrofuran-3-yloxy-1H-benzimidazol-5-yl)acetamide

[0914]

[0915] Step 1a: 2-Chloro-1H-benzimidazol-5-amine

[0916]

[0917] 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 hour. After cooling to room temperature, the mixture was passed through (filter material) and the filtrate was partitioned between EtOAc (100 mL) and saturated NH4Cl (100 mL). The phases were separated and the organic portion was washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound as a beige foam.

[0918] LC-MS (Method B): Rt 0.15 min; MS m / z 168.0 / 170.0 = [M+H] + (100% ELS)

[0919] 1H NMR (500MHz, 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).

[0920] Step 1b: 2-(2-Adamantyl)acetyl chloride

[0921]

[0922] 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 x 10 mL) to give the title compound as a yellow oil.

[0923] Step 2: 2-(2-Adamantyl)-N-(2-chloro-1H-benzimidazol-5-yl)acetamide

[0924]

[0925] In 5min, a solution of 2-(2-adamantyl)acetyl chloride (step 1b) (100%, 657mg, 3.09mmol) in DCM (15mL) was added dropwise to a suspension of 2-chloro-1H-benzimidazole-5-amine (step 1a) (518mg, 3.09mmol) and DIPEA (807 μL, 4.63mmol) in DCM (15mL). After standing at room temperature for 16 hours, the mixture was diluted with water (30mL). Each phase was separated, and the aqueous portion was extracted with DCM (4x5mL) and EtOAc (5mL). The organic portion combined was concentrated in vacuo and the resulting residue was suspended in DCM (10mL). Solid was collected by filtration, washed with DCM and dried in vacuo to obtain the title compound, which was a cream solid.

[0926] LC-MS (Method B): Rt 1.18 min; MS m / z 344.1 / 346.1 = [M+H]+ (97% @ 215 nm)

[0927] 1H NMR(500MHz,DMSO-d6)δ13.08(s,1H),9.93(s,1H),8.01(s,1H),7.50–7.11(m,2H),2.46(d, J=7.7Hz,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).

[0928] Step 3: 1:1 mixture of 2-(adamantan-2-yl)-N-(2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazole-5-yl)acetamide and 2-(adamantan-2-yl)-N-(2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzoimidazol-6-yl)acetamide

[0929]

[0930] 2-(Chloromethoxy)ethyl-trimethyl-silane (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 hours. Another portion of 2-(chloromethoxy)ethyl-trimethyl-silane (39 μL, 0.22 mmol) was added and stirring was continued at room temperature overnight. The resulting mixture was distributed between EtOAc (10 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (5 mL) and separated by phase separation. The product was purified by chromatography on silica gel using a gradient of 0-100% EtOAc in heptane to afford the title compound.

[0931] LC-MS (Method B): Rt 1.54 and 1.57 min; MS m / z 474.2 / 476.2 = [M+H]+ (89% @ 215 nm)

[0932] Step 4: 2-(2-Adamantyl)-N-(2-tetrahydrofuran-3-yloxy-1H-benzimidazol-5-yl)acetamide

[0933] 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-benzoimidazol-6-yl)acetamide (step 3) (50 mg, 0.11 mmol) and tetrahydrofuran-3-ol (0.085 mL, 0.11 mmol) was dissolved in DMF (1 mL). A 60% dispersion of NaH in mineral oil (6 mg, 0.16 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours and then at 55° C. for 3 hours. Add another portion of tetrahydrofuran-3-ol (0.085mL, 0.11mmol) pretreated with 60% dispersion (6mg, 0.16mmol) of NaH in mineral oil in DMF (1mL) solution, and the mixture was stirred at 55 ℃ for 24 hours. After cooling to room temperature, the reaction was quenched with water, and the mixture was distributed between EtOAc (20mL) and water (20mL). Separate each layer, and the organic part was washed with brine (20mL), dried over Na2SO4 and concentrated in vacuo. The crude residue was dissolved in DCM (10mL) and treated with TFA (1mL). After stirring for 24 hours, the mixture was concentrated in vacuo. The crude residue was dissolved in MeOH (1mL) and filtered through 1g SCX column, eluting with MeOH (10 mL) and 7N NH3 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.

[0934] Gilson LC system using Waters CSH column (19mm x 100mm, 5μM; room temperature), gradient 5%-25% (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) for 2 minutes, then 25%-40% for 14 minutes, then 95% B for 2 minutes, injection volume 1500μL, flow rate 40mL / min. UV spectra were recorded at 215nm using Gilson detector.

[0935] LC-MS (Method A): Rt 3.07 min; MS m / z 396.3 = [M+H]+ (97% @ 215 nm)

[0936] 1H NMR(500MHz,DMSO-d6)δ9.72(s,1H),7.73(s,1H),7.17(d,J=8.5Hz,1H),7.07(d,J=8 .3Hz,1H),5.55–5.49(m,1H),3.89(d,J=3.0Hz,2H),3.88–3.83(m,1H),3.78(td,J=8. 4,4.5Hz,1H),2.43(d,J=7.6Hz,2H),2.31–2.19(m,2H),2.13–2.06(m,1H),1.98–1.9 1(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).

[0937] Example 10

[0938] N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide

[0939]

[0940] Step 1: 2-[(2-methoxyphenyl)methyl]-1,3-benzoxazole-5-carboxylic acid methyl ester

[0941]

[0942] To a solution of 2-(2-methoxyphenyl)acetic acid (239mg, 1.44mmol) in DMF (6mL), DIPEA (0.25mL, 1.44mmol), HATU (546mg, 1.44mmol) were added, followed by 3-amino-4-hydroxybenzoic acid methyl ester (200mg, 1.2mmol), and the mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (5mL) and extracted with EtOAc (2x10mL). The organic extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was dissolved in acetic acid (6mL) 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 sodium bicarbonate aqueous solution (10mL), brine (10mL), dried over Na2SO4 and concentrated in vacuo. The crude residue was absorbed onto silica gel and purified by silica gel chromatography eluting with 0-50% EtOAc in heptane to give the title compound.

[0943] LC-MS (Method B): Rt 1.20 min; MS m / z 298.0 = [M+H]+ (93% @ 215 nm)

[0944] 1H NMR (250 MHz, CHLOROFORM-d) δ8.36 (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).

[0945] Step 2: 2-[(2-Methoxyphenyl)methyl]-1,3-benzoxazole-5-carboxylic acid

[0946]

[0947] To a solution of 2-[(2-methoxyphenyl)methyl]-1,3-benzoxazole-5-carboxylic acid methyl ester (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 hour. After cooling to room temperature, the mixture was acidified to pH 2 using 1M HCl solution. The resulting mixture was diluted with water (5 mL) and extracted with IPA / CHCl (1: 1, 2x5 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo to give the title compound as a light yellow solid.

[0948] LC-MS (Method B): Rt 1.09 min; MS m / z 284.0 = [M+H]+ (92% @ 215 nm)

[0949] Step 3: N-(Cycloheptylmethyl)-2-[(2-methoxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide

[0950]

[0951] 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 cycloheptylmethylamine (28 μL, 0.2 mmol), and the mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with EtOAc and washed with water (5 mL) and brine (5 mL). The organic portion was separated, dried over Na2SO4, and concentrated in vacuo. The crude residue was absorbed onto silica gel and purified by silica gel chromatography, eluting with 0-50% EtOAc in heptane to give the title compound as a colorless glass.

[0952] LC-MS (Method B): Rt 1.31 min; MS m / z 393.1 = [M+H]+ (99% @ 215 nm)

[0953] 1H NMR (500MHz, chloroform-d) δ8.01 (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=6.2Hz,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).

[0954] Step 4: N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide

[0955] The title compound was prepared in analogy to Example 5 from N-(cycloheptylmethyl)-2-[(2-methoxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide (Step 3) and 1 M BBr3 in DCM.

[0956] LC-MS (Method A): Rt 3.61 min; MS m / z 379.3 = [M+H]+ (99% @ 215 nm)

[0957] 1H NMR(500MHz,DMSO-d6)δ9.59(s,1H),8.50(t,J=5.8Hz,1H),8.13(d,J=1.4Hz,1H),7.85(dd,J=8.5, 1.7Hz,1H),7.70(d,J=8.4Hz,1H),7.20(dd,J=7.5,1.5Hz,1H),7.12(td,J=7.9,1.7Hz,1H),6.83(dd ,J=8.1,1.0Hz,1H),6.78(td,J=7.4,1.1Hz,1H),4.24(s,2H),3.11(t,J=6.3Hz,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).

[0958] Example 11

[0959] 2-(1-adamantyl)-N-[3-amino-2-[(2-hydroxyphenyl)methyl]indazol-6-yl]acetamide

[0960]

[0961] Step 1: 2-[(2-Methoxyphenyl)methyl]-6-nitro-indazol-3-amine

[0962]

[0963] DIPEA (1.51mL, 8.67mmol) is added to a mixture of 2-fluoro-4-nitro-benzonitrile (240mg, 1.44mmol) and (2-methoxyphenyl) methylhydrazine hydrochloride (545mg, 2.89mmol) in tert-butanol (5mL). The resulting mixture is stirred at room temperature for 1 hour, then heated to 140°C overnight. After being cooled to room temperature and standing for 3 days, the mixture is diluted with saturated sodium bicarbonate aqueous solution (20mL) and EtOAc (20mL). Each phase is separated, and the organic portion is washed with saturated sodium bicarbonate aqueous solution (20mL), brine (20mL), through Na2SO4, dried and concentrated in vacuo. The crude product is purified by preparative HPLC (acidic pH, standard method) to obtain the title compound, which is a bright red solid.

[0964] LC-MS (Method B): Rt 1.10 min; MS m / z 299.0 = [M+H]+ (100% @ 215 nm)

[0965] 1H NMR (500MHz, DMSO-d6) δ8.17(d,J=1.7Hz,1H),7.89(d,J=9.0Hz,1H),7.41(dd,J=9.1,2.0Hz,1H),7.27(td,J=8.2,1.6Hz,1 H),7.05(d,J=7.8Hz,1H),6.84(td,J=6.7,0.9Hz,1H),6.61(s,2H),6.54(dd,J=7.5,1.4Hz,1H),5.40(s,2H),3.85(s,3H).

[0966] Step 2: N-tert-Butyloxycarbonyl-N-[2-[(2-methoxyphenyl)methyl]-6-nitro-indazol-3-yl]carbamic acid tert-butyl ester

[0967]

[0968] A 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 sequentially with Boc anhydride (97 mg, 0.45 mmol) and DMAP (5 mg, 0.04 mmol) and stirred at room temperature for 18 hours.

[0969] Additional Boc anhydride (40mg) was added and the reaction mixture was stirred for another 3 hours. The obtained mixture was concentrated in vacuo, and the residue was distributed between EtOAc (15mL) and 1:1 water: brine (15mL). Each phase was separated, and the aqueous part was extracted with EtOAc (15mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluted with a heptane solution of 0-80% EtOAc, and the title compound was obtained as a yellow / orange solid.

[0970] LC-MS (Method B): Rt 1.42 min; MS m / z 499.1 = [M+H]+ (99% @ 215 nm)

[0971] 1H NMR (500MHz, DMSO-d6) δ8.69–8.67(m,1H),7.86(dd,J=9.1,1.9Hz,1H),7.80(d,J=9.2Hz,1H),7.35–7.29(m,1H), 7.12(dd,J=7.6,1.5Hz,1H),7.07(d,J=8.1Hz,1H),6.90(t,J=7.3Hz,1H),5.56(s,2H),3.81(s,3H),1.21(s,18H).

[0972] Step 3: N-[6-amino-2-[(2-methoxyphenyl)methyl]indazol-3-yl]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

[0973]

[0974] A mixture of N-tert-butyloxycarbonyl-N-[2-[(2-methoxyphenyl)methyl]-6-nitro-indazol-3-yl]carbamic acid tert-butyl ester (step 2) (85%, 135 mg, 0.23 mmol) in 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 stirred by (filter material), washing with EtOAc, and the filtrate concentrated in vacuo to give the title compound as a light orange foam.

[0975] LC-MS (Method B): Rt 1.19 min; MS m / z 469.3 = [M+H]+ (90% @ 215 nm)

[0976] 1H NMR (500MHz, DMSO-d6) δ7.28–7.23(m,1H),7.11(d,J=8.8Hz,1H),7.02(dd,J=7.8,0.7Hz,1H),6.93(dd,J=5.9,1.8Hz,1H),6.84 (td,J=7.4,0.9Hz,1H),6.57(dd,J=8.9,1.8Hz,1H),6.45(d,J=1.1Hz,1H),5.25(s,2H),5.12(s,2H),3.81(s,3H),1.23(s,18H).

[0977] Step 4: N-[6-[[2-(1-adamantyl)acetyl]amino]-2-[(2-methoxyphenyl)methyl]indazol-3-yl]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

[0978]

[0979] The title compound was prepared in analogy to Example 1, Step 1, from N-[6-amino-2-[(2-methoxyphenyl)methyl]indazol-3-yl]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (Step 3) and 2-(1-adamantyl)acetic acid.

[0980] LC-MS (Method B): Rt 1.51 min; MS m / z 645.4 = [M+H]+ (95% @ 215 nm)

[0981] 1H NMR(500MHz,DMSO-d6)δ9.78(s,1H),8.05(s,1H),7.37(dd,J=8.9,0.4Hz,1H),7.30–7.25(m,1H),7.12(dd,J=9.0,1.6Hz,1H),7.04(d,J=7.9Hz,1H), 6.99(dd,J=7.6,1.6Hz,1H),6.85(td,J=7.5,1.0Hz,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).

[0982] Step 5: 2-(1-adamantyl)-N-[3-amino-2-[(2-methoxyphenyl)methyl]indazol-6-yl]acetamide

[0983]

[0984] The title compound was prepared in analogy to Example 3, Step 2, from N-[6-[[2-(1-adamantyl)acetyl]amino]-2-[(2-methoxyphenyl)methyl]indazol-3-yl]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (Step 4) and TFA.

[0985] LC-MS (Method A): Rt 2.79 min; MS m / z 445.3 = [M+H]+ (91% @ 215 nm)

[0986] 1H NMR(500MHz,MeOH-d4)δ7.54–7.52(m,1H),7.46–7.43(m,1H),7.16(td,J=8.2,1.7Hz,1H),6.90(d,J=7.9Hz,1H),6.79 –6.73(m,2H),6.67(dd,J=7.6,1.5Hz,1H),5.23(s,2H),3.80(s,3H),2.01(s,2H),1.87(br.s,3H),1.67–1.58(m,12H).

[0987] Step 6: 2-(1-adamantyl)-N-[3-amino-2-[(2-hydroxyphenyl)methyl]indazol-6-yl]acetamide

[0988] The title compound was prepared in analogy to Example 5 from 2-(1-adamantyl)-N-[3-amino-2-[(2-methoxyphenyl)methyl]indazol-6-yl]acetamide (Step 5) and 1 M BBr3 in DCM.

[0989] LC-MS (Method A): Rt 2.60 min; MS m / z 431.3 = [M+H]+ (95% @ 215 nm)

[0990] 1H NMR(500MHz,DMSO-d6)δ9.56(s,1H),7.66(d,J=1.0Hz,1H),7.51(d,J=8.8Hz,1H),7.13–7.08(m,1H),6.88(dd,J=7.6,1.5Hz,1H),6.82 (dd,J=8.0,0.7Hz,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).

[0991] Example 12

[0992] 2-Cyclohexyl-N-(2-isopropyl-1,3-benzoxazol-5-yl)acetamide

[0993]

[0994] 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. 2-Cyclohexylacetyl chloride (55 mg, 0.34 mmol) was added dropwise to the mixture and stirring was continued at room temperature for 1 hour.

[0995] The resulting mixture was diluted with DCM and washed with NaCO (3x5mL). The organic portion was dried (hydrophobic glass frit) and concentrated in vacuo. The crude product was purified by preparative HPLC (alkaline pH, early elution method) to give the title compound as an off-white solid.

[0996] LC-MS (Method A): Rt 3.56 min; MS m / z 301.1 = [M+H]+ (94% @ 215 nm)

[0997] 1H NMR(500MHz,DMSO-d6)δ9.95(s,1H),8.00(d,J=1.9Hz,1H),7.56(d,J=8.7Hz,1H),7.45(dd,J=8.8,2.0Hz,1H),3.27–3.18(m, 1H), 2.19(d,J=7.1Hz,2H),1.83–1.73(m,1H),1.73–1.57(m,5H),1.36(d,J=6.9Hz,6H),1.30–1.08(m,3H),1.03–0.93(m,2H).

