Imidazole derivatives as potassium channel inhibitors

Abstract

The invention relates to compounds of general formula (I). The compounds of formula (I) are useful in the treatment of cardiac diseases, disorders or conditions in mammals. # imgabs0 #

Description

Technical Field

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

[0002] The heart is a muscle that pumps blood in the circulation by contracting 1-3 times per second. The heartbeat is caused by the simultaneous contraction of individual heart muscle cells (cardiac myocytes). The synchronization of cell contractions is controlled by the cardiac electrical impulse (cardiac action potential), which is generated in the pacemaker cells of the sinoatrial node and rapidly propagated to the heart via a specialized conduction system.

[0003] Disturbances in impulse generation and impulse conduction may be the result of disease, medication, or electrolyte imbalances. Such disturbances of impulses are called arrhythmias or dysrhythmias, and they may lead to restlessness, embolism, syncope, or sudden death. In its simplest form, arrhythmias encompass everything that differs from the normal sinus rhythm of the heart. Disturbances can range from simple palpitations to devastating ventricular fibrillation, including bradycardia and tachycardia.

[0004] At the molecular level, a group of proteins called ion channels underlie the electrical activity of the heart, as they are able to conduct electrical currents across cell membranes. Different types of ion channels therefore play a role in the generation and conduction of cardiac action potentials, in the regulation of heart rate by the autonomic nervous system, and in the contraction of individual heart cells. Different types of ion channels are therefore obvious targets for antiarrhythmic heart drugs, and many antiarrhythmic drugs on the market do exert their effects by interacting with ion channels.

[0005] Antiarrhythmic drugs are generally divided into four major classes, based on the so-called Singh Vaughan Williams classification: Class I compounds all inhibit cardiac voltage-dependent sodium channels. Some Class I compounds do have the additional effect of affecting the cardiac action potential, which is the basis for a further subdivision into three subclasses:

[0006] Class IA compounds are sodium channel inhibitors, such as Quinidine, Procainamide, or Disopyramid, which prolong the action potential;

[0007] Class IB compounds are sodium channel inhibitors, such as lidocaine, mexiletine, tocainide, or phenytoin, which shorten the action potential; and

[0008] Class IC compounds are sodium channel inhibitors, such as Flecainide, Moricizine, or Propafenone, which do not alter action potential duration.

[0009] Class I compounds interact with sodium channels in their open or inactivated state and dissociate from the channels in their closed state (diastole). The dissociation rate determines whether they exhibit frequency-dependent channel inhibition. In addition to sodium channel inhibition, some Class I compounds inhibit subtypes of potassium- or calcium-permeable channels.

[0010] Class II compounds are beta-adrenergic receptor inhibitors and include drugs such as Atenolol, Metoprolol, Timolol, or Propranolol. Beta-adrenergic receptor inhibitors are selective for cardiac beta-1 receptors or have affinity for both beta-1 and beta-2 receptors. Some compounds also have intrinsic beta-stimulatory effects.

[0011] Class III compounds are potassium channel inhibitors, such as amiodarone, dronedarone, sotalol, ibutilide, and dofetilide, which prolong the action potential.

[0012] Class IV compounds are L-type calcium channel inhibitors, such as Verapamil.

[0013] Small conductance calcium-activated potassium (SK) channels belong to the Ca 2+ Activate K + Family of channels. Three SK channel isoforms have been cloned: SK1, SK2, and SK3 (corresponding to KCNN1-3 using genomic nomenclature). The activity of these channels is regulated by free intracellular calcium ([Ca 2+ ]i) is determined by calmodulin, which is constitutively bound to the channel. SK channels are regulated by [Ca 2+ ]i is strictly regulated, in [Ca 2+ ]i is closed up to about 0.1 μM, but 2+ ]i is fully activated at 1 μM. Due to its selectivity for potassium, open or active SK channels have a hyperpolarizing effect on the membrane potential of the cell. SK channels are widely expressed in the central nervous system (CNS) and peripheral tissues including the heart.

[0014] The hyperpolarizing effect of active SK channels plays an important role in controlling the firing pattern and excitability of excitable cells. SK channel inhibitors (e.g., apamin and N-methyl bicuculline) have been shown to increase excitability, whereas the SK channel opener 1-EBIO reduces electrical activity. In non-excitable cells, Ca influx through a voltage-independent pathway 2+ The amount of calcium is highly sensitive to membrane potential; activation of SK channels will increase the driving force, whereas inhibitors of SK channels will have a depolarizing effect, thereby reducing the calcium driving force.

