Imidazole derivatives as potassium channel inhibitors.

Abstract

The present invention relates to compounds of general formula (I): The compounds of formula (I) are useful for treating cardiac diseases, disorders or conditions in mammals.

Description

[Technical field]

[0001] The present invention relates to novel compounds, their use as medicaments, and the manufacture of medicaments for treating cardiac diseases, disorders or conditions in mammals. The present invention also relates to pharmaceutical compositions comprising the novel compounds. [Background technology]

[0002] The heart is a muscle that pumps blood through the circulation by contracting one to three times per second. Heartbeats are caused by the simultaneous contraction of individual cardiomyocytes (cardiac muscle cells). Synchronization of cellular contractions is governed by an electrical cardiac impulse (cardiac action potential) that is generated in pacemaker cells in the sinus node and spreads rapidly over the heart via a specialized conduction system.

[0003] Disturbances in impulse generation and impulse conduction can occur as a result of disease, medication, or electrolyte imbalance. Such impulse disturbances are called arrhythmias or dysrhythmias and can lead to anxiety, embolism, fainting, or sudden death. In its simplest form, arrhythmia covers anything that differs from normal cardiac sinus rhythm. Disturbances can cover anything from simple palpitations to destructive ventricular fibrillation, including bradycardia and tachycardia.

[0004] At the molecular level, a group of proteins called ion channels can conduct electric current across cell membranes, and thus underlie electrical events in the heart. Different types of ion channels thus play a role in the generation and conduction of cardiac action potentials, the regulation of heart rate by the autonomic nervous system, and the contraction process in individual heart cells. Thus, various types of ion channels are obvious targets for antiarrhythmic cardiac drugs, and many antiarrhythmic drugs on the market exert their effects by interacting with ion channels.

[0005] Antiarrhythmic drugs are usually divided into four main classes according to the so-called Singh Vaughan Williams classification: Class I compounds all inhibit cardiac voltage-gated sodium channels. Some Class I compounds have additional effects that affect the cardiac action potential, which is the basis for a further subdivision into three subclasses: Class IA compounds are sodium channel inhibitors, such as quinidine, procainamide or disopyramide, which prolong action potentials; Class IB compounds are sodium channel inhibitors, such as lidocaine, mexiletine, tocainide, or phenytoin, that shorten the action potential; and Class IC compounds are sodium channel inhibitors such as flecainide, moricizine or propafenone that do not alter action potential duration.

[0006] Class I compounds interact with sodium channels during their open or inactivated state and dissociate from the channels during their closed (relaxed) state. The rate of dissociation determines whether they exhibit frequency-dependent channel inhibition. Some of the Class I compounds, in addition to their sodium channel inhibitory effects, also inhibit potassium or calcium permeable channel subtypes.

[0007] Class II compounds are β-adrenergic receptor inhibitors, including drugs such as atenolol, metoprolol, timolol or propranolol. β-adrenergic receptor inhibitors can be selective for cardiac β1 receptors, or have affinity for β1 and β2 receptors. Some compounds also have intrinsic β-stimulatory effects.

[0008] Class III compounds are potassium channel inhibitors such as amiodarone, dronedarone, sotalol, ibutilide and dofetilide, which prolong the action potential.

[0009] Class IV compounds are inhibitors of L-type calcium channels, such as verapamil.

[0010] Small-conductance calcium-activated potassium (SK) channels are Ca 2+ activation K + They belong to a family of channels. Three SK channel subtypes have been cloned: SK1, SK2, and SK3 (corresponding to KCNN1-3 using the genomic nomenclature). The activity of these channels is regulated by the upregulation of free intracellular calcium ([Ca 2+ ]i) is determined by the concentration of [Ca]i. SK channels have a maximum [Ca 2+ ]i, but 1 μM [Ca 2+ ]i within the physiological range of [Ca 2+ ]i. Selective for potassium, open or active SK channels have a hyperpolarizing effect on the membrane potential of cells. SK channels are widely expressed in the central nervous system (CNS) and peripheral tissues, including the heart.

[0011] The hyperpolarizing action of active SK channels plays an important role in controlling the firing pattern and excitability of excitable cells. SK channel inhibitors such as apamin and N-methylbicuculline have been demonstrated to increase excitability, whereas the SK channel opener 1-EBIO can reduce electrical activity. Ca via a voltage-independent pathway 2+ In non-excitable cells, where the amount of influx is highly sensitive to the membrane potential, activation of SK channels increases the driving force, whereas inhibitors of SK channels have a depolarizing effect, thus decreasing the driving force for calcium.

[0012] SK channel inhibitors inhibit Ca 2+ Activation small conductance K + Potassium ions (K + ) conduction. The disorder can occur, for example, when the Ca channel is depleted of its essential function. 2+ This can be achieved by direct inhibition of ion conductance due to prevention of binding, or by any reduction in current due to reduced calcium sensitivity.

[0013] Reviews of SK channels and SK channel modulators can be found in Wulff H et al.: "Modulators of Small-and Intermediate-Conductance Calcium-Activated Potassium Channels and their Therapeutic Indications", Current Medicinal Chemistry 2007 14 1437-1457; and Liegeois JF et al.: "Modulation of small conductance calcium-activated potassium (SK) channels: a new challenge in medicinal chemistry", Current Medicinal Chemistry 2003 10 625-647.

[0014] [Ca 2+ Based on the important role of SK channels in coupling β-acetylglucosamine to membrane potential, SK channels are an interesting target for developing novel therapeutic agents, and the potential of SK channel inhibitors for use in antiarrhythmic therapy has been recently established (see, e.g., Nattel S; J.Physiol.2009 587 1385-1386; Diness JG, Sоrensen US, Nissen JD, Al-Shahib B, Jespersen T, Grunnet M, Hansen RS; Circ.Arrhythm.Electrophysiol.2010 3 380-90; and Diness et al; Hypertension 2011 57 1129-1135).

[0015] WO 2006 / 013210 describes certain 2-aminobenzimidazole derivatives and their use as modulators of small conductance calcium-activated potassium channels. Summary of the Invention

[0016] The compounds of the present invention are inhibitors or negative modulators of small conductance calcium-activated potassium (SK) channels, with IC50 values ​​of less than 30 μM as demonstrated in the automated patch clamp system described herein, and are considered strong drug candidates. A particular selection of these compounds has significantly improved IC50 values ​​of less than 1 μM. Some of these compounds also have important physicochemical properties suitable for drug substances and for producing pharmaceutical formulations, and may have beneficial properties in terms of pharmacological selectivity profile, in vivo absorption / bioavailability, toxicity and safety profile, and manufacturability. In addition, some of these compounds have pharmacokinetic properties that make them suitable for use as pharmaceuticals.

[0017] In a broad aspect, the present invention provides a compound of formula (I): [ka] (In the formula, R1 is hydrogen and C 1-6 alkyl; R2 to R3 are independently hydrogen and C 1-6 is a group selected from alkyl; or R2 and R3 together with the carbon atom to which they are attached represent C 3-4 Forming a cycloalkyl; R4 to R6 are independently hydrogen, halogen, or C 1-4 alkyl; R7 is hydrogen and C 1-4 is selected from the group consisting of alkyl, R8 is C 1-6 Alkyl, C substituted with one OH 1-6 Alkyl and one OC 1-3 Alkyl-substituted C 1-6 alkyl; or R7 and R8 together with the carbon atom to which they are attached form a C3-4 cycloalkyl; R9 to R13 are independently selected from hydrogen, halogen, and C substituted with at least one halogen.1-6 Alkyl, C 1-6 Alkoxy, C substituted with at least one halogen 1-6 Alkoxy, C 1-6 A group selected from alkylthio and cyano; R14 is H, C 1-6 Alkyl or C 1-6 alkoxy; R15 is H, C 1-6 Alkyl, C substituted with at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted with at least one halogen 1-6 Alkoxy or C 3-4 cycloalkyl; or R14 and R15, together with the nitrogen atom to which they are attached, contain 1 to 2 nitrogen atoms, optionally 1 oxygen atom, and optionally 1 sulfur atom, halogen, C 1-6 Alkyl, C substituted with at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted with at least one halogen 1-6 forming a 4- to 6-membered non-aromatic heterocyclic ring, optionally substituted with at least one group selected from alkoxy; or a pharma- ceutically acceptable salt thereof.

[0018] In one embodiment, R1 is selected from hydrogen (H) and methyl. In another embodiment, R1 is H.

[0019] In a further embodiment, R2-R3 are independently selected from H and C 1-3 In yet a further embodiment, R2 and R3 are independently a group selected from H and methyl. In a further embodiment, R2-R3 are both H.

[0020] In still further embodiments, R4-R6 are independently groups selected from H, F, and methyl.

[0021] In a further embodiment, R7 is selected from H and C 1-3 alkyl. Typically, R7 is methyl or ethyl.

[0022] In yet a further embodiment, R is a C substituted with one OH. 1-4 Alkyl and one OC 1-3 Alkyl-substituted C 1-4 alkyl. Typically, R8 is selected from CH2OH, CH2CH2OH, CH2OCH3, and CH2CH2O-CH3.

[0023] In a further embodiment, R9-R13 are independently selected from H, halogen, C substituted with at least one halogen, 1-6 Alkyl and C substituted with at least one halogen 1-6 Alkoxy is a group selected from the group consisting of alkoxy.

[0024] In still further embodiments, R9, R12 and R13 are all H, and R10-R11 are independently H, halogen, C substituted with at least one halogen. 1-6 Alkyl and C substituted with at least one halogen 1-6 alkoxy, with the proviso that both R10 and R11 are not H.

[0025] In a further embodiment, R14 is selected from H and C 1-6 Typically, R14 is H, methyl or ethyl.

[0026] In still further embodiments, R15 is H, C 1-6 Alkyl, C substituted with at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted with at least one halogen 1-6 Alkoxy or C 3-4cycloalkyl. Typically, R15 is methyl, ethyl, methoxy, cyclopropyl, CH2CH2CF3, or CH2CH2OCF3.

[0027] In another embodiment, R14 and R15 together with the nitrogen atom to which they are attached form a 4-6 membered non-aromatic heterocycle containing one nitrogen atom and optionally one oxygen atom, optionally substituted with at least one halogen, such as azetidinyl, piperidinyl, morpholinyl and isoxazolidinyl, optionally substituted with at least one F.

[0028] In still further embodiments, the compound of formula (I) is selected from any one of the exemplified compounds of Examples 1-21b; or a pharma- ceutically acceptable salt thereof.

[0029] In a further aspect, the present invention relates to a compound of formula (I) as defined above for use as a medicament.

[0030] In a still further aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above and optionally a pharma- ceutically acceptable excipient, such as a carrier or diluent.

[0031] In a further aspect, the present invention relates to a compound of formula (I) as defined above for use in a method for treating a cardiac disease, disorder or condition in a mammal, such as a human. In one embodiment, the cardiac disease, disorder or condition is selected from cardiac diseases, disorders or conditions where the disease, disorder or condition is associated with abnormal rhythms of the heart or variants and exercise-induced angina. In another embodiment, the cardiac disease, disorder or condition is selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmia, and abnormal rhythms occurring after cardiac surgery or cardiac ablation procedures.

[0032] According to a further aspect of the present specification there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt thereof, in combination with a pharma- ceutically acceptable excipient.

[0033] According to a further aspect of the present specification, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt thereof for use in treating a cardiac disease, disorder or condition in a mammal, such as a human. In one embodiment, the cardiac disease, disorder or condition is selected from cardiac diseases, disorders or conditions in which the disease, disorder or condition is associated with abnormal rhythms of the heart or variants and exercise-induced angina. In another embodiment, the cardiac disease, disorder or condition is selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmia, and abnormal rhythms occurring after cardiac surgery or cardiac ablation procedures.

[0034] According to a further aspect of the present specification there is provided a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0035] According to a further aspect of the present specification there is provided a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0036] According to a further aspect of the present specification there is provided a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

[0037] According to a further aspect of the present specification there is provided a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis or treatment of a mammal, such as a human.

[0038] According to a further aspect of the present specification there is provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a mammal, such as a human.

[0039] According to a further aspect of the present specification, there is provided a method for preventing or treating a cardiac disease, disorder or condition in a mammal, such as a human. In one embodiment, the cardiac disease, disorder or condition is selected from cardiac diseases, disorders or conditions associated with abnormal rhythms of the heart or variants and exercise-induced angina. In another embodiment, the cardiac disease, disorder or condition is selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmia, and abnormal rhythms occurring after cardiac surgery or cardiac ablation procedures, in a mammal, such as a human, in need of treatment comprising administering to the animal an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, as defined herein.

[0040] In a further aspect, the present invention relates to a method for treating a cardiac disease, disorder or condition in a mammal, such as a human, comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound of formula (I) as defined above. In one embodiment, the cardiac disease, disorder or condition in the mammal is selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmia, and abnormal rhythms occurring after cardiac surgery or cardiac ablation procedures.

[0041] In yet a further aspect, the present invention relates to processes for preparing compounds of formula I or pharma- ceutically acceptable salts or solvates thereof, as well as intermediates, comprising the steps described in connection with Reaction Schemes 1-9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] In a broad aspect, the present invention provides a compound of formula (I): [ka] (wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are as defined above). The present invention relates to a compound of the formula:

[0043] In certain embodiments, C 1-6 Alkyl or C 1-6 Whenever an alkoxy is substituted with at least one halogen, such C 1-6 Alkyl or C 1-6 It is preferred that the alkoxy is substituted with 1 to 3 halogen, for example 1 to 3 F atoms, with CF3 and OCF3 being preferred.

[0044] In one embodiment, R1 is H. In another embodiment, R1 is C 1-6 It is an alkyl.

[0045] In a further embodiment, R2 is selected from hydrogen and C 1-6 alkyl. Typically, R2 is H. In another embodiment, R2 is methyl.

[0046] In still further embodiments, R3 is selected from hydrogen and C 1-6 alkyl. Typically, R3 is H. In another embodiment, R3 is methyl.

[0047] In further embodiments, R and R together with the carbon atom to which they are attached form a C alkyl group, such as cyclopropyl. 3-4 Forms a cycloalkyl.

[0048] In still further embodiments, R4 is selected from the group consisting of hydrogen, halogen and C 1-4 alkyl. Typically, R4 is H. In another embodiment, R4 is a halogen, such as Cl or F.

[0049] In a further embodiment, R5 is selected from hydrogen, halogen and C 1-4 R5 is a group selected from alkyl. Typically, R5 is H.

[0050] In still further embodiments, R6 is selected from the group consisting of hydrogen, halogen and C 1-4 R6 is a group selected from alkyl. Typically, R6 is H.

[0051] In a further embodiment, R7 is H. In a further embodiment, R7 is C 1-4 In a further embodiment, R7 is methyl. In yet a further embodiment, R7 is ethyl.

[0052] In yet a further embodiment, R8 is C 1-6 It is an alkyl.

[0053] In a further embodiment, R is a C substituted with one OH. 1-6 In yet a further embodiment, R8 is CH2OH. In a further embodiment, R8 is CH2CH2OH.

[0054] In still further embodiments, R8 is one O-C 1-3 Alkyl-substituted C 1-6 In a further embodiment, R8 is one O-C. 1-3 Alkyl-substituted C 1-4 In yet a further embodiment, R8 is CH2OCH3. In a further embodiment, R8 is CH2CH2OCH3.

[0055] In still further embodiments, R7 and R8, together with the carbon atom to which they are attached, are C 3-4 Typically, R7 and R8 together with the carbon atom to which they are attached form a cyclopropyl.

[0056] In a further embodiment, R9 is hydrogen, halogen, C substituted with at least one halogen.1-6 Alkyl, C 1-6 Alkoxy, C substituted with at least one halogen 1-6 Alkoxy, C 1-6 In yet further embodiments, R is a group selected from H, halogen, C substituted with at least one halogen. 1-6 Alkyl and C substituted with at least one halogen 1-6 Typically, R9 is H.

[0057] In a further embodiment, R is hydrogen, halogen, C substituted with at least one halogen. 1-6 Alkyl, C 1-6 Alkoxy, C substituted with at least one halogen 1-6 Alkoxy, C 1-6 In yet further embodiments, R is a group selected from H, halogen, C substituted with at least one halogen. 1-6 Alkyl and C substituted with at least one halogen 1-6 In a further embodiment, R10 is H, unless R11 is H. In a further embodiment, R10 is a halogen, such as Cl. In a further embodiment, R10 is a C substituted with at least one halogen, such as CF3. 1-6 In yet a further embodiment, R is a C substituted with at least one halogen, such as OCF. 1-6 It is an alkoxy.

[0058] In a further embodiment, R is hydrogen, halogen, C substituted with at least one halogen. 1-6 Alkyl, C 1-6 Alkoxy, C substituted with at least one halogen 1-6 Alkoxy, C 1-6 In yet further embodiments, R is a group selected from H, halogen, C substituted with at least one halogen. 1-6Alkyl and C substituted with at least one halogen 1-6 In a further embodiment, R11 is H unless R10 is H. In a further embodiment, R11 is a halogen, such as F or Cl.

[0059] In a further embodiment, R12 is hydrogen, halogen, C substituted with at least one halogen. 1-6 Alkyl, C 1-6 Alkoxy, C substituted with at least one halogen 1-6 Alkoxy, C 1-6 In yet further embodiments, R is a group selected from H, halogen, C substituted with at least one halogen. 1-6 Alkyl and C substituted with at least one halogen 1-6 Typically, R12 is H.

[0060] In a further embodiment, R13 is hydrogen, halogen, C substituted with at least one halogen. 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkoxy, C 1-6 In yet further embodiments, R is a group selected from H, halogen, C substituted with at least one halogen. 1-6 Alkyl and C substituted with at least one halogen 1-6 Typically, R13 is H.

[0061] In a further embodiment, R14 is H. In a further embodiment, R14 is C, such as methyl or ethyl. 1-6 It is an alkyl.

[0062] In a further embodiment, R15 is H. In a further embodiment, R15 is C, such as methyl or ethyl. 1-6In a further embodiment, R is selected from C substituted with at least one halogen. 1-6 In yet a further embodiment, R15 is a C substituted with at least one F, such as CH2CH2CF3. 1-4 In yet a further embodiment, R is C alkyl, such as methoxy. 1-6 In a further embodiment, R15 is C substituted with at least one halogen. 1-6 In yet a further embodiment, R15 is a C substituted with at least one F, such as CH2CH2OCF3. 1-3 In a further embodiment, R is C alkoxy, such as cyclopropyl. 3-4 It is cycloalkyl.

[0063] In another embodiment, R14 and R15, together with the nitrogen atom to which they are attached, contain one nitrogen atom and optionally one oxygen atom, halogen, C 1-6 Alkyl, C substituted with at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted with at least one halogen 1-6 In a further embodiment, R14 and R15 together with the nitrogen atom to which they are attached form a 4-6 membered non-aromatic heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, optionally substituted with at least one halogen, such as azetidinyl, piperidinyl, morpholinyl and isoxazolidinyl, optionally substituted with at least one F.

[0064] In still further embodiments, the compound of formula (I) is selected from any one of the exemplified compounds of Examples 1-21b; or a pharma- ceutically acceptable salt thereof.

[0065] In certain embodiments, C 1-6 Alkyl or C 1-6Whenever an alkoxy is substituted with halogen, such C 1-6 Alkyl or C 1-6 It is preferred that the alkoxy is substituted with 1 to 3 halogen, for example 1 to 3 F atoms, with CF3 and OCF3 being preferred.

[0066] Each of the compounds described in the experimental section constitutes an embodiment of the invention in any form, such as a salt or free base, and claims may be made to such compounds or their salts.

[0067] In still further embodiments, the compound of formula (I) is selected from the pharma- ceutically acceptable acid salts of any one of the compounds of Examples 1-21b.

[0068] Heart disease In the context of the present invention, a cardiac disease, disorder or condition is any cardiac disease, disorder or condition, including but not limited to cardiac abnormal rhythms or variants and exercise-induced angina.

[0069] In more specific embodiments, the cardiac disease, disorder or condition is any disease, disorder or condition associated with abnormal cardiac rhythms or variants and exercise-induced angina.

[0070] In a more specific embodiment, the cardiac disease, disorder or condition is any disease, disorder or condition associated with abnormal rhythm of the heart.

[0071] In more specific embodiments, the cardiac disease, disorder or condition associated with abnormal cardiac rhythm is selected from cardiac arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, and bradyarrhythmia.

[0072] In another embodiment, the cardiac disease, disorder or condition of the present invention is an abnormal rhythm caused by myocardial ischemia, myocardial infarction, cardiac hypertrophy or cardiomyopathy.

[0073] In another embodiment, the cardiac disease, disorder or condition of the present invention is abnormal rhythms occurring following cardiac surgery or cardiac ablation procedures.

[0074] In a further particular embodiment, the cardiac disease, disorder or condition associated with abnormal rhythm of the heart is a cardiac arrhythmia caused by a genetic disease.

[0075] In a further preferred embodiment, the cardiac disease, disorder or condition associated with abnormal rhythm of the heart is cardiac arrhythmia.

[0076] In a preferred embodiment, the cardiac disease, disorder or condition associated with abnormal rhythm of the heart is atrial fibrillation.

[0077] In certain embodiments, the compounds of formula (I) of the present invention are useful for the treatment of atrial fibrillation by acute cardioversion to normal sinus rhythm.

[0078] In another particular embodiment, the compounds of formula (I) of the present invention are useful for the treatment of atrial fibrillation by maintaining normal sinus rhythm and avoiding or reducing the occurrence of new episodes of atrial fibrillation.

[0079] Pharmacological Treatment of Atrial Fibrillation In the context of the present invention, and as will be understood by those skilled in the art, the treatment of atrial fibrillation is either acute cardioversion or maintenance of sinus rhythm or both. Conversion is defined as the application of a compound with the ability to convert atrial fibrillation to normal cardiac sinus rhythm. Normal sinus rhythm is defined as a regular stable heart beat at a frequency of 40-100 beats per minute at rest in an adult with normal regular p-waves on a standard 12-lead electrocardiogram. Maintenance of sinus rhythm is defined as the ability of a compound to maintain normal stable sinus rhythm over time without relapse to atrial fibrillation, or the ability of a compound to significantly reduce the incidence of relapse from atrial fibrillation to normal sinus rhythm compared to untreated controls.

[0080] General Process Description Schemes 1-9 outline one synthetic approach that can be used to prepare compounds of general formula (I).

[0081] Scheme 1: Route to intermediate 8 [ka]

[0082] Numerous ketones and aldehydes (1) are commercially available or can be readily prepared by many routes described in the literature. Ketones and aldehydes (1) can be converted to hydantoin derivatives (2) by a wide range of methods, for example, by reaction of (1) with potassium cyanide under the influence of an ammonium salt (e.g., ammonium carbonate) upon heating in solvents such as water and alcohols (e.g., ethanol). Hydantoin derivatives (2) can be converted to amino acid derivatives (3) by hydrolysis under the influence of a strong base (e.g., sodium hydroxide) and heat in water. There are many other well-established methods for the preparation of amino acids described in the literature. Many amino acid derivatives are also readily commercially available. Amino acids (3) can be protected as N-(tert-butoxy)carbonyl derivatives (4) by treatment with di-tert-butyl dicarbonate and base (e.g., sodium bicarbonate) in a suitable solvent (e.g., tetrahydrofuran, water). Intermediate (4) can be reduced to alcohol derivative (5) by a variety of methods including hydride reducing agents (e.g., sodium borohydride or lithium aluminum hydride). This can be accomplished by first activating the acid group of (4) by direct reduction of the acid group (e.g., with lithium aluminum hydride in tetrahydrofuran) or by conversion to a mixed anhydride (e.g., with isobutyl chloroformate and triethylamine in tetrahydrofuran) followed by reduction with sodium borohydride (e.g., in water). Alcohol derivative (5) may require protection such as conversion to an ester (e.g., 2,2-dimethylpropanoate ester) by reaction with 2,2-dimethylpropanoyl chloride and a base (e.g., triethylamine) in a solvent (e.g., dichloromethane). Intermediate (6) can be deprotected to amine derivative (7) by treatment with an acid (e.g., hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g., dioxane or dichloromethane). Intermediate (7) can be converted to the isothiocyanate derivative (8) by reaction with thiophosgene in a suitable solvent (eg dichloromethane) under the influence of a base (eg sodium bicarbonate).

[0083] Scheme 2: Route to intermediates 14 and 16 [ka]

[0084] Ketones and aldehydes (1) can be converted to sulfinamide derivatives (9) by reaction of (1) with 2-methylpropane-2-sulfinamide under the influence of a Lewis acid (e.g., titanium(IV) ethoxide) and heating in a suitable solvent (e.g., tetrahydrofuran). The sulfinamide derivatives (9) can be converted to β-amino acid esters (10) by reaction with methyl 2-bromoacetate under the influence of zinc with heating in a solvent (e.g., tetrahydrofuran). There are many other well-established methods for the preparation of β-amino acids described in the literature. Some β-amino acid derivatives are also readily commercially available. The β-amino acid esters (10) can be reduced to alcohol derivatives (11) by a variety of methods, including hydride reducing agents (e.g., sodium borohydride, lithium aluminum hydride) in a suitable solvent (e.g., tetrahydrofuran). The alcohol derivatives (11) may require protection such as conversion to esters (e.g., 2,2-dimethylpropanoate esters) by reaction with 2,2-dimethylpropanoyl chloride and a base (such as triethylamine) in a solvent (e.g., dichloromethane). Intermediate (12) can be deprotected to amine derivatives (13) by treatment with an acid (e.g., hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g., dioxane or dichloromethane). Intermediate (13) can be converted to isothiocyanate derivatives (14) by reaction with thiophosgene in a suitable solvent (e.g., dichloromethane) under the influence of a base (e.g., sodium bicarbonate).

[0085] Intermediate (10) can be deprotected to amine derivative (15) by treatment with an acid (e.g., hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g., dioxane or dichloromethane). Intermediate (15) can be converted to isothiocyanate derivative (16) by reaction with thiophosgene in a suitable solvent (e.g., dichloromethane) under the influence of a base (e.g., sodium bicarbonate).

[0086] Scheme 3: Route to intermediate 19 [ka]

[0087] The alcohol derivative (5) can be alkylated on the alcohol oxygen atom by reaction with methyl iodide under the influence of a metal oxide (e.g., silver oxide) in a solvent (e.g., acetonitrile) and converted to intermediate (17). Intermediate (17) can be deprotected to amine derivative (18) by treatment with an acid (e.g., hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g., dioxane or dichloromethane). Intermediate (18) can be converted to the isothiocyanate derivative (19) by reaction with thiophosgene in a suitable solvent (e.g., dichloromethane) under the influence of a base (e.g., sodium bicarbonate).

[0088] Scheme 4: Route to intermediate 21 [ka]

[0089] There is a wide range of intermediates (20) that are either readily commercially available or can be prepared by methods described in the literature. Intermediate (20) can be converted to the isothiocyanate derivative (21) by reaction with thiophosgene in a suitable solvent (e.g. dichloromethane) under the influence of a base (e.g. sodium bicarbonate).

[0090] Scheme 5: Route to intermediate 28 [ka]

[0091] There is a wide range of benzene-1,2-diamine intermediates (22) that are readily commercially available or can be prepared by methods described in the literature. Intermediate (22) can be converted to 2,1,3-benzothiadiazole derivatives (23) by reaction with thionyl chloride in pyridine. Intermediate (23) can be converted to benzyl bromide derivatives (24) by reaction with N-bromosuccinimide in a solvent (e.g. chloroform) under the influence of a radical initiator (e.g. benzoyl peroxide) upon heating. Intermediate (24) can be reacted with tert-butyl N-tert-butoxycarbonylcarbamate under the influence of a base (e.g. potassium carbonate) upon heating in a solvent (e.g. acetonitrile) to give intermediate (25). Intermediate (25) can be deprotected to amine derivatives (26) by treatment with an acid (e.g. hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g. dioxane or dichloromethane). Intermediate (26) can be converted to urea derivative (27) by reaction with a wide range of commercially available carbamoyl chlorides under the influence of a base (e.g., triethylamine) in a suitable solvent (e.g., dichloromethane). Intermediate (27) can be converted to benzene-1,2-diamine derivative (28) by desulfurization with hydrogen gas under the influence of a metal catalyst (e.g., Raney nickel) in a suitable solvent (e.g., methanol).