[0998] Example 13

[0999] N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]indazole-6-carboxamide

[1000]

[1001] Step 1: N-(Cycloheptylmethyl)-1H-indazole-6-carboxamide

[1002]

[1003] The solution of 1H-indazole-6-formic acid (200mg, 1.23mmol) in DMF (4mL) is processed with cycloheptylmethylamine (0.2mL, 1.36mmol), DIPEA (0.26mL, 1.48mmol) and HATU (563mg, 1.48mmol) successively, and the gained mixture is stirred at room temperature for 30 minutes. The mixture is diluted with EtOAc (30mL) and water (30mL), and each phase is separated. The organic part is washed with water (2x30mL), brine (30mL), through Na2SO4, dried and concentrated in vacuo. The crude product is purified by C18 reverse phase chromatography, eluted with the aqueous solution (0.1% formic acid modifier) ​​of 10%-100%MeCN, to obtain the title compound, which is a light orange solid.

[1004] LC-MS (Method B): Rt 1.12 min; MS m / z 272.2 = [M+H]+ (100% @ 215 nm)

[1005] 1H NMR (250MHz, DMSO-d6) δ13.31(s,1H),8.55(t,J=5.7Hz,1H),8.13(s,1H),8.05–7.97(m,1H),7.80(dd,J=8 .5, 0.6Hz, 1H), 7.57 (dd, J=8.5, 1.4Hz, 1H), 3.12 (t, J=6.3Hz, 2H), 1.86–1.30 (m, 11H), 1.27–1.07 (m, 2H).

[1006] Step 2: N-(Cycloheptylmethyl)-2-[(2-methoxyphenyl)methyl]indazole-6-carboxamide

[1007]

[1008] A mixture of 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 was 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.

[1009] The crude product was purified by C18 reverse phase chromatography eluting with 10%-100% MeCN in water (0.1% formic acid modifier) ​​to afford the title compound as a white solid.

[1010] LC-MS (Method A): Rt 3.90 min; MS m / z 392.3 = [M+H]+ (100% @ 215 nm)

[1011] 1H NMR (500MHz, DMSO-d6) δ8.44(t,J=5.7Hz,1H),8.39(d,J=0.7Hz,1H),8.14–8.10(m,1H),7.73( dd,J=8.8,0.7Hz,1H),7.47(dd,J=8.7,1.4Hz,1H),7.33(td,J=8.3,1.8Hz,1H),7.06(d,J=7.7H z,1H),7.00(dd,J=7.5,1.7Hz,1H),6.91(td,J=7.5,0.9Hz,1H),5.63(s,2H),3.83(s,3H),3.1 1(t,J=6.3Hz,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).

[1012] Step 3: N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]indazole-6-carboxamide

[1013] The title compound was prepared in analogy to Example 5 from N-(cycloheptylmethyl)-2-[(2-methoxyphenyl)methyl]indazole-6-carboxamide (Step 2) and 1 M BBr3 in DCM.

[1014] LC-MS (Method A): Rt 3.54 min; MS m / z 378.2 = [M+H]+ (100% @ 215 nm)

[1015] 1H NMR(500MHz,DMSO-d6)δ9.86(s,1H),8.44(t,J=5.8Hz,1H),8.37(d,J=0.7Hz,1H),8.15–8.10(m,1H) ,7.73(dd,J=8.8,0.8Hz,1H),7.47(dd,J=8.7,1.4Hz,1H),7.15(td,J=8.0,1.7Hz,1H),7.00(dd,J=7. 6,1.6Hz,1H),6.87(dd,J=8.1,1.0Hz,1H),6.76(td,J=7.5,1.1Hz,1H),5.59(s,2H),3.11(t,J=6.3Hz ,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).

[1016] Example 14

[1017] 2-(1-Adamantyl)-N-(2-benzyl-3H-imidazo[4,5-c]pyridin-6-yl)acetamide

[1018]

[1019] Step 1a: 2-(1-adamantyl)acetamide

[1020]

[1021] 2-(1-adamantyl)acetic acid (2.5g, 12.87mmol) is dissolved in thionyl chloride (10.21mL, 140.70mmol) and heated at 50 DEG C for 30min. The obtained mixture is concentrated in vacuo and azeotroped with DCM to remove thionyl chloride. The residue is cooled in an ice bath and treated dropwise with concentrated ammonium hydroxide (12mL, 12.87mmol), stirred for 2 hours. The obtained solid is ultrasonically treated and collected by filtration, washed with excessive water. The colloidal solid is vacuum dried overnight to obtain a white solid. The solid is suspended in EtOAc (200mL) and ultrasonically treated until dissolved. The organic mixture is washed with 2M sodium carbonate solution (2x50mL), water (2x50mL), saline (10mL), filtered and concentrated in vacuo by hydrophobic glass frit to obtain the title compound, which is a white solid.

[1022] LC-MS (Method B): Rt 1.01 min; MS m / z 194.1 = [M+H]+ (88% @ 215 nm)

[1023] 1H NMR (500MHz, DMSO-d6) δ7.12(s,1H),6.62(s,1H),1.95–1.88(m,3H),1.78(s,2H),1.70–1.49(m,12H).

[1024] Step 1b: tert-Butyl N-(2-bromo-5-nitro-4-pyridyl)carbamate

[1025]

[1026] To a solution of 2-bromo-5-nitro-pyridine-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 warmed to room temperature and stirred for 3 hours. Another solution of Boc anhydride (0.54 g, 2.48 mmol) in DMF (1 mL) was added, and stirring was continued at room temperature overnight. The mixture was re-treated with solid Boc anhydride (0.54 g, 2.48 mmol) in batches, and stirred at room temperature overnight. 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 (3x20 mL), saturated sodium bicarbonate aqueous solution (3x20 mL), brine (20 mL), and dried over Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography, eluting with a heptane solution of 0-100% EtOAc, gave a white colloidal solid. The solid was dissolved in MeOH and purified by reverse phase chromatography of C18, eluting with an aqueous solution of 10%-100% MeCN (containing 0.1% formic acid), to give the title compound as a white solid.

[1027] LC-MS (Method B): Rt 1.32 min; MS m / z 318.0 / 320.0 = [M+H]+ (100% @ 215 nm)

[1028] 1H NMR (500MHz, DMSO-d6) δ10.00(s,1H),8.92(s,1H),8.15(s,1H),1.48(s,9H).

[1029] Step 2: tert-Butyl N-[2-[[2-(1-adamantyl)acetyl]amino]-5-nitro-4-pyridinyl]carbamate

[1030]

[1031] 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) are suspended in dioxane (18 mL). The mixture is placed under a nitrogen atmosphere, treated with cuprous iodide (94 mg, 0.5 mmol) and heated at 110 ° C using microwave radiation stirring for 1 hour. The resulting mixture is filtered, and the filtrate is concentrated in vacuo. The residue is distributed between EtOAc (10 mL) and water (10 mL), and the organic layer is separated, washed with water (10 mL), and concentrated in vacuo by a hydrophobic glass frit. The resulting solid was purified by silica gel chromatography eluting with 0-100% EtOAc in heptanes then triturated with diethyl ether to afford the title compound as a pale yellow solid.

[1032] LC-MS (Method B): Rt 1.57 min; MS m / z 431.2 = [M+H]+ (100% @ 215 nm)

[1033] 1H NMR(500MHz,DMSO-d6)δ10.91–10.74(m,1H),9.97–9.82(m,1H),9.01–8.86(m,2 H),2.25–2.13(m,2H),1.98–1.86(m,3H),1.72–1.54(m,12H),1.52–1.43(m,9H).

[1034] Step 3: tert-Butyl N-[2-[[2-(1-adamantyl)acetyl]amino]-5-amino-4-pyridinyl]carbamate

[1035]

[1036] The title compound was prepared in analogy to Example 11, Step 3, from tert-butyl N-[2-[[2-(1-adamantyl)acetyl]amino]-5-nitro-4-pyridinyl]carbamate (Step 2) and 10% Pd / C.

[1037] LC-MS (Method B): Rt 1.09 min; MS m / z 401.7 = [M+H]+ (97% @ 215 nm)

[1038] 1H NMR(500MHz,DMSO-d6)δ9.73(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).

[1039] Step 4: tert-Butyl N-[2-[[2-(1-adamantyl)acetyl]amino]-5-[(2-phenylacetyl)amino]-4-pyridinyl]carbamate

[1040]

[1041] 2-phenylacetic acid (0.07g, 0.5mmol), HATU (0.21g, 0.55mmol) and DIPEA (0.26mL, 1.5mmol) are dissolved in DMF (1mL) and stirred at room temperature for 10min. In this mixture, add N-[2-[[2-(1-adamantyl) acetyl] amino]-5-amino-4-pyridyl] carbamic acid tert-butyl ester (step 3) (0.2g, 0.5mmol) in DMF (2mL), and continue to stir overnight at room temperature. Another portion of DMF (0.5mL) solution comprising 2-phenylacetic acid (0.035g, 0.25mmol), HATU (0.11g, 0.28mmol) and DIPEA (0.13mL, 0.75mmol) pre-stirred for 10min is added to the main reaction mixture and continues to stir for 2 hours. The gained mixture is distributed between water (8mL) and EtOAc (8mL). The organic layer is separated and washed with 10% potassium carbonate solution (2x10mL), water (2x10mL) and passed through a hydrophobic glass frit. The filtrate is concentrated in vacuo, and the crude material is purified by silica gel chromatography, eluted with a heptane solution of 0-100% EtOAc to obtain a brown oil. The oil is purified by C18 reverse phase chromatography, eluted with an aqueous solution of 10%-100% MeCN and 0.2% ammonium hydroxide to obtain the title compound as a white solid.

[1042] LC-MS (Method B): Rt 1.37 min; MS m / z 519.8 = [M+H]+ (97% @ 215 nm)

[1043] 1H NMR(500MHz,DMSO-d6)δ10.18(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).

[1044] Step 5: N-[6-[[2-(1-adamantyl)acetyl]amino]-4-amino-3-pyridinyl]-2-phenyl-acetamide

[1045]

[1046] The title compound was prepared in analogy to Example 6, Step 2, from tert-butyl N-[2-[[2-(1-adamantyl)acetyl]amino]-5-[(2-phenylacetyl)amino]-4-pyridinyl]carbamate (Step 5) and 4M HCl.

[1047] LC-MS (Method B): Rt 1.03 min; MS m / z 419.7 = [M+H]+ (99% @ 215 nm)

[1048] 1H NMR(500MHz,DMSO-d6)δ9.81(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).

[1049] Step 6: 2-(1-Adamantyl)-N-(2-benzyl-3H-imidazo[4,5-c]pyridin-6-yl)acetamide

[1050] A solution of N-[6-[[2-(1-adamantyl)acetyl]amino]-4-amino-3-pyridinyl]-2-phenyl-acetamide (step 5) (68 mg, 0.16 mmol) in acetic acid (1 mL) was placed in a sealed container under nitrogen atmosphere 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 solution (5 mL). The layers were separated and the organic portion was separated by phase separation. The resulting oil was purified by C18 reverse phase chromatography eluting with 10% to 100% MeCN in water (+0.2% ammonium hydroxide) to afford the title compound as a white solid.

[1051] LC-MS (Method A): Rt 2.86 min; MS m / z 401.3 = [M+H]+ (98% @ 215 nm)

[1052] 1H NMR(500MHz,DMSO-d6)δ12.51(br.s,1H),10.23–10.00(m,1H),8.54–8.45(m,1H),8.24–8.11(m,1H ),7.40–7.18(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).

[1053] Example 15

[1054] 2-Benzyl-N-(cycloheptylmethyl)imidazo[1,2-a]pyridine-7-carboxamide

[1055]

[1056] Step 1: 2-Benzyl-7-bromo-imidazo[1,2-a]pyridine

[1057]

[1058] 1- bromo-3-phenyl-propan-2-one (203mg, 0.95mmol) is added to the solution of 4- bromopyridine -2- amine (150mg, 0.87mmol) in EtOH (2mL), then NaHCO (219mg, 2.6mmol) is added. The resulting mixture is stirred at room temperature overnight, then concentrated in vacuo. The crude residue is distributed between EtOAc (20mL) and water (20mL), and the organic part is separated, washed with brine (20mL), through Na SO Drying and vacuum concentration. The crude product is purified by C18 reverse phase chromatography, eluted with the aqueous solution (0.1% formic acid modifier) ​​of 0-100% MeCN, to obtain the title compound, which is a pale solid.

[1059] LC-MS (Method B): Rt 0.85 min; MS m / z 287.0 / 289.0 = [M+H]+ (100% @ 215 nm)

[1060] 1H NMR (250MHz, DMSO-d6) δ8.43(dd,J=7.2,0.7Hz,1H),7.82–7.72(m,1H),7.67–7.65(m,1H),7.33–7.15(m,5H),6.99(dd,J=7.2,2.0Hz,1H),4.02(s,2H).

[1061] Step 2: 2-Benzyl-N-(cycloheptylmethyl)imidazo[1,2-a]pyridine-7-carboxamide

[1062] All reagents were loaded into the COware device (carbon monoxide generation system) according to the following procedure;

[1063] Chamber A was loaded 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 (third generation G3 Buchwald precatalyst) (36 mg, 0.04 mmol). Toluene (4 mL) was added, followed by cycloheptylmethylamine (73 mg, 0.57 mmol). The reaction mixture was degassed with nitrogen for 5 min. A solution of formic acid (43 μL, 1.15 mmol) in toluene (5 mL) was added to chamber B, followed by methanesulfonyl 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 EtOAc:THF solution (20:1) (25 mL) and washed with water (2 x 25 mL). The organic portion was concentrated in vacuo and purified by preparative HPLC (basic pH, early elution method) to give the title compound as a white solid.

[1064] LC-MS (Method A): Rt 2.40 min; MS m / z 362.2 = [M+H]+ (99% @ 215 nm)

[1065] 1H NMR (500MHz, DMSO-d6) δ8.57(t,J=5.7Hz,1H),8.49(dd,J=7.1,0.8Hz,1H),8.01–7.99(m,1H),7.72(s,1H),7.33–7.27(m,4H),7.24(dd,J=7.1, 1.7Hz,1H),7.22–7.17(m,1H),4.07(s,2H),3.11(t,J=6.3Hz,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).

[1066] Example 16

[1067] 2-(1-Adamantyl)-N-(2-benzylindazol-6-yl)acetamide

[1068]

[1069] Step 1: 2-(1-Adamantyl)-N-(1H-indazol-6-yl)acetamide

[1070]

[1071] A solution of 1H-indazole-6-amine (250mg, 1.88mmol), HATU (785mg, 2.07mmol), DIPEA (0.49mL, 2.82mmol) and 2-(1-adamantyl)acetic acid (365mg, 1.88mmol) in DMF (2mL) was stirred for 2 hours. The resulting mixture was distributed between EtOAc (25mL) and water (25mL). The organic layer was separated, washed with water (25mL), brine (2x25mL), dried over MgSO4 and concentrated in vacuo to give a brown solid. The solid was purified by silica gel chromatography, eluted with a heptane solution of 0-100% EtOAc to give the title compound as an off-white solid.

[1072] LC-MS (Method B): Rt 1.21 min; MS m / z 311.0 = [M+H]+ (85% @ 215 nm)

[1073] 1H NMR (500MHz, DMSO-d6) δ12.84(s,1H),9.87(s,1H),8.16(s,1H),7.94(s,1H),7.62(d,J=8. 6Hz, 1H), 7.06 (dd, J = 8.7, 1.7Hz, 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

[1074] Toluene bromide (0.04mL, 0.36mmol) is added to an ice-cold suspension of 2-(1-adamantyl)-N-(1H-indazole-6-yl)acetamide (step 1) (100mg, 0.32mmol) and potassium carbonate (134mg, 0.97mmol) in 1,4-dioxane (2mL), and heated to 110°C for 20 hours. The resulting mixture is cooled to room temperature and distributed between DCM (10mL) and water (10mL). The organic layer is passed through a hydrophobic glass frit and concentrated in vacuo. The resulting red oil is purified by preparative HPLC (acidic pH, early elution method) to obtain the title compound as an off-white solid.

[1075] LC-MS (Method A): Rt 4.09 min; MS m / z 400.3 = [M+H]+ (100% @ 215 nm)

[1076] 1H NMR(500MHz,DMSO-d6)δ9.72(s,1H),8.39–8.31(m,1H),8.05(s,1H),7.59(d,J=8.8Hz,1H),7.37–7.31(m,2H ),7.31–7.27(m,3H),7.06(dd,J=9.0,1.7Hz,1H),5.58(s,2H),2.07(s,2H),1.93(s,3H),1.70–1.56(m,12H).