[0015] SK channel inhibitors are drugs that weaken the potassium ion (K + ) through Ca 2+ The small conductance K of the activation + This impairment can be obtained by any reduction in current flow due to, for example, direct inhibition of ionic conduction to prevent the Ca 2+ binding (which is an essential requirement for channel activation) or a decrease in calcium sensitivity.

[0016] For a review of SK channels and SK channel modulators, see Wulff H et al.: “Modulators of Small-and Intermediate-Conductance Calcium-Activated Potassium Channels and their Therapeutic Indications”, Currrent 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.

[0017] Based on the SK channel in the connection [Ca 2+ ]i and membrane potential, SK channels are interesting targets for the development of new therapeutic agents, and the potential of SK channel inhibitors for antiarrhythmic therapy has recently been demonstrated, see for example Nattel S; J. Physiol. 2009 587 1385-1386; Diness JG, US, Nissen JD, Al-Shahib B, Jespersen T, Grunnet M, Hansen RS; Circ. Arrhythm. Electrophysiol. 2010 3380-90; and Diness et al; Hypertension 2011 57 1129-1135.

[0018] WO 2006 / 013210 describes certain 2-aminobenzimidazole derivatives and their use as modulators of small conductance calcium-activated potassium channels. Summary of the invention

[0019] The compounds of the present invention are inhibitors or negative regulators of small conductance calcium-activated potassium (SK) channels and have IC values ​​below 30 μM. 50 values, as demonstrated in the automated patch clamp system described herein, and are considered to be effective drug candidates. Certain selections of these compounds have significantly improved IC values ​​below 1 μM. 50 Some of these compounds also have physicochemical properties that are suitable for drug substances and are important for the preparation of pharmaceutical formulations, and may have beneficial properties in terms of pharmacological selectivity characteristics, in vivo absorption / bioavailability, toxicity and safety characteristics, and manufacturability. In addition, some of these compounds have pharmacokinetic properties that make them suitable for use as drugs.

[0020] In a broad sense, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0021]

[0022] in

[0023] R1 is selected from hydrogen and C 1-6 alkyl;

[0024] R2-R3 are independently selected from hydrogen and C 1-6 Alkyl groups;

[0025] or R2 and R3 together with the carbon atom to which they are attached form C 3-4 Cycloalkyl;

[0026] R4-R6 are independently selected from hydrogen, halogen and C 1-4 Alkyl groups;

[0027] R7 is selected from hydrogen and C 1-4 The group consisting of alkyl groups,

[0028] R8 choose free C 1-6 Alkyl, C substituted with one OH 1-6Alkyl and an OC 1-3 Alkyl substituted C 1-6 The group consisting of alkyl groups,

[0029] or R7 and R8 together with the carbon atom to which they are attached form C 3-4 Cycloalkyl;

[0030] R9-R13 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 Alkoxy, C 1-6 Alkylthio, and cyano groups;

[0031] R14 is selected from H, C 1-6 Alkyl or C 1-6 Alkoxy;

[0032] R15 is selected from H, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 Alkoxy, or C 3-4 Cycloalkyl;

[0033] or R14 and R15 together with the nitrogen atom to which they are attached form a 4-6 membered non-aromatic heterocyclic ring containing 1-2 nitrogen atoms, optionally 1 oxygen atom and optionally 1 sulfur atom, optionally substituted by at least one selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 Alkoxy groups are substituted.

[0034] In one embodiment, R1 is selected from hydrogen (H) and methyl. In another embodiment, R1 is H.

[0035] In another embodiment, R2-R3 are independently selected from H and C 1-3 In yet another embodiment, R2 and R3 are independently selected from H and methyl. In another embodiment, R2-R3 are all H.

[0036] In yet another embodiment, R4-R6 are independently selected from H, F and methyl.

[0037] In another embodiment, R7 is selected from H and C 1-3 Typically, R7 is methyl or ethyl.

[0038] In yet another embodiment, R8 is selected from C substituted with one OH 1-4 Alkyl and an OC 1-3 Alkyl substituted C 1-4 Typically, R8 is selected from CH2OH, CH2CH2OH, CH2OCH3 and CH2CH2O-CH3.

[0039] In another embodiment, R9-R13 are independently selected from H, halogen, C substituted with at least one halogen 1-6 Alkyl and C substituted by at least one halogen 1-6 Alkoxy group.

[0040] In yet another embodiment, R9, R12 and R13 are all H, and R10-R11 are independently selected from H, halogen, C substituted with at least one halogen. 1-6 Alkyl and C substituted by at least one halogen 1-6 an alkoxy group; provided that R10 and R11 are not both H.