[0092] Scheme 6: Route 1 to examples and separation of enantiomers [ka]

[0093] The benzene-1,2-diamine derivatives (28) can be reacted with isothiocyanates (8) or (14) in a suitable solvent (e.g., dichloromethane) to give a mixture of thiourea products (29) and (30). A wide range of other benzene-1,2-diamine derivatives are commercially available or can be easily prepared by well-established methods described in the literature (e.g., by nitration and subsequent reduction of commercially available substituted benzene starting materials). The thiourea derivatives (29) and (30) can be converted to the 2-aminobenzimidazole derivatives (31) by a ring formation reaction that occurs under the influence of iodoacetic acid and heating in a suitable solvent (e.g., methanol or acetonitrile). The cyclization of (29) and (30) to give (31) can also occur under the influence of mercury salts (e.g., mercuric oxide) with heating in a suitable solvent (e.g., acetonitrile). The 2-aminobenzimidazole ester derivatives (31) can be converted to compounds of formula (I) by deprotection of the ester under the influence of a base (e.g., sodium hydroxide) in a suitable solvent (e.g., methanol).

[0094] The 2-aminobenzimidazole derivatives of formula (I) may be racemic mixtures, which can be separated into the two enantiomers A and B by various methods, including chromatography using chiral stationary phases. This may be normal phase or reverse phase chromatography, using a suitable solvent mixture as eluent (e.g., chloroform, dichloromethane, ethanol, ethyl acetate, methanol, ethanol), sometimes with an additive (e.g., ammonia, triethylamine, trifluoroacetic acid, acetic acid).

[0095] Scheme 7: Route 2 to examples and separation of enantiomers [ka]

[0096] The benzene-1,2-diamine derivative (28) can be reacted with isothiocyanate (16) in a suitable solvent (e.g. dichloromethane) to give a mixture of thiourea products (32) and (33). A wide range of other benzene-1,2-diamine derivatives are commercially available or can be easily prepared by well-established methods described in the literature (e.g. by nitration and subsequent reduction of commercially available substituted benzene starting materials). The thiourea derivatives (32) and (33) can be converted to the derivative (34) by a ring formation reaction that occurs under the influence of iodoacetic acid and heating in a suitable solvent (e.g. methanol or acetonitrile). The cyclization of (32) and (33) to give (34) can also occur under the influence of a mercury salt (e.g. mercuric oxide) with heating in a suitable solvent (e.g. acetonitrile, methanol). The derivative (34) can be converted to a compound of formula (I) by reduction under the influence of a hydride reducing agent (e.g. sodium borohydride) with heating in a suitable solvent (e.g. tetrahydrofuran).

[0097] The 2-aminobenzimidazole derivatives of formula (I) may be racemic mixtures, which can be separated into the two enantiomers A and B by various methods, including chromatography using chiral stationary phases. This may be normal phase or reverse phase chromatography, using a suitable solvent mixture as eluent (e.g., chloroform, dichloromethane, ethanol, ethyl acetate, methanol, ethanol), sometimes with an additive (e.g., ammonia, triethylamine, trifluoroacetic acid, acetic acid).

[0098] Scheme 8: Route 3 to examples and separation of enantiomers [ka]

[0099] Intermediate (25) can be converted to benzene-1,2-diamine derivative (35) by desulfurization with hydrogen gas under the influence of a metal catalyst (e.g. Raney nickel) in a suitable solvent (e.g. methanol). Derivative (35) can be reacted with isothiocyanate (8) in a suitable solvent (e.g. dichloromethane, acetonitrile) to give a mixture of thiourea products (36) and (37). Thiourea derivatives (36) and (37) can be converted to 2-aminobenzimidazole derivative (38) by a ring formation reaction that occurs under the influence of iodoacetic acid and heating in a suitable solvent (e.g. methanol or acetonitrile). Cyclization of (36) and (37) to give aminobenzimidazole derivative (38) can also occur under the influence of mercury salts (e.g. mercuric oxide) with heating in a suitable solvent (e.g. acetonitrile, methanol). Intermediate (38) can be deprotected to amine derivative (39) by treatment with an acid (e.g., hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g., dioxane or dichloromethane). Intermediate (39) can be converted to urea derivative (40) by reaction with a wide range of commercially available carbamoyl chlorides or isocyanates under the influence of a base (e.g., triethylamine) in a suitable solvent (e.g., dichloromethane). 2-Aminobenzimidazole ester derivative (40) can be converted to a compound of formula (I) by deprotecting the ester under the influence of a base (e.g., sodium hydroxide) in a suitable solvent (e.g., ethanol). 2-Aminobenzimidazole derivatives of formula (I) can be racemic mixtures, which can be separated into two enantiomers A and B by various methods, including chromatography using chiral stationary phases. This can be normal phase or reverse phase chromatography, which uses suitable solvent mixtures as eluents (e.g., chloroform, dichloromethane, ethanol, ethyl acetate, methanol, ethanol), sometimes with an additive (e.g., ammonia, triethylamine, trifluoroacetic acid, acetic acid).

[0100] Scheme 9: Route to Example 4 [ka]

[0101] The benzene-1,2-diamine derivatives (28) can be reacted with isothiocyanates (19) or (21) in a suitable solvent (e.g. dichloromethane) to give a mixture of thiourea products (41) and (42). The thiourea derivatives (41) and (42) can be converted to the 2-aminobenzimidazole derivatives of formula (I) by a ring formation reaction that occurs under the influence of iodoacetic acid and heating in a suitable solvent (e.g. methanol or acetonitrile). The cyclization of (41) and (42) to give the derivatives of formula (I) can also occur under the influence of mercury salts (e.g. mercuric oxide) with heating in a suitable solvent (e.g. acetonitrile, methanol). The 2-aminobenzimidazole derivatives of formula (I) can be racemic mixtures, which can be separated into the two enantiomers A and B by various methods, including chromatography using chiral stationary phases. This can be normal phase or reverse phase chromatography, which uses suitable solvent mixtures as eluents (e.g., chloroform, dichloromethane, ethanol, ethyl acetate, methanol, ethanol), sometimes with an additive (e.g., ammonia, triethylamine, trifluoroacetic acid, acetic acid).

[0102] Those skilled in the art will understand that it may be necessary to adjust or change the order of steps in the above processes, and that such changes in order are encompassed within the aspects of the processes described above in the reaction schemes and the accompanying description of the process steps.

[0103] Moreover, those skilled in the art will appreciate that the processes described above and below may require that the functional groups of intermediate compounds be protected by protecting groups.

[0104] Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include optionally substituted and / or unsaturated alkyl groups (e.g. methyl, allyl, benzyl or tert-butyl), trialkylsilyl or diarylalkylsilyl groups (e.g. t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), AcO (acetoxy), 2,2-dimethylpropanoate, TBS (t-butyldimethylsilyl), TMS (trimethylsilyl), PMB (p-methoxybenzyl) and tetrahydropyranyl. Suitable protecting groups for carboxylic acid include (C1-C6)-alkyl or benzyl esters. Suitable protecting groups for amino include t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy-methyl or 2-trimethylsilylethoxycarbonyl (Teoc). Suitable protecting groups for S include SC(=N)NH2, TIPS.

[0105] Protection and deprotection of functional groups can be carried out before or after any of the reactions in the above processes.

[0106] Furthermore, those skilled in the art will appreciate that the individual process steps described herein above may be performed in a different order and / or the individual reactions may be performed at different stages throughout the pathway (i.e., substituents may be added to intermediates and / or chemical transformations may be performed that are different from those described herein above in connection with a particular reaction) in order to obtain the compounds of the invention in an alternative, and in some cases more convenient, manner, which may negate or make necessary the need for protecting groups.

[0107] The compounds of formula (I) have at least one asymmetric center, and may have additional asymmetric centers, and it is intended that any optical isomers (i.e., enantiomers or diastereomers) in the form of separated, pure or partially purified optical isomers, and any mixtures thereof, including racemic mixtures, i.e., mixtures of stereoisomers, are included within the scope of the present invention. In particular, the carbon atom of formula (I) is an asymmetric center with four valence bonds attached to R7, R8, NH, and phenyl, giving rise to two optical isomers, the R form and the S form. In one embodiment, the compounds of the present invention have the S form. In another embodiment, the compounds of the present invention have the R form. In a further embodiment, the compounds of the present invention are racemic mixtures.

[0108] In this context, when specifying an enantiomeric form, it is understood that the compound is in enantiomeric excess, e.g., in essentially pure monoenantiomeric form.Accordingly, one embodiment of the present invention relates to a compound of the present invention having an enantiomeric excess of at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%.

[0109] Racemates can be resolved into their optical antipodes in known manner, for example by separation of their diastereomeric salts with an optically active acid and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into their optical antipodes is based on chromatography on an optically active matrix. The compounds of the present invention can also be resolved by the formation of diastereomeric derivatives.

[0110] Additional methods for the resolution of optical isomers known to those skilled in the art may be used. Such methods include those discussed in J. Jaques, A. Collet and S. Wilen, "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials.

[0111] Furthermore, when double bonds or fully or partially saturated ring systems are present in the molecule, geometric isomers may be formed. Any geometric isomers, either as separated, pure or partially purified geometric isomers or mixtures thereof, are intended to be included within the scope of the present invention. Similarly, molecules with bonds that are restricted in rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.

[0112] Additionally, the compounds of the present invention of general formula I have a benzimidazole structure that exists in tautomeric forms, and as used herein, all tautomers are included in the compounds of formula I, although only one is shown.

[0113] The tautomers of formula (I) are [ka] It is.

[0114] The benzimidazole tautomers of formula I above mean that the hydrogen switches back and forth from one nitrogen to the other, resulting in the double bond switching back and forth between the point of attachment to the nitrogen and the carbon NH group. Additionally, when structures are presented with benzimidazole as part of a general structure or as an individual specific compound, it should be understood that benzimidazole covers all tautomers, and thus all are included, even though only one tautomer is shown.

[0115] "A compound of formula (I)", whenever used herein, unless otherwise indicated herein or clearly contradicted by context, means a compound of formula (I) in any form, including free form, or as a salt thereof, for example a pharma- ceutically acceptable salt thereof.

[0116] Whenever substituents are disclosed as R1-R15, it means that any and all successive possibilities are disclosed, for example, R2-R4 means R2, R3 and R4, for example, R9-R13 means R9, R10, R11, R12 and R13. In yet a further embodiment, compound I is in free form. In one embodiment, the free form is anhydrous. In another embodiment, the free form is a solvate, for example a hydrate.

[0117] In a further embodiment, the compound is in a crystalline form. One skilled in the art can conduct tests to find polymorphs, and such polymorphs are intended to be encompassed by the term "crystalline form" as used herein.

[0118] When the compounds and pharmaceutical compositions disclosed herein are used for the above treatments, a therapeutically effective amount of at least one compound is administered to a mammal in need of treatment.

[0119] The term "free form" as used herein means a compound of formula (I) that is the free base or free acid, as the case may be, and not in any salt form.

[0120] As used herein, "C 1-x The term "alkyl" refers to an alkyl group containing 1 to x carbon atoms, e.g., C 1-3 , C 1-4 , C 1-5 , or C 1-6 , for example, methyl, ethyl, propyl, butyl, pentyl or hexyl; 3-6 Also included are alkyl groups such as isopropyl, isobutyl, tert-butyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. 1-6 C such as alkyl 1-xWhen an alkyl is substituted with a group such as a halogen, such as F, it means that such F, e.g., three F, are bonded to one carbon (CF), or to two carbons (CF-CF), or even to three carbons (CF-CF-CF).

[0121] As used herein, "C 1-x The term "alkylene" refers to an alkylene group containing 1 to x carbon atoms, e.g., C 1-3 , C 1-4 , C 1-5 , or C 1-6 , for example methylene, ethylene, propylene, butylene, pentylene or hexylene; 3-6 Also included are alkylenes such as isopropylene, isobutylene, tert-butylene, isopentylene, 3-methylbutylene, 2,2-dimethylpropylene, n-hexylene, 2-methylpentylene, 2,2-dimethylbutylene, and 2,3-dimethylbutylene.

[0122] As used herein, "C 1-x Alkoxy" or "OC 1-x The term "alkyl" (used interchangeably) refers to an alkyl group containing 1 to x carbon atoms, e.g., C 1-5 Or C 1-6 "N-alkyl" means an oxygen atom covalently bonded to the aryl group, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, n-pentyloxy or n-hexyloxy.

[0123] As used herein, "C 1-x Alkylthio" or "SC 1-x The term "alkyl" (used interchangeably) refers to an alkyl group containing 1 to x carbon atoms, e.g., C 1-5 Or C 1-6 "N" means a sulfur atom covalently bonded to the radical, e.g., methylthio, ethylthio, n-propylthio, and the like.

[0124] As used herein, "C 3-4The term "cycloalkyl" means a cyclic alkyl group containing 3 to 4 carbon atoms, such as cyclopropyl or cyclobutyl.

[0125] The term "CN" as used herein means cyano or nitrile (C and N linked by a triple bond).

[0126] As used herein, "C substituted with at least one halogen" refers to 1-6 The term "alkyl" refers to any C alkyl group as defined herein, such as CHFCF or CF. 1-6 It means one or more halogen atoms, as defined herein, linked to one or more carbon atoms of an alkyl.

[0127] As used herein, "C substituted with at least one halogen" refers to 1-6 The term "alkoxy" refers to any C alkyl group, as defined herein, such as OCH2CHF2 or OCF3. 1-6 Alkoxy means one or more halogen atoms, as defined herein, linked to one or more carbon atoms of the alkyl group.

[0128] As used herein, "C substituted with one OH" refers to 1-4 The term "alkyl" refers to any alkyl group as defined herein, such as CHOH, CHCHOH, or CHOHCH. 1-4 It means one OH group attached via an oxygen to one or more carbon atoms of an alkyl.

[0129] As used herein, "one O.C. 1-3 Alkyl-substituted C 1-4 The term "alkyl" refers to any C alkyl group as defined herein, such as CH2OCH3 or CH2CH2OCH3. 1-4 One or more OC's attached via oxygen to one or more carbon atoms of the alkyl 1-3 It means an alkyl group.

[0130] The term "halogen" as used herein means an atom selected from chloro (Cl), fluoro (F), iodo (I) and bromo (Br).

[0131] As used herein, the term "5- or 6-membered aromatic heterocycle containing at least one nitrogen atom and optionally one oxygen atom and optionally one sulfur atom" refers to a chemically stable monoaromatic ring system containing at least one nitrogen, preferably 1-3 N, and up to 5 carbon atoms, optionally one oxygen atom, and / or one sulfur atom, such as, but not limited to, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyridinyl, diazinyl, pyridazinyl, triazinyl, and tetrazinyl.

[0132] The term "4-6 membered non-aromatic heterocycle containing 1-2 nitrogen atoms, optionally 1 oxygen atom, and optionally 1 sulfur atom" as used herein means a monocyclic ring system having 1 or 2 nitrogen atoms and optionally 1 oxygen and optionally 1 sulfur atom forming a saturated or unsaturated 4-, 5- or 6-membered ring system such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolidinyl, isothiazolidinyl, and isoxazolidinyl.

[0133] The terms "treatment" and "treating" as used herein refer to the management and care of a patient for the purpose of combating a condition, such as a disease or disorder. This term is intended to include the full range of treatments for a given condition suffered by a patient, such as the administration of active compounds to alleviate symptoms or complications, to delay the progression of a disease, disorder or condition, to alleviate or relieve symptoms and complications, and / or to cure or eliminate a disease, disorder or condition, as well as to prevent symptoms, where prevention is to be understood as the management and care of a patient for the purpose of combating a disease, condition or disorder, and includes the administration of active compounds to prevent the onset of symptoms or complications. Treatment can be performed acutely or chronically. The patient to be treated is preferably a mammal; in particular a human, but can also include animals such as dogs, cats, cows, sheep and pigs.

[0134] The term "pharmaceutically acceptable salt" as used herein is used to specify that the salt is suitable for use in the human or animal body. An exemplary list of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use, P.H. Stahl and C.G. Wermuth, editors, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. The pharmaceutically acceptable salt of the compound of formula (I) includes those salts that can be formed in the human or animal body after the compound is administered to the human or animal body.

[0135] The term "therapeutically effective amount" of the compound of formula (I) of the present invention as used herein means an amount sufficient to cure, alleviate or partially stop the clinical manifestations of a given disease and its complications. An amount sufficient to achieve this is defined as a "therapeutically effective amount". The effective amount for each purpose depends on the severity of the disease or injury and the weight and general condition of the subject. It will be understood that determining the appropriate dosage can be accomplished using routine experimentation by constructing a matrix of values ​​and testing different points within the matrix, all of which is within the ordinary skill of a trained physician or veterinarian.

[0136] In yet a further aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and optionally a pharma- ceutically acceptable excipient, such as a carrier or excipient.Typically, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable excipient, such as a carrier or excipient.

[0137] As used herein, "pharmaceutically acceptable excipients" are intended to include, but are not limited to, carriers, excipients, diluents, adjuvants, colorants, flavorings, preservatives, and the like that a person skilled in the art would consider using when formulating a compound of the present invention to make a pharmaceutical composition.

[0138] Adjuvants, diluents, excipients and / or carriers that may be used in the compositions of the present invention must be pharma- ceutically acceptable in the sense that they are compatible with the compound of formula (1) and other components of the pharmaceutical composition and are not harmful to the recipient. The compositions preferably do not contain materials that may cause adverse reactions, such as allergic reactions. Adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical compositions of the present invention are well known to those skilled in the art.

[0139] As mentioned above, the compositions and especially pharmaceutical compositions disclosed herein may further comprise at least one pharma- ceutically acceptable adjuvant, diluent, excipient and / or carrier in addition to the compounds disclosed herein. In some embodiments, the pharmaceutical composition comprises 1-99% by weight of at least one pharma- ceutically acceptable adjuvant, diluent, excipient and / or carrier and 1-99% by weight of the compounds disclosed herein. The total amount of active ingredient and pharma- ceutically acceptable adjuvant, diluent, excipient and / or carrier may not constitute more than 100% by weight of the composition, especially the pharmaceutical composition.

[0140] In some embodiments, only one compound disclosed herein is used for the above purposes.

[0141] In some embodiments, two or more of the compounds disclosed herein are used in combination for the above purposes.

[0142] Compositions, particularly pharmaceutical compositions, comprising the compounds described herein may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual or subcutaneous administration, or for administration via the respiratory tract, for example in the form of an aerosol or air-suspended fine powder. Thus, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, powder, nanoparticle, crystal, amorphous material, liquid, transdermal patch or suppository.

[0143] Further embodiments of this process are described in the experimental section herein, with each individual process and each starting material constituting an embodiment that may form part of an embodiment.

[0144] The above embodiments should be considered to refer to any one of the aspects described herein (such as "method of treatment," "pharmaceutical composition," "compound for use as a medicament," or "compound for use in a method") and any one of the embodiments described herein, unless specified that the embodiment relates to one or more particular aspects of the invention.

[0145] All references cited in this specification, including publications, patent applications, and patents, are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0146] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0147] Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0148] As used in the context of describing the invention, the terms "a" and "an" and "the" and similar referents should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0149] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. Unless otherwise indicated, all exact values ​​provided herein represent corresponding approximations (e.g., all exact exemplary values ​​provided with respect to a particular factor or measure can also be considered to provide corresponding approximate measures modified by "about" where appropriate).

[0150] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0151] The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended merely to better clarify the invention and does not limit the scope of the invention unless specifically stated. No language in the specification should be construed as indicating any element as essential to the practice of the invention unless expressly stated.

[0152] Citation and incorporation of patent documents herein is done for convenience only and does not reflect any opinion of the validity, patentability and / or enforceability of such patent documents.

[0153] Any description herein of any aspect or embodiment of the invention using terms such as "comprising," "having," "including," or "containing" in reference to one or more elements is intended to support similar aspects or embodiments of the invention that "consists of," "consists essentially of," or "substantially comprises" that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

[0154] This invention includes all modifications and equivalents of the subject matter recited in the aspects or claims presented herein to the maximum extent permitted by applicable law.

[0155] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples, both separately and in any combination thereof, may be material for realizing the invention in diverse forms thereof.

[0156] Experimental procedure Automated patch clamp Human SK3 channel (hK Ca Automated whole-cell patch clamp recordings were performed on HEK-293 cells stably expressing hK using the QPatch 16 HT system and a single-hole Qplate (Biolin Scientific, Sophion, Denmark). Cells were cultured and prepared for experiments using normal cell culture procedures. A total of 4-5 million cells were used per experiment. Qpatch automatically generates gigaseals, whole-cell formation, compound application and current recording. hK Ca 2.3 Currents were measured using an intracellular solution consisting of, in mM: KCl 108; KOH / EGTA (ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid) 31.25 / 10; CaCl2 8.1; MgCl2 1.2; HEPES (2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid) 10; KOH 15 (adjusted to pH = 7.2 with HCl). + The free calcium concentration was calculated to be 400 nM. The extracellular solution consisted in mM of KCl 150; CaCl2 0.1; MgCl2 3; HEPES 10; glucose 10 (pH = 7.4 with KOH). Cells were held at 0 mV and hK Ca2.3 Currents were evoked by a linear voltage ramp from -80 mV to +80 mV (200 ms duration) applied every 5 s. The compound application protocol consisted of 12 recording periods lasting 50-200 s: 1) baseline recording in extracellular solution; 2) application of the positive control N-methylbicuculline (100 µM), characterized by full potency, fast on- and off-rates; 3-4) wash-out; 5-9) increasing concentrations of test compounds to establish IC50 values; 10-11) wash-out; 12) positive control with compound NS8593 (N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-1H-benzimidazol-2-amine) (1 µM). Data were sampled at 10 kHz, with a fourth-order Bessel filter and a cut-off frequency of 3 kHz. Currents were compensated for run-down. Potency was quantified as the concentration required to inhibit half of the SK channel activity and reported as IC50 values. All effects of compounds of the invention tested were normalized to the observed inhibitory effect of N-methylbicuculin.

[0157] result The examples described are potent inhibitors of the SK3 channel, with IC values ​​of 100-150 in the automated patch clamp assay described above. 50 Showed: Examples: 1, 1b, 2, 2a, 2b, 3, 3a, 3b, 4, 4a, 4b, 5, 5a, 5b, 6, 6a, 6b, 7, 7a, 7b, 8, 8a, 8b, 9, 9b, 10, 10a, 10b, 11, 11a, 12, 12a, 12b, 13, 13a, 13b, 14, 14a, 14b, 15, 15a, 15b, 16, 16a, 16b, 17, 17a, 18, 18a, 18b, 19, 19a, 20, 20a and 21b are less than 1 μM IC 50 has.

[0158] Examples: 1a, 9a, 11b, 17b, 19b, 20b, 21 and 21a all have IC values ​​of less than 3 μM 50 has.

[0159] Materials and Methods Commercially available reagents were used without further purification unless otherwise stated. Detection was by fluorescence and immersion in KMnO4 solution [recipe for KMnO4 solution: dissolve 1.5 g KMnO4, 10 g K2CO3, and 1.25 mL 10% NaOH in 200 mL water] followed by carbonization, using silica gel 60-F 254 Analytical TLC was performed using Merck. Purification of the compounds was achieved by column chromatography on silica gel (60-120 mesh, Swambe Chemicals, India). 1 H, 13 NMR spectra such as C and 2D COSY were recorded on a Bruker AV 400 MHz spectrometer ( 1 H is 400MHz, 13 C at 100 MHz at ambient temperature. Chemical shifts are reported in δ parts per million (ppm). ESI-MS were recorded on an Agilent LC1200 Series MS single quadrupole 6130 mass spectrometer.

[0160] Abbreviations used in the experimental section: BOP = (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate PyBOP = (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate EDC.HCl = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride HBTU = N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate. DCM = dichloromethane; DMF = N,N-dimethylformamide; TEA = triethylamine TFA = trifluoroacetic acid; Boc anhydride = di-tert-butyl dicarbonate; Boc = di-tert-butyl; Piv = 2,2-dimethylpropanoate; THF = tetrahydrofuran; t-BuOH = 2-methylpropan-2-ol; DEA = diethylamine; DIEA = ethylbis(propan-2-yl)amine; IPA = propan-2-ol; Pd / C = palladium on carbon; RT = ambient temperature; MeOH = methanol.

[0161] Grace Flash Chromatography System: Sample purification was performed by flash chromatography using pre-packed silica flash cartridges using the Grace REVELERIS® Prep Purification System: Columns used: High purity flash column silica (normal phase); 12g, 60A, max pressure 350psi (24bar), 24g, 60A, max pressure 350psi (24 bar), 40g, 60A, max pressure 350psi (24bar), 80g, 60A, max pressure 350psi (24 bar). Solvents: Hexane, EtOAc, CHCl3 and MeOH.

[0162] Example 1: Preparation of 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka]

[0163] Example 1, Step 1: Preparation of 5-methyl-5-(3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione [ka] To a stirred solution of 3-trifluoromethylacetophenone (commercially available) (45.00 g, 239.00 mmol) in a mixture of solvent ethanol / water (1:1, 1000 mL) was added ammonium carbonate (115.00 g, 1200.00 mmol) followed by potassium cyanide (18.70 g, 287.00 mmol) and the mixture was stirred at 60° C. for 16 hours. The reaction mass was poured into ice-cold water (1500 mL) and stirred for 30 minutes. The solid formed was filtered off and dried to give 5-methyl-5-(3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione (61.00 g) as an off-white solid which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.78(d,1H,J=7.70 Hz),7.72(d,2H,J=8.90 Hz),7.65(t,1H,J=7.70 Hz),1.69(s,3H); MS: m / z 259(M+1).

[0164] Example 1, Step 2: Preparation of 2-amino-2-(3-(trifluoromethyl)phenyl)propanoic acid [ka] 5-Methyl-5-(3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione (from Example 1, Step 1) (110.00 g, 426.00 mmol) was added to 10% aqueous sodium hydroxide (600 mL) and the mixture was refluxed for 48 h. The reaction mixture was neutralized with 6.0 N HCl (250 mL) (adjusted pH=7) and the solid formed was filtered and dried to give 2-amino-2-(3-(trifluoromethyl)phenyl)propanoic acid (100.00 g) as a white solid, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.85(s,1H),7.79(d,1H,J=8.00 Hz),7.65(d,1H,J=7.60 Hz),7.60(t,1H,J=7.60 Hz),1.68(s,3H); MS: m / z 234.1(M+1).

[0165] Example 1, Step 3: Preparation of 2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)propanoic acid [ka] To a suspension of 2-amino-2-(3-(trifluoromethyl)phenyl)propanoic acid (from Example 1, step 2) (100.00 g, 429.00 mmol) in a mixture of tetrahydrofuran:water (1:1, 1400 mL) was added sodium bicarbonate (216.00 g, 2570.00 mmol) followed by di-tert-butyl dicarbonate (148.00 mL, d=0.95 g / cm 3 , 643.00 mmol) was added and the whole mixture was stirred at ambient temperature for 72 h. The reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (4×2000 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)propanoic acid (140.00 g) as a yellowish gum, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.64(s,1H),7.57(s,1H),7.47(d,2H,J=4.40 Hz),1.47(s,3H),1.35(s,9H); MS: m / z 234.1 [(M+1)-Boc].

[0166] Example 1, Step 4: Preparation of tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate [ka] To a solution of 2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)propanoic acid (from Example 1, Step 3) (140.00 g, 378.00 mmol) in dry tetrahydrofuran (1000 mL) at 0° C. was added triethylamine (158.00 mL, d=0.726 g / cm 3 , 1130.00 mmol), followed by isobutyl chloroformate (68.80 mL, d = 1.053 g / cm 3 , 529.00 mmol) was added and stirred at the same temperature for 4 hours. The solid formed was filtered off at 0° C. and the residue was washed with dry tetrahydrofuran (400 mL). The combined filtrate was added to a cooled mixture of sodium borohydride (85.80 g, 2270.00 mmol) in water (200 mL). The reaction mass was allowed to warm slowly to ambient temperature and stirred for 30 hours. The reaction mass was quenched with ice cold water (1000 mL) and extracted with ethyl acetate (4×2000 mL) and the combined organic layers were washed with brine (250 mL), dried over sodium sulfate, filtered and concentrated to obtain crude (200 g) yellowish liquid. The liquid was purified by flash chromatography using 60-120 silica gel and the product was eluted with 30-35% ethyl acetate in petroleum ether to give tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate (63.00 g) as a colorless liquid. 1 H NMR(400 MHz,DMSO-d6)δ 7.61(t,2H,J=6.80 Hz),7.57(s,1H),7.53(t,1H,J=7.20 Hz),6.92(bs,1H),4.98(t,1H,J=5.20 Hz),3.50(d,2H,J=6.00 Hz),1.59(s,3H),1.35(s,9H); MS: m / z 221.2 [(M+1)-Boc].