[1077] Example 17

[1078] 2-(1-Adamantyl)-N-(2-benzyl-3-methyl-indazol-6-yl)acetamide

[1079]

[1080] Step 1: 2-(1-Adamantyl)-N-(3-methyl-1H-indazol-6-yl)acetamide

[1081]

[1082] The title compound was prepared in analogy to Example 16, Step 1, from 2-(1-adamantyl)acetic acid and 3-methyl-1H-indazol-6-amine.

[1083] LC-MS (Method B): Rt 1.23 min; MS m / z 325.0 = [M+H]+ (100% @ 215 nm)

[1084] 1H NMR(500MHz,DMSO-d6)δ12.38(s,1H),9.82(s,1H),8.06–8.04(m,1H),7.55(d,J=8.6Hz,1H), 7.03(dd,J=8.6,1.6Hz,1H),2.42(s,3H),2.08(s,2H),1.97–1.90(m,3H),1.70–1.57(m,12H).

[1085] Step 2: 2-(1-Adamantyl)-N-(2-benzyl-3-methyl-indazol-6-yl)acetamide

[1086] The title compound was prepared in analogy to Example 16, Step 2, from 2-(1-adamantyl)-N-(3-methyl-1H-indazol-6-yl)acetamide (Step 1) and benzyl bromide.

[1087] LC-MS (Method C): Rt 5.30 min; MS m / z 414.2 = [M+H]+ (100% @ 215 nm)

[1088] 1H NMR(500MHz,DMSO-d6)δ9.69(s,1H),7.99(s,1H),7.55(d,J=8.9Hz,1H),7.34–7.29(m,2H),7.29–7.24(m,1H),7.16–7 .12(m,2H),7.01(dd,J=9.0,1.6Hz,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).

[1089] Example 18

[1090] N-(2-tert-Butyl-1H-benzoimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide

[1091]

[1092] Step 1 :2-tert-butyl-5-nitro-1H-benzimidazole

[1093]

[1094] The title compound was prepared in analogy to Example 8, Step 1, from 4-nitrobenzene-1,2-diamine and 2,2-dimethylpropionic acid.

[1095] LC-MS (Method B): Rt 0.87 min; MS m / z 220.0 = [M+H]+ (100% @ 215 nm)

[1096] 1H NMR (500MHz, DMSO-d6) δ 12.80 (br.s, 1H), 8.38 (br.s, 1H), 8.07 (dd, J = 8.8, 2.2Hz, 1H), 7.65 (d, J = 8.5Hz, 1H), 1.43 (s, 9H).

[1097] Step 2: 2-tert-Butyl-1H-benzimidazol-5-amine

[1098]

[1099] The title compound was prepared in analogy to Example 8, Step 2, from 2-tert-butyl-5-nitro-1H-benzimidazole (Step 1) and 10% Pd / C.

[1100] 1H NMR (500MHz, MeOH-d4) δ7.28 (d, J = 6.9 Hz, 1H), 6.87 (s, 1H), 6.69 (dd, J = 8.5, 2.0 Hz, 1H), 1.43 (s, 9H).

[1101] Step 3: N-(2-tert-Butyl-1H-benzoimidazol-5-yl)-2-(5-chloro-2-methoxy-phenyl)acetamide

[1102]

[1103] 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 hours, then diluted with EtOAc and washed with water (5 mL) and brine (5 mL). The organic portion was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 50%-100% EtOAc in heptane to give the title compound as a colorless powder.

[1104] LC-MS (Method B): Rt 1.04 min; MS m / z 372.0 / 374.1 = [M+H]+ (88% @ 215 nm)

[1105] 1H NMR(500MHz,DMSO-d6)δ11.94(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=8.4Hz,1H),3.77(s,3H),3.65(s,2H),1.38(s,9H).

[1106] Step 4: N-(2-tert-Butyl-1H-benzoimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide

[1107] The title compound was prepared in analogy 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.

[1108] LC-MS (Method A): Rt 1.76 min; MS m / z 358.2 / 359.2 = [M+H]+ (99% @ 215 nm)

[1109] 1H NMR(500MHz,MeOH-d4)δ7.93(br.s,1H),7.44(br.s,1H),7.33–7.12(m,2H), 7.09 (dd, J=8.6, 2.6Hz, 1H), 6.80 (d, J=8.6Hz, 1H), 3.69 (s, 2H), 1.45 (s, 9H).

[1110] Example 19

[1111] tert-Butyl N-[3-[(2-Benzyl-1H-benzimidazole-5-carbonyl)amino]-2,2-dimethyl-propyl]carbamate

[1112]

[1113] The title compound was prepared in analogy to Example 10, Step 3, from 2-benzyl-1H-benzimidazole-5-carboxylic acid and tert-butyl N-(3-amino-2,2-dimethyl-propyl)carbamate.

[1114] LC-MS (Method A): Rt 2.35 min; MS m / z 437.3 = [M+H]+ (97% @ 215 nm)

[1115] 1H NMR (500MHz, DMSO-d6) δ8.31(t,J=6.3Hz,1H),8.00(s,1H),7.66(dd,J=8.4,1.4Hz,1H),7.51(d,J=8.3Hz,1H),7.34–7.30(m,4H ),7.28–7.20(m,1H),6.88(t,J=6.6Hz,1H),4.20(s,2H),3.09(d,J=6.4Hz,2H),2.79(d,J=6.6Hz,2H),1.40(s,9H),0.81(s,6H).

[1116] Example 20

[1117] 2-tert-Butyl-N-(cycloheptylmethyl)-3H-benzimidazole-5-carboxamide

[1118]

[1119] Step 1: 3,4-Diamino-N-(cycloheptylmethyl)benzamide

[1120]

[1121] TBTU (5.06 g, 15.77 mmol) and TEA (5.5 mL, 39.43 mmol) were added to a solution of cycloheptylmethylamine (2.27 mL, 15.77 mmol) and 3,4-diaminobenzoic acid (2 g, 13.14 mmol) in THF (50 mL) and DMF (20 mL). 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 (2x25 mL). The aqueous portion was stripped with EtOAc (3x50 mL), and organic extracts were combined, washed with brine (2x25 mL), dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by C18 reverse phase chromatography, eluted with an aqueous solution of 0-100% MeCN, to give the title compound as a light brown solid.

[1122] LC-MS (Method B): Rt 0.96 min; MS m / z 262.1 = [M+H]+ (95% @ 215 nm)

[1123] 1H NMR (250 MHz, CHLOROFORM-d) δ7.22 (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

[1124] A mixture of 2,2-dimethylpropionic acid (23mg, 0.23mmol), HATU (87mg, 0.23mmol) and TEA (67μL, 0.38mmol) in DMF (1.91mL) was stirred at room temperature. After 1 hour, a DMF (1mL) solution of 3,4-diamino-N-(cycloheptylmethyl)benzamide (step 1) (50mg, 0.19mmol) was added and continued to stir for 18 hours. The resulting mixture was diluted with EtOAc (10mL) and washed with saturated sodium bicarbonate aqueous solution (2x10mL). The organic part was dried over Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in acetic acid (1.91mL) and stirred at 60°C for 3 hours. The mixture was diluted with EtOAc (20mL) and washed with saturated sodium bicarbonate aqueous solution (3x20mL). The organic part was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane followed by 0-100% MeOH in EtOAc to afford the title compound as a colorless solid.

[1125] LC-MS (Method A): Rt 2.12 min; MS m / z 328.2 = [M+H]+ (100% @ 215 nm)

[1126] 1H NMR (500MHz, DMSO-d6) δ12.34–12.17(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=6.3Hz,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).

[1127] Example 21

[1128] 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide

[1129]

[1130] Step 1: 2-(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)acetic acid

[1131]

[1132] The solution of 2-(2-fluoro-5-methoxy-phenyl)acetic acid (5.0g, 27.15mmol) in DCE (181mL) is treated with tert-butyl alcohol (31.16mL, 325.8mmol) and concentrated sulfuric acid (17.37mL, 325.8mmol). After 1 hour, additional tert-butyl alcohol (10.0mL, 105mmol) and concentrated sulfuric acid (5.8mL, 109mmol) are added, and the reaction is stirred overnight. The resulting mixture is diluted with water (150mL), and each phase is separated. The water layer is extracted with DCM (3x150mL). The organic extracts merged are washed with salt water, dried over Na2SO4 and concentrated in vacuo. The crude residue is diluted with MeOH (100mL) and treated with a MeOH solution (100mL, freshly prepared by thionyl chloride) of 2M HCl. The reaction mixture is heated to reflux for 40min. Then the resulting mixture is cooled to room temperature and concentrated in vacuo. Residue is dissolved in DCM (150mL) and washed with saturated sodium bicarbonate aqueous solution (150mL).Separate organic layer, and further extract water-containing part with DCM (3x100mL).Organic extract is merged, through Na SO Dry, and vacuum concentration.By silica gel column chromatography purification, eluting with the heptane solution of 0-10%EtOAc, the methyl esters of required product are obtained.This material is dissolved in the mixture of 1M LiOH aqueous solution (80mL) and THF (80mL) and stirred 1 hour.Volatile matter is removed in vacuum then, and with 1M HCl acidified aqueous solution, this causes required product precipitation.Obtain solid by filtration, wash and dry with excessive water, obtain 2-(4-tert-butyl-2-fluoro-5-methoxy-phenyl) acetic acid (5.22g, 21.3mmol, productive rate 78%), it is light yellow solid.

[1133] 1H NMR (500MHz, DMSO-d6) δ6.93 (d, J = 6.1Hz, 1H), 6.92 (s, 1H), 3.77 (s, 3H), 3.54 (s, 2H), 1.31 (s, 9H).

[1134] Step 2: 2-[(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid methyl ester

[1135]

[1136] 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 hours. 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 (2x10 mL), dried over Na SO 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 distributed between saturated NaHCO (10 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine (2x10 mL), dried over Na SO and concentrated in vacuo. Purification by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptanes afforded the title compound as a viscous brown oil.

[1137] LC-MS (Method B): Rt 1.20 min; MS m / z 371.1 = [M+H]+ (87% @ 215 nm)

[1138] 1H NMR(500MHz,DMSO-d6)δ12.66–12.56(m,1H),8.16–8.02(m,1H),7.83–7.73(m,1H),7.62–7.49(m,1 H),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).

[1139] Step 3: 2-[(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid

[1140]

[1141] A solution of 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid methyl ester (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 continued for 1 hour. Additional solid LiOH (32 mg, 1.32 mmol) was added and stirred for an additional 3 h. The resulting mixture was diluted in EtOAc (5 mL) and H2O (5 mL). The pH was adjusted to 4 using 2M KHSO4. The layers were separated and the aqueous portion was extracted with EtOAc (5 mL). The organic extracts were combined, dried over Na2SO4 and concentrated in vacuo and azeotroped with EtOAc in heptane to give the title compound as a beige solid.

[1142] LC-MS (Method B): Rt 1.06 min; MS m / z 357.3 = [M+H]+ (93% @ 215 nm)

[1143] 1H NMR(500MHz,DMSO-d6)δ12.75–12.25(m,2H),8.17–7.96(m,1H),7.81–7.70(m,1H),7.61–7.44 (m,1H),7.05(d,J=6.7Hz,1H),6.97(d,J=11.8Hz,1H),4.20(s,2H),3.78(s,3H),1.31(s,9H).

[1144] Step 4: 2-[(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide

[1145]

[1146] To a stirred solution of HATU (73 mg, 0.19 mmol), 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid (85%, 80 mg, 0.19 mmol) and 1-(trifluoromethyl)cyclopropylamine 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)cyclopropylamine 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 NaHCO (4 mL) and EtOAc (4 mL). The organic layer was separated, washed with brine (2x4 mL), dried over Na SO and concentrated in vacuo. Purification by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptanes afforded the title compound as an orange solid.

[1147] LC-MS (Method D): Rt 0.97 min; MS m / z 464.2 = [M+H]+ (86% @ 215 nm)

[1148] 1H NMR (400MHz, methanol-d4) δ8.15–7.91(m,1H),7.75–7.68(m,1H),7.64–7.45(m,1H),7.01(d,J=11.9Hz,1H) ,6.92(d,J=6.6Hz,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).

[1149] Step:5: 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide

[1150]

[1151] 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 (20 ° C). The residue was treated with saturated NaHCO3 aqueous solution (2 mL) and extracted with EtOAc (2x2 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 was 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.

[1152] LC-MS (Method A): Rt 2.74 min; MS m / z 450.3 = [M+H]+ (100% @ 215 nm)

[1153] 1H NMR(500MHz, methanol-d4)δ8.04(br.s,1H),7.74–7.69(m,1H),7.60–7.48(m,1H),6.94(d,J=12.0H z,1H),6.58(d,J=6.8Hz,1H),4.19(s,2H),1.40–1.37(m,2H),1.35(s,9H),1.24–1.20(m,2H).

[1154] Example 21.1

[1155] 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide

[1156]

[1157] Step 1: 2-[(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide

[1158]

[1159] The title compound was prepared in analogy to Example 21, Step 4, from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid (Example 21, Step 3) and [1-(trifluoromethyl)cyclopropyl]methanamine hydrochloride.

[1160] LC-MS (Method D): Rt 1.00 min; MS m / z 478.2 = [M+H]+ (99% @ 215 nm)

[1161] 1H NMR (500MHz, DMSO-d6) δ12.70–12.29(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. 7Hz,1H),6.97(d,J=11.8Hz,1H),4.19(s,2H),3.77(s,3H),3.61(d,J=6.1Hz,2H),1.31(s,9H),0.97–0.92(m,2H),0.92–0.87(m,2H).

[1162] Step 2: 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide

[1163] The title compound was prepared in analogy to Example 21, Step 5, from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide (Step 1) and BBr3.

[1164] LC-MS (Method A): Rt 2.82 min; MS m / z 464.3 = [M+H]+ (89% @ 215 nm)

[1165] 1H NMR (500MHz, methanol-d4) δ8.03(s,1H),7.71(dd,J=8.5,1.6Hz,1H),7.57(d,J=7.9Hz,1H),6.96(d,J =12.0Hz,1H),6.60(d,J=6.8Hz,1H),4.21(s,2H),3.73(s,2H),1.37(s,9H),1.03–0.95(m,4H).

[1166] Example 21.2

[1167] 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide

[1168]

[1169] Step 1: 2-[(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide

[1170]

[1171] The title compound was prepared in analogy to Example 21, Step 4, from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid (Example 21, Step 3) and 3,3,3-trifluoropropan-1-amine hydrochloride.

[1172] LC-MS (Method B): Rt 1.13 min; MS m / z 452.7 = [M+H]+ (89% @ 215 nm)

[1173] 1H NMR (500MHz, DMSO-d6) δ12.61–12.37(m,1H),8.65–8.53(m,1H),8.12–7.86(m,1H),7.71–7.42(m,2H),7.04(d,J= 6.7Hz,1H),6.97(d,J=11.8Hz,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).

[1174] Step 2: 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide

[1175] The title compound was prepared in analogy to Example 21, Step 5, from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide (Step 1) and BBr3.

[1176] LC-MS (Method A): Rt 2.61 min; MS m / z 438.5 = [M+H]+ (97% @ 215 nm)

[1177] 1H NMR (500MHz, methanol-d4) δ8.02(br.s,1H),7.70(d,J=8.3Hz,1H),7.55(br.s,1H),6.94(d,J=12.0Hz,1H), 6.58(d,J=6.8Hz,1H), 4.19(s,2H), 3.64(t,J=7.0Hz,2H), 2.54(qt,J=11.0,7.1Hz,2H), 1.35(s,9H).

[1178] Example 21.3

[1179] 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide

[1180]

[1181] Step 1: 2-[(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)methyl]-1,3-benzoxazole-5-carboxylic acid methyl ester

[1182]

[1183] The title compound was prepared in analogy to Example 21, Step 2, from 2-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)acetic acid (Example 21, Step 1) and 3-amino-4-hydroxy-benzoic acid methyl ester.

[1184] LC-MS (Method D): Rt 1.21 min; MS m / z 372.3 = [M+H]+ (98% @ 215 nm)

[1185] 1H NMR(500MHz,DMSO-d6)δ8.25–8.21(m,1H),8.00(dd,J=8.6,1.7Hz,1H),7.82(dd,J=8.6,0.5Hz,1H) ,7.10(d,J=6.7Hz,1H),7.01(d,J=11.8Hz,1H),4.37(s,2H),3.88(s,3H),3.79(s,3H),1.32(s,9H).

[1186] Step 2: 2-[(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)methyl]-1,3-benzoxazole-5-carboxylic acid

[1187]

[1188] The title compound was prepared in analogy to Example 21, Step 3, from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1,3-benzoxazole-5-carboxylic acid methyl ester (Step 1) and 2M lithium hydroxide.