[0041] In another embodiment, R14 is selected from H and C 1-6 Typically, R14 is H, methyl or ethyl.

[0042] In yet another embodiment, R15 is selected from H, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 Alkoxy, or C 3-4 Typically, R15 is methyl, ethyl, methoxy, cyclopropyl, CH2CH2CF3 or CH2CH2OCF3.

[0043] In another embodiment, R14 and R15 together with the nitrogen atom to which they are attached form a 4-6 membered non-aromatic heterocyclic ring containing 1 nitrogen atom and optionally 1 oxygen atom, optionally substituted by at least one halogen, for example, the 4-6 membered non-aromatic heterocyclic ring is azetidinyl, piperidinyl, morpholinyl and isoxazolidinyl, optionally substituted by at least one F.

[0044] In yet another embodiment, the compound of formula (I) is selected from any one of the exemplary compounds of Example 1 to Example 21b; or a pharmaceutically acceptable salt thereof.

[0045] In another aspect, the invention relates to compounds of formula (I) as defined above for use as medicaments.

[0046] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above and optionally a pharmaceutically acceptable additive such as a carrier or excipient.

[0047] In another aspect, the invention relates to a compound of formula (I) as defined above for use in a method of treating a cardiac disease, disorder or condition in a mammal (e.g., a human). In one embodiment, the cardiac disease, disorder or condition is selected from a cardiac disease, disorder or condition, wherein the disease, disorder or condition is associated with abnormal or variable heart rhythms and exercise-induced angina. In another embodiment, the cardiac disease, disorder or condition is selected from arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal heart rhythms occurring after cardiac surgery or cardiac ablation.

[0048] According to another aspect of the description, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0049] According to another aspect of the specification, a pharmaceutical composition is provided, which comprises a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, for treating a cardiac disease, disorder or condition in a mammal (e.g., a human being). In one embodiment, the cardiac disease, disorder or condition is selected from a cardiac disease, disorder or condition, wherein the disease, disorder or condition is associated with abnormal heart rhythm or variation and exercise-induced angina. In another embodiment, the cardiac disease, disorder or condition is selected from arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmia and abnormal heart rhythm occurring after cardiac surgery or cardiac ablation surgery.

[0050] According to another aspect of the description, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use as a medicament.

[0051] According to another aspect of the description, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in therapy.

[0052] According to another aspect of the description, there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

[0053] According to another aspect of the specification, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in the prevention or treatment of a mammal (eg, a human).

[0054] According to another aspect of the specification, there is provided use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a mammal (eg, a human).

[0055] According to another aspect of the specification, a method for preventing or treating a cardiac disease, disorder or condition in a mammal (e.g., a human being) is provided. In one embodiment, the cardiac disease, disorder or condition is selected from a cardiac disease, disorder or condition in which the disease, disorder or condition is associated with abnormal or variable heart rhythm and exercise-induced angina. In another embodiment, the cardiac disease, disorder or condition is selected from the group consisting of the following items in a mammal (e.g., a human being) in need of such treatment: arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmia and abnormal heart rhythm occurring after cardiac surgery or cardiac ablation surgery, the treatment comprising administering to the animal an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0056] In another aspect, the invention relates to a method for treating a cardiac disease, disorder or condition in a mammal (e.g., a human), wherein a therapeutically effective amount of at least one compound of formula (I) as defined above is administered to a mammal in need of such treatment. In one embodiment, the cardiac disease, disorder or condition of the mammal is selected from arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal heart rhythms occurring after cardiac surgery or cardiac ablation procedures.

[0057] In another aspect, the present invention relates to a method for preparing a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and an intermediate, which comprises the steps described in conjunction with Reaction Scheme 1 to Reaction Scheme 9. DETAILED DESCRIPTION

[0058] In a broad sense, the present invention relates to compounds of formula (I)

[0059]

[0060] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are as defined above.

[0061] In certain embodiments, whenever C 1-6 Alkyl or C 1-6 When the alkoxy group is substituted with at least one halogen, it is preferred that the C 1-6 Alkyl or C1-6 The alkoxy group is substituted by 1 to 3 halogens (eg 1 to 3 F atoms), preferably CF3 and OCF3.

[0062] In one embodiment, R1 is H. In another embodiment, R1 is C 1-6 alkyl.

[0063] In another embodiment, R2 is selected from hydrogen and C 1-6 Typically, R2 is H. In another embodiment, R2 is methyl.