[0167] Example 1, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of tert-butyl N-[2-hydroxy-1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl]carbamate (from Example 1, Step 4) (63.00 g, 197.00 mmol) in anhydrous dichloromethane (800 mL) under a nitrogen atmosphere was added triethylamine (96.2 mL, d = 0.726 g / cm 3 , 691.00 mmol), followed by pivaloyl chloride (36.40 mL, d = 0.985 g / cm 3 , 296.00 mmol) was added dropwise at 0 °C and the whole reaction mixture was stirred at ambient temperature for 36 h. The reaction mixture was quenched with ice-cold water (500 mL) and extracted with dichloromethane (4 x 1000 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown liquid (110.00 g) which was purified by flash chromatography using 60-120 silica gel and the product was eluted with 20% ethyl acetate in hexane to give 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (70.00 g) as a yellowish liquid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.61(d,2H,J=6.80 Hz),7.55(t,1H,J=7.60 Hz),7.51(s,1H),4.26(q,2H,J=10.40 Hz),1.52(s,3H),1.35(s,9H),1.05(s,9H); MS: m / z 305.2 [(M+1)-Boc].

[0168] Example 1, Step 6: Preparation of 2-amino-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate hydrochloride [ka] To a solution of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 1, step 5) (70.00 g, 174.00 mmol) in dry dichloromethane (700 mL) under nitrogen atmosphere, 4 M HCl in dioxane solution (127.00 mL, 521.00 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated under high vacuum to give 2-amino-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate hydrochloride (60.00 g) as a yellowish gum, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.88(s,1H),7.84(d,1H,J=8.00 Hz),7.79(d,1H,J=7.60 Hz),7.71(t,1H,J=7.60 Hz),4.49(d,1H,J=12.00 Hz),4.27(d,1H,J=12.00 Hz),1.72(s,3H),1.01(s,9H); MS: m / z 304.1 [(M+1)-HCl].

[0169] Example 1, Step 7: Preparation of 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-amino-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate hydrochloride (from Example 1, step 6) (40.00 g, 118.00 mmol) in dry dichloromethane (500 mL) was added 10% aqueous sodium bicarbonate (500 mL) at 0° C. After 15 min, thiophosgene (14.40 mL, d=1.5 g / cm 3, 188.00 mmol) was added and stirred at the same temperature for 1 h. The reaction mass was extracted with dichloromethane (3×1000 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to get a yellow liquid (75.00 g) which was purified by column chromatography using 60-120 mesh silica gel and 5% ethyl acetate in hexane as eluent to get 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (44.00 g) as a yellow liquid. 1 H NMR(400 MHz,DMSO-d6)δ 7.85(s,1H),7.81(d,1H,J=7.20 Hz),7.76(d,1H,J=7.60 Hz),7.69(t,1H,J=8.40 Hz),4.51(q,2H,J=15.20 Hz),1.83(s,3H),1.35(s,9H); MS: m / z 344.0 (M-1).

[0170] Example 1, Step 8: Preparation of 4-methylbenzo[c][1,2,5]thiadiazole [ka] A solution of 3-methylbenzene-1,2-diamine (commercially available) (330.00 g, 2700.00 mmol) in dry pyridine (1800 mL) was diluted with thionyl chloride (500.00 mL, d = 1.64 g / cm 3, 6750.00 mmol) was added dropwise at 0° C. over 60 minutes. During this addition, the internal temperature was maintained below 45° C. and then the reaction mass was stirred at ambient temperature for 3 hours. The reaction mixture was quenched by dropwise addition of concentrated hydrochloric acid (1300 mL) until the pH of the reaction was adjusted to 2-3, during this step the internal temperature was maintained below 65° C. The reaction mass was diluted with water (1500 mL) and ethyl acetate (2000 mL) and stirred for 2 hours. It was then filtered through a bed of celite, the organic layer was separated and then the aqueous layer was further extracted with ethyl acetate (3×1500 mL). The combined organic layers were washed with brine solution (300 mL), dried over sodium sulfate, filtered and concentrated to give 4-methylbenzo[c][1,2,5]thiadiazole (380.00 g) as a brown liquid which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 7.90(d,1H,J=8.80 Hz),7.61(t,1H,J=8.80 Hz),7.51(d,1H,J=6.80 Hz),2.69(s,3H); MS: m / z 151.2(M+1).

[0171] Example 1, Step 9: Preparation of 4-(bromomethyl)benzo[c][1,2,5]thiadiazole [ka] To a stirred solution of 4-methylbenzo[c][1,2,5]thiadiazole (from Example 1, step 8) (100.00 g, 666.00 mmol) in dry chloroform (1200 mL) under nitrogen atmosphere was added benzoyl peroxide (3.23 g, 13.30 mmol) followed by N-bromosuccinimide (118.00 g, 666.00 mmol) and the reaction mixture was refluxed for 28 h. The reaction mass was cooled and the succinimide precipitate was removed by filtration. The filtrate was concentrated to give a brown semi-solid (170.00 g) which was dissolved in methanol (1000 mL) and stirred for 30 min. The solid was filtered and dried under high vacuum to give 4-(bromomethyl)benzo[c][1,2,5]thiadiazole (110.00 g) as a yellow solid which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 8.09(d,1H,J=8.60 Hz),7.87(d,1H,J=8.80 Hz),7.71(t,1H,J=8.40 Hz),5.13(s,2H); MS: no molecular ion observed.

[0172] Example 1, Step 10: Preparation of tert-butyl N-[(2,1,3-benzothiadiazol-4-yl)methyl]-N-[(tert-butoxy)carbonyl]carbamate [ka] To a solution of 4-(bromomethyl)benzo[c][1,2,5]thiadiazole (from Example 1, step 9) (300.00 g, 1310.00 mmol) in dry tetrahydrofuran (2500 mL) under nitrogen atmosphere, potassium carbonate (543.00 g, 3930.00 mmol) was added followed by tert-butyl N-tert-butoxycarbonylcarbamate (427.00 g, 1960 mmol) and the mixture was stirred at 70° C. for 48 hours. The reaction mass was filtered to remove inorganic solids and the filtrate was concentrated. The residue was dissolved in water (1500 mL) which was then extracted with ethyl acetate (5×3000 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give tert-butyl N-[(2,1,3-benzothiadiazol-4-yl)methyl]-N-[(tert-butoxy)carbonyl]carbamate (350.00 g) as an off-white solid, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 7.99(d,1H,J=8.80 Hz),7.31(t,1H,J=8.00 Hz),7.34(d,1H,J=6.80 Hz),5.21(s,2H),1.39(s,18H); MS: m / z 166.2 [(M+1)-2xBoc].

[0173] Example 1, Step 11: Preparation of 2,1,3-benzothiadiazol-4-ylmethanamine hydrochloride [ka] To a solution of tert-butyl N-[(2,1,3-benzothiadiazol-4-yl)methyl]-N-[(tert-butoxy)carbonyl]carbamate (from Example 1, step 10) (650.00 g, 1780.00 mmol) in dichloromethane (2400 mL) was added 4 M hydrochloric acid in 1,4-dioxane (2223.00 mL, 8890.00 mmol) at 0° C. and stirred at ambient temperature for 75 hours. The reaction mass was concentrated under reduced pressure to give a yellow solid (370.00 g), which was triturated with hexane (2×1000 mL), filtered and dried to give 2,1,3-benzothiadiazol-4-ylmethanamine hydrochloride (340.00 g) as a white solid, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 8.94(bs,3H),8.10(d,1H,J=8.80 Hz),7.91(t,1H,J=6.40 Hz),7.79(d,1H,J=6.80 Hz),4.52(s,2H); MS: m / z 166.1 [(M+1)-HCl].

[0174] Example 1, Step 12: Preparation of 1-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-3-methylurea [ka] To a solution of 2,1,3-benzothiadiazol-4-ylmethanamine hydrochloride (from Example 1, Step 11) (6.00 g, 29.80 mmol) in dry dichloromethane (100 mL) under a nitrogen atmosphere was added triethylamine (12.40 mL, d: 0.726 g / cm 3, 89.30 mmol) followed by N-methylcarbamoyl chloride (4.17 g, 44.60 mmol) were added at 0° C. and then stirred at room temperature for 1 h. The reaction mass was quenched with ice cold water (75 mL) and the aqueous layer was extracted with dichloromethane (4×500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 1-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-3-methylurea (4.20 g) as a yellow gum which was used in next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.94(d,1H,J=8.80 Hz),7.68(t,1H,J=7.84 Hz),7.47(d,1H,J=6.84 Hz),4.68(s,2H),2.57(s,3H); MS: m / z 223.0(M+1).

[0175] Example 1, Step 13: Preparation of 1-(2,3-diaminobenzyl)-3-methylurea [ka] To a degassed solution of 1-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-3-methylurea (from Example 1, step 12) (5.00 g, 22.00 mmol) in dry methanol (150 mL) was added Raney nickel (10.00 g, 200% w / w, pre-washed 5 times with dry methanol) and the resulting reaction mixture was heated under a hydrogen atmosphere at a bladder pressure (approximately 1.5 kg / cm 2 ) at ambient temperature for 24 h. The reaction mixture was filtered through a bed of Celite and the bed was washed with methanol (3×1000 mL). The combined filtrate was concentrated to give 1-(2,3-diaminobenzyl)-3-methylurea (3.50 g) as a brown solid, which was used in the next step without further purification. 1H NMR(400 MHz,DMSO-d6:D2O)δ 6.48(d,1H,J=7.20 Hz),6.37(t,1H,J=7.20 Hz),6.32(d,1H,J=7.32 Hz),4.03(s,2H),2.54(s,3H); MS: m / z 195.1 (M+1).

[0176] Example 1, Step 14: 2-{[(2-amino-6-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and Preparation of 2-{[(2-amino-3-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 1-(2,3-diaminobenzyl)-3-methylurea (from Example 1, step 13) (7.00 g, 36.00 mmol) in a mixture of solvent acetonitrile:methanol (4:1, 120 mL) was added 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 1, step 7) (14.33 g, 43.00 mmol) and the mixture was stirred at ambient temperature for 16 hours. The reaction mass was concentrated to give a brown gum (20.00 g). This was purified by flash column chromatography using 230-300 silica gel and the product was eluted with 40-45% ethyl acetate in hexane to give 2-{[(2-amino-6-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a mixture of regioisomers) (16.00 g) was obtained as a brown solid, which was used in the next step without further purification. MS: m / z 540.1(M+1).

[0177] Example 1, Step 15: Preparation of 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-6-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a mixture of regioisomers) (from Example 1, step 14) (16.00 g, 30.00 mmol) in methanol (160 mL) was added iodoacetic acid (6.62 g, 36.00 mmol) and the mixture was stirred at 65° C. for 2 hours. The reaction mass was concentrated to remove the solvent and the residue was dissolved in 10% aqueous sodium bicarbonate solution (150 mL) and extracted with ethyl acetate (3×1000 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give a brown gum (15.00 g), which was purified by chromatography on normal phase silica gel 60 oPurification by Grace chromatography using a 120.00 g prepacked flash cartridge packed with 40–63 μm A, and eluting the product with 2–4% methanol in chloroform gave 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (12.50 g) as a yellow solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.92(s,1H),7.90(d,1H,J=7.60 Hz),7.72(d,1H,J=8.00 Hz),7.65(t,1H,J=7.60 Hz),7.35(d,1H,J=8.00 Hz),7.18(t,1H,J=8.00 Hz),7.10(d,1H,J=7.60 Hz),4.65(d,1H,J=11.60 Hz),4.56(d,1H,J=11.60 Hz),4.41(d,2H,J=6.80 Hz),2.70(s,3H),2.05(s,3H),1.16(s,9H); MS: m / z 506.2(M+1).

[0178] Example 1: Preparation of 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka] To a solution of 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 1, step 15) (0.130 g, 0.257 mmol) in ethanol (10 mL) was added sodium hydroxide pellets (0.031 g, 0.771 mmol) and the mixture was stirred at ambient temperature for 2 hours. The reaction mass was concentrated and the residue was diluted with 10% aqueous sodium bicarbonate solution (15 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a brown gum (0.110 g) which was purified by column chromatography on silica gel (60° A, 40–63 μm) and the product eluted with 3–5% methanol in chloroform to give 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea (0.040 g) as a yellow solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.84(d,1H,J=8.40 Hz),7.68(d,1H,J=8.00 Hz),7.60(t,1H,J=8.00 Hz),7.31(d,1H,J=7.20 Hz),7.17(t,1H,J=7.60 Hz),7.12(d,1H,J=6.80 Hz),4.46(q,2H,J=15.20 Hz),4.29(d,1H,J=12.00 Hz),4.07(d,1H,J=12.00 Hz),2.69(s,3H),1.88(s,3H); MS: m / z 422.1(M+1).

[0179] Example 1, 15a: (+) 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 15b: (-) 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 1, step 15) was separated into its two enantiomers by chiral SFC chromatography using the following procedure: Column: Chiral Pak OX-H; Flow rate: 3.0 mL / min; Co-solvent: 20%; Co-solvent name: 0.5% diethylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 15a and 15b.

[0180] The (+) enantiomer 15a eluted first from the column. [ka]

[0181] Fraction-1 was the first to elute from the SFC column and was concentrated to give 100% ee of (+) 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (0.270 g) as a yellow solid.

[0182] The (-) enantiomer 15b eluted second from the column. [ka]

[0183] Fraction-2 was the second to elute from the SFC column and was concentrated to give 100% ee of (−)2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (0.300 g) as a yellow solid.

[0184] Example 1a: Preparation of (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka] To a solution of (+)2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (compound 15a, fraction 1 from step 15) (0.300 g, 0.593 mmol) in ethanol (15 mL) was added sodium hydroxide (0.071 g, 2.00 mmol) pellets which was stirred at ambient temperature for 2 hours. The reaction mass was concentrated and the residue was diluted with water (20 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea (isomer a, 0.180 g) as a yellow solid. 1H NMR(400 MHz,AcOH-d4):δ 7.86(s,1H),7.83(d,1H,J=8.00 Hz),7.67(d,1H,J=7.76 Hz),7.59(t,1H,J=7.76 Hz),7.30(d,1H,J=7.76 Hz),7.17(t,1H,J=7.80 Hz),7.11(d,1H,J=7.36 Hz),4.45(q,2H,J=15.24 Hz),4.28(d,1H,J=12.00 Hz),4.06(d,1H,J=11.96 Hz),2.68(s,3H),1.87(s,3H); MS: m / z 422.2 (M+1); [α] D 22.3 (+)12.00(MeOH,c=0.1).

[0185] Example 1b: Preparation of (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka] To a solution of (-)2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (compound 15b, fraction 2 from step 15) (0.270 g, 0.534 mmol) in ethanol (15 mL) was added sodium hydroxide pellets (0.071 g, 2.00 mmol) which was stirred at ambient temperature for 2 hours. The reaction mass was concentrated and the residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give (−)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea (isomer b, 0.175 g) as a yellow solid. 1H NMR(400 MHz,AcOH-d4)δ 7.86(s,1H),7.83(d,1H,J=7.96 Hz),7.67(d,1H,J=7.64 Hz),7.59(t,1H,J=7.72 Hz),7.30(d,1H,J=7.88 Hz),7.16(t,1H,J=7.84 Hz),7.11(d,1H,J=7.52 Hz),4.45(q,2H,J=15.20 Hz),4.28(d,1H,J=11.92 Hz),4.06(d,1H,J=11.92 Hz),2.68(s,3H),1.87(s,3H); MS: m / z 422.2 (M+1); [α] D 22.5 (-)12.00 (MeOH, c=0.1).

[0186] Example 2: Preparation of 3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea [ka]

[0187] Example 2, Step 1: Preparation of 3-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1,1-dimethylurea [ka] To a solution of 2,1,3-benzothiadiazol-4-ylmethanamine hydrochloride (from Example 1, Step 11) (10.00 g, 49.6 mmol) in dry dichloromethane (100 mL) cooled to 0 °C under a nitrogen atmosphere was added triethylamine (17.30 mL, d: 0.726 g / cm 3 , 124.00 mmol), followed by N,N-dimethylcarbamoyl chloride (6.85 mL, d: 1.168 g / cm 3, 74.40 mmol) was added and the mixture was then stirred at room temperature for 2 hours. The above reaction mass was quenched with ice cold water (50 mL) and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow gum (12.00 g). This was purified by chromatography on a Grace instrument using a 120.0 g pre-packed cartridge packed with 60-120 silica gel and the product was eluted with 8% methanol in chloroform to give 3-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1,1-dimethylurea (6.00 g) as a colorless gum which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 7.95(d,1H,J=8.70 Hz),7.70(t,1H,J=7.58 Hz),7.47(d,1H,J=6.80 Hz),7.01(t,1H,J=5.44 Hz),4.74(d,2H,J=5.60 Hz),2.87(s,6H); MS: m / z 237.2(M+1).

[0188] Example 2, Step 2: Preparation of 3-(2,3-diaminobenzyl)-1,1-dimethylurea [ka] To a degassed solution of 3-(2,1,3-benzothiadiazol-4-ylmethyl)-1,1-dimethyl-urea (from Example 2, step 1) (9.00 g, 38.1 mmol) in dry methanol (1000 mL) was added Raney nickel (18.00 g, 200% w / w, pre-washed 5 times with dry methanol) and the resulting reaction mixture was heated under a hydrogen atmosphere with a bladder pressure (approximately 1.5 kg / cm 2 The mixture was stirred at ambient temperature for 24 h under 1000 mL of hexane. The reaction mixture was filtered through a bed of Celite and the bed was washed with methanol (3×1000 mL). The combined filtrate was concentrated to give 3-(2,3-diaminobenzyl)-1,1-dimethylurea (6.00 g) as a brown solid, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 6.63(bs,1H),6.45(s,1H),6.40(s,1H),6.34(d,1H,J=6.40 Hz),4.62(bs,2H),4.37(bs,2H),4.09(bs,2H),2.80(s,6H); MS: m / z 209.2(M+1).

[0189] Example 2, Step 3: Preparation of 2-{[(2-amino-6-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (mixture of regioisomers) [ka] To a stirred solution of 3-(2,3-diaminobenzyl)-1,1-dimethylurea (from Example 2, Step 2) (0.600 g, 2.88 mmol) in acetonitrile (10 mL) was added [2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl]2,2-dimethylpropanoate (from Example 1, Step 7) (0.995 g, 2.88 mmol) and stirred at room temperature for 16 hours. The reaction mixture was concentrated to give 2-{[(2-amino-6-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regioisomers) were obtained as a yellowish gum (1.50 g) which was used in the next step without further purification. MS: m / z 554.3(M+1).

[0190] Example 2, Step 4: Preparation of 2-[(4-{[(dimethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-6-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regioisomers) (from Example 2, step 3) (1.50 g, 2.71 mmol) in methanol (20 mL) was added iodoacetic acid (1.01 g, 5.42 mmol) and the reaction mixture was heated at 65° C. for 2 h. The reaction mixture was concentrated, the residue was dissolved in dichloromethane (100 mL), washed with 10% aqueous sodium bicarbonate (2×10 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated to give a reddish gum (1.40 g), which was purified by flash column chromatography using 230-400 silica gel and the product was eluted with 70% ethyl acetate in petroleum ether to give 2-[(4-{[(dimethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (0.450 g) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6)δ 10.57(s,1H),7.87(s,2H),7.59-7.56(m,2H),7.33(s,1H),6.96(s,2H),6.80-6.75( m,2H),4.54(s,2H),4.29(s,2H),2.81(s,3H),2.67(s,3H),1.85(s,3H),1.03(s,9H); MS: m / z 520.2(M+1).

[0191] Example 2: Preparation of 3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea [ka] To a solution of 2-[(4-{[(dimethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 2, step 4) (0.450 g, 0.866 mmol) in ethanol (10 mL) was added sodium hydroxide pellets (0.346 g, 8.66 mmol) and stirred at room temperature for 0.5 h. The reaction mixture was concentrated, the residue was dissolved in water (30 mL) and extracted with ethyl acetate (3×150 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated to give a crude brown gum (0.370 g) which was purified by preparative HPLC to give 3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea (0.260 g) as an off-white solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.85(t,2H,J=7.60 Hz),7.67(d,1H,J=7.60 Hz),7.60(t,1H,J=7.60 Hz),7.34(d,1H,J=7.20 Hz),7.17(t,1H,J=8.00 Hz),7.10(d,1H,J=6.80 Hz),4.51(d,1H,J=14.80 Hz),4.40(d,1H,J=15.20 Hz),4.25(d,1H,J=11.60 Hz),4.06(d,1H,J=11.60 Hz),2.86(s,6H),1.90(s,3H); MS: m / z 436.2(M+1).

[0192] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: Chiral Pak OX-H; Flow rate: 3.0 mL / min; Co-solvent: 30%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 2a and bb.

[0193] Example 2a: (+)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea The (+) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.85(t,2H,J=7.60 Hz),7.67(d,1H,J=7.60 Hz),7.60(t,1H,J=7.60 Hz),7.34(d,1H,J=7.20 Hz),7.17(t,1H,J=8.00 Hz),7.10(d,1H,J=6.80 Hz),4.51(d,1H,J=14.80 Hz),4.40(d,1H,J=15.20 Hz),4.25(d,1H,J=11.60 Hz),4.06(d,1H,J=11.60 Hz),2.86(s,6H),1.90(s,3H); MS: m / z 436.2(M+1); [α]D 22.4 (+)44.0(MeOH,c=0.1).

[0194] Example 2b: (-)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea The (-) enantiomer eluted second from the column. 1H NMR(400 MHz,AcOH-d4)δ 7.85(t,2H,J=7.60 Hz),7.67(d,1H,J=7.60 Hz),7.60(t,1H,J=7.60 Hz),7.34(d,1H,J=7.20 Hz),7.17(t,1H,J=8.00 Hz),7.10(d,1H,J=6.80 Hz),4.51(d,1H,J=14.80 Hz),4.40(d,1H,J=15.20 Hz),4.25(d,1H,J=11.60 Hz),4.06(d,1H,J=11.60 Hz),2.86(s,6H),1.90(s,3H); MS: m / z 436.2(M+1); [α]D 22.5 (-)20.0(MeOH,c=0.1).

[0195] Example 3: Preparation of 1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka]

[0196] Example 3, Step 1: Preparation of tert-butyl N-{1-methoxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate [ka] To a stirred solution of tert-butyl N-(1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)carbamate (from Example 1, step 4) (5.00 g, 15.70 mmol) in acetonitrile (75 mL) was added silver oxide (11.1 g, 78.30 mmol) followed by methyl iodide (6.00 mL, 95 mmol) and stirred at room temperature in the absence of light for 48 h. The reaction mixture was filtered and concentrated to give a brown gum (5.20 g) which was purified by flash column chromatography on 230-400 silica gel and the product was eluted with 30% ethyl acetate in petroleum ether to give tert-butyl N-{1-methoxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate (2.50 g) as a brown gum. 1 H NMR(400 MHz,DMSO-d6)δ 7.65-7.53(m,4H),7.12(s,1H),3.55-3.47(m,2H),3.23(s,3H),1.58(s,3H),1.34(s,9H); MS: m / z 234.1 [(M+1)-Boc].

[0197] Example 3, Step 2: 1-Methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-amine hydrochloride [ka] To a stirred solution of tert-butyl N-{1-methoxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate (from Example 3, step 1) (2.50 g, 7.50 mmol) in dichloromethane (30 mL) was added 4.0 M HCl in dioxane (2 mL) at 0° C. and the reaction mixture was allowed to warm slowly to room temperature and stirred for 2 h. The reaction mixture was concentrated to give 1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-amine hydrochloride (1.80 g) as a brown gum, which was used in the next step without further purification. 1H NMR(400 MHz,DMSO-d6)δ 8.74(s,2H),7.87-7.71(m,3H),3.76(d,1H,J=10.00 Hz),3.65(d,1H,J=10.00 Hz),3.57(d,2H,J=2.40 Hz),3.35(s,3H),1.62(s,3H); MS: m / z 234.1(M+1).

[0198] Example 3, Step 3: 1-(2-isothiocyanato-1-methoxypropan-2-yl)-3-(trifluoromethyl)benzene [ka] To a stirred solution of 1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-amine hydrochloride (from Example 3, step 2) (1.70 g, 7.29 mmol) in dichloromethane (15 mL) was added 10% sodium bicarbonate solution followed by thiophene (0.55 mL, 7.29 mmol) at 0° C. and the reaction mixture was allowed to warm slowly to room temperature and stirred for 2 h. The reaction mixture was diluted with dichloromethane (100 mL) and the organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a brown gum (2.00 g) which was purified by flash column chromatography on 230-400 silica gel and the product was eluted with 20% ethyl acetate in petroleum ether to give 1-(2-isothiocyanato-1-methoxypropan-2-yl)-3-(trifluoromethyl)benzene (0.700 g) as an off-white gum. 1 H NMR(400 MHz,DMSO-d6)δ 7.82-7.74(m,3H),7.70-7.67(m,1H),3.76(s,2H),3.33(s,3H),1.77(s,3H);

[0199] Example 3, Step 4: 1-(3-amino-2-(3-(1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)thioureido)benzyl)-3-methylurea and 1-(2-amino-3-(3-(1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)thioureido)benzyl)-3-methylurea (mixture of regioisomers) [ka] To a stirred solution of 1-(2,3-diaminobenzyl)-3-methylurea (from Example 1, Step 13) (0.494 g, 2.54 mmol) in dichloromethane (20 mL) was added 1-(2-isothiocyanato-1-methoxypropan-2-yl)-3-(trifluoromethyl)benzene (from Example 3, Step 3) (0.700 g, 2.54 mmol) and stirred at room temperature for 16 hours. The reaction mixture was concentrated to give 1-(3-amino-2-(3-(1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)thioureido)benzyl)-3-methylurea and 1-(2-amino-3-(3-(1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)thioureido)benzyl)-3-methylurea (as a 1:1 mixture of regioisomers) (1.00 g) as a brown gum, which was used in the next step without further purification. MS: m / z 470.2(M+1).

[0200] Example 3: Preparation of 1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka] To a solution of 1-(3-amino-2-(3-(1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)thioureido)benzyl)-3-methylurea and 1-(2-amino-3-(3-(1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)thioureido)benzyl)-3-methylurea (as a 1:1 mixture of regioisomers) (from Example 3, step 4) (1.00 g, 2.13 mmol) in methanol (20 mL) was added iodoacetic acid (0.594 g, 3.19 mmol) and heated at 65° C. for 3 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (100 mL), washed with 10% aqueous sodium bicarbonate solution (2×20 mL), dried over sodium sulfate, filtered, and concentrated to give a brown gum (0.900 g). This was purified by flash column chromatography on 230-400 silica gel and the product was eluted with 50% ethyl acetate in petroleum ether to give 1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea (0.45 g) as an off-white solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.85-7.82(m,2H),7.69(d,1H,J=7.20 Hz),7.61(t,1H,J=7.60 Hz,1H),7.30(d,1H,J=7.60 Hz),7.20-7.14(m,2H),4.47(d,2H,J=10.00 Hz),4.02(d,1H,J=10.40 Hz),3.84(d,1H,J=10.00 Hz),3.48(s,3H),2.71(s,3H),1.91(s,3H); MS: m / z 436.2(M+1).

[0201] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: Chiral Pak OX-H; Flow rate: 3.0 mL / min; Co-solvent: 40%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 10.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 3a and 3b.

[0202] Example 3a: (+)-1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (+) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.85-7.82(m,2H),7.69(d,1H,J=7.20 Hz),7.61(t,1H,J=7.60 Hz),7.30(d,1H,J=7.60 Hz),7.20-7.14(m,2H),4.47(d,2H,J=10.00 Hz),4.02(d,1H,J=10.40 Hz),3.84(d,1H,J=10.00 Hz),3.48(s,3H),2.71(s,3H),1.91(s,3H); MS: m / z 436.2(M+1); [α]D 22.4 (+)13.59(MeOH,c=0.1).