[1189] LC-MS (Method D): Rt 1.07 min; MS m / z 358.2 = [M+H]+ (86% @ 215 nm)

[1190] 1H NMR (400MHz, DMSO-d6) δ13.03(br.s,1H),8.20(s,1H),7.98(d,J=8.5Hz,1H),7.78(d,J=8.5H z, 1H), 7.10 (d, J = 6.6Hz, 1H), 7.01 (d, J = 11.8Hz, 1H), 4.36 (s, 2H), 3.79 (s, 3H), 1.32 (s, 9H).

[1191] Step 3: 2-[(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide

[1192]

[1193] The title compound was prepared in analogy to Example 21, Step 4, from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1,3-benzoxazole-5-carboxylic acid (Step 2) and 1-(trifluoromethyl)cyclopropylamine hydrochloride.

[1194] LC-MS (Method D): Rt 1.13 min; MS m / z 465.3 = [M+H]+ (79% @ 215 nm)

[1195] 1H NMR (400MHz, DMSO-d6) δ9.22(s,1H),8.18(d,J=1.4Hz,1H),7.89(dd,J=8.6,1.8Hz,1H),7.76(d,J=8.5Hz,1H), 7.09(d,J=6.7Hz,1H),7.01(d,J=11.8Hz,1H),4.36(s,2H),3.79(s,3H),1.34–1.30(m,11H),1.20–1.16(m,2H).

[1196] Step 4: 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide

[1197] The title compound was prepared in analogy to Example 21, Step 5, from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide (Step 3) and 1M BBr3.

[1198] LC-MS (Method A): Rt 3.87 min; MS m / z 451.2 = [M+H]+ (96% @ 215 nm)

[1199] 1H NMR (400MHz, DMSO-d6) δ9.39(s,1H),9.23(s,1H),8.19(d,J=1.3Hz,1H),7.90(dd,J=8.6,1.8Hz,1H),7.76(d,J =8.9Hz,1H),6.92(d,J=12.0Hz,1H),6.75(d,J=6.9Hz,1H),4.27(s,2H),1.35–1.30(m,11H),1.21–1.15(m,2H).

[1200] Example 21.4

[1201] 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1,3-benzoxazole-5-carboxamide

[1202]

[1203] Step 1: 2-[(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1,3-benzoxazole-5-carboxamide

[1204]

[1205] The title compound was prepared in analogy to Example 21, Step 4, from 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-1,3-benzoxazole-5-carboxylic acid (Example 21.3, Step 2) and [1-(trifluoromethyl)cyclopropyl]methanamine hydrochloride.

[1206] LC-MS (Method D): Rt 1.15 min; MS m / z 479.3 = [M+H]+ (48% @ 215 nm)

[1207] 1H NMR (500MHz, DMSO-d6) δ8.66(t,J=6.1Hz,1H),8.14(d,J=1.4Hz,1H),7.86(dd,J=8.6,1.7Hz,1H),7.76(d,J=8.5Hz,1H),7.1 0(d,J=6.7Hz,1H),7.01(d,J=11.8Hz,1H),4.36(s,2H),3.79(s,3H),3.61(d,J=6.1Hz,2H),1.32(s,9H),0.97–0.89(m,4H).

[1208] Step 2: 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1,3-benzoxazole-5-carboxamide

[1209] The title compound was prepared in analogy to Example 21, Step 5, from 2-[(4-tert-butyl-2-fluoro-5-methoxyphenyl)methyl]-N-{[1-(trifluoromethyl)cyclopropyl]methyl}-1,3-benzoxazole-5-carboxamide (Step 1) and 1M BBr3.

[1210] LC-MS (Method A): Rt 4.03 min; MS m / z 465.2 = [M+H]+ (95% @ 215 nm)

[1211] 1H NMR (400MHz, DMSO-d6) δ9.38(s,1H),8.67(t,J=6.0Hz,1H),8.16(d,J=1.3Hz,1H),7.87(dd,J=8.5,1.7Hz,1H),7.76(d,J=8. 6Hz, 1H), 6.92 (d, J = 12.0Hz, 1H), 6.75 (d, J = 6.9Hz, 1H), 4.27 (s, 2H), 3.62 (d, J = 6.1Hz, 2H), 1.32 (s, 9H), 0.98–0.89 (m, 4H).

[1212] Example 22

[1213] 2-[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide

[1214]

[1215] Step 1: 5-Nitro-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole

[1216]

[1217] HATU (993 mg, 2.61 mmol) was added 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), and the reaction mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, and the residue was distributed between saturated NaHCO (15 mL) and EtOAc (15 mL). The phases were separated, and the organic layer was washed with brine (2x10 mL), dried over Na2SO4, 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 distributed between saturated NaHCO (25 mL) and EtOAc (25 mL). The organic layer was separated, washed with water (2x15 mL), dried over Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptanes afforded the title compound as a light yellow solid.

[1218] LC-MS (Method B): Rt 1.06 min; MS m / z 272.0 = [M+H]+ (99% @ 215 nm)

[1219] 1H NMR (500MHz, DMSO-d6) δ 13.27 (br.s, 1H), 8.45 (s, 1H), 8.13 (dd, J = 8.8, 1.8Hz, 1H), 7.72 (d, J = 7.6Hz, 1H), 1.60 (s, 4H).

[1220] Step 2: 2-[1-(Trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-amine

[1221]

[1222] 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 purified by Filter and wash with EtOH (10 mL).The filtrate was concentrated in vacuo and azeotroped with DCM to give the title compound as a beige solid.

[1223] 1H NMR (500MHz, DMSO-d6) δ12.12–11.84(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).

[1224] Step 3: 2-[5-Benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide

[1225]

[1226] 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 Na2SO4 and concentrated in vacuo. Purification by preparative HPLC (acidic pH, early elution method) gave the title compound as an off-white solid.

[1227] LC-MS (Method D): Rt 0.88 min; MS m / z 542.2 = [M+H]+ (91% @ 215 nm)

[1228] Step 4: 2-[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide

[1229] 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 and the filtrate was concentrated in vacuo.The crude residue was purified by preparative HPLC (acidic pH, standard elution method) to afford the title compound as an off-white solid.

[1230] LC-MS (Method A): Rt 2.16 min; MS m / z 452.2 = [M+H]+ (95% @ 215 nm)

[1231] 1H NMR (400MHz, DMSO-d6, VT at 354.7K) δ12.23(br.s,1H),9.88(s,1H),9.44(br.s,1H),7.94(s,1H),7.49–7.39(m,1H),7.2 9(br.s,1H),7.05(d,J=11.4Hz,1H),6.77(d,J=6.7Hz,1H),5.55(br.s,1H),3.61(s,2H),1.52(s,6H),1.52–1.47(m,4H).

[1232] Example 23

[1233] 2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide

[1234]

[1235] Step 1: 2-(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide

[1236]

[1237] To a stirred solution of 2-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)acetic acid (Example 21, Step 1) (90 mg, 0.37 mmol), 2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-amine (Example 22, Step 2) (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 NaHCO (10 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine (2x10 mL), dried over Na2SO4, and then concentrated in vacuo. Purification by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane gave the title compound as a beige solid.

[1238] LC-MS (Method B): Rt 1.25 min; MS m / z 464.2 = [M+H]+ (97% @ 215 nm)

[1239] 1H NMR(500MHz,DMSO-d6)δ12.45(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 = 6.7Hz, 1H), 6.95 (d, J = 11.7Hz, 1H), 3.79 (s, 3H), 3.68 (s, 2H), 1.48 (s, 4H), 1.32 (s, 9H).

[1240] Step 2: 2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide

[1241] 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 H2O (+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.

[1242] LC-MS (Method A): Rt 3.02 min; MS m / z 450.3 = [M+H]+ (97% @ 215 nm)

[1243] 1H NMR(500MHz,DMSO-d6)δ12.53–12.40(m,1H),10.23–10.09(m,1H),9.29(s,1H),8.10–7.86 (m,1H),7.52–7.18(m,2H),6.89–6.73(m,2H),3.61–3.56(m,2H),1.48(s,4H),1.32(s,9H).

[1244] Example 24

[1245] 2-Benzyl-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide

[1246]

[1247] 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 at room temperature under nitrogen for 10 min, treated with (3,3,3-trifluoropropan-1-amine (25 mg, 0.22 mmol) and then stirred at room temperature for 16 h. 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, early elution method) gave the title compound as a white solid.

[1248] LC-MS (Method A): Rt 1.70 min; MS m / z 348.1 = [M+H]+ (99% @ 215 nm)

[1249] 1H NMR(500MHz,DMSO-d6)δ12.47(br.s,1H),8.58(t,J=5.5Hz,1H),7.99(s,1H),7.65(dd,J=8.4,1.6Hz,1H),7.50 (d,J=8.4Hz,1H),7.35–7.29(m,4H),7.26–7.21(m,1H),4.20(s,2H),3.50(q,J=6.9Hz,2H),2.61–2.52(m,2H).

[1250] Example 24.1

[1251] 2-Benzyl-N-(cyclopentylmethyl)-1H-benzimidazole-5-carboxamide

[1252]

[1253] The title compound was prepared in analogy to Example 24 from commercially available 2-benzyl-1H-benzimidazole-5-carboxylic acid and cyclopentylmethylamine.

[1254] LC-MS (Method A): Rt 2.02 min; MS m / z 334.2 = [M+H]+ (99% @ 215 nm)

[1255] 1H NMR (500MHz, DMSO-d6) δ12.48(br.s,1H),8.37(t,J=5.7Hz,1H),8.00(s,1H),7.66(dd,J=8.4,1.5Hz,1H),7.49(d,J=8.2Hz,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).

[1256] Example 24.2

[1257] 2-Benzyl-N-(cycloheptylmethyl)-1H-benzimidazole-5-carboxamide

[1258]

[1259] The title compound was prepared in analogy to Example 24 from commercially available 2-benzyl-1H-benzimidazole-5-carboxylic acid and cycloheptylmethylamine.

[1260] LC-MS (Method A): Rt 2.43 min; MS m / z 362.2 = [M+H]+ (96% @ 215 nm)

[1261] 1H NMR (500MHz, DMSO-d6) δ12.47(br.s,1H),8.36(t,J=5.6Hz,1H),8.00(br.s,1H),7.66(d,J=8.4Hz,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=6.3Hz,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).

[1262] Example 25

[1263] N-(Cycloheptylmethyl)-2-[(2-fluoro-6-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide

[1264]

[1265] Step 1: 2-[(2-Fluoro-6-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid methyl ester

[1266]

[1267] HATU (517 mg, 1.36 mmol) was added 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). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo and the residue was distributed 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 h. The resulting mixture was concentrated in vacuo and the residue was distributed between EtOAc (50 mL) and water (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 5% - 75% EtOAc in heptane to afford the title compound as an off-white solid.

[1268] LC-MS (Method B): Rt 0.92 min; MS m / z 315.4 = [M+H]+ (94% @ 215 nm)

[1269] 1H NMR(500MHz,DMSO-d6)δ12.43(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=8.4Hz,1H),6.86(t,J=8.8Hz,1H),4.19(s,2H),3.85(s,3H),3.79(s,3H).

[1270] Step 2: 2-[(2-Fluoro-6-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylic acid

[1271]

[1272] 2M LiOH aqueous solution (3.2 mL, 6.4 mmol) was added to a solution of methyl 2-[(2-fluoro-6-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxylate (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 2M HCl aqueous solution. 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 light orange powder.

[1273] LC-MS (Method B): Rt 0.85 min; MS m / z 301.0 = [M+H]+ (94% @ 215 nm)

[1274] 1H NMR (500MHz, DMSO-d6) δ8.19 (s, 1H), 7.98 (dd, J=8.5, 1.3Hz, 1H), 7.73 (d, J= 8.6Hz,1H),7.54–7.38(m,1H),6.97–6.89(m,2H),4.42(s,2H),3.77(s,3H).

[1275] Step 3: N-(Cycloheptylmethyl)-2-[(2-fluoro-6-methoxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide

[1276]

[1277] 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 cycloheptylmethylamine (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 Na2SO4, and concentrated in vacuo. Purification by preparative HPLC (basic pH, standard elution method) gave the title compound as a white powder.

[1278] LC-MS (Method A): Rt 2.50 min; MS m / z 410.3 = [M+H]+ (85% @ 215 nm)

[1279] 1H NMR(500MHz,DMSO-d6)δ12.35–12.20(m,1H),8.40–8.26(m,1H),8.05–7.85 (m,1H),7.63(dd,J=24.2,7.9Hz,1H),7.44(dd,J=32.0,8.4Hz,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).

[1280] Step 4: N-(Cycloheptylmethyl)-2-[(2-fluoro-6-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide

[1281] 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 1M BBr 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 (~5 mL) and concentrated in vacuo. Purification by preparative HPLC (basic pH, early elution method) gave the title compound as a white powder.

[1282] LC-MS (Method A): Rt 2.32 min; MS m / z 396.2 = [M+H]+ (100% @ 215 nm)

[1283] 1H NMR(500MHz,DMSO-d6)δ8.36–8.30(m,1H),7.96(s,1H),7.64(dd,J=8.4,1. 3Hz,1H),7.45(d,J=8.3Hz,1H),7.17–7.10(m,1H),6.71(d,J=8.3Hz,1H),6. 66(t,J=8.7Hz,1H),4.14(s,2H),3.10(t,J=6.3Hz,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).

[1284] The compounds listed below (Table 1) were prepared analogously to Example 25, Steps 1-4 by substituting the appropriate commercially available phenylacetic acid for 2-(2-fluoro-6-methoxy-phenyl)acetic acid (Step 1).

[1285] Table 1

[1286]

[1287]

[1288] Example 25.5

[1289] N-(Cycloheptylmethyl)-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide

[1290] Step 1: 2-[(3-Benzyloxyphenyl)methyl]-1H-benzimidazole-5-carboxylic acid methyl ester

[1291]

[1292] 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, and then 3,4-diaminobenzoic acid methyl ester (1.38 g, 8.3 mmol) was added. After stirring at room temperature for 18 h, the resulting mixture was concentrated in vacuo and the residue was distributed between saturated NaHCO (100 mL) and EtOAc (125 mL). The organic layer was separated, washed with water (2x75 mL) and brine (2x75 mL), dried over Na2SO4, and then concentrated in vacuo. The resulting material was ground 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 NaHCO3 (100 mL) and EtOAc (125 mL). The organic layer was separated, washed with water (2x75 mL), brine (2x75 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound as an off-white powder.

[1293] LC-MS (Method B): Rt 1.05 min; MS m / z 373.0 = [M+H]+ (98% @ 215 nm)

[1294] 1H NMR (500MHz, DMSO-d6) δ8.20–7.99(m,1H),7.79(dd,J=8.4,1.6Hz,1H),7.56(d,J=8.4Hz,1H),7.48–7.39(m,2H),7.39–7.33( m,2H),7.33–7.27(m,1H),7.24(t,J=7.9Hz,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).

[1295] Step 2: 2-[(3-Hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxylic acid methyl ester

[1296]

[1297] 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 h. The resulting mixture was washed with water by Filter and wash with EtOH (45 mL).Concentrate the filtrate in vacuo to afford the title compound as a light orange / brown solid.

[1298] LC-MS (Method B): Rt 0.83 min; MS m / z 283.1 = [M+H]+ (98% @ 215 nm)

[1299] 1H NMR (500MHz, DMSO-d6) δ8.09(s,1H),7.78(dd,J=8.4,1.6Hz,1H),7.55(d,J=8.4Hz,1H),7.10(t,J=7.8H z,1H),6.74(d,J=7.7Hz,1H),6.72–6.69(m,1H),6.62(dd,J=8.0,1.8Hz,1H),4.12(s,2H),3.85(s,3H).

[1300] Step 3: 2-[(3-Hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxylic acid

[1301]

[1302] 2M LiOH aqueous solution (2.53mL, 5.06mmol) is added to a solution of 2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-formic acid methyl ester (step 2) (95%, 501mg, 1.69mmol) in THF (8mL), and the reaction mixture is stirred at 50°C for 4h. The resulting mixture is partially concentrated (to remove THF), and the remaining aqueous layer is acidified to pH 4 and extracted with 3:1 chloroform:IPA (3x30mL). The combined organic extracts are dried over NaSO and concentrated in vacuo to obtain the title compound as a light orange powder.

[1303] LC-MS (Method B): Rt 0.73 min; MS m / z 269.1 = [M+H]+ (95% @ 215 nm)

[1304] 1H NMR (500MHz, DMSO-d6) δ13.48–11.55(m,2H),9.37(s,1H),8.10(s,1H),7.81(dd,J=8.4,1.5Hz,1H),7.57(d,J=8.4 Hz,1H),7.12(t,J=7.8Hz,1H),6.75(d,J=7.7Hz,1H),6.73–6.70(m,1H),6.64(dd,J=8.0,1.8Hz,1H),4.16(s,2H).

[1305] Step 4: N-(Cycloheptylmethyl)-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide

[1306] The title compound was prepared in analogy to Example 25, Step 3, from 2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxylic acid (Step 3) and cycloheptylmethylamine.

[1307] LC-MS (Method A): Rt 2.18 min; MS m / z 378.3 = [M+H]+ (100% @ 215 nm)

[1308] 1H NMR (500MHz, methanol-d4) δ8.53–8.42(m,1H),8.04(d,J=1.2Hz,1H),7.73(dd,J=8.5,1.6H z,1H),7.57(d,J=8.5Hz,1H),7.16(t,J=7.9Hz,1H),6.80(d,J=7.7Hz,1H),6.78–6.7 4(m,1H),6.70(dd,J=8.1,2.0Hz,1H),4.21(s,2H),3.26(t,J=6.4Hz,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).

[1309] Example 26

[1310] 2-(5-Chloro-2-hydroxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide

[1311]

[1312] Step 1: N-(4-Amino-3-nitro-phenyl)-2-(5-chloro-2-methoxy-phenyl)acetamide

[1313]

[1314] To a solution of 2-(5-chloro-2-methoxy-phenyl)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). The formed precipitate was filtered from the biphasic mixture, and the layers were separated. The organic portion was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography, eluted with 10%-70% EtOAc in heptane to give the title compound as a yellow powder.

[1315] LC-MS (Method B): Rt 1.10 min; MS m / z 336.0 / 338.0 = [M+H]+ (100% @ 215 nm)

[1316] 1H NMR (500 MHz, CHLOROFORM-d) δ7.93 (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).

[1317] Step 2: 2-(5-Chloro-2-methoxy-phenyl)-N-(3,4-diaminophenyl)acetamide

[1318]

[1319] 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 warmed to room temperature and stirred for 45 min. The resulting mixture was washed with water and then stirred for 2 hours. Filter and rinse with MeOH. The filtrate is concentrated in vacuo and the crude residue is dissolved in EtOAc and washed with saturated NaHCO3 solution. The organic portion is separated, washed with water, brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a red / brown solid.

[1320] LC-MS (Method B): Rt 0.91 min; MS m / z 306.0 / 308.0 = [M+H]+ (98% @ 215 nm)

[1321] 1H NMR (500MHz, chloroform-d) δ7.33(br.s,1H),7.28(d,J=2.6Hz,1H),7.24(dd,J=8.7,2.6Hz,1H),7.07(d,J=2.3Hz ,1H),6.85(d,J=8.7Hz,1H),6.59(d,J=8.2Hz,1H),6.52(dd,J=8.2,2.3Hz,1H),3.88(s,3H),3.62(s,2H).

[1322] Step 3: 2-(5-Chloro-2-methoxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide

[1323]

[1324] To a solution of 3,3-dimethylbutyric 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 1M HCl aqueous solution. The organic portion was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was dissolved in acetic acid (2.5 mL) and heated at 60°C for 2 h, then at 80°C for 4 h. After standing at room temperature for 3 days, the mixture was concentrated in vacuo and the residue was dissolved in EtOAc and washed with saturated NaHCO3 solution and brine in sequence. The organic portion was separated, dried over Na2SO4 and concentrated in vacuo. The crude residue was adsorbed onto silica gel and purified by chromatography eluting with 50%-100% EtOAc in heptane followed by preparative HPLC (acidic pH, standard elution method) to afford the title compound as a colorless solid.

[1325] LC-MS (Method B): Rt 1.04 min; MS m / z 386.1 / 388.1 = [M+H]+ (98% @ 215 nm)

[1326] 1H NMR (500 MHz, CHLOROFORM-d) δ7.84–7.80 (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).

[1327] Step 4: 2-(5-Chloro-2-hydroxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide

[1328] 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 1M BBr3 in DCM (54 μL, 0.05 mmol), and the mixture was warmed to room temperature and stirred overnight. The reaction was quenched by adding saturated NaHCO3 solution (5 drops), and the resulting mixture was concentrated by removing DCM under a stream of nitrogen. The residue was dissolved in EtOAc (3 mL) and washed with saturated NaHCO3 solution (1 mL). The organic layer was separated and dried over Na2SO4. The solution was filtered and concentrated under a stream of nitrogen and dried in a vacuum oven to give the title compound as a colorless glass.

[1329] LC-MS (Method A): Rt 1.95 min; MS m / z 372.2 / 374.3 = [M+H]+ (100% @ 215 nm)

[1330] 1H NMR (500MHz, methanol-d4) δ7.92(d,J=1.4Hz,1H),7.44(d,J=8.6Hz,1H),7.24–7.20(m,2H),7. 09(dd,J=8.6,2.6Hz,1H),6.80(d,J=8.6Hz,1H),3.69(s,2H),2.73(s,2H),1.03(s,9H).

[1331] Example 27

[1332] N-(2-tert-Butyl-1H-benzoimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide

[1333]

[1334] Step 1: 2-tert-Butyl-5-nitro-1H-benzimidazole

[1335]

[1336] To 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.

[1337] Add another 1 equivalent of 2,2-dimethylpropionic acid, DIPEA and HATU and continue stirring overnight. The reaction mixture is diluted with EtOAc and washed with water (10mL) and brine (10mL). The organic extract is dried over Na2SO4 and concentrated in vacuo. The crude residue is dissolved in acetic acid (7mL) and heated at 60°C for 2h, then heated at 70°C for another 2 hours. After cooling to room temperature, the reaction mixture is stirred for 3 days. Acetic acid is removed in vacuo and the residue is dissolved in EtOAc, then washed with saturated NaHCO3 solution. The organic portion is separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material is purified by silica gel chromatography, eluted with a heptane solution of 30%-100% EtOAc to obtain the title compound.

[1338] LC-MS (Method B): Rt 0.87 min; MS m / z 220.0 = [M+H]+ (100% @ 215 nm)

[1339] 1H NMR (500MHz, DMSO-d6) δ 12.80 (br.s, 1H), 8.38 (br.s, 1H), 8.07 (dd, J = 8.8, 2.2Hz, 1H), 7.65 (d, J = 8.5Hz, 1H), 1.43 (s, 9H).

[1340] Step 2: 2-tert-Butyl-1H-benzimidazol-5-amine

[1341]

[1342] To a solution of 2-tert-butyl-5-nitro-1H-benzimidazole (step 1) (70 mg, 0.32 mmol) in EtOH (4 mL) was added Pd / C (10%, 15 mg, 0.14 mmol) under N2 atmosphere. The nitrogen atmosphere was replaced with hydrogen atmosphere and the mixture was stirred at room temperature overnight. The resulting mixture was washed with water by Filter and wash with MeOH. Concentrate the filtrate in vacuo to give the title compound as a light pink glass.

[1343] 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).

[1344] Step 3: N-(2-tert-Butyl-1H-benzoimidazol-5-yl)-2-(5-chloro-2-methoxy-phenyl)acetamide

[1345]

[1346] 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-benzimidazole-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. The crude material was purified by silica gel chromatography, eluted with 50%-100% EtOAc in heptane to give the title compound as a colorless powder.

[1347] LC-MS (Method B): Rt 1.04 min; MS m / z 372.0 / 374.1 = [M+H]+ (88% @ 215 nm)

[1348] 1H NMR(500MHz,DMSO-d6)δ11.94(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=8.4Hz,1H),3.77(s,3H),3.67–3.61(m,2H),1.38(s,9H).

[1349] Step 4: N-(2-tert-Butyl-1H-benzoimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide

[1350] To a cooling (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 1M BBr3 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 NaHCO3 solution (5 mL). The resulting mixture was diluted with EtOAc and washed with saturated NaHCO3 solution. The organic portion was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give a light pink powder. The powder was ground 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.

[1351] LC-MS (Method A): Rt 1.76 min; MS m / z 358.2 / 360.2 = [M+H]+ (99% @ 215 nm)

[1352] 1H NMR(500MHz, methanol-d4)δ7.93(br.s,1H),7.44(br.s,1H),7.33–7.12(m,2H),7.0 9(dd,J=8.6,2.6Hz,1H),6.80(d,J=8.6Hz,1H),3.71-3.65m,2H),1.45(s,9H).

[1353] Example 28

[1354] N-(Cycloheptylmethyl)-2-(1-methylcyclobutyl)-3H-benzimidazole-5-carboxamide

[1355]

[1356] Step 1: 3,4-Diamino-N-(cycloheptylmethyl)benzamide

[1357]

[1358] A solution of cycloheptylmethylamine (209mg, 1.64mmol), 3,4-diaminobenzoic acid (250mg, 1.64mmol), DCC (373mg, 1.81mmol) and DMAP (221mg, 1.81mmol) in DCM (30mL) was stirred at room temperature for 18h. The obtained mixture was concentrated in vacuo, and the crude material was purified by silica gel chromatography, eluted with a heptane solution of 10%-100% EtOAc. The obtained yellow solid was distributed between EtOAc (30mL) and water (30mL). The organic layer was washed with water (2x30mL), brine (30mL), dried over NaSO and concentrated in vacuo to obtain the title compound, which was a light yellow solid.

[1359] LC-MS (Method B): Rt 0.95 min; MS m / z 262.1 = [M+H]+ (96% @ 215 nm)

[1360] 1H NMR (500MHz, DMSO-d6) δ7.85(t,J=5.8Hz,1H),7.06(d,J=1.4Hz,1H),6.98(dd,J=8.0,1.4Hz,1H),6.49(d,J=8.1Hz,1H ), 4.93 (br.s, 4H), 3.01 (t, J = 6.3Hz, 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).

[1361] Step 2: N-(Cycloheptylmethyl)-2-(1-methylcyclobutyl)-3H-benzimidazole-5-carboxamide

[1362] 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 hour, then treated with a DMF (1 mL) solution of 3,4-diamino-N-(cycloheptylmethyl)benzamide (step 1) (50 mg, 0.19 mmol), and the mixture was stirred for 18 h. The resulting mixture was diluted with EtOAc (10 mL) and washed with saturated sodium bicarbonate aqueous solution (2x10 mL). The organic layer was dried over Na2SO4, filtered, and then concentrated under vacuum. 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 sodium bicarbonate aqueous solution (3x20 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane then 0-100% MeOH in EtOAc to afford the title compound as a colorless solid.

[1363] LC-MS (Method A): Rt 2.17 min; MS m / z 340.3 = [M+H]+ (99% @ 215 nm)

[1364] 1H NMR(500MHz,DMSO-d6)δ12.41–12.22(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=6.3Hz,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).

[1365] Example 29

[1366] 2-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide

[1367]

[1368] Step 1: 3,4-Diamino-N-[[1-(trifluoromethyl)cyclopropyl]methyl]benzamide

[1369]

[1370] A solution of 3,4-diaminobenzoic acid (150mg, 0.99mmol), [1-(trifluoromethyl)cyclopropyl]methylamine hydrochloride (173mg, 0.99mmol), EDCI (208mg, 1.08mmol) and DMAP (132mg, 1.08mmol) in DCM (10mL) was stirred at room temperature.DIPEA (344μL, 1.97mmol) was added and the reaction mixture was stirred for 3 days under an inert atmosphere. The resulting mixture was diluted with DCM (20mL), washed with water (2x20mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography, eluted with 0-100% MeOH in EtOAc solution to obtain the title compound, which was a tan residue.

[1371] 1H NMR(500MHz,DMSO-d6)δ7.96(t,J=6.2Hz,1H),7.02(d,J=2.0Hz,1H),6.95(dd,J=8.1,2.0Hz,1 H), 6.48 (d, J = 8.1Hz, 1H), 4.96 (s, 2H), 4.55 (s, 2H), 3.54 (d, J = 6.2Hz, 2H), 0.92–0.81 (m, 4H).

[1372] Step 2: 2-[(5-Fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide

[1373]

[1374] The title compound was prepared in analogy to Example 25, Step 1, 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).

[1375] LC-MS (Method D): Rt 0.80 min; MS m / z 476.2 = [M+H]+ (53% @ 215 nm)

[1376] 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

[1377] 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 LiBH4 (4M in THF) (154 μL, 0.61 mmol) and the reaction mixture was stirred for 18 h. Additional THF (1 mL) and LiBH4 (4M 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, vacuum concentrated and further purified by silica gel chromatography, eluting with 0-100% EtOAc in heptane and 0-100% MeOH in EtOAc. The product fractions were combined, vacuum concentrated and further purified by preparative HPLC (acidic pH, standard elution method). The product fractions were combined and vacuum concentrated to remove most of the organic matter. The aqueous portion was treated with NaHCO (saturated aqueous solution) (7.5 mL) and EtOAc (20 mL), and the organic layer was separated, dried over Na SO, filtered and vacuum concentrated to obtain the title compound.

[1378] LC-MS (Method A): Rt 2.13 min; MS m / z 480.3 = [M+H]+ (100% @ 215 nm)

[1379] 1H NMR (500MHz, DMSO-d6) δ9.46(s,1H),8.67(s,1H),8.09(s,1H),7.81(d,J=8.7Hz,1H),7.67(d,J=8.2Hz,1H),6.95(d,J=12.2Hz, 1H),6.67(d,J=6.9Hz,1H),4.27(s,2H),3.62(d,J=6.1Hz,2H),3.59(s,2H),1.24(s,6H),0.99–0.94(m,2H),0.94–0.89(m,2H).

[1380] Example 29.1

[1381] 2-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide

[1382]

[1383] Step 1:3,4-diamino-N-(3,3,3-trifluoropropyl)benzamide

[1384]

[1385] 3,3,3-trifluoropropane-1-amine hydrochloride (108mg, 0.72mmol) and 3,4-diaminobenzoic acid (100mg, 0.66mmol) are suspended in 1,4-dioxane (2mL) and treated with DIPEA (241μL, 1.38mmol), TBTU (211mg, 0.66mmol) and DCM (0.5mL). The reaction mixture is stirred for 1h and then concentrated in vacuo. The residue is purified by silica gel chromatography, eluted with a heptane solution gradient of 0 to 100% EtOAc and an EtOAc solution gradient of 0 to 100% MeOH successively, to obtain the title compound, which is a purple residue.

[1386] LC-MS (Method C): Rt 1.16 min; MS m / z 248.3 = [M+H]+ (41% @ 215 nm)

[1387] 1H NMR(500MHz,DMSO-d6)δ8.05(t,J=5.6Hz,1H),7.02(d,J=2.0Hz,1H),6.92(dd,J=8.1,2.0Hz ,1H),6.46(d,J=8.1Hz,1H),4.95(s,2H),4.54(s,2H),3.42–3.35(m,2H),2.65–2.57(m,2H).

[1388] Step 2: 2-[(5-Fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide

[1389]

[1390] The title compound was prepared in analogy to Example 25, Step 1, 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).

[1391] LC-MS (Method D): Rt 0.75 min; MS m / z 450.2 = [M+H]+ (54% @ 215 nm)

[1392] 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

[1393] The title compound was prepared in analogy to Example 29, Step 3, 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.

[1394] LC-MS (Method A): Rt 1.90 min; MS m / z 454.3 = [M+H]+ (95% @ 215 nm)

[1395] 1H NMR (500MHz, DMSO-d6) δ12.58(br.s,1H),9.34(br.s,1H),8.60(t,J=5.1Hz,1H),8.01(s,1H),7.66(d,J=8.2Hz,1H),7.51(s,1H),6.91(d ,J=12.1Hz,1H),6.62(d,J=7.0Hz,1H),4.73(br.s,1H),4.10(s,2H),3.58(s,2H),3.51(q,J=6.9Hz,2H),2.63–2.51(m,2H),1.24(s,6H).

[1396] Example 30

[1397] N-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide

[1398]

[1399] Step 1: 2-[1-(Trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxylic acid methyl ester

[1400]

[1401] HATU (915 mg, 2.41 mmol) was added 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), and the mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo and the residue was distributed between saturated NaHCO (25 mL) and EtOAc (25 mL). The organic layer was separated, washed with brine (2x25 mL), dried over Na2SO4 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 distributed 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 silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptanes afforded the title compound as a brown viscous oil.

[1402] LC-MS (Method B): Rt 1.04 min; MS m / z 285.1 = [M+H]+ (93% @ 215 nm)

[1403] 1H NMR (500MHz, DMSO-d6) δ12.93(br.s,1H),8.15(s,1H),7.84(d,J=8.4Hz,1H),7.68–7.54(m,1H),3.86(s,3H),1.60-1.53(s,4H).

[1404] step 2: 2-[1-(Trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxylic acid

[1405]

[1406] A solution of 2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-formic acid methyl ester (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 continued to stir for 5 h. The resulting mixture was diluted in EtOAc (15 mL) and H2O (15 mL). 2M KHSO4 was used to adjust the pH to 4, separate the layers and extract the aqueous layer with EtOAc (15 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound as a beige viscous / gelatinous solid.