[0203] Example 3b: (-)-1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (-) enantiomer eluted second from the column. 1H NMR(400 MHz,AcOH-d4)δ 7.85-7.82(m,2H),7.69(d,1H,J=7.20 Hz),7.61(t,1H,J=7.60 Hz),7.30(d,1H,J=7.60 Hz),7.20-7.14(m,2H),4.47(d,2H,J=10.00 Hz),4.02(d,1H,J=10.40 Hz),3.84(d,1H,J=10.00 Hz),3.48(s,3H),2.71(s,3H),1.91(s,3H); MS: m / z 436.2(M+1); [α]D 23.5 (-)12.60(MeOH,c=0.1).

[0204] Example 4: Preparation of 1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazol-4-yl]methyl}-3-methoxy-3-methylurea [ka]

[0205] Example 4, Step 1: Preparation of 3-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1-methoxy-1-methylurea [ka] To a stirred solution of benzo[c][1,2,5]thiadiazol-4-ylmethanamine hydrochloride (Example 1, Step 11) (20.00 g, 99.20 mmol) in dichloromethane (200 mL) was added trimethylamine (42.5 mL, d = 0.724 gm / cm 3, 305.00 mmol) was added and the reaction mixture was stirred for 5 min. N-Methoxy-N-methyl-carbamoyl chloride (12.91 mL, 129.00 mmol) was then added dropwise to the reaction mixture over 5 min at 0 °C and the mixture was allowed to warm slowly to room temperature and stirred for 2 h. The reaction was quenched with ice-cold water (100 mL), the organic phase was separated and the aqueous phase was further extracted with dichloromethane (3 x 500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a colorless gum (25.00 g) which was purified by flash column chromatography on 230-400 silica gel and the product was eluted with 45% ethyl acetate in petroleum ether to give 3-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1-methoxy-1-methylurea (15.00 g) as a colorless gum. 1 H NMR(400 MHz,DMSO-d6)δ 7.98(dd,1H,J=8.80,0.80 Hz),7.89(t,1H,J=6.00 Hz),7.72(q,1H,J=6.80 Hz),7.47(dd,1H,J=7.00,0.80 Hz),4.77(d,2H,J=6.00 Hz),3.67(s,3H),3.00(s,3H); MS: m / z 253.0(M+1).

[0206] Example 4, Step 2: Preparation of 3-(2,3-diaminobenzyl)-1-methoxy-1-methylurea [ka] To a stirred solution of 3-(2,1,3-benzothiadiazol-4-ylmethyl)-1-methoxy-1-methyl-urea (from Example 4, step 1) (15.00 g, 59.50 mmol) in methanol (450 mL) was added Raney Nickel (45.00 g, 300% wt / wt) and the reaction mixture was heated at room temperature for 4 hours using a bladder at 1.5 kg / cm 2The reaction mixture was filtered through a bed of Celite and the filtrate was concentrated to give a yellow solid (13.00 g), which was purified by flash column chromatography on 230-400 silica gel and the product was eluted with 100% ethyl acetate to give 3-(2,3-diaminobenzyl)-1-methoxy-1-methylurea (7.00 g) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.53-7.49(m,1H),6.47(dd,1H,J=7.40,1.60 Hz),6.42(dd,1H,J=7.40,1.20 Hz),6.34(t,1H,J=7.60 Hz),4.52(s,2H),4.42(s,2H),4.09(d,2H,J=6.4 Hz),3.58(s,3H),2.95(s,3H); MS: m / z 225.2(M+1).

[0207] Example 4, Step 3: 2-({[2-amino-6-({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and Preparation of 2-({[2-amino-3-({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a stirred solution of 3-[(2,3-diaminophenyl)methyl]-1-methoxy-1-methyl-urea (from Example 4, step 2) (0.390 g, 1.74 mmol) in acetonitrile (6 mL) was added [2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl]2,2-dimethylpropanoate (from Example 1, step 7) (0.6 g, 1.74 mmol) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated to give 2-({[2-amino-6-({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-({[2-amino-3({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regioisomers) (0.980 g) was obtained as a yellowish gum, which was used in the next step without further purification. MS: m / z 570.2(M+1).

[0208] Example 4, Step 4: Preparation of 2-{[4-({[methoxy(methyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] 2-({[2-amino-6-({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and To a solution of 2-({[2-amino-3({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regioisomers) (from Example 4, step 3) (0.98 g, 1.72 mmol) in methanol (10 mL) was added iodoacetic acid (0.64 g, 3.40 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and the residue was dissolved in dichloromethane (100 mL), washed with 10% aqueous sodium bicarbonate solution (2×10 mL), dried over sodium sulfate, filtered, and concentrated to give a reddish gum (0.90 g). This was purified by flash column chromatography on 230-400 silica gel and the product was eluted with 2% methanol in dichloromethane to give 2-{[4-({[methoxy(methyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (0.700 g) as a reddish gum. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.76(s,2H),7.58(t,2H,J=7.60 Hz),7.03(s,1H),6.90-6.80(m,2H),4.52(s,2H),4.29(s,2H),3.52(s,3H),2.93(s,3H),1.83(s,3H),0.99(s,9H); MS: m / z 536.6(M+1).

[0209] Example 4: Preparation of 1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazol-4-yl]methyl}-3-methoxy-3-methylurea [ka] To a solution of [2-[[4-[[[methoxy(methyl)carbamoyl]amino]methyl]-1H-benzimidazol-2-yl]amino]-2-[3-(trifluoromethyl)phenyl]propyl]2,2-dimethylpropanoate (from Example 4, step 4) (0.70 g, 1.31 mmol) in methanol (25 mL) was added 0.5 N sodium hydroxide solution in methanol (10.50 ml, 5.23 mmol) and stirred at room temperature for 1 h. The reaction mixture was quenched with 1.5 N hydrochloride solution (3 mL) and concentrated under reduced pressure at 30° C. to give a brown gum (0.600 g). This was purified by preparative HPLC using 0.1% TFA in acetonitrile:water to give 1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazol-4-yl]methyl}-3-methoxy-3-methylurea (0.410 g) as an off-white solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.84(d,1H,J=7.60 Hz),7.67(d,1H,J=8.00 Hz),7.60(t,1H,J=7.60 Hz),7.36(d,1H,J=8.00 Hz),7.19(t,1H,J=7.60 Hz),7.13(d,1H,J=7.20 Hz),4.45(q,2H,J=15.20 Hz),4.26(d,1H,J=12.00 Hz),4.06(d,1H,J=11.60 Hz),3.60(s,3H),3.02(s,3H),1.89(s,3H); MS: m / z 452.2(M+1).

[0210] The above product was resolved into its two enantiomers by Chiral SFC using the following procedure; Column: Lux C4; Flow rate: 3.0 mL / min; Co-solvent: 30%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 4a and 4b.

[0211] Example 4a: (+)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea The (+) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.84(d,1H,J=7.60 Hz),7.67(d,1H,J=8.00 Hz),7.60(t,1H,J=7.60 Hz),7.36(d,1H,J=8.00 Hz),7.19(t,1H,J=7.60 Hz),7.13(d,1H,J=7.20 Hz),4.45(q,2H,J=15.20 Hz),4.26(d,1H,J=12.00 Hz),4.06(d,1H,J=11.60 Hz),3.60(s,3H),3.02(s,3H),1.89(s,3H); MS: m / z 452.2 (M+1); [α] D 25.0 (+)15.40(MeOH,c=1.0).

[0212] Example 4b: (-)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea The (-) enantiomer eluted second from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.84(d,1H,J=7.60 Hz),7.67(d,1H,J=8.00 Hz),7.60(t,1H,J=7.60 Hz),7.36(d,1H,J=8.00 Hz),7.19(t,1H,J=7.60 Hz),7.13(d,1H,J=7.20 Hz),4.45(q,2H,J=15.20 Hz),4.26(d,1H,J=12.00 Hz),4.06(d,1H,J=11.60 Hz),3.60(s,3H),3.02(s,3H),1.89(s,3H); MS: m / z 452.2 (M+1); [α] D 25.2 (-)16.20 (MeOH, c=1.0).

[0213] Example 5: Preparation of 1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methylurea [ka]

[0214] Example 5, Step 1: Preparation of 3-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1-ethyl-1-methylurea [ka] To a solution of 2,1,3-benzothiadiazol-4-ylmethanamine hydrochloride (from Example 1, Step 11) (25.00 g, 124.00 mmol) in dry dichloromethane (800 mL) cooled to 0° C. under a nitrogen atmosphere was added triethylamine (52.00 mL, d: 0.726 g / cm 3 , 372.00 mmol), followed by N-ethyl-N-methyl-carbamoyl chloride (20.50 mL, d: 1.11 g / cm 3 , 186.00 mmol) was added and the mixture was then stirred at room temperature for 2 h. The reaction mixture was quenched with ice-cold water (200 mL) and the aqueous layer was extracted with dichloromethane (3×1000 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow gum (31.00 g). This was purified by column chromatography on normal phase silica gel 60 o A, Purification by chromatography using a Grace instrument using a 220.0 g prepacked flash cartridge packed with 40–63 μm and eluting the product with 26% ethyl acetate in petroleum ether gave 3-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1-ethyl-1-methylurea (27.00 g) as a yellow gum. 1 H NMR(400 MHz,DMSO-d6;D2O)δ 7.94(d,1H,J=8.80 Hz),7.67(d,1H,J=6.80 Hz),7.42(dd,1H,J=7.20,1.20 Hz),4.72(s,2H),3.25(d,2H,J=7.20 Hz),2.83(s,3H),1.02(t,3H,J=7.20 Hz); MS: m / z 251.1(M+1).

[0215] Example 5, Step 2: Preparation of 3-(2,3-diaminobenzyl)-1-ethyl-1-methylurea [ka] To a degassed solution of 3-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1-ethyl-1-methylurea (from Example 5, step 1) (27.00 g, 108.00 mmol) in dry methanol (1500 mL) was added Raney nickel (54.00 g, 200% w / w, pre-washed 5 times with dry methanol) and the resulting reaction mixture was heated under a hydrogen atmosphere at a bladder pressure (approximately 1.5 kg / cm 2 ) at ambient temperature for 24 hours. The reaction mixture was filtered through a bed of Celite and the bed was washed with methanol (3×2500 mL). The combined filtrate was concentrated to give 3-(2,3-diaminobenzyl)-1-ethyl-1-methylurea (22.00 g) as a dark green solid, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 6.45(d,1H,J=7.42 Hz),6.40(d,1H,J=7.24 Hz),7.33(t,1H,J=7.50 Hz),4.07(s,2H),3.20(d,2H,J=7.00 Hz),2.75(s,3H),0.97(t,3H,J=7.00 Hz); MS: m / z 223.3(M+1).

[0216] Example 5, Step 3: 2-({[2-amino-6-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and Preparation of 2-({[2-amino-3-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-(2,3-diaminobenzyl)-1-ethyl-1-methylurea (from Example 5, step 2) (9.00 g, 40.40 mmol) in a mixture of solvent dichloromethane:methanol (4:1, 200 mL) was added 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 1, step 7) (14.00 g, 40.50 mmol) and the mixture was stirred at ambient temperature for 48 hours. The reaction mass was concentrated to give a brown gum (23.00 g), which was chromatographed on normal phase silica gel 60 o A, purified by chromatography on a Grace instrument using a 120.0 g prepacked flash cartridge packed with 40-63 μm and the product was eluted with 5% methanol in chloroform. 2-({[2-amino-6-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-({[2-amino-3-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 4:1 mixture of regioisomers) (17.00 g) was obtained as a yellow solid. MS: m / z 568.3(M+1).

[0217] Example 5, Step 4: Preparation of 2-{[4-({[ethyl(methyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] 2-({[2-amino-6-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and Starting from 2-({[2-amino-3-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 4:1 mixture of regioisomers) (from Step 3 of Example 5) and using the procedure described in Step 15 of Example 1, the product 2-{[4-({[ethyl(methyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (11.50 g) was obtained as an off-white solid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.82(s,1H),7.77(d,1H,J=8.00 Hz),7.57(d,2H,J=11.20 Hz),6.97(d,1H,J=10.40 Hz),6.79(t,1H,J=9.60 Hz),6.73(t,1H,J=11.60 Hz),4.49(d,2H,J=11.20 Hz),4.28(s,2H),3.23(t,1H,J=9.60 Hz),3.14(t,1H,J=4.80 Hz),2.77(s,3H),1.89(s,3H),1.01(s,9H),0.96(t,3H,J=9.20 Hz); MS: m / z 534.2(M+1).

[0218] Example 5: Preparation of 1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methylurea [ka] To a solution of 2-{[4-({[ethyl(methyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 5, step 4) (10.00 g, 18.70 mmol) in methanol (200 mL) solvent, sodium hydroxide pellets (2.25 g, 56.20 mmol) were added and the mixture was stirred at ambient temperature for 2 hours. The reaction mass was concentrated to remove the solvent methanol and the residue was dissolved in water (100 mL) and extracted with ethyl acetate (4×500 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (9.00 g). This was purified by column chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 220.0 g prepacked flash cartridge packed with A, 40–63 μm and eluting the product with 5–7% methanol in chloroform gave 1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methylurea (8.00 g) as an off-white solid. 1H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.84(d,1H,J=8.00 Hz),7.67(d,1H,J=7.60 Hz),7.60(t,1H,J=8.00 Hz),7.33(d,1H,J=8.00 Hz),7.17(t,1H,J=8.00 Hz),7.11(d,1H,J=7.20 Hz),4.46(q,2H,J=15.20 Hz),4.25(d,1H,J=12.00 Hz),4.06(d,1H,J=12.00 Hz),3.27(d,2H,J=7.20 Hz),2.87(s,3H),1.91(s,3H),1.08(t,3H,J=6.80 Hz); MS: m / z 450.1 (M+1).

[0219] The above product was resolved into its two enantiomers by Chiral SFC using the following procedure; Column: Chiralcel OX-H; Flow rate: 3.0 mL / min; Co-solvent: 30%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 5a and 5b.

[0220] Example 5a: (+)-1-Ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methylurea The (+) enantiomer eluted first from the column. 1H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.82(d,1H,J=8.00 Hz),7.67(d,1H,J=7.60 Hz),7.60(t,1H,J=7.60 Hz),7.33(d,1H,J=7.60 Hz),7.17(t,1H,J=7.60 Hz),7.10(d,1H,J=7.20 Hz),4.48(q,2H,J=15.20 Hz),4.24(d,1H,J=12.00 Hz),4.06(d,1H,J=11.60 Hz),3.27(d,2H,J=7.20 Hz),2.84(s,3H),1.90(s,3H),1.08(t,3H,J=7.20 Hz); MS: m / z 450.3 (M+1); [α] D 23.8 (+) 71.16 (MeOH, c=1.0).

[0221] Example 5b: (-)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methylurea The (-) enantiomer eluted second from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.84(d,1H,J=7.60 Hz),7.67(d,1H,J=7.60 Hz),7.58(t,1H,J=7.60 Hz),7.33(d,1H,J=7.60 Hz),7.17(t,1H,J=7.60 Hz),7.10(d,1H,J=7.60 Hz),4.50(q,2H,J=14.80 Hz),4.23(d,1H,J=12.00 Hz),4.06(d,1H,J=11.60 Hz),3.27(d,2H,J=6.80 Hz),2.84(s,3H),1.90(s,3H),1.08(t,3H,J=7.20 Hz); MS: m / z 450.3 (M+1); [α] D 23.7 (-)61.12(MeOH,c=1.0).

[0222] Example 6: Preparation of 3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea [ka]

[0223] Example 6, Step 1: Preparation of 5-fluoro-4-methylbenzo[c][1,2,5]thiadiazole [ka] A solution of 4-fluoro-3-methylbenzene-1,2-diamine (commercially available) (4.00 g, 28.50 mmol) in dry pyridine (24 mL) was diluted with thionyl chloride (5.00 mL, d = 1.64 g / cm 3 , 68.50 mmol) was added dropwise at 0° C. over 60 min, maintaining the internal temperature below 45° C. during the addition, and then the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was quenched by dropwise addition of concentrated hydrochloric acid (30 mL) until the pH of the reaction was adjusted to 2-3, maintaining the internal temperature below 65° C. during this step. The reaction mixture was diluted with water (100 mL) and ethyl acetate (200 mL) and stirred for 2 h. It was then filtered through a bed of celite, the organic layer was separated, and the aqueous layer was further extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate, filtered, and concentrated to give 5-fluoro-4-methylbenzo[c][1,2,5]thiadiazole (4.50 g) as a brown liquid, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 7.82(d,1H,J=4.80 Hz),7.43(t,1H,J=9.60Hz),2.65(s,3H); MS: m / z 169.0(M+1).

[0224] Example 6, Step 2: Preparation of 4-(bromomethyl)-5-fluorobenzo[c][1,2,5]thiadiazole [ka] To a stirred solution of 5-fluoro-4-methylbenzo[c][1,2,5]thiadiazole (from Example 6, step 1) (4.50 g, 26.80 mmol) in dry chloroform (100 mL) under nitrogen atmosphere was added benzyl peroxide (0.130 g, 0.535 mmol) followed by N-bromosuccinimide (5.24 g, 29.40 mmol) and the reaction mixture was refluxed for 16 hours. The reaction mass was cooled and the succinimide solid was removed by filtration. The filtrate was concentrated to give a brown semi-solid (7.00 g). Crystallization from ethyl acetate (50 mL) was performed and the solid formed was filtered and dried under high vacuum to give 4-(bromomethyl)-5-fluorobenzo[c][1,2,5]thiadiazole (3.50 g) as a yellow solid which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 8.00(d,1H,J=9.52 Hz),7.47(t,1H,J=9.40 Hz),5.00(s,2H);

[0225] Example 6, Step 3: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(5-fluoro-2,1,3-benzothiadiazol-4-yl)methyl]carbamate [ka] To a solution of 4-(bromomethyl)-5-fluorobenzo[c][1,2,5]thiadiazole (from Example 6, step 2) (2.50 g, 10.10 mmol) in dry tetrahydrofuran (50 mL) under nitrogen atmosphere was added potassium carbonate (7.00 g, 50.60 mmol) followed by tert-butyl N-tert-butoxycarbonylcarbamate (commercially available) (2.20 g, 10.10 mmol) and the mixture was stirred at 70° C. for 24 hours. The reaction mass was filtered to remove inorganic solids and the filtrate was concentrated. The residue was dissolved in water (50 mL) and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give a yellow solid (4.00 g). This was purified by column chromatography on normal phase silica gel 60 o A, purification by chromatography on a Grace instrument using a 40.0 g prepacked flash cartridge packed with 40–63 μm and eluting the product with 1–2% ethyl acetate in hexane gave tert-butyl N-[(tert-butoxy)carbonyl]-N-[(5-fluoro-2,1,3-benzothiadiazol-4-yl)methyl]carbamate (3.80 g) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.10(d,1H,J=9.52 Hz),7.72(t,1H,J=10.32 Hz),5.22(s,2H),1.35(s,18H); MS: m / z 283.0 [(M+1)-Boc].

[0226] Example 6, Step 4: Preparation of (5-fluorobenzo[c][1,2,5]thiadiazol-4-yl)methanamine hydrochloride [ka] To a solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(5-fluoro-2,1,3-benzothiadiazol-4-yl)methyl]carbamate (from Example 6, step 3) (4.40 g, 11.50 mmol) in dichloromethane (100 mL) was added 4M hydrochloric acid in 1,4-dioxane (14.50 mL, 57.5 mmol) at 0° C. and then stirred at ambient temperature for 16 hours. The reaction mass was concentrated under reduced pressure to give a yellow solid (3.00 g). This was triturated with hexane (2×100 mL) and the supernatant layer was decanted and dried to give (5-fluorobenzo[c][1,2,5]thiadiazol-4-yl)methanamine hydrochloride (2.50 g) as a white solid which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 8.20(d,1H,J=12.00 Hz),7.77(t,1H,J=8.00 Hz),4.47(s,2H); MS: m / z 184.1 [(M+1)-HCl].

[0227] Example 6, Step 5: Preparation of 3-((5-fluorobenzo[c][1,2,5]thiadiazol-4-yl)methyl)-1,1-dimethylurea [ka] To a solution of the obtained (5-fluorobenzo[c][1,2,5]thiadiazol-4-yl)methanamine hydrochloride (from Example 6, Step 4) (2.00 g, 9.10 mmol) in dry dichloromethane (50 mL) under nitrogen atmosphere at 0 °C, triethylamine (3.81 mL, d: 0.726 g / cm 3 , 27.30 mmol), followed by N,N-dimethylcarbamoyl chloride (commercially available) (1.26 mL, d: 1.168 g / cm 3, 13.70 mmol) was added and the mixture was then stirred at room temperature for 2 hours. The reaction mass was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with dichloromethane (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow gum (2.50 g). This was purified by column chromatography on normal phase silica gel 60 o A, 40-63 μm packed flash cartridge and the product was eluted with 5-8% methanol in chloroform to give 3-((5-fluorobenzo[c][1,2,5]thiadiazol-4-yl)methyl)-1,1-dimethylurea (1.50 g) as a pale yellow liquid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 8.04(d,1H,J=9.60 Hz),7.66(t,1H,J=9.60 Hz),4.68(s,2H),2.74(s,6H); MS: m / z 255.0(M+1).

[0228] Example 6, Step 6: Preparation of 3-(2,3-diamino-6-fluorobenzyl)-1,1-dimethylurea [ka] To a degassed solution of 3-((5-fluorobenzo[c][1,2,5]thiadiazol-4-yl)methyl)-1,1-dimethylurea (from Example 6, step 5) (1.50 g, 5.90 mmol) in dry methanol (60 mL) was added Raney nickel (3.00 g, 200% w / w, pre-washed 5 times with dry methanol) and the resulting reaction mixture was heated under a hydrogen atmosphere with a bladder pressure (approximately 1.5 kg / cm 2 ) at ambient temperature for 16 h. The reaction mixture was then filtered through a bed of Celite and the bed was washed with methanol (3×200 mL). The combined filtrate was concentrated to give 3-(2,3-diamino-6-fluorobenzyl)-1,1-dimethylurea (1.20 g) as a dark green solid, which was used in the next step without further purification. 1H NMR(400 MHz,CD3OD)δ 6.59(t,1H,J=7.80 Hz),6.27(t,1H,J=9.20 Hz),4.36(s,2H),2.85(s,6H); MS: m / z 227.2(M+1).

[0229] Example 6, Step 7: Preparation of 2-{[(6-amino-2-{[(dimethylcarbamoyl)amino]methyl}-3-fluorophenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(dimethylcarbamoyl)amino]methyl}-4-fluorophenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate. (Mixture of Regioisomers) [ka] To a solution of 3-(2,3-diamino-6-fluorobenzyl)-1,1-dimethylurea (from Example 6, step 6) (0.270 g, 1.19 mmol) in a mixture of solvent dichloromethane:methanol (4:1, 20 mL) was added 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 1, step 7) (0.412 g, 1.19 mmol) and the mixture was stirred at ambient temperature for 48 hours. The reaction mass was concentrated to give a brown gum (0.682). This was chromatographed on normal phase silica gel 60 oPurification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with SiO2, 40-63 μm and eluting the product with 80-85% ethyl acetate in hexane gave 2-{[(6-amino-2-{[(dimethylcarbamoyl)amino]methyl}-3-fluorophenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(dimethylcarbamoyl)amino]methyl}-4-fluorophenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regioisomers) (0.460 g) as a yellow solid. MS: m / z 572.2(M+1).

[0230] Example 6, Step 8: Preparation of 2-[(4-{[(dimethylcarbamoyl)amino]methyl}-5-fluoro-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(6-amino-2-{[(dimethylcarbamoyl)amino]methyl}-3-fluorophenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(dimethylcarbamoyl)amino]methyl}-4-fluorophenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regioisomers) (from Example 6, step 7) (0.460 g, 0.805 mmol) in anhydrous methanol (20 mL) under nitrogen atmosphere, iodoacetic acid (0.195 g, 1.05 mmol) was added and the mixture was stirred at 70° C. for 1 hour. The reaction mass was concentrated to remove methanol solvent and the residue was diluted with 10% aqueous sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine solution (30 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.450 g), which was purified by chromatography on normal phase silica gel 60 o A, purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with 40–63 μm and eluting the product with 3–5% methanol in chloroform gave 2-[(4-{[(dimethylcarbamoyl)amino]methyl}-5-fluoro-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (0.380 g) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6)δ 10.69(s,1H),7.78(s,2H),7.61(t,1H,J=10.80 Hz),7.54(d,1H,J=10.00 Hz),7.50(s,1H),7.00(d,1H,J=10.80 Hz),6.92(d,1H,J=6.00 Hz),6.65(t,1H,J=15.20 Hz),4.57(q,2H,J=8.00 Hz),4.35(t,2H,J=13.20 Hz),2.82(s,6H),1.83(s,3H),1.02(s,9H); MS: m / z 538.3(M+1).

[0231] Example 6: Preparation of 3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea [ka] To a solution of 2-[(4-{[(dimethylcarbamoyl)amino]methyl}-5-fluoro-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 6, step 8) (0.160 g, 0.298 mmol) in methanol (10 mL) was added sodium hydroxide pellets (0.060 g, 1.49 mmol) and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated to remove the solvent methanol and the residue was dissolved in water (20 mL) and extracted with ethyl acetate (4×50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.140 g). This was purified by column chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 12.0 g prepacked flash cartridge packed with A, 40–63 μm and eluting the product with 5–8% methanol in chloroform gave 3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea (0.090 g) as an off-white solid. 1H NMR(400 MHz,AcOH-d4)δ 7.88(s,1H),7.83(d,1H,J=7.84 Hz),7.67(d,1H,J=7.72 Hz),7.61(d,1H,J=7.76 Hz),7.34(d,1H,J=7.32 Hz),6.98(t,1H,J=9.92 Hz),4.48(s,2H),4.22(d,1H,J=11.84 Hz),4.03(d,1H,J=11.90 Hz),2.85(s,6H),1.91(s,3H); MS: m / z 454.1(M+1).

[0232] The above product was resolved into its two enantiomers by Chiral SFC using Method; Column: RR-Whelk-01; Flow rate: 3.0 mL / min; Co-solvent: 40%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 7.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 6a and 6b.

[0233] Example 6a: (+)-3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea The (+) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.88(s,1H),7.83(d,1H,J=8.08 Hz),7.67(d,1H,J=7.72 Hz),7.60(d,1H,J=8.00 Hz),7.32(d,1H,J=8.00 Hz),6.98(t,1H,J=10.24 Hz),4.48(s,2H),4.23(d,1H,J=12.04 Hz),4.03(d,1H,J=11.90 Hz),2.84(s,6H),1.91(s,3H); MS: m / z 454.2(M+1); [α] D 21.2 (+)18.40(MeOH,c=0.5).

[0234] Example 6b: (-)-3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea The (-) enantiomer eluted second from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.88(s,1H),7.83(d,1H,J=8.04 Hz),7.67(d,1H,J=7.84 Hz),7.60(t,1H,J=7.90 Hz),7.34(d,1H,J=8.80 Hz),6.98(t,1H,J=10.28 Hz),4.48(s,2H),4.22(d,1H,J=11.90 Hz),4.04(d,1H,J=11.80 Hz),2.85(s,6H),1.91(s,3H); MS: m / z 454.2(M+1); [α] D 21.3 (-)14.80(MeOH,c=0.5).

[0235] Example 7: Preparation of 1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea [ka]

[0236] Example 7, Step 1: Preparation of 1-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-3-cyclopropylurea [ka] To a solution of 2,1,3-benzothiadiazol-4-ylmethanamine hydrochloride (from Example 1, Step 11) (5.00 g, 24.80 mmol) in dry dichloromethane (100 mL) cooled to 0 °C under a nitrogen atmosphere was added triethylamine (10.40 mL, d: 0.726 g / cm 3, 74.40 mmol) followed by isocyanatocyclopropane (2.90 g, 34.80 mmol) were added and then the mixture was stirred at room temperature for 1 h. The reaction mass was diluted with ice-cold water (50 mL) and the formed precipitate was filtered and washed with dichloromethane (50 mL). The solid was dried under vacuum to give 1-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-3-cyclopropylurea (3.80 g) as an off-white solid which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 7.96(d,1H,J=8.80 Hz),7.70(t,1H,J=8.80 Hz),7.48(d,1H,J=6.80 Hz),6.59(s,1H),6.40(s,1H),4.72(d,2H,J=5.60 Hz),2.46(q,1H,J=3.60 Hz),0.59(q,2H,J=6.40 Hz),0.37(t,2H,J=7.60 Hz); MS: m / z 249.1 (M+1).

[0237] Example 7, Step 2: Preparation of 1-cyclopropyl-3-(2,3-diaminobenzyl)urea [ka] To a degassed solution of 1-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-3-cyclopropylurea (from Example 7, step 1) (3.80 g, 15.30 mmol) in dry methanol (150 mL) was added Raney nickel (7.60 g, 200% w / w, pre-washed 5 times with dry methanol) and the resulting reaction mixture was heated under a hydrogen atmosphere with a bladder pressure (approximately 1.5 kg / cm 2 ) at ambient temperature for 24 hours. The reaction mixture was then filtered through a bed of Celite and the bed was washed with methanol (3×1000 mL). The combined filtrate was concentrated to give 1-cyclopropyl-3-(2,3-diaminobenzyl)urea (3.20 g) as a brown solid, which was used in the next step without further purification. 1H NMR(400 MHz,CD3OD)δ 6.69(d,1H,J=7.28 Hz),6.63(t,1H,J=6.60 Hz),6.57(d,1H,J=7.48 Hz),4.29(s,2H),2.47(s,1H),0.69(d,2H,J=5.20 Hz),0.46(s,2H); MS: m / z 221.2(M+1).

[0238] Example 7, Step 3: Preparation of 2-{[(2-amino-3-{[(cyclopropylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{[(cyclopropylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (mixture of regioisomers) [ka] A solution of 1-cyclopropyl-3-(2,3-diaminobenzyl)urea (from Example 7, step 2) (0.250 g, 1.13 mmol) and 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 1, step 7) (0.390 g, 1.13 mmol) in a mixture of solvent dichloromethane:methanol (4:1, 10.0 mL) was stirred at ambient temperature for 16 hours. The reaction mass was concentrated to give 2-{[(2-amino-3-{[(cyclopropylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{[(cyclopropylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regio-isomers) (0.700 g) as a brown gum which was used in next step without further purification. MS: m / z 566.2(M+1).

[0239] Example 7, Step 4: Preparation of 2-[(4-{[(cyclopropylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-3-{[(cyclopropylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{[(cyclopropylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regio-isomers) (from Example 7, step 3) (0.500 g, 0.884 mmol) in methanol (20.0 mL) was added iodoacetic acid (0.329 g, 1.768 mmol) and stirred at 70° C. for 2 hours. The reaction was concentrated, the residue was diluted with 10% aqueous sodium bicarbonate (30 mL), and the aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated to give 2-[(4-{[(cyclopropylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (0.450 g) as a brown gum, which was used in the next step without further purification. MS: m / z 532.1(M+1).

[0240] Example 7: Preparation of 1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea [ka] To a stirred solution of 2-[(4-{[(cyclopropylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 7, step 4) (0.450 g, 0.845 mmol) in methanol (10 mL) was added sodium hydroxide pellets (0.170 g, 4.23 mmol) and the mixture was stirred at ambient temperature for 1 h. The reaction mass was concentrated and the residue was diluted with water (30.0 mL). The aqueous layer was extracted with ethyl acetate (3×70.0 mL) and the combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered and concentrated to give a dark brown gum (0.350 g). This was purified by preparative HPLC to give 1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea (0.210 g) as a brown gum. 1 H NMR(400 MHz,AcOH-d4)δ 7.84(t,2H,J=8.08 Hz),7.68(d,1H,J=7.80 Hz),7.61(t,1H,J=7.64 Hz),7.35(d,1H,J=8.00 Hz),7.21-7.15(m,2H),4.52(d,2H,J=15.44 Hz),4.31(d,1H,J=11.96 Hz),4.09(d,1H,J=12.00 Hz),2.41(d,1H,J=3.28 Hz),1.88(s,3H),0.72(t,2H,J=1.72 Hz),0.53-0.50(m,2H); MS: m / z 448.1(M+1).

[0241] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: (S,S) WHELK-01; Flow rate: 3.0 mL / min; Co-solvent: 30%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 12.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 7a and 7b.

[0242] Example 7a: (-)-1-Cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea The (-) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.81(s,1H),7.82(d,1H,J=8.00 Hz),7.67(d,1H,J=7.60 Hz),7.60(t,1H,J=8.00 Hz),7.33(d,1H,J=8.00 Hz),7.21-7.13(m,2H),4.51(t,2H,J=16.80 Hz),4.29(d,1H,J=12.00 Hz),4.08(d,1H,J=12.00 Hz),2.41(t,1H,J=3.20 Hz),1.87(s,3H),0.71(q,2H,J=4.80 Hz),0.51(q,2H,J=7.20 Hz); MS: m / z 448.2(M+1); [α] D 22.5 (-)16.80 (MeOH, c=1.0).

[0243] Example 7b: (+)-1-Cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea The (+) enantiomer eluted second from the column. 1H NMR(400 MHz,AcOH-d4)δ 7.86(s,1H),7.82(d,1H,J=7.60 Hz),7.67(d,1H,J=7.60 Hz),7.60(t,1H,J=7.60 Hz),7.32(d,1H,J=8.00 Hz),7.21-7.13(m,2H),4.51(d,2H,J=1.60 Hz),4.29(d,1H,J=12.00 Hz),4.08(d,1H,J=12.00 Hz),2.41(q,1H,J=3.60 Hz),1.87(s,3H),0.72(q,2H,J=2.00 Hz),0.52(t,2H,J=2.40 Hz); MS: m / z 448.2(M+1); [α] D 22.5 (+) 15.47 (MeOH, c=1.0).

[0244] Example 8: Preparation of N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide [ka]

[0245] Example 8, Step 1: Preparation of N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)azetidine-1-carboxamide [ka] To a solution of benzo[c][1,2,5]thiadiazol-4-ylmethanamine (from Example 1, Step 11, free base) (50.00 g, 303.00 mmol) in dry dichloromethane (850 mL) at 0 °C was added triethylamine (127.00 mL, d = 0.726 g / cm 2, 908.00 mmol) was added and then stirred for 15 min. 4-Nitrophenyl chloroformate (90.00 g, 272.00 mmol) was added and the reaction was stirred at the same temperature for 2 h. Complete consumption of starting material with formation of a new non-polar intermediate spot was confirmed by TLC. Azetidine hydrochloride (28.00 g, 300.00 mmol) was then added followed by triethylamine (38.00 mL, d=0.726 g / cm 2 , 272.00 mmol) was added and the reaction was then stirred at ambient temperature for 16 hours. The reaction mixture was diluted with aqueous sodium hydroxide (300 mL) and extracted with dichloromethane (5×1000 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to give a yellow solid (68.00 g). This was purified by column chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 330.0 g prepacked flash cartridge packed with 40-63 μm cellulose A and the product was eluted with 10% ethyl acetate in petroleum ether to give a yellow solid. The solid was washed with 15% ethyl acetate in petroleum ether (3×300 mL) (to remove the by-product 4-nitrophenol), stirred for 30 minutes, filtered and dried under vacuum to give N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)azetidine-1-carboxamide (15.0 gm) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.94(d,1H,J=6.80 Hz),7.70(t,1H,J=7.60 Hz),7.48(d,1H,J=7.20 Hz),4.68(d,2H,J=5.20 Hz),3.87(t,4H,J=7.60 Hz),2.20-2.13(m,2H); MS: m / z 249.0(M+1).

[0246] Example 8, Step 2: Preparation of N-(2,3-diaminobenzyl)azetidine-1-carboxamide [ka] To a degassed solution of N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)azetidine-1-carboxamide (from Example 8, step 1) (15.00 g, 60.40 mmol) in dry methanol (1200 mL) was added Raney Nickel (30.0 g, 200% w / w, pre-washed 5 times with dry methanol) and the resulting reaction mixture was heated under a hydrogen atmosphere at bladder pressure (approximately 1.5 kg / cm 2 ) at ambient temperature for 48 h. The reaction mixture was filtered through a bed of Celite and the bed was washed with methanol (3×2000 mL). The combined filtrate was concentrated to give N-(2,3-diaminobenzyl)azetidine-1-carboxamide (12.50 g) as a brown solid, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 6.46(d,1H,J=7.24 Hz),6.38(d,1H,J=6.84 Hz),6.34(t,1H,J=7.40 Hz),4.02(d,2H,J=4.52 Hz),3.77(t,4H,J=7.40 Hz),2.14-2.07(m,2H); MS: m / z 221.1 (M+1).

[0247] Example 8, Step 3: Preparation of 2-{[(2-amino-6-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (mixture of regioisomers) [ka] To a solution of N-(2,3-diaminobenzyl)azetidine-1-carboxamide (from Example 8, step 2) (0.500 g, 2.00 mmol) in a mixture of solvent dichloromethane / methanol (4:1; 40 mL) was added 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 1, step 7) (1.69 g, 5.00 mmol) and the mixture was stirred at ambient temperature for 4 days. The reaction mass was concentrated to give a brown gum (1.300 g). This was chromatographed on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 40.0 g prepacked flash cartridge packed with 1000 μm pores, 40-63 μm, and elution of the product with 2-3% methanol in chloroform gave 2-{[(2-amino-6-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regioisomers) (0.200 g) as a yellow solid. MS: m / z 566.3(M+1).

[0248] Example 8, Step 4: Preparation of 2-[(4-{[(azetidine-1-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-6-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regioisomers) (from Example 8, step 3) (0.900 g, 0.999 mmol) in dry methanol (30 mL) under nitrogen atmosphere, iodoacetic acid (0.372 g, 2.00 mmol) was added and the mixture was stirred at 70° C. for 1 hour. The reaction mass was concentrated to remove methanol solvent and the residue was diluted with 10% aqueous sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine solution (30 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.540 g), which was purified by chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with A, 40–63 μm and eluting the product with 1–2% methanol in chloroform gave 2-[(4-{[(azetidine-1-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (0.430 g) as a yellow solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.92(s,1H),7.89(d,1H,J=7.72 Hz),7.72(d,1H,J=7.48 Hz),7.64(t,1H,J=7.68 Hz),7.31(d,1H,J=7.80 Hz),7.17(t,1H,J=7.84 Hz),7.10(d,1H,J=7.32 Hz),4.65(d,1H,J=11.52 Hz),4.57(d,1H,J=11.52 Hz),4.40(q,2H,J=15.04 Hz),3.96(t,4H,J=7.28 Hz),2.25(q,2H,J=7.44 Hz), 2.05(s,3H), 1.16(s,9H); MS: m / z 532.3(M+1).

[0249] Example 8: Preparation of N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide [ka] To a solution of 2-[(4-{[(azetidine-1-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 8, step 4) (0.410 g, 0.756 mmol) in methanol (30 mL) solvent, sodium hydroxide pellets (0.756 g, 19.00 mmol) were added and the mixture was stirred at ambient temperature for 3 hours. The reaction mass was concentrated to remove the solvent methanol and the residue was dissolved in water (25 mL) and extracted with ethyl acetate (3×125 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.350 g). This was purified by column chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with A, 40-63 μm and eluting the product with 8% methanol in chloroform gave N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide (0.320 g) as an off-white solid. 1H NMR(400 MHz,CD3OD)δ 7.82(s,1H),7.79(d,1H,J=7.88 Hz),7.69(d,1H,J=7.76 Hz),7.64(t,1H,J=7.56 Hz),7.27(d,1H,J=7.84 Hz),7.21(t,1H,J=7.88 Hz),7.14(d,1H,J=7.40 Hz),4.35(s,2H),4.01-3.88(m,6H),2.25(q,2H,J=7.44 Hz),1.90(s,3H); MS: m / z 448.2(M+1).

[0250] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: Lux-A1; Flow rate: 3.0 mL / min; Co-solvent: 20%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 8a and 8b.

[0251] Example 8a: (-)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide The (-) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.84(d,1H,J=8.00 Hz),7.68(d,1H,J=7.60 Hz),7.61(t,1H,J=7.60 Hz),7.33(d,1H,J=8.00 Hz),7.17(t,1H,J=8.00 Hz),7.11(d,1H,J=7.20 Hz),4.45(q,2H,J=15.20 Hz),4.33(d,1H,J=12.00 Hz),4.09(d,1H,J=12.00 Hz),4.00-3.91(m,4H),2.24(t,2H,J=7.20 Hz),1.87(s,3H); MS: m / z 448.2(M+1); [α] D 22.0(-) 38.46 (MeOH, c = 0.104).

[0252] Example 8b: (+)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide The (+) enantiomer eluted second from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.84(d,1H,J=8.40 Hz),7.68(d,1H,J=8.00 Hz),7.61(t,1H,J=7.60 Hz),7.33(d,1H,J=8.40 Hz),7.17(t,1H,J=7.60 Hz),7.11(d,1H,J=7.60 Hz,),4.45(q,2H,J=15.20 Hz),4.33(d,1H,J=12.40 Hz),4.09(d,1H,J=12.00 Hz),4.00-3.93(m,4H),2.24(t,2H,J=7.20 Hz), 1.87(s,3H); MS: m / z 448.2(M+1); [α] D 22.3 (+) 34.62 (MeOH, c=0.104).

[0253] Example 9: Preparation of 3-ethyl-1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazol-4-yl]methyl}urea [ka]

[0254] Example 9, Step 1: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2,3-diaminophenyl)methyl]carbamate [ka] To a stirred solution of tert-butyl N-[(2,1,3-benzothiadiazol-4-yl)methyl]-N-[(tert-butoxy)carbonyl]carbamate (from Example 1, step 10) (20.00 g, 55.00 mmol) in anhydrous methanol (1000 mL) was added Raney Nickel (40.00 g, 200% w / w, pre-washed 5 times with dry methanol) and the mixture was hydrogenated for 24 hours at ambient temperature using balloon pressure. The reaction mass was filtered through a bed of Celite and washed with methanol (5×500 ml). The combined filtrate was concentrated to give tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2,3-diaminophenyl)methyl]carbamate (14.00 g) as a dark green gum which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 6.46(d,1H,J=7.20 Hz),6.36(t,1H,J=7.60 Hz),6.25(d,1H,J=7.20 Hz),4.51(s,2H),1.39(s,18H); MS: m / z 238.2 [(M+1)-Boc].

[0255] Example 9, Step 2: 2-({[2-amino-6-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and Preparation of 2-({[2-amino-3-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2,3-diaminophenyl)methyl]carbamate (from Example 9, step 1) (2.44 g, 7.00 mmol) in a mixture of solvents acetonitrile:methanol (4:1, 16 mL), 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 1, step 7) (2.50 g, 7.00 mmol) was added and the mixture was stirred at ambient temperature for 48 hours. The reaction mass was concentrated to give 2-({[2-amino-6-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-({[2-amino-3-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 3:2 mixture of regioisomers) (4.90 g) was obtained as a brown gum which was used in the next step without further purification. MS: m / z 683.3(M+1).

[0256] Example 9, Step 3: Preparation of 2-{[4-({bis[(tert-butoxy)carbonyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] 2-({[2-amino-6-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and To a solution of 2-({[2-amino-3-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 3:2 mixture of regioisomers) (from Example 9, step 2) (4.90 g, 7.00 mmol) in methanol (50 mL) was added mercuric oxide (2.52 g, 11.00 mmol) followed by elemental sulfur (0.116 g, 4.00 mmol) and the whole mixture was stirred at 65° C. for 3 hours. The reaction mass was filtered through a celite bed and washed with methanol (3×500 mL). The combined filtrate was concentrated to give a brown liquid (4.70 g) which was purified by gravity column chromatography using 60-120 silica gel and the product was eluted with 5-8% ethyl acetate in hexane to give 2-{[4-({bis[(tert-butoxy)carbonyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (2.80 g) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.75(d,2H,J=5.20 Hz),7.56(dd,2H,J=7.60,1.60 Hz),6.98(d,1H,J=8.00 Hz),6.82(t,1H,J=7.60 Hz),6.59(t,1H,J=7.60 Hz),4.75(s,2H),4.57(d,2H,J=7.60 Hz),1.82(s,3H),1.39(s,18H),1.02(s,9H); MS: m / z 649.3(M+1).

[0257] Example 9, Step 4: Preparation of 2-{[4-(aminomethyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[4-({bis[(tert-butoxy)carbonyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 9, step 3) (0.800 g, 1.00 mmol) in dichloromethane (25 mL) was added 4M HCl in dioxane (0.925 mL, 4.00 mmol) at 0° C. and the reaction mass was stirred at ambient temperature for 16 hours. The reaction mass was concentrated and the residue was diluted with 10% aqueous sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (3×150 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown gum (0.70 g). This was purified by preparative HPLC to give 2-{[4-(aminomethyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate, isolated as the trifluoroacetate salt (0.400 g) as an off-white solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.87(d,2H,J=8.40 Hz),7.73(d,1H,J=8.00 Hz),7.65(t,1H,J=8.00 Hz),7.44(dd,1H,J=2.00 Hz),7.28(d,1H,J=1.60 Hz),7.27(s,1H),4.57(s,2H),4.54(t,2H,J=5.20 Hz),1.82(s,3H),1.18(s,9H); MS: m / z 449.2 [(M+1)].

[0258] Example 9, Step 5: Preparation of 2-[(4-{[(ethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[4-(aminomethyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid (from Example 9, step 4) (0.700 g, 1.00 mmol) in dry dichloromethane (30 mL) was added triethylamine (7.97 mL, d = 0.724 g / cm 3 , 6.00 mmol) followed by ethyl isocyanate (0.154 g, 2.00 mmol) were added and the mixture was stirred at ambient temperature for 16 h. The reaction mass was concentrated and the residue was diluted with 10% aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown gum (0.915 g) which was purified by preparative HPLC to give 2-[(4-{[(ethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate, the trifluoroacetate salt (0.350 g) was isolated as a yellow solid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.81(d,2H,J=10.40 Hz),7.73(d,1H,J=7.60 Hz),7.65(t,1H,J=8.00 Hz),7.27(d,1H,J=8.00 Hz),7.18(t,1H,J=7.60 Hz),7.10(d,1H,J=7.20 Hz),4.48(q,2H,J=12.00 Hz),4.21(s,2H),2.97(q,2H,J=7.20 Hz),1.91(s,3H),1.02(s,9H),0.96(t,3H,J=7.20 Hz); MS: m / z 520.1 [(M+1)].

[0259] Example 9: Preparation of 3-ethyl-1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazol-4-yl]methyl}urea [ka] To 2-[(4-{[(ethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid (from Example 9, step 5) (0.300 g, 0.470 mmol) in ethanol (10 mL) was added sodium hydroxide pellets (0.057 g, 1.41 mmol) and the mixture was stirred at ambient temperature for 4 hours. The reaction mass was concentrated and the residue was diluted with 10% aqueous sodium bicarbonate solution (15 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown gum (0.320 g). This was purified by preparative HPLC to give 3-ethyl-1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazol-4-yl]methyl}urea, isolated as a yellow solid in the trifluoroacetate salt (0.040 g). 1 H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.84(d,1H,J=7.60 Hz),7.68(d,1H,J=7.60 Hz),7.61(t,1H,J=8.00 Hz),7.30(d,1H,J=7.60 Hz),7.19(d,1H,J=7.60 Hz),7.15(t,1H,J=6.40 Hz),4.47(q,2H,J=15.20 Hz);4.29(d,1H,J=12.00 Hz),4.08(d,1H,J=11.60 Hz),3.13(q,2H,J=6.80 Hz),1.90(s,3H),1.11(t,3H,J=7.20 Hz); MS: m / z 436.3 [(M+1)].

[0260] 2-[(4-{[(ethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid (from Example 9, step 5) was resolved into its two enantiomers by Chiral SFC using Method: Column: Chiral Pak OX-H; Flow rate: 3.0 mL / min; Co-solvent: 30%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 40° C. to give the two enantiomers shown in steps 5a and 5b.

[0261] Example 9, 5a: 2-[(4-{[(ethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate, enantiomer 1. [ka]

[0262] Fraction-1 was the first to elute from the SFC column and was concentrated to give Enantiomer 1 (0.120 g) in 100% ee, isolated as a trifluoroacetate salt as a yellow solid.

[0263] Example 9, 5b: 2-[(4-{[(ethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate, enantiomer 2. [ka]

[0264] Fraction-2 was the second to elute from the SFC column and was concentrated to give enantiomer 2 (0.120 g) in 100% ee, isolated as a yellow solid as the trifluoroacetate salt.

[0265] Example 9a: Preparation of (+)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea [ka] To a solution of 2-[(4-{[(ethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid (from step 5, fraction 1) (0.150 g, 0.24 mmol) in ethanol (5 mL) was added sodium hydroxide (0.077 g, 1.92 mmol) pellets which was stirred at ambient temperature for 2 hours. The reaction mass was concentrated and the residue was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give (+)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea (0.080 g) as a yellow solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.83(d,1H,J=8.00 Hz),7.68(d,1H,J=7.60 Hz),7.60(t,1H,J=7.60 Hz),7.31(d,1H,J=7.20 Hz),7.17(t,1H,J=7.60 Hz),7.12(d,1H,J=6.80 Hz),4.46(q,2H,J=15.20 Hz),4.27(d,1H,J=12.00 Hz),4.07(d,1H,J=12.00 Hz),3.12(q,2H,J=7.20 Hz),1.89(s,3H),1.10(t,3H,J=7.20 Hz); MS: m / z 436.3 (M+1); [α] D 22.5 (+)57.48, (MeOH, c=1.0).

[0266] Example 9b: Preparation of (-)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea [ka] To a solution of 2-[(4-{[(ethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid, enantiomer 2 (from step 5, fraction 2) (0.150 g, 0.24 mmol) in ethanol (5 mL) was added sodium hydroxide (0.077 g, 1.92 mmol) pellets which was stirred at ambient temperature for 2 hours. The reaction mass was concentrated and the residue was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give (−)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea (0.090 g) as a yellow solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.87(s,1H),7.83(d,1H,J=8.00 Hz),7.68(d,1H,J=7.60 Hz),7.60(t,1H,J=7.60 Hz),7.31(d,1H,J=8.00 Hz),7.18(d,1H,J=7.60 Hz),7.13(t,1H,J=6.80 Hz),4.46(q,2H,J=15.20 Hz),4.27(d,1H,J=12.00 Hz),4.07(d,1H,J=12.00 Hz),3.12(q,2H,J=7.20 Hz),1.89(s,3H),1.11(t,3H,J=7.20 Hz); MS: m / z 436.3 (M+1); [α] D 22.6 (-) 59.68 (MeOH, c = 1.0).

[0267] Example 10: Preparation of 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka]

[0268] Example 10, Step 1: Preparation of 5-ethyl-5-(3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione [ka] To a stirred solution of 1-(3-(trifluoromethyl)phenyl)propan-1-one (commercially available) (45.00 g, 223.00 mmol) in solvent ethanol / water (1:1, 1000 mL) mixture, ammonium carbonate (107.00 g, 1110.00 mmol) was added followed by potassium cyanide (17.10 g, 263.00 mmol) and the mixture was stirred at 60° C. for 16 hours. The reaction mass was poured into ice-cold water (1500 mL) and stirred for 30 minutes. The solid formed was filtered off and dried to give 5-ethyl-5-(3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione (55.00 g) as an off-white solid which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.78(d,1H,J=7.68 Hz),7.75(s,1H),7.68(d,1H,J=7.84 Hz),7.63(t,1H,J=7.76 Hz),2.08(q,1H,J=7.20 Hz),1.90(q,1H,J=7.32 Hz),0.78(t,3H,J=7.24 Hz); MS: m / z 271.1 (M-1).

[0269] Example 10, Step 2: Preparation of 2-amino-2-(3-(trifluoromethyl)phenyl)butanoic acid [ka] 5-Ethyl-5-(3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione (from Example 10, step 1) (55.00 g, 202.00 mmol) was dissolved in 10% aqueous sodium hydroxide (350 mL) and the mixture was refluxed for 48 h. The reaction mixture was neutralized with 6.0 N HCl (200 mL) (adjusted pH=7) and the solid formed was filtered and dried to give 2-amino-2-(3-(trifluoromethyl)phenyl)butanoic acid (31.00 g) as a white solid, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.86(s,1H),7.80(d,1H,J=7.60 Hz),7.62(d,1H,J=7.60 Hz),7.57(t,1H,J=7.60 Hz),2.14-2.08(m,2H),0.81(t,3H,J=7.60 Hz); MS: m / z 248.2(M+1).

[0270] Example 10, Step 3: Preparation of 2-amino-2-(3-(trifluoromethyl)phenyl)butan-1-ol [ka] To a solution of 2-amino-2-(3-(trifluoromethyl)phenyl)butanoic acid (from Example 10, step 2) (40.00 g, 162.00 mmol) in dry tetrahydrofuran (1200 mL) was added 2M solution of lithium aluminum hydride in tetrahydrofuran (202.00 mL, 405.00 mmol) at 0° C. and the reaction mass was allowed to warm slowly to ambient temperature and stirred for 3 hours. The reaction mixture was cooled to 0° C. and quenched by dropwise addition of ethyl acetate (120 mL) and stirred for 30 minutes. It was then finally quenched by dropwise addition of a saturated solution of ammonium chloride (150 mL) and stirred at 0° C. for 15 minutes. The resulting precipitate was separated by filtration and the filtrate was concentrated under reduced pressure to give a yellow gum (40.00 g). This was diluted with 10% sodium hydroxide solution (100 mL) and extracted with ethyl acetate (4×1000 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2-amino-2-(3-(trifluoromethyl)phenyl)butan-1-ol (18.50 g) as a yellow oil, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 7.85(s,1H),7.75(d,1H,J=6.00 Hz),7.53(d,2H,J=6.40 Hz),4.76(t,1H,J=5.60 Hz),3.54(dd,2H,J=10.20,5.60 Hz),1.84(s,2H),1.75(q,1H,J=7.60 Hz),1.62(q,1H,J=6.80 Hz),0.61(t,3H,J=7.60 Hz); MS: m / z 234.1(M+1).

[0271] Example 10, Step 4: Preparation of tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]butan-2-yl}carbamate [ka] A suspension of 2-amino-2-(3-(trifluoromethyl)phenyl)butan-1-ol (from Example 10, step 3) (18.50 g, 51.60 mmol) in a mixture of the solvents dichloromethane:1,4-dioxane (4:1, 500 mL) was treated with di-tert-butyl dicarbonate (13.50 mL, d: 0.950 g / cm 3 , 61.90 mmol) was added dropwise at 0° C. and the mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (4×1000 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a yellow gum (18.00 g). This was purified by column chromatography on normal phase silica gel 60 o A, Purification by chromatography on a Grace instrument using a 220.0 g prepacked flash cartridge packed with 40–63 μm and eluting the product with 25–30% ethyl acetate in hexane gave tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]butan-2-yl}carbamate (11.50 g) as a colorless gum. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.58(s,1H),7.56(d,2H,J=2.16 Hz),7.53(t,1H,J=6.32 Hz),3.61(t,2H,J=12.40 Hz),1.97(q,2H,J=7.64 Hz),1.46(s,9H),0.61(t,3H,J=7.60 Hz); MS: m / z 234.2 [(M+1)-Boc].

[0272] Example 10, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate [ka] To a solution of tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]butan-2-yl}carbamate (from Example 10, Step 4) (11.50 g, 34.50 mmol) in dry dichloromethane (300 mL) under a nitrogen atmosphere was added triethylamine (31.30 mL, d = 0.726 g / cm 3 , 224.00 mmol), followed by pivaloyl chloride (12.70 mL, d = 0.985 g / cm 3 , 103.00 mmol) was added dropwise at 0° C. and the entire reaction mixture was then stirred at ambient temperature for 48 h. The reaction mixture was quenched with ice-cold water (100 mL) and extracted with dichloromethane (4×500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown gum (15.00 g). This was purified by column chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 120.0 g prepacked flash cartridge packed with A, 40–63 μm and eluting the product with 15–20% ethyl acetate in hexane gave 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (10.00 g) as a colorless gum. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.61(s,1H),7.59(d,2H,J=7.52 Hz),7.58(t,1H,J=7.00 Hz),4.38(q,2H,J=14.40 Hz),1.95(q,2H,J=7.28 Hz),1.39(s,9H),1.11(s,9H),1.09(t,3H,J=6.08 Hz); MS: m / z 318.2 [(M+1)-Boc].