[1407] LC-MS (Method B): Rt 0.89 min; MS m / z 270.9 = [M+H]+ (98% @ 215 nm)

[1408] 1H NMR (500MHz, DMSO-d6) δ12.95–12.83 (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%

[1409] Step 3: N-[(2-Fluoro-5-methoxy-phenyl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide

[1410]

[1411] 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)methylamine (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 NaHCO (10 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine (2x10 mL), dried over Na SO, and then concentrated in vacuo. Purified by silica gel chromatography, eluted with 0-100% EtOAc in heptane, to give the title compound as a viscous brown oil.

[1412] LC-MS (Method D): Rt 0.80 min; MS m / z 408.2 = [M+H]+ (82% @ 215 nm)

[1413] 1H NMR (500MHz, methanol-d4) δ8.12 (br.s, 1H), 7.83–7.78 (m, 1H), 7.66–7.58 (m, 1H), 7.01 (t, J = 9.3Hz, 1H), 6.95 (dd, J = 6.0, 3.2Hz, 1H), 6.82 (dt, J = 8.9, 3.6Hz, 1H), 4.62 (s, 2H), 3.75 (s, 3H), 1.60–1.56 (m, 2H), 1.55–1.51 (m, 2H). NMR purity 69%

[1414] Step 4: N-[(4-Bromo-2-fluoro-5-methoxy-phenyl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide

[1415]

[1416] 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 at room temperature overnight. The reaction was carefully quenched with 10% aqueous sodium sulfite solution (10 mL), then diluted with saturated aqueous NaHCO3 solution (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 Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a 0-75% EtOAc in heptane gradient followed by C18 reverse phase chromatography eluting with 10-100% MeCN in water (with 0.1% formic acid modifier) ​​to afford the title compound as a yellow viscous oil.

[1417] LC-MS (Method D): Rt 0.89 min; MS m / z 486.1 / 488.1 = [M+H]+ (84% @ 215 nm)

[1418] 1H NMR (500MHz, methanol-d4) δ8.12(s,1H),7.80(dd,J=8.5,1.5Hz,1H),7.62(d,J=8.5Hz,1H),7.35(d,J=9 .1Hz,1H),7.10(d,J=6.5Hz,1H),4.61(s,2H),3.83(s,3H),1.61–1.56(m,2H),1.55–1.50(m,2H).

[1419] Step 5: N-[(4-bromo-2-fluoro-5-methoxy-phenyl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1-(2-trimethylsilylethoxymethyl)benzimidazole-5-carboxamide

[1420]

[1421] The title compound was prepared in analogy to Example 9, Step 3, from N-[(4-bromo-2-fluoro-5-methoxy-phenyl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Step 4) and 2-(chloromethoxy)ethyl-trimethyl-silane.

[1422] LC-MS (Method D): Rt 1.21 min; MS m / z 616.2 / 618.2 = [M+H]+ (86% @ 215 nm)

[1423] 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 regioisomer mixture that was not separated and used as a mixture in the next step]

[1424] 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

[1425]

[1426] The title compound was prepared in analogy to Intermediate B, Step 4, 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-enyloxy)-trimethyl-silane.

[1427] LC-MS (Method E): Rt 1.80 min; MS m / z 638.4 = [M+H]+ (87% @ 215 nm)

[1428] 1H NMR (500MHz, methanol-d4) δ8.24–8.21(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),4.66–4.6 2(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).

[1429] Step 7: N-[(5-Fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide

[1430]

[1431] Under N2, BBr3 (299 μL, 0.3mmol) was added to a cooled (0°C) stirred solution of 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 (step 6) (87%, 73mg, 0.1mmol) in DCM (300 μL), and the mixture was warmed to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo (30°C). The residue was quenched and azeotroped with MeCN:H2O (1:1). Purification by C18 reverse phase chromatography, eluting with 10%-100% MeCN in water (containing 0.1% formic acid modifier), gave the title compound as an orange viscous oil.

[1432] LC-MS (Method D): Rt 0.86 min; MS m / z 462.2 = [M+H]+ (73% @ 215 nm)

[1433] Step 8: N-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide

[1434] The title compound was prepared in analogy to Example 29, Step 3, from N-[(5-fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)methyl]-2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Step 7).

[1435] LC-MS (Method A): Rt 2.50 min; MS m / z 466.1 = [M+H]+ (96% @ 215 nm)

[1436] 1H NMR (500MHz, methanol-d4) δ8.15(br.s,1H),7.83(dd,J=8.5,1.5Hz,1H),7.64(d,J=7.8Hz,1H),6.96(d,J=12.3Hz,1 H), 6.80 (d, J = 6.8Hz, 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).

[1437] Example 31

[1438] 2-[[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide

[1439]

[1440] Step 1: 2-[[5-Benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-1H-benzimidazole-5-carboxylic acid methyl ester

[1441]

[1442] The title compound was prepared in analogy to Example 22, Step 1, from 2-[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]acetic acid (Intermediate A) and methyl 3,4-diaminobenzoate.

[1443] LC-MS (Method C): Rt 1.63 min; MS m / z 449.3 = [M+H]+ (86% @ 215 nm)

[1444] Step 2: 2-[[5-Benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-1H-benzimidazole-5-carboxylic acid

[1445]

[1446] To a solution of 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-1H-benzimidazole-5-carboxylic acid methyl ester (step 1) (86%, 415 mg, 0.79 mmol) in THF (1.2 mL) was added 2M LiOH (1.2 mL, 2.4 mmol), and the resulting mixture was vigorously stirred at room temperature for 6 h. Additional 2M LiOH (0.6 mL, 1.2 mmol) was added, and the mixture was heated to 50 ° C for 1 h, and then allowed to stand at room temperature for 3 days. The 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 NH4Cl aqueous solution and 1M HCl. The mixture was extracted with EtOAc (3x25 mL), and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound as a brown viscous oil.

[1447] LC-MS (Method C): Rt 1.12 min; MS m / z 435.3 = [M+H]+ (97% @ 215 nm)

[1448] 1H NMR (500MHz, methanol-d4) δ8.31–8.29(m,1H),8.09(dd,J=8.6,1.5Hz,1H),7.69–7.66(m,1H),7.41(d,J=11.5Hz ,1H),7.39–7.35(m,2H),7.31–7.23(m,3H),7.02(d,J=6.2Hz,1H),5.12(s,2H),4.42(s,2H),1.57(s,6H).

[1449] Step 3: 2-[[5-Benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide

[1450]

[1451] 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 NaHCO (4 mL) and EtOAc (4 mL). The organic layer was separated, washed with brine (2x4 mL), dried over Na SO and concentrated in vacuo. Purified by NH- silica gel chromatography, eluted with 0-100% EtOAc in heptane to give the title compound as a yellow viscous oil.

[1452] LC-MS (Method C): Rt 1.60 min; MS m / z 530.5 = [M+H]+ (98% @ 215 nm)

[1453] 1H NMR(400MHz, methanol-d4)δ8.03(br.s,1H),7.73(dd,J=8.4,1.4Hz,1H),7.60–7.50(m,1H),7.37–7.30(m,3H),7.28–7.20(m, 3H), 6.94 (d, J = 6.3Hz, 1H), 5.07 (s, 2H), 4.25 (s, 2H), 3.66 (t, J = 7.0Hz, 2H), 2.55 (qt, J = 11.0, 7.0Hz, 2H), 1.56 (s, 6H).

[1454] NMR analysis indicated 25% w / w EtOAc.

[1455] Step 4: 2-[[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide

[1456] 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 H2O] (5%, 31 mg, 0.015 mmol). The reaction was placed under H2 atmosphere and stirred for 2 h. The resulting mixture was purified by The mixture was stirred for 2 hours at 4 ℃ for 10 minutes.Then the mixture was stirred for 2 hours at 4 ℃ for 3 hours ...

[1457] LC-MS (Method A): Rt 1.78 min; MS m / z 440.2 = [M+H]+ (98% @ 215 nm)

[1458] 1H NMR(500MHz, methanol-d4)δ8.03(br.s,1H),7.73–7.67(m,1H),7.61–7.48(m,1H),7.03(d,J=11.2Hz, 1H), 6.66 (d, J=6.6Hz, 1H), 4.21 (s, 2H), 3.64 (t, J=7.1Hz, 2H), 2.59–2.49 (m, 2H), 1.56 (s, 6H).

[1459] Example 31.1

[1460] 2-[[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide

[1461]

[1462] Step 1: 2-[[5-Benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide

[1463]

[1464] The title compound was prepared in analogy to Example 31, Step 3, from 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-1H-benzimidazole-5-carboxylic acid (Example 31, Step 2) and 1-(trifluoromethyl)cyclopropylamine hydrochloride.

[1465] LC-MS (Method C): Rt 1.61 min; MS m / z 542.4 = [M+H]+ (100% @ 215 nm)

[1466] 1H NMR (400 MHz, methanol-d4) δ8.04 (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).

[1467] Step 2: 2-[[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide

[1468] The title compound was prepared in analogy to Example 31, Step 4, from 2-[[5-benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide (Step 1).

[1469] LC-MS (Method A): Rt 1.86 min; MS m / z 452.2 = [M+H]+ (98% @ 215 nm)

[1470] 1H NMR (500MHz, methanol-d4) δ8.04(br.s,1H),7.74–7.69(m,1H),7.61–7.49(m,1H),7.03(d,J=11.2H z,1H),6.66(d,J=6.6Hz,1H),4.20(s,2H),1.56(s,6H),1.40–1.36(m,2H),1.24–1.20(m,2H).

[1471] Example 32

[1472] 2-[[5-Fluoro-2-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide

[1473]

[1474] Step 1: 2-[5-Fluoro-2-methoxy-3-[[5-[[1-(trifluoromethyl)cyclopropyl]methylcarbamoyl]-1H-benzimidazol-2-yl]methyl]phenyl]-2-methyl-propionic acid methyl ester

[1475]

[1476] 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 min, [2-amino-4-[[1-(trifluoromethyl)cyclopropyl]methylcarbamoyl]phenyl]ammonium formate (formate salt of Example 29 Step 1) (88%, 175 mg, 0.48 mmol) was added and the reaction mixture was stirred at room temperature for 4 h under an inert atmosphere. The resulting mixture was diluted with EtOAc (40 mL) and washed with water (2x25 mL), brine (25 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was dissolved in acetic acid (5 mL) and stirred at 80°C for 2 h. The obtained mixture was concentrated in vacuo and the residue was distributed between EtOAc (25 mL) and NaHCO (25 mL). The layers were separated and the aqueous portion was extracted with EtOAc (25 mL). The combined organic extracts were dried over Na SO and concentrated in vacuo. The crude material was purified by C18 reverse phase chromatography using a 10%-100% MeCN (+0.1% formic acid) in H O (+0.1% formic acid) solution gradient elution to obtain the title compound as a pale yellow solid.

[1477] LC-MS (Method B): Rt 1.09 min; MS m / z 522.3 = [M+H]+ (100% @ 215 nm)

[1478] 1H NMR (400MHz, methanol-d4) δ8.57 (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.

[1479] Step 2: 2-[(5-Fluoro-3,3-dimethyl-2-oxo-benzofuran-7-yl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide

[1480]

[1481] To a solution of 2-[5-fluoro-2-methoxy-3-[[5-[[1-(trifluoromethyl)cyclopropyl]methylcarbamoyl]-1H-benzimidazol-2-yl]methyl]phenyl]-2-methyl-propionic acid methyl ester (step 1) (100%, 78 mg, 0.15 mmol) in DCM (2.5 mL) was added 1 M BBr in DCM (0.45 mL, 0.45 mmol) under an inert atmosphere, resulting in the formation of a gum. The gum was scraped into a solid, sonicated for 5 min and stirred at room temperature for another 2 h. Another portion of 1 M BBr in DCM (0.45 mL, 0.45 mmol) was added, the resulting solid was scraped and sonicated, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was dissolved in MeCN:H2O and stirred for 1 h. The mixture was purified by C18 reverse phase chromatography eluting with a gradient of 10% to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid) to afford the title compound as a colorless oil.

[1482] LC-MS (Method D): Rt 0.91 min; MS m / z 476.2 = [M+H]+ (99% @ 215 nm)

[1483] 1H NMR (400MHz, methanol-d4) δ8.09(s,1H),8.02(d,J=1.3Hz,1H),7.71(dd,J=8.5,1.6Hz,1H),7.57(d,J=8.5Hz,1H),7.1 1(dd,J=7.6,2.7Hz,1H),7.03(dd,J=9.8,2.6Hz,1H),4.35(s,2H),3.70(s,2H),1.49(s,6H),1.03–0.92(m,4H).

[1484] 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

[1485] The title compound was prepared in analogy to Example 29, Step 3, 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 LiBH4 in THF.

[1486] LC-MS (Method A): Rt 2.25 min; MS m / z 480.3 = [M+H]+ (95% @ 215 nm)

[1487] 1H NMR (500MHz, methanol-d4) δ8.31 (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). The singlet at 8.31 was exchanged with the D part.

[1488] Example 33

[1489] 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyridine-7-carboxamide

[1490]

[1491] Step 1: 1-Bromo-3-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)propan-2-one

[1492]

[1493] 2 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 the addition of thionyl chloride (453 μL, 6.24 mmol), and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo, azeotroped with anhydrous MeCN and the residue was dissolved in anhydrous MeCN (20 mL). The mixture was cooled to 0°C, treated dropwise with 2M trimethylsilyldiazomethane in ether (0.94 mL, 1.87 mmol), and the resulting mixture was warmed to room temperature and stirred for 2 h. The mixture was recooled to 0°C, treated dropwise with HBr in acetic acid (33%, 1.08 mL, 6.24 mmol), and stirred for 1 h while warming to room temperature. The reaction was diluted with acetic acid (5 mL), water (80 mL), and EtOAc (80 mL). The organic matter is separated and further washed with water (2x40mL) and salt solution (40mL). The aqueous layer merged is extracted with EtOAc, and the organic extracts merged are dried over Na2SO4 and concentrated in vacuo. The crude material is purified by silica gel chromatography, eluted with a heptane solution of 0-100% EtOAc, to obtain the title compound as a yellow oil.

[1494] LC-MS (Method D): Rt 1.11 min (59% @ 215 nm)

[1495] 1H NMR (500MHz, DMSO-d6) δ6.97–6.93(m,1H),6.87–6.84(m,1H),4.48(s,2H),3.95(s,2H),3.77(s,3H),1.31(s,9H).

[1496] Step 2: 2-[(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)methyl]imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester

[1497]

[1498] To 1-bromo-3-(4-tert-butyl-2-fluoro-5-methoxy-phenyl)propan-2-one (step 1) (59%, 272mg, 0.51mmol) and 2-aminopyridine-4-methyl-formate (140mg, 0.92mmol) in DCE (10mL) solution, potassium iodide (92mg, 0.55mmol) is added, and the mixture is stirred at 100 ℃ for 4h in a pressure tube. The resulting mixture is cooled to room temperature, diluted with DCM (40mL) and washed with water (2x25mL). The organic portion is dried over Na2SO4, and concentrated in vacuo. The crude material is purified by silica gel chromatography, eluted with a heptane solution of 0-100% EtOAc to obtain the title compound as a brown oil.

[1499] LCMS (Method G): Rt 0.72 min; MS m / z 371.3 = [M+H]+ (92% @ 215 nm)

[1500] 1H NMR(500MHz,DMSO-d6)δ8.56(dd,J=7.1,0.9Hz,1H),8.07–8.04(m,1H),7.84(s,1H),7.28(dd,J=7.1,1.7H z,1H),7.01(d,J=6.8Hz,1H),6.96(d,J=11.8Hz,1H),4.07(s,2H),3.88(s,3H),3.76(s,3H),1.30(s,9H).

[1501] Step 3: 2-[(4-tert-Butyl-2-fluoro-5-methoxy-phenyl)methyl]imidazo[1,2-a]pyridine-7-carboxylic acid

[1502]

[1503] 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]imidazo[1,2-a]pyridine-7-formic acid methyl ester (step 2) (92%, 100mg, 0.25mmol) was added to a solution of THF (5mL) with 2M lithium hydroxide (0.37mL, 0.75mmol), and the reaction mixture was stirred at 40°C for 1h, then at 50°C for 4h. After cooling to room temperature, the organic matter was removed in vacuo and the resulting solid was dissolved in water (10mL). The solution was acidified to pH 4-5 using 2M HCl aqueous solution (about 1mL) and the resulting precipitate was extracted into EtOAc (3x10mL). The combined organic extracts were washed with brine (10mL), dried over Na2SO4 and concentrated in vacuo to give the title compound as a light brown solid.