[0273] Example 10, Step 6: Preparation of 2-amino-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate hydrochloride [ka] To a solution of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (from Example 10, step 5) (10.00 g, 24.00 mmol) in dry dichloromethane (300 mL) under nitrogen atmosphere, 4 M HCl in dioxane solution (15.00 mL, 59.90 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated and the residue was triturated with hexane (3×250 mL). The supernatant layer was decanted and the solid was dried to give 2-amino-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate hydrochloride (8.50 g) as a colorless gum, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.74(s,1H),7.68(d,2H,J=13.60 Hz),7.56(t,1H,J=8.84 Hz),4.56(d,1H,J=12.08 Hz),4.22(d,1H,J=12.12 Hz),2.17-1.97(m,2H),1.02(s,9H),0.78(t,3H,J=7.36 Hz); MS: m / z 318.2 [(M+1)-HCl].

[0274] Example 10, Step 7: Preparation of 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate [ka] To a solution of 2-amino-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate hydrochloride (from Example 10, Step 6) (8.50 g, 24.00 mmol) in dry dichloromethane (300 mL) was added 10% aqueous sodium bicarbonate (300 mL) at 0° C. After 30 min, the solution was diluted with thiophosgene (11.00 mL, d=1.5 g / cm 3, 144.00 mmol) was added and stirred at the same temperature for 1 h. The reaction mass was extracted with dichloromethane (3×500 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude yellow liquid (9.00 g). This was purified by column chromatography on normal phase silica gel 60 o A, Purification by chromatography on a Grace instrument using a 60.0 g prepacked flash cartridge packed with 40–63 μm and eluting the product with 5–10% ethyl acetate in hexane gave 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (6.50 g) as a yellow liquid. 1 H NMR(400 MHz,DMSO-d6)δ 7.62(s,1H),7.59(d,2H,J=7.16 Hz),7.56(t,1H,J=7.76 Hz),4.39(d,2H,J=4.04 Hz),2.21(q,1H,J=7.20 Hz),2.07(q,1H,J=6.96 Hz),1.16(s,9H),0.91(t,3H,J=7.12 Hz);

[0275] Example 10, Step 8: Preparation of 2-{[(2-amino-6-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (mixture of regioisomers) [ka] To a solution of 1-(2,3-diaminobenzyl)-3-methylurea (from Example 1, step 13) (0.200 g, 10.00 mmol) in a mixture of solvent dichloromethane / methanol (4:1, 20 mL) was added 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (from Example 10, step 7) (0.598 g, 20.00 mmol) and the mixture was stirred at ambient temperature for 24 hours. The reaction mass was concentrated to give a brown gum (0.600 g). This was chromatographed on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with SiO.A, 40-63 μm and eluting the product with 2-3% methanol in chloroform gave 2-{[(2-amino-6-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (as a 4:1 mixture of regioisomers) (0.200 g) as a yellow solid. MS: m / z 554.3(M+1).

[0276] Example 10, Step 9: Preparation of 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-6-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(methylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (as a 4:1 mixture of regioisomers) (from Example 10, step 8) (0.550 g, 0.993 mmol) in dry methanol (30 mL) under nitrogen atmosphere, iodoacetic acid (0.369 g, 1.99 mmol) was added and refluxed for 1 hour. The reaction mass was concentrated to remove methanol solvent and the residue was diluted with 10% aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine solution (30 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.550 g), which was purified by chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with A, 40–63 μm and eluting the product with 1–2% methanol in chloroform gave 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (0.400 g) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.72(s,2H),7.57(d,2H,J=11.32 Hz),6.98(s,1H),6.83(d,1H,J=7.44 Hz),6.76(t,1H,J=7.32 Hz),4.66(t,2H,J=7.52 Hz),4.25(q,2H,J=12.88 Hz),2.58(d,2H,J=16.04 Hz),2.22(s,3H),1.00(s,9H),0.77(t,3H,J=4.40 Hz); MS: m / z 520.1 (M+1).

[0277] Example 10: Preparation of 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka] To a solution of 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (from Example 10, step 9) (0.600 g, 0.958 mmol) in methanol (30 mL) solvent, sodium hydroxide pellets (0.948 g, 24.00 mmol) were added and the mixture was stirred at ambient temperature for 3 hours. The reaction mass was concentrated to remove the solvent methanol and the residue was dissolved in water (30 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.420 g). This was purified by column chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with A, 40–63 μm and eluting the product with 8% methanol in chloroform gave 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea (0.370 g) as an off-white solid. 1H NMR(400 MHz,AcOH-d4)δ 7.81(s,1H),7.77(d,1H,J=7.80 Hz,1H),7.67(d,1H,J=7.92 Hz),7.60(t,1H,J=7.84 Hz),7.28(d,1H,J=7.48 Hz),7.16(t,1H,J=7.56 Hz),7.12(d,1H,J=6.24 Hz),4.54(q,2H,J=15.36 Hz),4.42(d,1H,J=15.28 Hz),4.27(d,1H,J=12.24 Hz),2.70(s,3H),2.21-2.05(m,2H),0.90(t,3H,J=8.32 Hz); MS: m / z 436.2(M+1).

[0278] The above product was resolved into its two enantiomers by Chiral SFC using the following procedure; Column: Lux-A1; Flow rate: 3.0 mL / min; Co-solvent: 20%; Co-solvent name: 0.5% di-ethylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 40° C. to give the two enantiomers 10a and 10b.

[0279] Example 10a: (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (-) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.81(s,1H),7.77(d,1H,J=7.88 Hz),7.67(d,1H,J=7.88 Hz),7.60(t,1H,J=7.76 Hz),7.27(d,1H,J=7.60 Hz),7.16(t,1H,J=7.60 Hz),7.12(d,1H,J=7.52 Hz),4.54(q,2H,J=15.28 Hz),4.42(d,1H,J=15.32 Hz),4.27(d,1H,J=12.24 Hz),2.70(s,3H),2.20-2.11(m,2H),0.91(t,3H,J=8.32 Hz); MS: m / z 436.3 (M+1); [α] D 24.6 (-)29.60(MeOH,c=0.5).

[0280] Example 10b: (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (+) enantiomer eluted second from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.81(s,1H),7.77(d,1H,J=8.04 Hz),7.67(d,1H,J=7.24 Hz),7.60(t,1H,J=7.44 Hz),7.27(d,1H,J=7.36 Hz),7.17(t,1H,J=7.52 Hz),7.12(d,1H,J=7.52 Hz),4.54(q,2H,J=15.64 Hz),4.42(d,1H,J=15.32 Hz),4.27(d,1H,J=12.00 Hz),2.70(s,3H),2.19-2.11(m,2H),0.91(t,3H,J=8.32 Hz); MS: m / z 436.1 (M+1); [α] D 24.6 (+)24.80(MeOH,c=0.5).

[0281] Example 11: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea [ka]

[0282] Example 11, Step 1: Preparation of 5-(3-chlorophenyl)-5-methylimidazolidine-2,4-dione [ka] To a stirred solution of 1-(3-chlorophenyl)ethan-1-one (commercially available) (120.00 g, 776.00 mmol) in solvent ethanol / water (1:1, 2400 mL) mixture, ammonium carbonate (448.00 g, 4660.00 mmol) was added followed by potassium cyanide (45.60 g, 931.00 mmol) and the mixture was stirred at 60° C. for 16 hours. The reaction mass was poured into ice-cold water (1500 mL) and stirred for 30 minutes. The solid formed was filtered off and dried to give 5-(3-chlorophenyl)-5-methylimidazolidine-2,4-dione (160.00 g) as an off-white solid which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 10.87(bs,1H),8.63(s,1H),7.50(d,1H,J=1.60 Hz),7.47(d,1H,J=4.80 Hz),7.45(t,1H,J=2.40 Hz),7.42(dd,1H,J=2.40 Hz),1.65(s,3H); MS: m / z 225.2(M+1).

[0283] Example 11, Step 2: Preparation of 2-amino-2-(3-chlorophenyl)propanoic acid [ka] 5-(3-Chlorophenyl)-5-methylimidazolidine-2,4-dione (from Example 11, step 1) (160.00 g, 712.00 mmol) was placed in 10% aqueous sodium hydroxide (1200 mL) and the mixture was stirred for 72 h at 110° C. The reaction mixture was neutralized with 6.0 N HCl (500 mL) (adjusted pH=7) and the solid formed was filtered and dried to give 2-amino-2-(3-chlorophenyl)propanoic acid (205.00 g) as a white solid, which was used in the next step without further purification. 1H NMR(400 MHz,DMSO-d6:D2O)δ 7.56(s,1H),7.46(d,1H,J=7.60 Hz),7.37(t,1H,J=7.60 Hz),7.35(d,1H,J=7.60 Hz),1.65(s,3H); MS: m / z 200.1 (M+1).

[0284] Example 11, Step 3: Preparation of 2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)propanoic acid [ka] To a suspension of 2-amino-2-(3-chlorophenyl)propanoic acid (from Example 11, step 2) (286.00 g, 1430.00 mmol) in a mixture of solvent tetrahydrofuran:water (1:1, 5000 mL) was added sodium bicarbonate (842.00 g, 10000.00 mmol), followed by di-tert-butyl dicarbonate (658.00 mL, d: 0.950 g / cm 3 , 2870.00 mmol) was added and the whole mixture was stirred at ambient temperature for 15 days. The reaction mixture was diluted with water (2000 mL) and extracted with ethyl acetate (4 x 5000 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)propanoic acid (410.00 g) as a colorless gum, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 7.23(dd,2H,J=6.40 Hz),7.16(t,2H,J=6.40 Hz),1.70(s,3H),1.34(s,9H); MS: m / z 199.9 [(M+1)-Boc].

[0285] Example 11, Step 4: Preparation of tert-butyl N-[2-(3-chlorophenyl)-1-hydroxypropan-2-yl]carbamate [ka] To a solution of 2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)propanoic acid (from Example 11, Step 3) (250.00 g, 834.00 mmol) in dry tetrahydrofuran (2000 mL) at 0° C. was added triethylamine (349.00 mL, d=0.726 g / cm 3 , 2500.00 mmol), followed by isobutyl chloroformate (130.00 mL, d = 1.053 g / cm 3 , 1080.00 mmol) was added and stirred at the same temperature for 4 hours. The solid formed was filtered off at 0° C. and the residue was washed with tetrahydrofuran (400 mL). The combined filtrate was added to a cooled mixture of sodium borohydride (221.00 g, 5840.00 mmol) in water (500 mL). The reaction mass was allowed to warm slowly to ambient temperature and stirred for 48 hours. The reaction mass was quenched with ice cold water (1000 mL) and extracted with ethyl acetate (4×5000 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated to give a yellowish liquid (250.00 g), which was purified by gravity column chromatography using 60-120 silica gel and the product was eluted with 30-35% ethyl acetate in petroleum ether to give tert-butyl (2-(3-chlorophenyl)-1-hydroxypropan-2-yl)carbamate (95.00 g) as a colorless liquid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.34(s,1H),7.32(d,1H,J=7.60 Hz),7.28(t,1H,J=7.40 Hz),7.25(d,1H,J=7.20 Hz),3.57(d,2H,J=6.40 Hz),1.52(s,3H),1.34(s,9H); MS: m / z 186.1 [(M+1)-Boc].

[0286] Example 11, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate [ka] Under a nitrogen atmosphere, a solution of tert-butyl (2-(3-chlorophenyl)-1-hydroxypropan-2-yl)carbamate (from Example 11, Step 4) (170.00 g, 595.00 mmol) in anhydrous dichloromethane (1500 mL) was treated with triethylamine (250.00 mL, d = 0.726 g / cm 3 , 1780.00 mmol), followed by pivaloyl chloride (145.50 mL, d = 0.985 g / cm 3 , 1190.00 mmol) was added dropwise at 0° C. and the whole reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was quenched with ice-cold water (1000 mL) and extracted with dichloromethane (4×2500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown liquid (200.00 g). This was purified by chromatography on a Grace instrument using a 330.0 g pre-packed flash cartridge of 60-120 silica gel and the product was eluted with 20% ethyl acetate in hexane to give 2-{[(tert-butoxy)carbonyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (218.00 g) as a yellowish liquid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.35(d,1H,J=8.00 Hz),7.32(s,1H),7.30(d,1H,J=7.20 Hz),7.28(t,1H,J=6.80 Hz),4.30(d,1H,J=10.40 Hz),4.21(d,1H,J=10.80 Hz),1.50(s,3H),1.31(s,9H),1.10(s,9H); MS: m / z 271.8 [(M+1)-Boc].

[0287] Example 11, Step 6: Preparation of 2-amino-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate hydrochloride [ka] To a solution of 2-{[(tert-butoxy)carbonyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (from Example 11, step 5) (218.00 g, 589.00 mmol) in dry dichloromethane (1200 mL) under nitrogen atmosphere, 4M HCl in dioxane solution (442.00 mL, 1770.00 mmol) was added dropwise at 0° C., and the reaction mixture was then stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under high vacuum to give 2-amino-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate hydrochloride (180.00 g) as a yellowish gum, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.64(s,1H),7.51-7.47(m,3H),4.44(d,1H,J=11.60 Hz),4.26(d,1H,J=11.60 Hz),1.69(s,3H),1.04(s,9H); MS: m / z 270.1 [(M+1)-HCl].

[0288] Example 11, Step 7: Preparation of 2-(3-chlorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate [ka] To a solution of 2-amino-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate hydrochloride (from Example 11, step 6) (90.00 g, 294.00 mmol) in dry dichloromethane (900 mL) was added 10% aqueous sodium bicarbonate (900 mL) at 0° C. After 30 min, thiophosgene (33.80 mL, d=1.5 g / cm 3, 441.00 mmol) was added and stirred at the same temperature for 1 h. The reaction mass was extracted with dichloromethane (3×2000 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to get a yellow liquid (95.00 g) which was purified by gravity column chromatography on 60-120 mesh silica gel using 3-5% ethyl acetate in hexane as eluent to get 2-(3-chlorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate (75.00 g) as a yellow liquid. 1 H NMR(400 MHz,DMSO-d6)δ 7.55(s,1H),7.55-7.45(m,3H),4.45(dd,2H,J=11.20 Hz),1.79(s,3H),1.11(s,9H);

[0289] Example 11, Step 8: Preparation of 2-({[2-amino-6-({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-3-({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (mixture of regioisomers) [ka] To a stirred solution of 3-[(2,3-diaminophenyl)methyl]-1-methoxy-1-methyl-urea (from Example 4, step 2) (0.21 g, 0.936 mmol) in acetonitrile (4 mL) was added 2-(3-chlorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate (from Example 11, step 7) (0.35 g, 1.12 mmol) and stirred at room temperature for 48 hours. The reaction mixture was concentrated to give 2-({[2-amino-6-({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-3-({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a 4:1 mixture of regioisomers) (0.560 g) as a brown gum, which was used in the next step without further purification. MS: m / z 537.2(M+1).

[0290] Example 11, Step 9: Preparation of 2-(3-chlorophenyl)-2-{[4-({[methoxy(methyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate [ka] To a solution of 2-({[2-amino-6-({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-3-({[methoxy(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a 4:1 mixture of regioisomers) (from Example 11, step 8) (0.56 g, 1.04 mmol) in methanol (6 mL) was added iodoacetic acid (0.388 g, 2.09 mmol) and stirred at room temperature for 1.5 h. The reaction mixture was concentrated and the residue was dissolved in dichloromethane (100 mL) and washed with 10% aqueous sodium bicarbonate solution (2×10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a reddish gum (0.500 g) which was purified by flash column chromatography on 230-400 silica gel and the product was eluted with 2% methanol in dichloromethane as eluent to give 2-(3-chlorophenyl)-2-{[4-({[methoxy(methyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate (0.350 g) as a brown gum. 1 H NMR (400 MHz, DMSO-d 6: D2O)δ 7.51(s,1H),7.42(s,3H),7.26(d,1H,J=7.84 Hz),7.20(t,1H,J=7.80 Hz),7.13(d,1H,J=7.04 Hz),4.49(d,1H,J=11.44 Hz),4.39(d,1H,J=11.44 Hz),4.30(s,2H),3.53(s,3H),2.92(s,3H),1.83(s,3H),1.04(s,9H); MS: m / z 502.3 / 504.2(M+1).

[0291] Example 11: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea [ka] To a stirred solution of 2-(3-chlorophenyl)-2-{[4-({[methoxy(methyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate (from Example 11, step 9) (0.350 g, 0.697 mmol) in methanol (30 mL) was added 0.5 N sodium hydroxide solution in methanol (5.58 ml, 2.79 mmol) and stirred at room temperature for 1 h. The reaction mixture was quenched with 1.5 N hydrochloride solution (2 mL) and concentrated under reduced pressure at 30° C. to give a brown gum (0.300 g). This was purified by preparative HPLC using 0.1% TFA in acetonitrile:water to give 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea (0.230 g) as an off-white solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.58(s,1H),7.49(d,1H,J=7.32 Hz),7.41-7.35(m,3H),7.20-7.12(m,2H),4.48(d,2H,J=5.88 Hz),4.22(d,1H,J=11.92 Hz),4.02(d,1H,J=12.00 Hz),3.61(s,3H),3.05(s,3H),1.85(s,3H); MS: m / z 418.1 / 420.2 (M+1).

[0292] The above product was resolved into its two enantiomers by Chiral SFC using the following procedure; Column: Lux C4; Flow rate: 3.0 mL / min; Co-solvent: 30%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 11a and 11b.

[0293] Example 11a: (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea The (-) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.58(s,1H),7.49(d,1H,J=7.32 Hz),7.41-7.35(m,3H),7.20-7.12(m,2H),4.48(d,2H,J=5.88 Hz),4.22(d,1H,J=11.92 Hz),4.02(d,1H,J=12.00 Hz),3.61(s,3H),3.05(s,3H),1.85(s,3H); MS: m / z 418.1 / 420.2 (M+1); [α]D 23.2 (-)11.52(MeOH,c=1.0).

[0294] Example 11b: (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea The (+) enantiomer eluted second from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.58(s,1H),7.49(d,1H,J=7.32 Hz),7.41-7.35(m,3H),7.20-7.12(m,2H),4.48(d,2H,J=5.88 Hz),4.22(d,1H,J=11.92 Hz),4.02(d,1H,J=12.00 Hz),3.61(s,3H),3.05(s,3H),1.85(s,3H); MS: m / z 418.1 / 420.2 (M+1); [α]D 25.9 (+)11.04(MeOH,c=1.0).

[0295] Example 12: Preparation of 1-[[2-[[1-(3-chloro-4-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]amino]-1H-benzimidazol-4-yl]methyl]-3-methyl-urea [ka]

[0296] Example 12, Step 1: Preparation of [2-(3-chloro-4-fluoro-phenyl)-2-[[4-[(methylcarbamoylamino)methyl]-1H-benzimidazol-2-yl]amino]propyl] 2,2-dimethylpropanoate [ka] Starting with 1-(3-chloro-4-fluorophenyl)ethan-1-one instead of 1-[3-(trifluoromethyl)phenyl]ethan-1-one and using the method described in Example 1, steps 1 to 15, [2-(3-chloro-4-fluorophenyl)-2-[[4-[(methylcarbamoylamino)methyl]-1H-benzimidazol-2-yl]amino]propyl] 2,2-dimethylpropanoate (0.69 g) was obtained as an off-white solid, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 7.68(s,1H),7.49-7.47(m,1H),7.41-7.34(m,1H),7.10(bs,1H),7.00(bs,2H),5.97(bs,1H),4.47(q,2H,J=10.80 Hz),4.25(t,2H,J=8.40 Hz),3.74(s,3H),1.83(s,3H),1.06(s,9H); MS: m / z 490.2(M+1).

[0297] Example 12: Preparation of 1-[[2-[[1-(3-chloro-4-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]amino]-1H-benzimidazol-4-yl]methyl]-3-methyl-urea [ka] To a stirred solution of [2-(3-chloro-4-fluoro-phenyl)-2-[[4-[(methylcarbamoylamino)methyl]-1H-benzimidazol-2-yl]amino]propyl]2,2-dimethylpropanoate (from Example 12, step 1) (0.69 g, 1.41 mmol) in methanol (50.0 mL) was added sodium hydroxide pellets (0.39 g, 9.86 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mass was concentrated and the residue was diluted with water (30 mL). The aqueous layer was extracted with ethyl acetate (3×70 mL) and the combined organic layers were washed with water (30 mL) followed by brine solution (30 mL), dried over sodium sulfate, filtered and concentrated to give 1-[[2-[[1-(3-chloro-4-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]amino]-1H-benzimidazol-4-yl]methyl]-3-methyl-urea (0.49 g) as a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 10.62(s,1H),7.69-7.67(m,1H),7.53-7.50(m,1H),7.33(d,1H,J=7.80 Hz),7.25(t,1H,J=8.80 Hz),7.18(t,1H,J=7.80 Hz),7.11(d,1H,J=7.48 Hz),6.47(bs,1H),6.13(d,1H,J=5.40 Hz),5.87(d,1H,J=4.56 Hz),4.51(d,1H,J=15.24 Hz),4.42(d,1H,J=15.24 Hz),4.18-4.12(m,1H),4.01(d,1H,J=11.92 Hz),2.72(s,3H),1.84(s,3H); MS: m / z 406.1(M+1).

[0298] The above product was resolved into its two enantiomers by Chiral SFC using the following method; column: Lux C4; flow rate: 4.0 mL / min; co-solvent: 40%; co-solvent name: 0.5% isopropylamine in isopropyl alcohol; injection volume: 10.0 μL; outlet pressure: 100 bar; temperature: 35° C. to give the two enantiomers 12a and 12b.

[0299] Example 12a: (-)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (-) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.69-7.67(m,1H),7.54-7.50(m,1H),7.33(d,1H,J=7.84 Hz),7.25(t,1H,J=8.80 Hz),7.18(t,1H,J=7.84 Hz),7.12(d,1H,J=7.24 Hz),4.51(d,1H,J=15.28 Hz),4.42(d,1H,J=15.32 Hz),4.19(d,1H,J=11.92 Hz),4.01(d,1H,J=11.92 Hz),2.72(s,3H),1.84(s,3H); MS: m / z 406.1 (M+1); [α] D 22.5 (-) 7.31 (MeOH, c = 1.0).

[0300] Example 12b: (+)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (+) enantiomer eluted second from the column. 1H NMR(400 MHz,AcOH-d4)δ 7.69-7.67(m,1H),7.54-7.50(m,1H),7.33(d,1H,J=7.88 Hz),7.25(t,1H,J=8.80 Hz),7.18(t,1H,J=7.84 Hz),7.12(d,1H,J=7.36 Hz),4.51(d,1H,J=15.28 Hz),4.42(d,1H,J=15.16 Hz),4.19(d,1H,J=11.92 Hz),4.01(d,1H,J=11.92 Hz),2.72(s,3H),1.84(s,3H); MS: m / z 406.2(M+1); [α] D 22.5 (+) 6.46 (MeOH, c=1.0).

[0301] Example 13: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea [ka]

[0302] Example 13, Step 1: Preparation of 2-{[(2-amino-6-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (mixture of regioisomers) [ka] To a solution of 3-(2,3-diaminobenzyl)-1,1-dimethylurea (Example 2, step 2) (9.35 g, 44.90 mmol) in a mixture of solvent dichloromethane:methanol (4:1; 200 mL), 2-(3-chlorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate (Example 11, step 7) (14.00 g, 44.90 mmol) was added and the mixture was stirred at ambient temperature for 48 hours. The reaction mass was concentrated to give a brown gum (23.00 g). This was purified by chromatography on a Grace instrument using a 120.0 g prepacked column of 60-120 silica gel and the product was eluted with 75% ethyl acetate in hexane to give 2-{[(2-amino-6-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a 4:1 mixture of regioisomers) (17.00 g) as a yellow solid which was used in the next step without further purification. MS: m / z 521.2(M+1).

[0303] Example 13, Step 2: Preparation of 2-(3-chlorophenyl)-2-[(4-{[(dimethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-6-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(dimethylcarbamoyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a 4:1 mixture of regioisomers) (from Example 13, step 1) (17.00 g, 32.70 mmol) in dry methanol (200 mL) under nitrogen atmosphere, iodoacetic acid (6.08 g, 32.70 mmol) was added and the mixture was stirred at 70° C. for 1 hour. The above reaction mass was concentrated to remove methanol solvent and the residue was diluted with 10% aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine solution (100 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (15.00 g), which was purified by chromatography on a Grace instrument using an 80.0 g prepacked cartridge packed with a 60-120 silica gel column and the product was eluted with 5% methanol in chloroform to give 2-(3-chlorophenyl)-2-[(4-{[(dimethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]propyl 2,2-dimethylpropanoate (14.00 g) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 10.55(s,1H),7.59(s,1H),7.43(d,1H,J=7.60 Hz),7.35(t,1H,J=7.60 Hz),7.28(d,1H,J=7.60 Hz),7.25(s,1H),7.05(bs,1H),6.97b(d,1H,J=7.20 Hz),6.79(t,1H,J=7.60 Hz),6.73(d,1H,J=7.20 Hz),4.52(q,2H,J=10.80 Hz),4.29(d,2H,J=4.80 Hz),2.82(s,6H),1.80(s,3H),1.02(s,9H); MS: m / z 487.2(M+1).

[0304] Example 13: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea [ka] To a solution of 2-(3-chlorophenyl)-2-[(4-{[(dimethylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]propyl 2,2-dimethylpropanoate (from Example 13, step 2) (15.00 g, 30.90 mmol) in methanol (300 mL) solvent, sodium hydroxide pellets (3.70 g, 92.60 mmol) were added and the mixture was stirred at ambient temperature for 1 hour. The reaction mass was concentrated to remove the solvent methanol and the residue was dissolved in water (50 mL) and extracted with ethyl acetate (4×300 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (12.40 g). This was purified by chromatography on a Grace instrument using an 80.0 g prepacked cartridge filled with 60-120 silica gel and the product was eluted with 8% methanol in chloroform to give 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea (12.00 g) as an off-white solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.59(s,1H),7.50(d,1H,J=7.16 Hz),7.38(t,1H,J=7.60 Hz),7.33(d,2H,J=8.10 Hz),7.18(t,1H,J=7.70 Hz),7.11(d,1H,J=7.50 Hz),4.47(q,2H,J=15.04 Hz),4.20(d,1H,J=11.80 Hz),4.00(d,1H,J=11.80 Hz),2.87(s,6H),1.85(s,3H); MS: m / z 402.2(M+1).

[0305] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: Chiralcel OX-H; Flow rate: 3 mL / min; Co-solvent: 30%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 2.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 13a and 13b.

[0306] Example 13a: (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea The (-) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.57(s,1H),7.47(d,1H,J=7.60 Hz),7.36(t,1H,J=7.60 Hz),7.32(d,2H,J=7.20 Hz),7.15(t,1H,J=8.00 Hz),7.09(d,1H,J=7.20 Hz),4.46(q,2H,J=14.80 Hz),4.18(d,1H,J=12.00 Hz),4.00(d,1H,J=12.00 Hz),2.86(s,6H),1.83(s,3H); MS: m / z 402.2 (M+1); [α] D 24.4 (-)11.60 (MeOH, c=1.0).

[0307] Example 13b: (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea The (+) enantiomer eluted second from the column. 1H NMR(400 MHz,AcOH-d4)δ 7.57(s,1H),7.47(d,1H,J=7.60 Hz),7.36(t,1H,J=7.60 Hz),7.31(d,2H,J=7.20 Hz),7.15(t,1H,J=8.00 Hz),7.09(d,1H,J=6.80 Hz),4.46(q,2H,J=15.20 Hz),4.18(d,1H,J=11.60 Hz),4.00(d,1H,J=11.80 Hz),2.85(s,6H),1.83(s,3H); MS: m / z 402.2 (M+1); [α] D 24.3 (+)12.60(MeOH,c=1.0).