[1504] LCMS (Method G): Rt 0.44 mins; MS m / z 357.3 = [M+H]+ (95% @ 215 nm)

[1505] 1H NMR(500MHz,DMSO-d6)δ13.31(br.s,1H),8.52(dd,J=7.0,0.8Hz,1H),8.01(s,1H),7.81(s,1H),7.25(dd ,J=7.1,1.7Hz,1H),7.00(d,J=6.8Hz,1H),6.96(d,J=11.8Hz,1H),4.06(s,2H),3.76(s,3H),1.30(s,9H).

[1506] Step 4: 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyridine-7-carboxamide

[1507]

[1508] To a solution of 2-[(4-tert-butyl-2-fluoro-5-methoxy-phenyl)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)cyclopropylamine hydrochloride (59 mg, 0.37 mmol) and DIPEA (0.11 mL, 0.61 mmol) and the mixture was stirred at room temperature for 2 h under an inert atmosphere. Another portion of 1-(trifluoromethyl)cyclopropylamine hydrochloride (59 mg, 0.37 mmol) and DIPEA (0.11 mL, 0.61 mmol) were added and the mixture was heated at 40 °C for 2 h. The resulting mixture was diluted with EtOAc (25 mL) and washed with water (2 x 25 mL), brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography eluting with 0 to 100% EtOAc in heptanes afforded the title compound as a light brown solid.

[1509] LC-MS (Method C): Rt 1.90 min; MS m / z 464.3 = [M+H]+ (95% @ 215 nm)

[1510] 1H NMR(500MHz,DMSO-d6)δ9.28(s,1H),8.51(dd,J=7.1,0.8Hz,1H),8.04(s,1H),7.74(s,1H),7.24(dd,J=7.1,1.8Hz,1H),7 .00(d,J=6.8Hz,1H),6.96(d,J=11.8Hz,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).

[1511] Step 5: 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyridine-7-carboxamide

[1512] 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 NaHCO aqueous solution (10 mL), water (10 mL), dried over NaSO and concentrated in vacuo. The crude product was purified by preparative HPLC (high pH, ​​early elution method) to give the title compound as an off-white solid.

[1513] LCMS (Method A): Rt 2.71 mins; MS m / z 450.3 = [M+H]+ (97% @ 215 nm)

[1514] 1H NMR (400MHz, DMSO-d6) δ9.28(s,1H),9.18(s,1H),8.53(dd,J=7.1,0.8Hz,1H),8.05–8.01(m,1H),7.77(s,1H),7.25(dd ,J=7.1,1.7Hz,1H),6.87(d,J=12.0Hz,1H),6.65(d,J=7.0Hz,1H),3.96(s,2H),1.36–1.28(m,11H),1.20–1.15(m,2H).

[1515] Preparation of intermediate compounds

[1516] Intermediate A

[1517] 2-[5-Benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]acetic acid

[1518]

[1519] Step 1: (3-Bromo-4-fluoro-phenyl)acetate

[1520]

[1521] The cooling (0°C) solution of 3-bromo-4-fluoro-phenol (5g, 26.18mmol) and TEA (6.86mL, 39.27mmol) in DCM (100mL) was treated dropwise with acetyl chloride (2.61mL, 36.65mmol), and the mixture was stirred at room temperature for 45min. The resulting mixture was diluted with DCM (100mL) and washed with 0.5M HCl (120mL), water (120mL), saturated NaHCO (120mL) and brine (120mL) successively. The organic portion was dried over Na SO and concentrated in vacuo to give the title compound as a tan solid.

[1522] LC-MS (Method B): Rt 1.14 mins (85% @ 215 nm)

[1523] 1 H NMR (500MHz, DMSO-d6) δ7.59 (dd, J=6.0, 2.8Hz, 1H), 7.43 (t, J=8.8Hz, 1H), 7.26–7.17 (m, 1H), 2.26 (s, 3H).

[1524] Step 2: 1-(4-Bromo-5-fluoro-2-hydroxy-phenyl)ethanone

[1525]

[1526] A mixture of (3-bromo-4-fluoro-phenyl)acetate (step 1) (90%, 6.3 g, 24.33 mmol) and aluminum chloride (5.84 g, 43.8 mmol) was stirred at 165°C for 3 hours. The melt was allowed to cool to room temperature and the resulting solid was suspended in DCM (100 mL). 2N HCl (100 mL) was added and the mixture was stirred for 3 hours. The insoluble material was removed by filtration (filter 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 Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0-30% EtOAc in heptane to give the title compound as an off-white solid.

[1527] LC-MS (Method B): Rt 1.17 mins (96% @ 215 nm)

[1528] 1 H NMR (500MHz, DMSO-d6) δ11.62(s,1H),7.79(d,J=9.4Hz,1H),7.33(d,J=5.8Hz,1H),2.61(s,3H).

[1529] Step 3: 1-(2-Benzyloxy-4-bromo-5-fluoro-phenyl)ethanone

[1530]

[1531] Benzyl bromide (3.23mL, 27.19mmol) is added to a stirred mixture of 1-(4-bromo-5-fluoro-2-hydroxy-phenyl)ethanone (step 2) (96%, 5.5g, 22.66mmol) and KCO (7.83g, 56.65mmol) in DMF (25mL), and the mixture is stirred at 80°C for 1 hour. The resulting mixture is cooled to room temperature and distributed between EtOAc (150mL) and water (150mL). The aqueous layer is further extracted with EtOAc (100mL). The combined organic extracts are washed with water (2x150mL), brine (150mL), dried over NaSO and concentrated in vacuo. The crude material is purified by silica gel chromatography, eluted with a heptane solution of 0-60% EtOAc to obtain the title compound as an off-white solid.

[1532] LC-MS (Method B): Rt 1.35 mins (87% @ 215 nm)

[1533] 1 H NMR (500MHz, DMSO-d6) δ7.65(d,J=5.5Hz,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).

[1534] Step 4: 2-(2-Benzyloxy-4-bromo-5-fluoro-phenyl)propan-2-ol

[1535]

[1536] 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 (3M 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 hour. The resulting mixture was diluted with saturated NH4Cl aqueous solution (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.

[1537] LC-MS (Method B): Rt 1.31 mins; MS m / z 320.9 / 322.9 [M+H-H2O]+ (95% @ 215 nm)

[1538] 1 H NMR (400MHz, DMSO-d6) δ7.57–7.27(m,7H),5.23(s,1H),5.14(s,2H),1.45(s,6H).

[1539] Step 5: 2-[5-Benzyloxy-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]acetic acid

[1540] To a stirred solution of potassium 3-ethoxy-3-oxo-propionate (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 N2 for 5 min. Diallylpalladium 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 2M LiOH aqueous solution (0.44 mL, 0.88 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with 2M NaOH (10mL) and extracted with EtOAc (3x10mL). The organic extract was discarded and the aqueous portion was acidified to pH 3 using the 2M HCl aqueous solution. The mixture was extracted with EtOAc (3x10mL), and the combined organic extracts were dried over NaSO and concentrated in vacuo to give the title compound as an off-white solid.

[1541] LC-MS (Method B): Rt 1.10 mins; MS m / z 301.0 [M+H-H2O]+ (93% @ 215 nm)

[1542] 1 H NMR(500MHz,DMSO-d6)δ12.40(s,1H),7.49–7.45(m,2H),7.45–7.40(m,2H),7.37–7.33(m,1H),7 .31(d,J=11.5Hz,1H),7.05(d,J=6.3Hz,1H),5.08(s,1H),5.06(s,2H),3.57(s,2H),1.46(s,6H).

[1543] Intermediate B

[1544] 2-(5-Fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)acetic acid

[1545]

[1546] Step 1: 2-(4-Bromo-2-fluoro-5-methoxy-phenyl)acetic acid

[1547]

[1548] In 10min, to a cooled (0°C) solution of 2-(2-fluoro-5-methoxy-phenyl)acetic acid (45g, 244.35mmol) in MeCN (1200mL) was added a solution of bromine (12.63mL, 219.92mmol) in MeCN (100mL). Without removing the ice bath, the mixture was gradually warmed to room temperature (~1.5h). A second solution of bromine (4.21mL, 73.31mmol) in MeCN (50mL) was added dropwise at 0°C and stirring continued for 3.5h at room temperature. A third solution of bromine (4.21mL, 73.31mmol) in MeCN (50mL) was added at room temperature and stirring continued for 30min. The reaction was carefully quenched with saturated aqueous sodium sulfite solution (~700mL) until the bright orange color disappeared. The colorless solution was diluted with brine (200mL) and EtOAc (200mL), stirred vigorously for 10min, and then left to stand at room temperature overnight. The organic layer was separated and the aqueous layer was further extracted with EtOAc (200mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give a crude product as a white solid. The solid was recrystallized by being dissolved in AcOH (700mL) and treated with water (4L). The mixture was stirred and kept at room temperature for 1h, then kept at 0°C for 3h. The resulting solid was filtered, washed with water (200mL) and dried in vacuo at 40°C to give the title compound as a loose white solid.

[1549] LC-MS (Method B): Rt 1.07 min; MS m / z 523.2 / 525.1 / 527.0 = [2M-H]- (99% @ 215 nm)

[1550] 1H NMR (500MHz, DMSO-d6) δ 12.55 (br.s, 1H), 7.50 (d, J = 8.9Hz, 1H), 7.13 (d, J = 6.6Hz, 1H), 3.81 (s, 3H), 3.61 (d, J = 1.3Hz, 2H).

[1551] Step 2:2-(4-Bromo-2-fluoro-5-hydroxy-phenyl)acetic acid

[1552]

[1553] Under N2, a solution of 1M BBr3 in DCM (112.9 mL, 112.9 mmol) was added dropwise 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) over 1 h. 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 give the title compound as an off-white powder.

[1554] LC-MS (Method D): Rt 0.67 min (90% @ 215 nm)

[1555] 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).

[1556] Step 3: Benzyl 2-(5-Benzyloxy-4-bromo-2-fluoro-phenyl)acetate

[1557]

[1558] To a solution of 2-(4-bromo-2-fluoro-5-hydroxy-phenyl)acetic acid (step 2) (90%, 9.2g, 33.25mmol) in DMF (90mL) was added KCO(13.79g, 99.75mmol) and bromotoluene (8.69mL, 73.15mmol), and the reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (300mL) and water (300mL). The aqueous layer was further extracted with EtOAc (150mL). The combined organic extracts were washed with saturated NaHCO(150mL), brine (2x150mL), dried over NaSO and concentrated in vacuo. Purified by silica gel chromatography, eluted with a heptane solution of 0-100% TBME, to obtain the title compound as an off-white solid.

[1559] LC-MS (Method E): Rt 1.84 min (98% @ 215 nm)

[1560] 1H NMR(500MHz,DMSO-d6)δ7.56(d,J=8.9Hz,1H),7.49–7.45(m,2H),7.43–7.32 (m,8H),7.28(d,J=6.6Hz,1H),5.13(s,2H),5.12(s,2H),3.80–3.77(m,2H).

[1561] Step 4: 2-[2-Benzyloxy-4-(2-benzyloxy-2-oxo-ethyl)-5-fluoro-phenyl]-2-methyl-propionic acid methyl ester

[1562]

[1563] A solution of 2-(5-benzyloxy-4-bromo-2-fluoro-phenyl)acetic acid benzyl ester (step 3) (98%, 12.5 g, 28.54 mmol), ZnF2 (2951 mg, 28.54 mmol) and Pd(t-Bu3P)2 (1.46 g, 2.85 mmol) in DMF (100 mL) was bubbled with N2 at room temperature for 10 min. (1-Methoxy-2-methyl-prop-1-enyloxy)-trimethyl-silane (11.59 mL, 57.07 mmol) was added and the reaction mixture was heated to 80°C overnight. The resulting mixture was purified by The mixture was filtered through a pad of 4% paraformaldehyde (5% paraformaldehyde) and washed with EtOAc (3 x 100 mL). The filtrate was washed with brine (500 mL), and the organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 0-100% TBME in heptane gave the title compound as a light yellow oil.

[1564] LC-MS (Method A): Rt 4.51 min; MS m / z 449.2 = [MH]- (81% @ 215 nm)

[1565] The sample was further purified by C18 reverse phase chromatography eluting with 10%-100% MeCN in water and 0.1% formic acid, and the NMR data refer to this sample.

[1566] 1H NMR(500MHz,DMSO-d6)δ7.43–7.35(m,5H),7.38–7.29(m,5H),7.13(d,J=11.0Hz,1H),7 .11(d,J=6.5Hz,1H),5.14(s,2H),5.00(s,2H),3.77(s,2H),3.33(s,3H),1.44(s,6H).

[1567] Step 5:2-(5-Fluoro-3,3-dimethyl-2-oxo-benzofuran-6-yl)acetic acid

[1568] A solution of 2-[2-benzyloxy-4-(2-benzyloxy-2-oxo-ethyl)-5-fluoro-phenyl]-2-methyl-propionic acid methyl ester (step 4) (70%, 10.7g, 16.63mmol) in DCM (250mL) was treated with 1M BBr in DCM (83.13mL, 83.13mmol) solution. The reaction mixture was warmed to room temperature and stirred overnight. The resulting mixture was poured on ice (500g) and stirred for another 30 minutes. The resulting emulsion was filtered through a sinter funnel to obtain a clear two-phase mixture. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2x200mL). The combined organic extracts were dried over NaSO and concentrated in vacuo. The crude material was purified by C18 reverse phase chromatography, eluted with an aqueous solution of 10-100% MeCN (0.1% formic acid modifier) ​​to give the title compound as an off-white solid.

[1569] LC-MS (Method F): Rt 1.31 min; MS m / z 237.2 = [MH]- (100% @ 215 nm)

[1570] 1H NMR (500MHz, DMSO-d6) δ 12.51 (br.s, 1H), 7.41 (d, J = 8.9Hz, 1H), 7.24 (d, J = 5.8Hz, 1H), 3.64 (d, J = 1.4Hz, 2H), 1.44 (s, 6H).

[1571] Intermediate C

[1572] 2-[5-Fluoro-2-methoxy-3-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)phenyl]acetic acid

[1573]

[1574] Step 1: 2-(3-Bromo-5-fluoro-2-methoxy-phenyl)acetic acid

[1575]

[1576] Bromine (3.74mL, 65.16mmol) is added to a stirred solution of 2-(5-fluoro-2-methoxy-phenyl)acetic acid (1.5g, 8.15mmol) in acetic acid (30mL), and the mixture is stirred at room temperature for 1h. The resulting mixture is cooled to 10 ° C and diluted with EtOAc (100mL). Saturated sodium thiosulfate aqueous solution (~50mL) is added under stirring until dark brown turns yellow. The mixture is diluted with water (100mL), and the organic layer is separated. The aqueous layer is extracted with 3: 1 chloroform: IPA mixture (3x50mL), and the combined organic extracts are washed with water (2x50mL), dried over Na2SO4 and concentrated in vacuo. The resulting crude material is purified by silica gel chromatography, eluted with a heptane solution of 0-100% EtOAc to obtain the title compound as a white solid.

[1577] LC-MS (Method D): Rt 0.91 min; MS m / z 261.0 / 263.0 = [MH]- (81% @ 215 nm)

[1578] 1H NMR (400MHz, DMSO-d6) δ 12.52 (br.s, 1H), 7.50 (dd, J = 8.0, 3.1Hz, 1H), 7.21 (dd, J = 9.0, 3.1Hz, 1H), 3.71 (s, 3H), 3.65 (s, 2H).

[1579] Step 2: tert-Butyl 2-(3-bromo-5-fluoro-2-methoxy-phenyl)acetate

[1580]

[1581] To a solution of 2-(3-bromo-5-fluoro-2-methoxy-phenyl)acetic acid (step 1) (260 mg, 0.99 mmol) in tert-butyl alcohol (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 x 25 mL), brine (25 mL), dried over NaSO and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to give the title compound as a colorless oil.

[1582] LC-MS (Method E): Rt 1.67 min (98% @ 215 nm)

[1583] 1H NMR (500MHz, DMSO-d6) δ7.51 (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).

[1584] Step 3: 2-[3-(2-tert-Butoxy-2-oxo-ethyl)-5-fluoro-2-methoxy-phenyl]-2-methyl-propionic acid methyl ester

[1585]

[1586] The title compound was prepared in analogy to Intermediate B, Step 4, from tert-butyl 2-(3-bromo-5-fluoro-2-methoxy-phenyl)acetate (Step 2) and (1-methoxy-2-methyl-prop-1-enyloxy)-trimethyl-silane.