[0308] Example 14: Preparation of 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-(3,3,3-trifluoropropyl)urea [ka]

[0309] Example 14, Step 1: Preparation of 2-[3-(trifluoromethyl)phenyl]-2-{[4-({[(3,3,3-trifluoropropyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate [ka] A solution of 2-{[4-(aminomethyl)-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid (from Example 9, step 4) (1.00 g, 2.00 mmol) in dichloromethane (50 mL) was diluted with triethylamine (0.56 mL, d = 0.726 g / cm 3, 4.00 mmol) was added and the mixture was cooled to -78 °C. Then 1,1,1-trifluoro-3-isocyanato-propane (0.310 g, 2.00 mmol) was added and the reaction was stirred at the same temperature for 30 min. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to give a brown gum (1.00 g). This was purified by preparative HPLC to give 2-[3-(trifluoromethyl)phenyl]-2-{[4-({[(3,3,3-trifluoropropyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate (0.650 g) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.79(s,1H),7.73(d,2H,J=7.70 Hz),7.64(t,1H,J=8.00 Hz),7.27(d,1H,J=7.84 Hz),7.18(t,1H,J=7.70 Hz),7.10(d,1H,J=7.52 Hz),4.48(q,2H,J=11.40 Hz),4.19(d,2H,J=5.04 Hz),3.24(dd,2H,J=6.90 Hz),2.35(d,2H,J=4.72 Hz),1.89(s,3H),1.03(s,9H); MS: m / z 588.1(M+1).

[0310] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: Chiralcel OX-H; Flow rate: 3.0 mL / min; Co-solvent: 20%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 14-1a and 14-1b.

[0311] Example 14-1a: (+)-2-[3-(trifluoromethyl)phenyl]-2-{[4-({[(3,3,3-trifluoropropyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate The (+) enantiomer eluted first from the column (fraction 1). MS: m / z 588.1 (M+1); [α] D 26.0 (+)14.00 (MeOH, c=1.0).

[0312] Example 14-1b: (-)-2-[3-(trifluoromethyl)phenyl]-2-{[4-({[(3,3,3-trifluoropropyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate The (-) enantiomer eluted second from the column (fraction 2). MS: m / z 588.1 (M+1); [α] D 26.0 (-) 14.44 (MeOH, c=1.0).

[0313] Example 14: Preparation of 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-(3,3,3-trifluoropropyl)urea [ka] To a solution of 2-[3-(trifluoromethyl)phenyl]-2-{[4-({[(3,3,3-trifluoropropyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate (from Example 14, step 1) (0.150 g, 0.255 mmol) in methanol (10 mL) was added sodium hydroxide pellets (0.051 g, 1.275 mmol) and the mixture was stirred at ambient temperature for 2 hours. The reaction mass was concentrated and the residue was diluted with 10% aqueous sodium bicarbonate solution (15 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown gum (0.130 g). This was purified by column chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 12.00 g prepacked flash cartridge packed with A, 40–63 μm and eluting the product with 3–5% methanol in chloroform gave 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-(3,3,3-trifluoropropyl)urea (0.110 g) as an off-white solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.89(s,1H),7.84(d,1H,J=8.00 Hz),7.69(d,1H,J=7.80 Hz),7.61(t,1H,J=7.90 Hz),7.28(d,1H,J=7.52 Hz),7.19(t,1H,J=7.60 Hz),7.15(d,1H,J=7.52 Hz),4.47(q,2H,J=15.32 Hz),4.29(d,1H,J=12.00 Hz),4.08(d,1H,J=12.00 Hz),3.42(d,2H,J=4.40 Hz),2.45-2.40(m,2H),1.89(s,3H); MS: m / z 504.2(M+1).

[0314] Example 14a: Preparation of (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-(3,3,3-trifluoropropyl)urea [ka] To a solution of (+)-2-[3-(trifluoromethyl)phenyl]-2-{[4-({[(3,3,3-trifluoropropyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate (from Example 14, step 1, compound 14-1a, fraction 1) (0.250 g, 0.425 mmol) in methanol (20 mL) was added sodium hydroxide (0.085 g, 2.125 mmol) pellets and stirred at ambient temperature for 2 hours. The reaction mass was concentrated and the residue was diluted with water (20 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown gum (0.214 g). This was purified by preparative HPLC to give (−)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-(3,3,3-trifluoropropyl)urea (0.140 g) as an off-white solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.88(s,1H),7.84(d,1H,J=7.90 Hz),7.68(d,1H,J=7.90 Hz),7.61(t,1H,J=7.80 Hz),7.29(d,1H,J=7.00 Hz),7.17(t,1H,J=7.64 Hz),7.12(d,1H,J=6.72 Hz),4.43(q,2H,J=15.40 Hz),4.29(d,1H,J=11.92 Hz),4.07(d,1H,J=12.00 Hz),3.41(t,2H,J=7.00 Hz),2.44-2.36(m,2H),1.89(s,3H); MS: m / z 504.2(M+1); [α]D 25.1 (-)12.03(MeOH,c=1.15).

[0315] Example 14b: Preparation of (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-(3,3,3-trifluoropropyl)urea [ka] To a solution of (-)-2-[3-(trifluoromethyl)phenyl]-2-{[4-({[(3,3,3-trifluoropropyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate (from Example 14, step 1, compound 14-1b, fraction 2) (0.250 g, 0.425 mmol) in methanol (20 mL) was added sodium hydroxide (0.085 g, 2.125 mmol) pellets and stirred at ambient temperature for 2 hours. The reaction mass was concentrated and the residue was diluted with water (20 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown gum (0.214 g). This was purified by preparative HPLC to give (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-(3,3,3-trifluoropropyl)urea (0.160 g) as an off-white solid. 1H NMR(400 MHz,AcOH-d4)δ 7.89(s,1H),7.84(d,1H,J=7.80 Hz),7.68(d,1H,J=8.00 Hz),7.61(t,1H,J=7.80 Hz),7.29(d,1H,J=7.70 Hz),7.18(t,1H,J=7.64 Hz),7.12(d,1H,J=6.84 Hz),4.43(q,2H,J=15.32 Hz),4.28(d,1H,J=11.92 Hz),4.07(d,1H,J=12.00 Hz),3.41(t,2H,J=7.12 Hz),2.43-2.36(m,2H),1.89(s,3H); MS: m / z 504.2(M+1); [α] D 25.2 (+)14.73(MeOH,c=1.20).

[0316] Example 15: Preparation of N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide [ka]

[0317] Example 15, Step 1: Preparation of 2-{[(2-amino-6-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (mixture of regioisomers) [ka] To a solution of N-(2,3-diaminobenzyl)azetidine-1-carboxamide (Example 8, step 2) (0.60 g, 2.72 mmol) in dichloromethane (25 mL) was added 2-(3-chlorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate (Example 11, step 7) (0.813 g, 2.61 mmol) and the mixture was stirred at ambient temperature for 24 hours. The reaction mass was concentrated to give a brown gum (1.5 g). This was purified by column chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with SiO.A, 40-63 μm and eluting the product with 65% ethyl acetate in hexane gave 2-{[(2-amino-6-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a 3:2 mixture of regioisomers) (0.90 g) as a yellow solid which was used in the next step without further purification. MS: m / z 533.2(M+1).

[0318] Example 15, Step 2: Preparation of 2-[(4-{[(azetidine-1-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-6-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(azetidine-1-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a 3:2 mixture of regioisomers) (from Example 15, step 1) (0.90 g, 1.69 mmol) in dry methanol (20 mL) under nitrogen atmosphere, iodoacetic acid (0.799 g, 4.23 mmol) was added and the mixture was stirred at 70° C. for 1 hour. The reaction mass was concentrated to remove methanol solvent and the residue was diluted with 10% aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine solution (20 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.85 g), which was purified by chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with A, 40–63 μm and eluting the product with 90% ethyl acetate in petroleum ether gave 2-[(4-{[(azetidine-1-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (0.83 g) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.45(s,1H),7.40(d,1H,J=7.60 Hz),7.34(t,1H,J=7.80 Hz),7.27(d,1H,J=7.70 Hz),6.97(d,1H,J=7.32 Hz),6.81(t,1H,J=7.50 Hz),6.73(d,1H,J=7.40 Hz),4.50(d,2H,J=10.60 Hz),4.43(d,2H,J=6.90 Hz),4.02(d,2H,J=4.64 Hz),3.78(t,2H,J=7.12 Hz),2.11(d,2H,J=6.60 Hz), 1.81(s,3H), 1.02(s,9H); MS: m / z 499.2(M+1).

[0319] Example 15: Preparation of N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide [ka] To a solution of 2-[(4-{[(azetidine-1-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (from Example 15, step 2) (0.83 g, 1.67 mmol) in methanol (20 mL) solvent, sodium hydroxide pellets (0.667 g, 1.67 mmol) were added and the mixture was stirred at ambient temperature for 3 hours. The reaction mass was concentrated to remove the solvent methanol and the residue was dissolved in water (25 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.69 g). This was purified by column chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with A, 40-63 μm and eluting the product with 8% methanol in chloroform gave N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide (0.65 g) as an off-white solid. 1H NMR(400 MHz,AcOH-d4)δ 7.57(s,1H),7.48(d,1H,J=7.20 Hz),7.39(d,1H,J=8.00 Hz),7.36(d,1H,J=1.20 Hz),7.32(t,1H,J=6.00 Hz),7.16(t,1H,J=7.60 Hz),7.10(d,1H,J=7.40 Hz),4.52(d,1H,J=15.10 Hz),4.38(d,1H,J=15.12 Hz),4.27(d,1H,J=12.00 Hz),4.02(d,1H,J=12.00 Hz),3.96(d,4H,J=7.04 Hz),2.24(t,2H,J=7.30 Hz),1.85(s,3H); MS: m / z 414.2(M+1).

[0320] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: Chiral Pak OX-H; Flow rate: 3.0 mL / min; Co-solvent: 30%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 7.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 15a and 15b.

[0321] Example 15a: (-)-(N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide The (-) enantiomer eluted first from the column. 1H NMR(400 MHz,AcOH-d4)δ 7.56(s,1H),7.46(d,1H,J=7.20 Hz),7.39(d,1H,J=8.00 Hz),7.36(d,1H,J=1.20 Hz),7.32(t,1H,J=6.00 Hz),7.14(t,1H,J=7.60 Hz),7.08(d,1H,J=7.20 Hz),4.48(d,1H,J=15.20 Hz),4.37(d,1H,J=15.20 Hz),4.26(d,1H,J=11.20 Hz),4.02(d,1H,J=12.00 Hz),3.96(d,4H,J=7.04 Hz),2.21(t,2H,J=7.30 Hz),1.79(s,3H); MS: m / z 414.2(M+1); [α] D 22.2 (-)18.40 (MeOH, c=1.0).

[0322] Example 15b: (+)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide The (+) enantiomer eluted second from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.56(s,1H),7.46(d,1H,J=7.20 Hz),7.39(d,1H,J=8.00 Hz),7.37(t,1H,J=8.40 Hz),7.30(d,1H,J=7.60 Hz),7.13(t,1H,J=7.60 Hz),7.08(d,1H,J=7.60 Hz),4.48(d,1H,J=15.20 Hz),4.38(d,1H,J=15.60 Hz),4.27(d,1H,J=12.40 Hz),4.02(d,1H,J=12.40 Hz),3.96(d,4H,J=7.04 Hz),2.22(t,2H,J=7.60 Hz),1.79(s,3H); MS: m / z 414.2(M+1); [α] D 22.6 (+)15.40(MeOH,c=1.0).

[0323] Example 16: Preparation of 1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka]

[0324] Example 16, Step 1: Preparation of 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate [ka] Starting with 1-[3-(trifluoromethoxy)phenyl]ethan-1-one instead of 1-[3-(trifluoromethyl)phenyl]ethan-1-one and using the method described for Example 1, steps 1-15, 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (0.200 g) was obtained as a brown gum. MS: m / z 522.1(M+1).

[0325] Example 16: Preparation of 1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka] To a solution of 2-[(4-{[(methylcarbamoyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (from Example 16, step 1) (0.120 g, 0.230 mmol) in methanol (10 mL) was added sodium hydroxide pellets (0.139 g, 3.45 mmol) and the mixture was stirred at ambient temperature for 1 h. The reaction mass was concentrated to remove the solvent methanol and the residue was dissolved in water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.110 g). This was purified by column chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 12.0 g prepacked flash cartridge packed with A, 40–63 μm and eluting the product with 3–5% methanol in chloroform gave 1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea (0.04 g) as a brown solid. 1 H NMR(400 MHz,CD3OD)δ 7.55(d,1H,J=7.60 Hz),7.54(s,1H),7.41(s,1H),7.29(t,1H,J=7.20 Hz),7.27(d,1H,J=7.80 Hz),7.22(t,1H,J=7.60 Hz),7.15(d,1H,J=7.60 Hz),4.37(s,2H),4.00(d,1H,J=11.20 Hz),3.88(d,1H,J=11.60 Hz),2.70(s,3H),1.89(s,3H); MS: m / z 438.1(M+1).

[0326] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: Lux A1; Flow rate: 3.0 mL / min; Co-solvent: 20%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 16a and 16b.

[0327] Example 16a: (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (-) enantiomer eluted first from the column. 1 H NMR(400 MHz,CD3OD)δ 7.54(d,1H,J=7.32 Hz),7.53(s,1H),7.41(s,1H),7.29(dd,1H,J=7.20 Hz),7.26(d,1H),7.21(t,1H,J=7.40 Hz),7.14(d,1H,J=7.40 Hz),4.36(s,2H),3.98(d,1H,J=11.44 Hz),3.87(d,1H,J=11.40 Hz),2.69(s,3H),1.88(s,3H); MS: m / z 438.1 (M+1); [α] D 20.5 (-)16.67(MeOH,c=0.60).

[0328] Example 16b: (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (+) enantiomer eluted second from the column. 1H NMR(400 MHz,CD3OD)δ 7.55(d,1H,J=7.20 Hz),7.53(s,1H),7.40(s,1H),7.29(t,1H,J=7.20 Hz),7.27(d,1H,J=8.32 Hz),7.16(t,1H,J=7.64 Hz),7.10(d,1H,J=7.32 Hz),4.37(s,2H),3.98(d,1H,J=11.50 Hz),3.87(d,1H,J=11.32 Hz),2.70(s,3H),1.86(s,3H); MS: m / z 438.1 (M+1); [α] D 21.0 (+)17.23,(MeOH,c=0.65).

[0329] Example 17: Preparation of 1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka]

[0330] Example 17, Step 1: Preparation of 2-chloro-1-fluoro-4-(2-isothiocyanato-1-methoxypropan-2-yl)benzene [ka] Starting with 1-(3-chloro-4-fluorophenyl)ethan-1-one instead of 1-[3-(trifluoromethyl)phenyl]ethan-1-one, and using the methods described in Example 1, steps 1-4 and Example 3, steps 1-3, 2-chloro-1-fluoro-4-(2-isothiocyanato-1-methoxypropan-2-yl)benzene (3.50 g) was obtained as a yellow liquid. 1 H NMR(400 MHz,DMSO-d6)δ 7.68-7.65(m,1H),7.50(d,1H,J=7.50 Hz),7.48-7.46(m,1H),3.69(s,2H),3.32(s,3H),1.72(s,3H);

[0331] Example 17, Step 2: Preparation of 1-(3-amino-2-(3-(2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)thioureido)benzyl)-3-methylurea and 1-(2-amino-3-(3-(2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)thioureido)benzyl)-3-methylurea (mixture of regioisomers) [ka] To a solution of 1-(2,3-diaminobenzyl)-3-methylurea (from Example 1, step 13) (0.200 g, 10.30 mmol) in dichloromethane (20 mL) was added 2-chloro-1-fluoro-4-(2-isothiocyanato-1-methoxypropan-2-yl)benzene (from Example 17, step 1) (0.250 g, 9.63 mmol) and the mixture was stirred at ambient temperature for 48 hours. The reaction mass was concentrated to give a brown gum (0.440 g). This was purified by chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with SiO.A, 40-63 μm and eluting the product with 75% ethyl acetate in hexane gave 1-(3-amino-2-(3-(2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)thioureido)benzyl)-methylurea and 1-(2-amino-3-(3-(2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)thioureido)benzyl)-3-methylurea (as a 4:1 mixture of regioisomers) (0.350 g) as a yellow solid. MS: m / z 454.1(M+1).

[0332] Example 17: Preparation of 1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka] To a solution of 1-(3-amino-2-(3-(2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)thioureido)benzyl)methylurea and 1-(2-amino-3-(3-(2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)thioureido)benzyl)-3-methylurea (4:1 mixture of regioisomers) (from Example 17, step 2) (0.350 g, 7.71 mmol) in anhydrous methanol (30 mL) under nitrogen atmosphere, iodoacetic acid (0.143 g, 7.71 mmol) was added and the mixture was stirred at 70° C. for 1 hour. The reaction mass was concentrated to remove methanol solvent and the residue was diluted with 10% aqueous sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine solution (30 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.350 g), which was purified by chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with A, 40-63 μm and eluting the product with 5% methanol in chloroform gave 1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea (0.240 g) as a yellow solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.67(d,1H,J=6.84 Hz),7.53-7.49(m,1H),7.32(d,1H,J=7.72 Hz),7.25(t,1H,J=8.84 Hz),7.18(t,1H,J=7.70 Hz),7.12(d,1H,J=7.12 Hz),4.46(q,2H,J=15.32 Hz),3.96(d,1H,J=10.00 Hz),3.77(d,1H,J=10.00 Hz),3.46(s,3H),2.72(s,3H),1.85(s,3H); MS: m / z 420.2(M+1).

[0333] The above product was resolved into its two enantiomers by Chiral SFC using the following procedure; Column: Lux C4; Flow rate: 3.0 mL / min; Co-solvent: 40%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 4.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 17a and 17b.

[0334] Example 17a: (+)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (+) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.66(d,1H,J=6.52 Hz),7.52(t,1H,J=4.40 Hz),7.31(d,1H,J=7.80 Hz),7.25(t,1H,J=8.80 Hz),7.17(t,1H,J=7.60 Hz),7.12(d,1H,J=7.50 Hz),4.46(q,2H,J=15.30 Hz),3.96(d,1H,J=10.00 Hz),3.77(d,1H,J=10.00 Hz),3.47(s,3H),2.73(s,3H),1.86(s,3H); MS: m / z 420.1 (M+1); [α] D 23.8 (+)13.20(MeOH,c=1.0).

[0335] Example 17b: (-)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (-) enantiomer eluted second from the column. 1H NMR(400 MHz,AcOH-d4)δ 7.66(d,1H,J=6.60 Hz),7.52(t,1H,J=4.60 Hz),7.32(d,1H,J=7.72 Hz),7.25(t,1H,J=8.80 Hz),7.18(t,1H,J=7.60 Hz),7.12(d,1H,J=7.44 Hz),4.47(q,2H,J=15.36 Hz),3.97(d,1H,J=10.00 Hz),3.77(d,1H,J=10.00 Hz),3.47(s,3H),2.73(s,3H),1.86(s,3H); MS: m / z 420.1 (M+1); [α] D 23.8 (-)11.36(MeOH,c=1.0).

[0336] Example 18: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea [ka]

[0337] Example 18, Step 1: Preparation of 2-({[2-amino-6-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-3-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (mixture of regioisomers) [ka] To a solution of 3-(2,3-diaminobenzyl)-1-ethyl-1-methylurea (from Example 5, step 2) (0.998 g, 4.49 mmol) in a mixture of solvent dichloromethane:methanol (4:1; 20 mL) was added 2-(3-chlorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate (from Example 11, step 7) (1.40 g, 4.49 mmol) and the mixture was stirred at ambient temperature for 16 hours. The reaction mass was concentrated to give a brown gum (2.40 g) which was separated by centrifugation on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 40.0 g prepacked flash cartridge packed with SiO.A, 40-63 μm and eluting the product with 60-65% ethyl acetate in hexane gave 2-({[2-amino-6-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-3-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a 4:1 mixture of regioisomers) (2.00 g) as a brown solid. MS: m / z 535.1(M+1).

[0338] Example 18, Step 2: Preparation of 2-(3-chlorophenyl)-2-{[4-({[ethyl(methyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate [ka] To a solution of 2-({[2-amino-6-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-3-({[ethyl(methyl)carbamoyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a 4:1 mixture of regioisomers) (from Example 18, step 1) (2.00 g, 3.74 mmol) in dry methanol (30 mL) under nitrogen atmosphere, iodoacetic acid (1.39 g, 7.49 mmol) was added and the mixture was stirred at 70° C. for 1 hour. The reaction mass was concentrated to remove methanol solvent and the residue was diluted with 10% aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate, filtered and concentrated to give 2-(3-chlorophenyl)-2-{[4-({[ethyl(methyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate (1.90 g) as a brown gum, which was used in the next step without further purification. MS: m / z 501.2(M+1).

[0339] Example 18: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea [ka] To a solution of 2-(3-chlorophenyl)-2-{[4-({[ethyl(methyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate (from Example 18, step 2) (2.10 g, 4.20 mmol) in methanol (50 mL) solvent, sodium hydroxide pellets (1.34 g, 3.36 mmol) were added and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mass was concentrated to remove the solvent methanol and the residue was dissolved in water (50 mL) and extracted with ethyl acetate (4×300 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea (1.30 g) as an off-white solid, which was used in the next step without further purification. 1 H NMR(400 MHz,AcOH-d4)δ 7.59(s,1H),7.49(t,1H,J=7.34 Hz),7.40(d,1H,J=8.00 Hz),7.36(d,1H,J=7.60 Hz),7.31(d,1H,=7.20 Hz),7.18(t,1H,J=7.60 Hz),7.14(d,1H,J=7.20 Hz),4.50(q,2H,J=15.20 Hz),4.22(d,1H,J=12.00 Hz),4.03(d,1H,J=12.00 Hz),3.30(q,2H,J=7.20 Hz),2.85(s,3H),1.86(s,3H),1.10(t,3H,J=7.20 Hz); MS: m / z 416.2(M+1).

[0340] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: Chiral Pak OX-H; Flow rate: 3.0 mL / min; Co-solvent: 30%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 18a and 18b.

[0341] Example 18a: (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea The (-) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.58(s,1H),7.48(t,1H,J=7.40 Hz),7.38(d,1H,J=8.00 Hz),7.35(d,1H,J=7.40 Hz),7.31(d,1H,J=8.40 Hz),7.16(t,1H,J=7.60 Hz),7.10(d,1H,J=7.20 Hz),4.52(d,1H,J=14.80 Hz),4.44(d,1H,J=14.80 Hz),4.20(d,1H,J=12.00 Hz),4.00(d,1H,J=12.00 Hz),3.29(q,2H,J=7.20 Hz),2.84(s,3H),1.84(s,3H),1.08(t,3H,J=7.20 Hz); MS: m / z 416.2 (M+1); [α] D 25.5 (-) 30.88 (MeOH, c = 1.0).

[0342] Example 18b: (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea The (+) enantiomer eluted second from the column. 1H NMR(400 MHz,AcOH-d4)δ 7.59(s,1H),7.49(t,1H,J=7.60 Hz),7.39(d,1H,J=8.00 Hz),7.36(d,1H,J=7.30 Hz),7.34(d,1H,J=7.60 Hz),7.16(t,1H,J=8.00 Hz),7.11(d,1H,J=7.20 Hz),4.53(d,1H,J=14.80 Hz),4.43(d,1H,J=15.20 Hz),4.20(d,1H,J=12.00 Hz),4.00(d,1H,J=12.00 Hz),3.30(q,2H,J=7.20 Hz),2.85(s,3H),1.86(s,3H),1.09(t,3H,J=7.20 Hz); MS: m / z 416.2 (M+1); [α] D 25.6 (+)22.92(MeOH,c=1.0).

[0343] Example 19: Preparation of N-[[2-[[1-(3-chlorophenyl)-2-hydroxy-1-methyl-ethyl]amino]-3H-benzimidazol-4-yl]methyl]isoxazolidine-2-carboxamide [ka]

[0344] Example 19, Step 1: Preparation of 2-({[2-amino-6-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-3-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (mixture of regioisomers) [ka] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(2,3-diaminophenyl)methyl]carbamate (from Example 9, step 1) (1.0 g, 2.963 mmol) in a mixture of solvents methanol:dichloromethane (1:4; 5.00 ml) was added 2-(3-chlorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate (from Example 11, step 7) (0.924 g, 2.963 mmol) and the mixture was stirred at ambient temperature for 16 hours. The reaction mass was concentrated to remove methanol and the crude product was obtained by elution with 60% ethanol. o A, purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with 40-63 μm normal phase silica gel and eluting the product with 40-45% ethyl acetate in hexane gave 2-({[2-amino-6-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-3-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of regioisomers) (1.30 g) as a brown solid. MS: m / z 649.3(M+1).

[0345] Example 19, Step 2: Preparation of 2-{[7-({bis[(tert-butoxy)carbonyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate [ka] To a solution of 2-({[2-amino-6-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-3-({bis[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamothioyl}amino)-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of regioisomers) (from Example 19, step 1) (1.30 g, 2.00 mmol) in anhydrous methanol (15 mL) was added iodoacetic acid (0.558 g, 3.003 mmol) and the mixture was stirred at 65° C. for 1.5 hours. The reaction mass was concentrated to remove methanol and the residue was diluted with dichloromethane (100 mL) and washed with 10% sodium bicarbonate solution (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown gum (1.30 g), which was purified by chromatography on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 40.0 g prepacked flash cartridge packed with 40-63 μm A, eluting the product with 50-55% ethyl acetate in hexane gave 2-{[7-({bis[(tert-butoxy)carbonyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (1.10 g) as a brown solid. MS: m / z 615.2(M+1).

[0346] Example 19, Step 3: Preparation of 2-{[7-(aminomethyl)-1H-1,3-benzodiazol-2-yl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate; trifluoroacetic acid [ka] To a stirred solution of 2-{[7-({bis[(tert-butoxy)carbonyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (from Example 19, step 2) (1.10 g, 1.79 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (0.41 mL, 5.36 mmol) at 0° C. and then stirred at ambient temperature for 16 hours. The reaction mass was concentrated under reduced pressure to give 2-{[7-(aminomethyl)-1H-1,3-benzodiazol-2-yl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate; trifluoroacetic acid (1.60 g) as a brown gum which was used in the next step without further purification. MS: m / z 415.1(M+1).

[0347] Example 19, Step 4: Preparation of 2-(3-chlorophenyl)-2-[(7-{[(1H-imidazole-1-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]propyl 2,2-dimethylpropanoate [ka] A suspension of 2-{[7-(aminomethyl)-1H-1,3-benzodiazol-2-yl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate; trifluoroacetic acid (from Example 19, Step 3) (1.00 g, 2.51 mmol) in dichloromethane (5 mL) was treated with triethylamine (1.05 mL, d=0.724 gm / cm 3, 7.52 mmol) was added and the mixture was stirred at ambient temperature for 1 h. Carbonyldiimidazole (0.610 g, 0.376 mmol) was then added portionwise at 0° C. and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(3-chlorophenyl)-2-[(7-{[(1H-imidazole-1-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]propyl 2,2-dimethylpropanoate (0.70 g) as a brown gum, which was used in the next step without further purification. MS: m / z 509.2(M+1).

[0348] Example 19, Step 5: Preparation of 2-(3-chlorophenyl)-2-[(7-{[(1,2-oxazolidine-2-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]propyl 2,2-dimethylpropanoate [ka] To a stirred solution of 2-(3-chlorophenyl)-2-[(7-{[(1H-imidazole-1-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]propyl 2,2-dimethylpropanoate (from Example 19, step 4) (1.0 g, 1.97 mmol) in dry tetrahydrofuran (30 mL) was added 1,2-oxazolidine hydrochloride (0.431 g, 3.93 mmol) followed by potassium carbonate (0.816 g, 5.91 mmol) and the mixture was stirred at 70° C. for 32 hours. The reaction mixture was then quenched with water (30 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(3-chlorophenyl)-2-[(7-{[(1,2-oxazolidine-2-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]propyl 2,2-dimethylpropanoate (1.00 g) as a brown gum, which was used in the next step without further purification. MS: m / z 514(M+1).