[1587] LC-MS (Method B): Rt 1.38 min; MS m / z 363.1 = [M+Na]+ (80% @ 215 nm)

[1588] 1H NMR (400MHz, DMSO-d6) δ7.09 (dd, J=10.1, 3.2Hz, 1H), 7.00 (dd, J=8.9, 3.1Hz, 1H), 3.59–3.56 (m, 5H), 3.56 (s, 3H), 1.42 (s, 6H), 1.39 (s, 9H).

[1589] Step 4: 2-[5-Fluoro-2-methoxy-3-(2-methoxy-1,1-dimethyl-2-oxo-ethyl)phenyl]acetic acid

[1590] To a solution of 2-[3-(2-tert-butoxy-2-oxo-ethyl)-5-fluoro-2-methoxy-phenyl]-2-methyl-propionic acid methyl ester (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 h. Another portion of TFA (387 μL, 5.05 mmol) was added and the reaction mixture was stirred at room temperature for 3 days.

[1591] The resulting mixture was concentrated in vacuo and azeotroped twice with DCM to give the title compound as a brown oil.

[1592] LC-MS (Method B): Rt 1.07 min; MS m / z 283.0 = [MH]- (88% @ 215 nm)

[1593] 1H NMR (400MHz, DMSO-d6) δ7.11–7.05(m,1H),7.02(dd,J=8.9,3.1Hz,1H),3.60(s,2H),3.58(s,3H),3.57–3.55(m,3H),1.42(s,6H).

[1594] Biological Examples

[1595] Automated whole-cell patch clamp assay for detecting TMEM16A activity in recombinant cells Cell culture and preparation

[1596] Fisher rat thyroid (FRT) cells stably expressing human TMEM16A (TMEM16Aabc variant; Dr Luis Galietta, Insituto Giannina, Italy) were cultured in Coon's modified (Sigma) Hams F-12 medium supplemented with 10% (v / v) fetal bovine serum, penicillin-streptomycin (10,000 U / mL / 10000 μg / mL), G-418 (750 μg / mL), L-glutamine (2 mM) and sodium bicarbonate solution (7.5% v / v) in T-75 flasks. Cells at ∼90% confluence were harvested for experiments by detaching with a 2:1 (v / v) mixture of Detachin (BMSBiotechnology) and 0.25% (w / v) trypsin-EDTA. The cells were diluted to 3.5-4.5 x 10 cells / mL in a medium consisting of CHO-S-SFM II (Sigma), 25 mM HEPES (Sigma) and soybean trypsin inhibitor (Sigma). 6 The density of cells / mL.

[1597] Whole-cell patch clamp recordings

[1598] FRT-TMEM16A cells were subjected to whole-cell patch clamping 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 were used in this assay (all reagents were Sigma):

[1599] 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, 325 mOsm and sucrose.

[1600] Extracellular solution (mM): N-methyl-D-glucamine 130, CaCl2 2, MgCl2 1, HEPES 10, pH 7.3, 320 mOsm and sucrose.

[1601] Intracellular solution to produce maximal TMEM16A-mediated current (EC of calcium ions) 20 ) is activated to a level required for ~20% buffering of intracellular calcium ions. The cell voltage is clamped at a holding potential of -70mV, and a combined voltage step (to +70mV) / clamp (-90mV to +90mV) is applied at 0.05Hz. After the current stabilizes for a period of time, the test compound dissolved in 100% (v / v) DMSO and subsequently diluted into the extracellular solution is used to generate a cumulative concentration response curve. Before adding the next concentration, each concentration of the test compound is incubated for 5 minutes. After testing the final concentration, super-maximal concentrations of known active positive regulators or TMEM16A inhibitors CaCCinhA01 (Del La Fuente et al, 2008) are added to define the upper and lower limits of the assay.

[1602] Compound activity was quantified by measuring the increase in current after compound addition and expressing it as a percentage increase in 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 Qpatch software or GraphpadPrism v6.05, providing the concentration that produced its maximal effect (EC 50 ) and the concentration of maximal efficacy (percent increase from baseline).

[1603] The calculation method is as follows Figure 1 , where an example trace from a Qpatch TMEM16A assay is shown. Figure 1 middle, I BL Equal to the baseline current, I [#1] Equal to the peak current during the incubation period of test compound concentration 1, and so on.

[1604] The peak TMEM16A current at +70 mV was plotted as a function of time during the assay. The baseline current (I BL The increase in current for each compound addition was determined by taking the peak current during the incubation period and subtracting the current during the previous recording period, then expressing it as a percentage of the baseline current. Figure 1 The test compound concentration in 1, which is:

[1605] (I [#1] -I BL / I BL )x100

[1606] For each additional concentration tested, the increase in current was determined by subtracting the current during the previous incubation period and normalizing to the baseline value - for Figure 1 The test concentration in 2, which is:

[1607] (I [#2] –I [#1} / I BL )x100

[1608] The values ​​for each test concentration are plotted as a cumulative function of the concentration, e.g. for test concentration two this would be the sum of the peak changes measured during concentration one plus concentration two.

[1609] The results of the exemplary compounds obtained are shown in Table 2, from which it can be seen that the compounds of the present invention can significantly increase the TMEM16A current level.

[1610] Table 2 - 3. Potentiation shown by 33 μM test compound solutions and calculated EC 50 value

[1611]

[1612]

[1613] All literature and patent documents cited herein are incorporated by reference as fully as possible.

[1614] References

[1615] Accurso FJ, Moss RB, Wilmott RW, Anbar RD, Schaberg AE, Durham TA, RamsayBW; TIGER-1Investigator Study Group(2011) Denufosol tetrasodium in patients with cystic fibrosis and normal to mildly impaired lung function. Am J RespirCrit Care Med, 183(5):627–634.

[1616] Boucher RC(2007)Evidence for airway surface dehydration as the initiating event in CF airway disease.J Intern Med.,261(1):5-16.

[1617] 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 proteinassociated with calcium-dependent chloride channel activity.Science,322(5901):590–594.

[1618] Del La Fuente R,Namkung W,Mills A&Verkman AS(2008)Small moleculescreen identifies inhibitors of a human intestinal calcium-activated chloridechannel.Mol Pharmacol,73(3):758-768.

[1619] 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 toPhase 2.Pulm Pharmacol Ther,21(4):600–607.

[1620] Kunzelmann K&Mall M(2003)Pharmacotherapy of the ion transport defectin cystic fibrosis:role of purinergic receptor agonists and other potentialtherapeutics.Am J Respir Med,2(4):299–309.

[1621] Matsui H,Grubb BR,Tarran R,Randell SH,Gatzy JT,Davis CW and BoucherRC(1998)Evidence for periciliary liquid layer depletion,not abnormal ioncomposition,in the pathogenesis of cystic fibrosis airways disease.Cell,95(7):1005-15.

[1622] Moss RB(2013)Pitfalls of drug development:lessons learned from trialsof denufosol in cystic fibrosis.J Pediatr,162(4):676–680.

[1623] Pedemonte N&Galietta LJ(2014)Structure and function of TMEM16proteins(anoctamins).Physiol Rev,94(2):419–459.

[1624] Pezzulo AA,Tang XX,Hoegger MJ,Abou Alaiwa MH,Ramachandran S,MoningerTO,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 pHimpairs bacterial killing in the porcine cystic fibrosis lung.Nature,487(7405):109–113.

[1625] 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-dependentchloride conductance.Nature,455(7217):1210–1215.

Claims

1. A compound of formula (IA), (IB), (IC), (ID) or (IE), including all tautomeric forms, all enantiomeric and isotopic variations and salts and solvates thereof: in X 5 for CH; R 1 CH(R 11 )(R 12 ); R 11 is H; R 12 Selected from: (i) a 3- to 8-membered cycloalkyl ring; (ii) a 5- or 6-membered oxygen-containing heterocycle; (iv) phenyl, the phenyl group having a hydroxyl group selected from OH, methoxy and optionally substituted by one or more C 1-4 A first optional substituent of a 5-membered heteroaryl ring substituted with alkyl; a second optional substituent selected from fluorine and chlorine; and, selected from C optionally substituted with OH or CN 1-4 a third optional substituent of the alkyl group; (vii) unsubstituted pyridyl or in the presence of CH(R 11 ) is pyridinyl having a single substituent selected from chlorine at adjacent ring positions to the atoms to which it is attached; and Z is a linker selected from -NH-C(O)- and -C(O)-NH-; Y is -CH 2 - or -CH(CH 3 )-; R 2 is phenyl optionally substituted by one or more substituents selected from fluorine, chlorine and OH, C optionally substituted by one or more substituents selected from OH and halogen 1-6 Alkyl, O(C 1-6 alkyl) and O(C 1-6 haloalkyl); 3 to 10 membered carbocyclic ring system; C optionally substituted with one or more substituents selected from halogen, OH and CN 1-6 alkyl; or Y and R 2 Together they form the group -CH 2 -C(R 17 )(R 18 )-CH 2 -N(R 19 )-C(O)OR 20 ; Where R 17 , R 18 and R 19 Each of the 1-4 Alkyl, or R 18 and R 19 Combined with the atoms to which they are attached, they form optionally C 1-3 an alkyl-substituted 5- or 6-membered heterocyclyl ring; and R 20 is C optionally substituted by one or more halo substituents 1-6 Alkyl; or Y and R 2 together to form C substituted with one or more substituents selected from halogen, OH and CN 3-10 an alkyl group; or Y and R 2 together to form a 3- to 8-membered carbocyclic ring, which is optionally replaced by one or more C 1-6 Alkyl substituted, the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen, OH and CN.

2. The compound according to claim 1, which is a compound of general formula (IA):

3. The compound according to claim 1, in: R 12 is a phenyl group, the phenyl group being substituted by a first substituent OH, a second substituent selected from fluorine and chlorine, and a C 3-4 The alkyl group is substituted with a third substituent; or enantiomers, isotopic variations, salts and / or solvates thereof.

4. The compound according to claim 1, wherein Y is CH 2 , or an enantiomer, isotopic variant, salt and / or solvate thereof.

5. The compound according to claim 1, wherein R 2 Selected from an unsubstituted bridged carbocyclic ring system selected from bicyclo-[2.2.2]octanyl or adamantyl; unsubstituted cyclopentyl, cyclohexyl or cycloheptyl; One or more selected from halogen, C 1-4 Alkyl and C 1-4 Cyclopropyl or cyclobutyl substituted with a haloalkyl substituent; and optionally substituted with one or more substituents selected from fluorine, chlorine, OH, optionally substituted with one or more substituents selected from OH and halogen 1-6 Alkyl, O(C 1-6 alkyl) and O(C 1-6 a phenyl ring substituted with a (haloalkyl) substituent; or an enantiomer, isotopic variation, salt and / or solvate thereof.

6. The compound according to claim 1, wherein Y and R 2 Together they form: C substituted with one or more halo substituents 3-4 an alkyl group; or Optionally, one or more selected from halogen, C 1-4 Alkyl and C 1-4 a cyclopropyl or cyclobutyl ring substituted with a haloalkyl substituent; or Group -CH 2 -C(R 17 )(R 18 )-CH 2 -N(R 19 )-C(O)OR 20 , where R 17 , R 18 , R 19 and R 20 Each of are independently H or methyl, or R 18 and R 19 Combined with the atoms to which they are attached, they form a 6-membered heterocyclic ring; and R 20 C 1-6 alkyl; 7. A compound selected from: 2-(1-adamantyl)-N-[2-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide; 2-(1-adamantyl)-N-[2-(tetrahydropyran-2-ylmethyl)-1H-benzimidazol-5-yl]acetamide; 2-(2-adamantyl)-N-(2-benzyl-1H-benzimidazol-5-yl); 2-(2-adamantyl)-N-[2-(2-phenylethyl)-1H-benzimidazol-5-yl]acetamide; 2-(2-adamantyl)-N-[2-[methoxy(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide; 2-(2-adamantyl)-N-[2-[(2-methoxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide; 2-(2-adamantyl)-N-[2-[(R)-methylamino(phenyl)methyl]-1H-benzimidazol-5-yl]acetamide; 2-(1-adamantyl)-N-[2-[(2-chloro-3-pyridyl)methyl]-1H-benzimidazol-5-yl]acetamide; 2-(2-adamantyl)-N-[2-[(2-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide; 2-(2-adamantyl)-N-[2-[(4-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide; 2-(2-adamantyl)-N-[2-[(5-chloro-2-hydroxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide; 2,2,2-trifluoroethyl N-[[5-[[2-(1-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate; 2-(1-adamantyl)-N-[2-[[3-(3,5-dimethylisoxazol-4-yl)phenyl]methyl]-3H-benzimidazol-5-yl]acetamide; tert-Butyl N-[[5-[[2-(2-adamantyl)acetyl]amino]-1H-benzimidazol-2-yl]methyl]carbamate; 2-(2-adamantyl)-N-(2-tetrahydrofuran-3-yloxy-1H-benzimidazol-5-yl)acetamide; N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1,3-benzoxazole-5-carboxamide; 2-(1-adamantyl)-N-[3-amino-2-[(2-hydroxyphenyl)methyl]indazol-6-yl]acetamide; 2-Cyclohexyl-N-(2-isopropyl-1,3-benzoxazol-5-yl)acetamide; N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]indazole-6-carboxamide; 2-Benzyl-N-(cycloheptylmethyl)imidazo[1,2-a]pyridine-7-carboxamide; 2-(1-adamantyl)-N-(2-benzylindazol-6-yl)acetamide; 2-(1-adamantyl)-N-(2-benzyl-3-methyl-indazol-6-yl)acetamide; N-(2-tert-Butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide; tert-Butyl N-[3-[(2-benzyl-1H-benzimidazole-5-carbonyl)amino]-2,2-dimethyl-propyl]carbamate; 2-tert-Butyl-N-(cycloheptylmethyl)-3H-benzimidazole-5-carboxamide; 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazole-5-carboxamide; 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide; 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide; 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]-1,3-benzoxazole-5-carboxamide; 2-[(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1,3-benzoxazole-5-carboxamide; 2-[2-Fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide; 2-(4-tert-Butyl-2-fluoro-5-hydroxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide; 2-Benzyl-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide; 2-Benzyl-N-(cyclopentylmethyl)-1H-benzimidazole-5-carboxamide; 2-Benzyl-N-(cycloheptylmethyl)-1H-benzimidazole-5-carboxamide; N-(Cycloheptylmethyl)-2-[(2-fluoro-6-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide; N-(Cycloheptylmethyl)-2-[(5-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide; N-(Cycloheptylmethyl)-2-[(3-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide; N-(Cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide; N-(Cycloheptylmethyl)-2-[(4-fluoro-2-hydroxy-phenyl)methyl]-1H-benzimidazole-5-carboxamide; N-(Cycloheptylmethyl)-2-[(3-hydroxyphenyl)methyl]-1H-benzimidazole-5-carboxamide; 2-(5-Chloro-2-hydroxy-phenyl)-N-[2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide; N-(2-tert-Butyl-1H-benzimidazol-5-yl)-2-(5-chloro-2-hydroxy-phenyl)acetamide; N-(Cycloheptylmethyl)-2-(1-methylcyclobutyl)-3H-benzimidazole-5-carboxamide; 2-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide; 2-[[2-Fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-(3,3,3-trifluoropropyl)-1H-benzimidazole-5-carboxamide; 2-[[5-Fluoro-2-hydroxy-3-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]methyl]-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-benzimidazole-5-carboxamide; 2-[(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)methyl]-N-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyridine-7-carboxamide; and salts and solvates thereof. 8 . The compound according to claim 7 , which is 2-(2-adamantyl)-N-[2-[(2-hydroxyphenyl)methyl]-1H-benzimidazol-5-yl]acetamide; or a salt thereof. 9 . The compound according to claim 7 , which is 2-(2-adamantyl)-N-[2-[(5-chloro-2-hydroxy-phenyl)methyl]-1H-benzimidazol-5-yl]acetamide; or a salt thereof.

10. The compound according to claim 7, which is 2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide; or a salt thereof.

11. The compound according to claim 7, which is N-(cycloheptylmethyl)-2-[(2-hydroxyphenyl)methyl]indazole-6-carboxamide; or a salt thereof.

12. The compound according to claim 7, which is 2-[2-fluoro-5-hydroxy-4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[2-[1-(trifluoromethyl)cyclopropyl]-1H-benzimidazol-5-yl]acetamide; or a salt thereof.

13. Use of a compound according to any one of claims 1 to 12 in the preparation of a medicament for the treatment or prevention of diseases and conditions affected by the modulation of TMEM16A, wherein the diseases and conditions affected by the modulation of TMEM16A are selected from respiratory diseases and conditions, and the respiratory diseases and conditions are selected from cystic fibrosis, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis including non-cystic fibrosis bronchiectasis, asthma and primary ciliary dyskinesia.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable excipient.

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