[0349] Example 19: Preparation of N-[[2-[[1-(3-chlorophenyl)-2-hydroxy-1-methyl-ethyl]amino]-3H-benzimidazol-4-yl]methyl]isoxazolidine-2-carboxamide [ka] To a solution of 2-(3-chlorophenyl)-2-[(7-{[(1,2-oxazolidine-2-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]propyl 2,2-dimethylpropanoate (from Example 19, step 5) (1.2 g, 2.33 mmol) in methanol (10 mL) was added sodium hydroxide pellets (0.467 g, 11.7 mmol) at 0° C. and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated to remove methanol and the residue was diluted with dichloromethane (200 mL) and washed with water (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a brown gum (0.580 g). This was purified by preparative HPLC (ammonium acetate method) to give N-[[2-[[1-(3-chlorophenyl)-2-hydroxy-1-methyl-ethyl]amino]-3H-benzimidazol-4-yl]methyl]isoxazolidine-2-carboxamide (0.450 g) as an off-white solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.59(s,1H),7.50(d,1H,J=7.08 Hz),7.40(d,1H,J=4.30 Hz),7.36(d,1H,J=8.92 Hz),7.34(t,1H,J=2.12 Hz),7.18(t,1H J=7.52 Hz),7.14(d,1H,J=1.00 Hz),4.48(d,2H,J=4.32 Hz),4.24(d,1H,J=11.96 Hz),4.02(d,1H J=11.96 Hz),3.85(t,2H,J=7.40 Hz),3.60-3.56(m,2H),2.24-2.16(m,2H),1.84(s,3H); MS: m / z 430.2(M+1).

[0350] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: YMC Cellulose-SC; Flow rate: 3.0 mL / min; Co-solvent: 40%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 7.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 19a and 19b.

[0351] Example 19a: (-)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-7-yl)methyl)isoxazolidine-2-carboxamide The (-) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.59(s,1H),7.50(d,1H,J=7.08 Hz),7.40(d,1H,J=4.30 Hz),7.37(t,1H,J=8.92 Hz),7.34(d,1H,J=4.20 Hz),7.19(t,1H,J=7.52 Hz),7.14(d,1H,J=7.56 Hz),4.47(d,2H,J=4.32 Hz),4.24(d,1H,J=11.96 Hz),4.02(d,1H,J=11.92 Hz),3.85(t,2H,J=7.04 Hz),3.56-3.60(m,2H),2.20(t,2H,J=7.28 Hz),1.84(s,3H); MS: m / z 430.2 (M+1); [α] D 22.2 (-)14.40 (MeOH, c=1.0).

[0352] Example 19b: (+)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-7-yl)methyl)isoxazolidine-2-carboxamide The (+) enantiomer eluted second from the column. 1H NMR(400 MHz,AcOH-d4)δ 7.59(d,1H,J=1.00 Hz),7.50(t,1H,J=5.40 Hz),7.39(s,1H),7.37(d,1H,J=1.44 Hz),7.34(d,1H,J=4.60 Hz),7.19(d,1H,J=7.64 Hz),7.15(t,1H,J=7.72 Hz),4.47(d,2H,J=4.32 Hz),4.24(d,1H,J=11.92 Hz),4.02(d,1H,J=11.92 Hz),3.85(t,2H,J=7.04 Hz),3.56-3.60(m,2H),2.20(t,2H,J=7.36 Hz),1.84(s,3H); MS: m / z 430.2 (M+1); [α] D 22.3 (+)17.0(MeOH,c=1.0).

[0353] Example 20: Preparation of 1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka]

[0354] Example 20, Step 1: Preparation of (E)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide [ka] To a solution of 1-(3-(trifluoromethyl)phenyl)ethan-1-one (commercially available) (125.00 g, 664.00 mmol) in dry tetrahydrofuran (1500 mL) under nitrogen atmosphere was added 2-methylpropane-2-sulfinamide (80.52 g, 664.00 mmol) followed by titanium(IV) ethoxide (278.60 mL, d=1.008 gm / mL, 1328.00 mmol) and the mixture was heated to 70° C. for 17 hours. The reaction mass was diluted with brine solution (200 mL), filtered and the filtrate was evaporated to give a yellowish gum (200.00 g). This was purified by gravity column chromatography using silica gel (60-120 mesh) and the product was eluted with 10% ethyl acetate in hexane to give (E)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (150.00 g) as a yellowish gum. 1 H NMR(400 MHz,CD3OD)δ 8.25(s,1H),8.23(d,1H,J=7.60 Hz),7.88(d,1H,J=7.60 Hz),7.72(t,1H,J=8.00 Hz),2.84(s,3H),1.35(s,9H); MS: m / z 292.3(M+1).

[0355] Example 20, Step 2: Preparation of methyl 3-[(2-methylpropane-2-sulfinyl)amino]-3-[3-(trifluoromethyl)phenyl]butanoate [ka] To a suspension of zinc dust (269.30 g, 4.120 gm atoms) in dry tetrahydrofuran (750 mL) was added copper(I) chloride (51.00, 515.00 mmol) and the mixture was stirred at 60° C. After 30 minutes, a solution of methyl 2-bromoacetate (122.00 mL, d=1.616 gm / mL, 1287.00 mmol) in dry tetrahydrofuran (500 mL) was added dropwise and this was then stirred at the same temperature for 30 minutes. A solution of (E)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (from Example 20, step 1) (150.00 g, 515.00 mmol) in dry tetrahydrofuran (500 mL) was added dropwise at 0-5° C. and stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL), the solid formed was filtered off and the filtrate was extracted with ethyl acetate (3 x 1000 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to give a brownish gum (250.00 g). This was purified by gravity column chromatography on 60-120 silica gel and the product was eluted with 70-75% ethyl acetate in hexane to give methyl 3-[(2-methylpropane-2-sulfinyl)amino]-3-[3-(trifluoromethyl)phenyl]butanoate (135.00 g) as a yellowish gum. 1 H NMR(400 MHz,AcOH-d4)δ 7.81(d,1H,J=7.6 Hz),7.74(d,1H,J=8.00 Hz),7.62(d,1H,J=7.60 Hz),7.56(t,1H,J=8.00 Hz),3.62(s,3H),3.20(q,2H,J=16.40 Hz),1.87(s,3H),1.35(s,9H); MS: m / z 366.2(M+1).

[0356] Example 20, Step 3: Preparation of methyl 3-amino-3-(3-(trifluoromethyl)phenyl)butanoate hydrochloride [ka] To a solution of methyl 3-[(2-methylpropane-2-sulfinyl)amino]-3-[3-(trifluoromethyl)phenyl]butanoate (from Example 20, step 2) (135.00 g, 369.00 mmol) in dioxane was added 4 M HCl in dioxane (461.00 mL, 1845.00 mmol) at 0° C. and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was evaporated to give methyl 3-amino-3-(3-(trifluoromethyl)phenyl)butanoate hydrochloride (100.00 g) as a brownish gum, which was used in the next step without further purification. 1 H NMR(400 MHz,AcOH-d4)δ 7.94(s,1H),7.91(d,J=8.80 Hz,1H),7.74(d,J=7.60 Hz,1H),7.70(t,J=7.60 Hz,1H),3.69(s,3H),3.48(s,2H),2.02(s,3H); MS: m / z 262.2 [(M+1)-HCl].

[0357] Example 20, Step 4: Preparation of methyl 3-isothiocyanato-3-(3-(trifluoromethyl)phenyl)butanoate [ka] To a solution of methyl 3-amino-3-(3-(trifluoromethyl)phenyl)butanoate hydrochloride (from Example 20, step 3) (13.00 g, 50.00 mmol) in dry dichloromethane (150 mL) was added 10% aqueous sodium bicarbonate (150 mL) at 0° C. After 15 min, thiophosgene (5.72 mL, d=1.5 g / cm 3 , 75.00 mmol) was added and stirred at the same temperature for 1 h. The reaction mass was extracted with dichloromethane (3×250 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow liquid (30.00 g). This was then transferred onto normal phase silica gel 60 oA, 40-63 μm and the product was eluted with 3-5% methanol in chloroform to give methyl 3-isothiocyanato-3-(3-(trifluoromethyl)phenyl)butanoate (15.00 g) as a yellow liquid. 1 H NMR(400 MHz,DMSO-d6)δ 7.83(s,1H),7.81(d,J=7.20 Hz,1H),7.72(d,J=8.00 Hz,1H),7.66(t,J=7.60 Hz,1H),3.53(s,3H),3.30(d,J=13.60 Hz,2H),1.86(s,3H); MS: m / z 304.1(M+1).

[0358] Example 20, Step 5: Preparation of methyl 3-(3-(2-amino-6-((3-methylureido)methyl)phenyl)thioureido)-3-(3-(trifluoromethyl)phenyl)butanoate and methyl 3-(3-(2-amino-3-((3-methylureido)methyl)phenyl)thioureido)-3-(3-(trifluoromethyl)phenyl)butanoate (mixture of regioisomers) [ka] To a solution of 1-(2,3-diaminobenzyl)-3-methylurea (from Example 1, step 13) (0.800 g, 4.00 mmol) in a mixture of solvents acetonitrile:methanol (4:1; 16 mL) was added methyl 3-isothiocyanato-3-(3-(trifluoromethyl)phenyl)butanoate (from Example 20, step 4) (1.249 g, 4.00 mmol) and the mixture was stirred at ambient temperature for 16 hours. The reaction mass was concentrated to give a yellow gum (2.05 g) which was separated by centrifugation on normal phase silica gel 60 oPurification by chromatography on a Grace instrument using a 40.00 g prepacked flash cartridge packed with 1000 μm A, 40-63 μm and eluting the product with 40-45% ethyl acetate in hexanes gave methyl 3-(3-(2-amino-6-((3-methylureido)methyl)phenyl)thioureido)-3-(3-(trifluoromethyl)phenyl)butanoate and methyl 3-(3-(2-amino-3-((3-methylureido)methyl)phenyl)thioureido)-3-(3-(trifluoromethyl)phenyl)butanoate (as a 7:3 mixture of regioisomers) (1.70 g) as a brown gum. MS: m / z 498.2(M+1).

[0359] Example 20, Step 6: Preparation of 1-methyl-3-((2-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidin-9-yl)methyl)urea [ka] To a solution of methyl 3-(3-(2-amino-6-((3-methylureido)methyl)phenyl)thioureido)-3-(3-(trifluoromethyl)phenyl)butanoate and methyl 3-(3-(2-amino-3-((3-methylureido)methyl)phenyl)thioureido)-3-(3-(trifluoromethyl)phenyl)butanoate (as a 7:3 mixture of regioisomers) (from Example 20, step 5) (2.20 g, 4.42 mmol) in methanol (50 mL) was added mercuric oxide (1.92 g, 8.84 mmol) followed by elemental sulfur (0.071 g, 2.21 mmol) and the mixture was stirred at 65° C. for 3 hours. The reaction mass was filtered through a bed of Celite and then washed with methanol (3×250 mL). The combined filtrate was concentrated to give a brown liquid (1.91 g). This was purified by chromatography on normal phase silica gel 60 oPurification by chromatography on a Grace instrument using an 80.00 g prepacked flash cartridge packed with 1,200 μl HCl, 40-63 μm and eluting the product with 2-4% methanol in chloroform to give 1-methyl-3-((2-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidin-9-yl)methyl)urea (1.70 g) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6:D2O)δ 7.92(s,1H),7.82(d,1H,J=7.20 Hz),7.63(d,2H,J=7.60 Hz),7.60(t,1H,J=7.20 Hz),7.05(d,1H,J=6.80 Hz),6.96(t,1H,J=8.00 Hz),4.41(s,2H),3.58(d,1H,J=16.40 Hz),3.37(d,1H,J=12.40 Hz),2.54(s,3H),1.91(s,3H); MS: m / z 432.2(M+1).

[0360] Example 20: Preparation of 1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea [ka] To a stirred solution of 1-methyl-3-((2-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidin-9-yl)methyl)urea (from Example 20, step 6) (1.50 g, 3.00 mmol) in dry tetrahydrofuran under nitrogen atmosphere was added sodium borohydride (0.395 g, 10.00 mmol) at 0° C., which was then stirred at 50° C. for 12 hours. The reaction mixture was quenched with a saturated aqueous solution of potassium sodium tartrate (50 mL) and extracted with ethyl acetate (4×500 mL). The combined organic layers were washed with brine solution (30 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (1.40 g). This was purified by preparative HPLC to give 1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea (0.400 g) as a brown solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.88(s,1H),7.85(d,1H,J=7.60 Hz),7.68(d,1H,J=7.56 Hz),7.61(t,1H,J=7.76 Hz),7.28(d,1H,J=7.96 Hz),7.17(t,1H,J=8.00 Hz),7.11(d,1H,J=7.44 Hz),4.42(s,2H),3.88-3.78(m,2H),2.69(s,3H),2.48-2.41(m,2H),2.03(s,3H); MS: m / z 436.2(M+1).

[0361] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: Chiral Pak OX-H; Flow rate: 3.0 mL / min; Co-solvent: 30%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 40° C. to give the two enantiomers 20a and 20b.

[0362] Example 20a: (-)-1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (-) enantiomer eluted first from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.89(s,1H),7.86(d,1H,J=7.60 Hz),7.68(d,1H,J=8.00 Hz),7.62(t,1H,J=7.60 Hz),7.30(d,1H,J=8.00 Hz),7.18(t,1H,J=7.60 Hz),7.11(d,1H,J=7.20 Hz),4.42(s,2H),3.88-3.79(m,2H),2.70(s,3H),2.51-2.40(m,2H),2.03(s,3H); MS: m / z 436.2(M+1); [α] D 22.4 (-)26.40(MeOH,c=0.1).

[0363] Example 20b: (+)-1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea The (+) enantiomer eluted second from the column. 1 H NMR(400 MHz,AcOH-d4)δ 7.89(s,1H),7.86(d,1H,J=8.00 Hz),7.68(d,1H,J=8.00 Hz),7.62(t,1H,J=7.60 Hz),7.31(d,1H,J=8.00 Hz),7.17(t,1H,J=8.00 Hz),7.10(d,1H,J=7.60 Hz),4.41(s,2H),3.88-3.79(m,2H),2.70(s,3H),2.51-2.40(m,2H),2.02(s,3H); MS: m / z 436.2(M+1); [α] D 22.0 (+)24.00(MeOH,c=0.1).

[0364] Example 21: Preparation of N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)morpholine-4-carboxamide [ka]

[0365] Example 21, Step 1: Preparation of N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)morpholine-4-carboxamide [ka] To a stirred solution of 2,1,3-benzothiadiazol-4-ylmethanamine; hydrochloride salt (from Example 1, Step 11) (13.00 g, 64.50 mmol) in dichloromethane (500 mL) at 0 °C was added triethylamine (27.00 mL, d: 0.726 g / cm 3 , 193.00 mmol) followed by morpholine-4-carbonyl chloride (9.05 mL, d=1.282 g / mL, 77.40 mmol) were added dropwise and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with ice-cold water (100 mL) and the aqueous layer was extracted with dichloromethane (4×750 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid (18.00 g). The solid was triturated with n-hexane (300 mL), the supernatant layer was discarded and the solid was dried to give N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)morpholine-4-carboxamide (14.5 g) as an off-white solid which was used in the next step without further purification. 1H NMR(400 MHz,DMSO-d6:D2O)δ 7.95(d,1H,J=8.76 Hz),7.70(t,1H,J=8.72 Hz),7.47(d,1H,J=6.72 Hz),4.75(s,2H),3.58(t,4H,J=4.92 Hz),3.34(t,4H,J=4.60 Hz); MS: m / z 279.1(M+1).

[0366] Example 21, Step 2: Preparation of N-(2,3-diaminobenzyl)morpholine-4-carboxamide. [ka] To a degassed solution of N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)morpholine-4-carboxamide (from Example 21, step 1) (11.00 g, 39.50 mmol) in dry methanol (1000 mL) was added Raney nickel (22.00 g, 200% w / w, pre-washed 5 times with dry methanol) and the resulting reaction mixture was heated under a hydrogen atmosphere with a bladder pressure (approximately 1.5 kg / cm 2 ) at ambient temperature for 48 h. The reaction mixture was filtered through a bed of Celite and the bed was washed with methanol (3×2000 mL). The combined filtrate was concentrated to give N-(2,3-diaminobenzyl)morpholine-4-carboxamide (9.00 g) as a green solid, which was used in the next step without further purification. 1 H NMR(400 MHz,DMSO-d6)δ 6.94(t,1H,J=5.20 Hz),6.47(d,1H,J=7.20 Hz),6.39(t,1H,J=12.00 Hz),6.33(d,1H,J=7.20 Hz),4.60(s,2H),4.42(s,2H),4.11(d,2H,J=5.20 Hz),3.54(t,4H,J=4.00 Hz),3.31(t,4H,J=4.40 Hz); MS: m / z 251.2(M+1).

[0367] Example 21, Step 3: Preparation of 2-{[(2-amino-6-{[(morpholine-4-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(morpholine-4-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (mixture of regioisomers) [ka] To a solution of N-(2,3-diaminobenzyl)morpholine-4-carboxamide (from Example 21, step 2) (0.22 g, 0.87 mmol) in a mixture of solvent dichloromethane:methanol (4:1; 10 mL) was added 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 1, step 7) (0.30 g, 0.87 mmol) and the mixture was stirred at ambient temperature for 26 hours. The reaction mass was concentrated to give a brown gum (0.53 g). This was chromatographed on normal phase silica gel 60 o Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash cartridge packed with SiO.A, 40-63 μm and eluting the product with 60-70% ethyl acetate in hexane gave 2-{[(2-amino-6-{[(morpholine-4-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(morpholine-4-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regioisomers) (0.25 g) as a brown gum. MS: m / z 596.2(M+1).

[0368] Example 21, Step 4: Preparation of 2-[(7-{[(morpholine-4-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-6-{[(morpholine-4-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-{[(2-amino-3-{[(morpholine-4-carbonyl)amino]methyl}phenyl)carbamothioyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a 1:1 mixture of regioisomers) (from Example 21, step 3) (1.60 g, 2.69 mmol) in dry methanol (20 mL) under nitrogen atmosphere, iodoacetic acid (0.50 g, 2.69 mmol) was added and the mixture was stirred at 70° C. for 1 h. The reaction mass was concentrated and the residue was poured into ice-cold water (100 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with saturated bicarbonate solution (30 mL) followed by brine (30 mL), dried over sodium sulfate, filtered and concentrated to give 2-[(7-{[(morpholine-4-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (1.20 g) as a brown solid. 1H NMR(400 MHz,DMSO-d6:D2O)δ 7.87(d,2H,J=12.80 Hz),7.72(d,1H,J=8.00 Hz),7.66(t,1H,J=7.60 Hz),7.29(d,1H,J=8.00 Hz),7.20(t,1H,J=7.60 Hz),7.13(d,1H,J=7.60 Hz),4.70(d,1H,J=11.60 Hz),4.57(d,1H,J=11.60 Hz),4.36(d,2H,J=6.40 Hz),3.65(s,2H),3.64-3.62(m,4H),3.36(d,2H,J=5.20 Hz), 1.98(s,3H), 1.16(s,9H); MS: m / z 562.2(M+1).

[0369] Example 21: Preparation of N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)morpholine-4-carboxamide [ka] To a stirred solution of 2-[(7-{[(morpholine-4-carbonyl)amino]methyl}-1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 21, step 4) (1.00 g, 1.78 mmol) in methanol (20.0 mL) was added sodium hydroxide pellets (0.22 g, 5.34 mmol) and the mixture was stirred at ambient temperature for 1 h. The reaction mass was concentrated and the residue was diluted with water (50 mL). The aqueous layer was extracted with dichloromethane (3×100 mL) and the combined organic layers were washed with water (25 mL) followed by brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.650 g). This was purified by preparative HPLC to give N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)morpholine-4-carboxamide (0.450 g) as an off-white solid. 1 H NMR(400 MHz,AcOH-d4)δ 7.88(s,1H),7.85(d,1H,J=8.00 Hz),7.68(d,1H,J=7.60 Hz),7.61(d,1H,J=7.60 Hz),7.34(d,1H,J=8.00 Hz),7.17(t,1H,J=8.00 Hz),7.11(d,1H,J=7.60 Hz),4.45(q,2H,J=14.80 Hz),4.23(d,1H,J=12.00 Hz),4.06(d,1H,J=11.60 Hz),3.69(t,4H,J=4.80 Hz),3.35(t,4H,J=3.60 Hz), 1.90(s,3H); MS: m / z 478.2(M+1).

[0370] The above product was resolved into its two enantiomers by Chiral SFC using the following method; Column: Chiralcel OX-H; Flow rate: 3.0 mL / min; Co-solvent: 30%; Co-solvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 35° C. to give the two enantiomers 21a and 21b.

[0371] Example 21a: (+)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)morpholine-4-carboxamide The (+) enantiomer eluted first from the column. 1 H NMR(400 MHz,CD3OD):δ 7.78(d,2H,J=12.80 Hz),7.58-7.52(m,2H),7.11(d,1H,J=7.60 Hz),6.96-6.88(m,2H),4.47(s,2H),3.99(d,1H,J=11.60 Hz),3.85(d,1H,J=11.20 Hz),3.64(t,4H,J=5.20 Hz),3.36(t,4H,J=5.20 Hz),1.78(s,3H); MS: m / z 478.2 (M+1); [α]D 22.5 (+)19.8(MeOH,c=1.0).

[0372] Example 21b: (-)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)morpholine-4-carboxamide The (-) enantiomer eluted second from the column. 1 H NMR(400 MHz,CD3OD):δ 7.78(t,2H,J=7.20 Hz),7.55(t,2H,J=7.20 Hz),7.11(d,1H,J=7.60 Hz),6.94(t,1H,J=8.00 Hz),6.89(d,1H,J=7.20 Hz),4.47(s,2H),3.99(d,1H,J=11.60 Hz),3.85(d,1H,J=11.20 Hz),3.64(t,4H,J=4.80 Hz),3.36(t,4H,J=4.80 Hz),1.78(s,3H); MS: m / z 478.2 (M+1); [α] D 22.5 (-)19.12(MeOH,c=1.0).

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, R1 is hydrogen and C １－６ Selected from alkyl groups; R2 to R3 independently contain hydrogen and C １－６ Is it a group selected from alkyl groups? Alternatively, R2 and R3, together with the carbon atoms to which they are bonded, form C ３－４ Forms a cycloalkyl group; R4 to R6 are independently hydrogen, halogen, and C １－４ A group selected from alkyl groups; R7 is hydrogen and C １－４ Selected from the group consisting of alkyl groups, R8 is C １－６ alkyl, C substituted with one OH １－６ alkyl, and C substituted with one OC １－３ alkyl, selected from the group consisting of １－６ alkyl, or Alternatively, R7 and R8, together with the carbon atoms to which they are bonded, form a C3-4 cycloalkyl group; R9 to R13 are independently hydrogen, halogen, and C substituted with at least one halogen. １－６ Alkyl, C １－６ alkoxy, C substituted with at least one halogen １－６ Alkoxy, C １－６ A group selected from alkylthio and cyano; R14 is H, C １－６ Alkyl or C １－６ Selected from alkoxy; R15 is H, C １－６ Alkyl, C substituted with at least one halogen １－６ Alkyl, C １－６ alkoxy, C substituted with at least one halogen １－６ Alkoxy, or C ３－４ Selected from cycloalkyl groups; Alternatively, R14 and R15, together with the nitrogen atom to which they are bonded, contain one or two nitrogen atoms, possibly one oxygen atom, and possibly one sulfur atom, and halogens, C １－６ Alkyl, C substituted with at least one halogen １－６ Alkyl, C １－６ alkoxy, C substituted with at least one halogen １－６ (Forms a 4- to 6-membered non-aromatic heterocycle, optionally substituted with at least one group selected from alkoxys.) Compounds of; or The pharmaceutically acceptable salt.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen (H) and methyl, for example, H.

3. R2 to R3 are independent of H and C １－３ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the group is selected from alkyl, for example, H and methyl.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein both R2 and R3 are H.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4 to R6 are independently selected from H, F, and methyl.

6. R7 is H and C １－３ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the group is an alkyl group, for example, selected from methyl and ethyl.

7. R8 is a C substituted with one OH group. １－４ Alkyl and one OC １－３ C substituted with alkyl １－４ Alkyl, for example, CH ２ OH, CH ２ CH ２ OH, CH ２ OCH ３ , and CH ２ CH ２ O-CH ３ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the group is selected from the above.

8. R9 to R13 are independently replaced by H, halogen, or at least one halogen C. １－６ C substituted with alkyl and at least one halogen １－６ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the group is selected from alkoxy groups.

9. R9, R12, and R13 are all H, and R10 to R11 are independently replaced by H, halogen, or at least one halogen C １－６ C substituted with alkyl and at least one halogen １－６ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the group is selected from alkoxy groups, provided that both R10 and R11 are not H.

10. R14 is H and C １－６ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from alkyl groups, such as H, methyl, and ethyl.

11. R15 is H, C １－６ Alkyl, C substituted with at least one halogen １－６ Alkyl, C １－６ alkoxy, C substituted with at least one halogen １－６ Alkoxy, or C ３－４ Cycloalkyl groups, e.g., methyl, ethyl, methoxy, cyclopropyl, CH ２ CH ２ CF ３ , or CH ２ CH ２ OCF ３ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the above.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R14 and R15, together with the nitrogen atom to which they are bonded, form a 4- to 6-membered non-aromatic heterocycle containing one nitrogen atom and optionally one oxygen atom, optionally substituted with at least one halogen, for example, azetidinyl, piperidinyl, morpholinyl, and isoxazolidinyl, optionally substituted with at least one F.

13. 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, 3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1,1-dimethylurea, (+)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1,1-dimethylurea, (-)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1,1-dimethylurea, 1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (+)-1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (-)-1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, 1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazole-4-yl]methyl}-3-methoxy-3-methylurea, (+)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1-methoxy-1-methylurea, (-)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1-methoxy-1-methylurea, 1-Ethyl-3-((2-((1-Hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1-methylurea, (+)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1-methylurea, (-)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1-methylurea, 3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1,1-dimethylurea, (+)-3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1,1-dimethylurea, (-)-3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1,1-dimethylurea, 1-Cyclopropyl-3-((2-((1-Hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)urea, (-)-1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)urea, (+)-1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)urea, N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)azetidine-1-carboxamide, (-)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)azetidine-1-carboxamide, (+)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)azetidine-1-carboxamide, 3-ethyl-1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazole-4-yl]methyl}urea, (+)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)urea, (-)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)urea, 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1-methoxy-1-methylurea, (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1-methoxy-1-methylurea, (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1-methoxy-1-methylurea, 1-[[2-[[1-(3-chloro-4-fluorophenyl)-2-hydroxy-1-methyl-ethyl]amino]-1H-benzimidazole-4-yl]methyl]-3-methylurea, (-)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (+)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1,1-dimethylurea, (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1,1-dimethylurea, (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1,1-dimethylurea, 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-(3,3,3-trifluoropropyl)urea, (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-(3,3,3-trifluoropropyl)urea, (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-(3,3,3-trifluoropropyl)urea, N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)azetidine-1-carboxamide, (-)-(N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)azetidine-1-carboxamide, (+)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)azetidine-1-carboxamide, 1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, 1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (+)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (-)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1-ethyl-1-methylurea, (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1-ethyl-1-methylurea, (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-1-ethyl-1-methylurea, N-[[2-[[1-(3-chlorophenyl)-2-hydroxy-1-methyl-ethyl]amino]-3H-benzimidazole-4-yl]methyl]isoxazolidine-2-carboxamide, (-)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-7-yl)methyl)isoxazolidine-2-carboxamide, (+)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazole-7-yl)methyl)isoxazolidine-2-carboxamide, 1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (-)-1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, (+)-1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)-3-methylurea, N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)morpholine-4-carboxamide, (+)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)morpholine-4-carboxamide, and (-)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazole-4-yl)methyl)morpholine-4-carboxamide; A compound according to claim 1, selected from any one of the following, or The pharmaceutically acceptable salt.

14. A compound according to claim 1 or 2 for use as a pharmaceutical.

15. A pharmaceutical composition comprising the compound described in claim 1 or 2, and optionally a pharmaceutically acceptable additive, such as a carrier or excipient.

16. The compound according to claim 1 or 2, for use in a method of treating heart disease, disorder, or symptoms in mammals such as humans.

17. The compound according to claim 1 or 2, for use in a method of treating a cardiac disease, disorder, or symptom in which the disease, disorder, or symptom is related to an abnormal rhythm or variant of the heart and exercise-induced angina.

18. The compound according to claim 1 or 2 for use in a method for treating a cardiac disease, disorder, or symptom selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal rhythms occurring after cardiac surgery or cardiac ablation procedures.

19. A method for treating a heart disease, disorder, or symptom in a mammal such as a human, comprising administering a therapeutically effective amount of at least one compound according to claim 1 or 2 to a mammal in need of treatment.

20. The method according to claim 19, wherein the cardiac disease, disorder, or symptom in a mammal is selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal rhythms occurring after cardiac surgery or cardiac ablation.

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