[0064] In yet another embodiment, R3 is selected from hydrogen and C 1-6 Typically, R3 is H. In another embodiment, R3 is methyl.

[0065] In another embodiment, R2 and R3 together with the carbon atom to which they are attached form C 3--4 Cycloalkyl, for example cyclopropyl.

[0066] In yet another embodiment, R4 is selected from hydrogen, halogen and C 1-4 Typically, R4 is H. In another embodiment, R4 is halogen, such as Cl or F.

[0067] In another embodiment, R5 is selected from hydrogen, halogen and C 1-4 Typically, R5 is H.

[0068] In yet another embodiment, R6 is selected from hydrogen, halogen and C 1-4 Typically, R6 is H.

[0069] In yet another embodiment, R7 is H. In yet another embodiment, R7 is C 1-4 In another embodiment, R7 is methyl. In yet another embodiment, R7 is ethyl.

[0070] In yet another embodiment, R8 is C 1-6 alkyl.

[0071] In another embodiment, R8 is C substituted with one OH 1-6 In yet another embodiment, R8 is CH2OH. In another embodiment, R8 is CH2CH2OH.

[0072] In yet another embodiment, R8 is replaced by an OC 1-3 Alkyl substituted C 1-6 In another embodiment, R8 is replaced by an OC 1-3 Alkyl substituted C 1-4In yet another embodiment, R8 is CH2OCH3. In another embodiment, R8 is CH2CH2OCH3.

[0073] In yet another embodiment, R7 and R8 together with the carbon atom to which they are attached form C 3-4 Typically, R7 and R8 together with the carbon atom to which they are attached form a cyclopropyl group.

[0074] In another embodiment, R9 is selected from hydrogen, halogen, C substituted with at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 Alkoxy, C 1-6 In another embodiment, R9 is selected from H, halogen, C substituted with at least one halogen. 1-6 Alkyl and C substituted by at least one halogen 1-6 Typically, R9 is H.

[0075] In another embodiment, R10 is selected from hydrogen, halogen, C substituted with at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 Alkoxy, C 1-6 In another embodiment, R10 is selected from H, halogen, C substituted with at least one halogen. 1-6 Alkyl and C substituted by at least one halogen 1-6 In another embodiment, R10 is H, provided that R11 is not H. In yet another embodiment, R10 is halogen, such as Cl. In another embodiment, R10 is C substituted with at least one halogen. 1-6 In another embodiment, R10 is C substituted with at least one halogen. 1-6 Alkoxy, such as OCF3.

[0076] In another embodiment, R11 is selected from hydrogen, halogen, C substituted with at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 Alkoxy, C 1-6 In another embodiment, R11 is selected from H, halogen, C substituted by at least one halogen. 1-6 Alkyl and C substituted by at least one halogen 1-6 In another embodiment, R11 is H, provided that R10 is not H. In yet another embodiment, R11 is halogen, such as F or Cl.

[0077] In another embodiment, R12 is selected from hydrogen, halogen, C substituted with at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 Alkoxy, C 1-6 In another embodiment, R12 is selected from H, halogen, C substituted with at least one halogen. 1-6 Alkyl and C substituted by at least one halogen 1-6 Typically, R12 is H.

[0078] In another embodiment, R13 is selected from 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 another embodiment, R13 is selected from H, halogen, C substituted with at least one halogen. 1-6 Alkyl and C substituted by at least one halogen 1-6 Typically, R13 is H.

[0079] In yet another embodiment, R14 is H. In yet another embodiment, R14 is C 1-6 Alkyl groups, such as methyl or ethyl.

[0080] In another embodiment, R15 is H. In yet another embodiment, R15 is selected from C 1-6 In another embodiment, R15 is C substituted by at least one halogen. 1-6 In another embodiment, R15 is C substituted with at least one F 1-4 In another embodiment, R15 is C 1-6 In another embodiment, R15 is C substituted by at least one halogen. 1-6 In another embodiment, R15 is C substituted with at least one F 1-3 In another embodiment, R15 is C 3-4 Cycloalkyl, for example cyclopropyl.

[0081] In another embodiment, R14 and R15 together with the nitrogen atom to which they are attached form a 4-6 membered non-aromatic heterocyclic ring containing 1 nitrogen atom and optionally 1 oxygen atom, optionally selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 In another embodiment, R14 and R15 together with the nitrogen atom to which they are attached form a 4-6 membered non-aromatic heterocyclic ring containing 1 nitrogen atom and optionally 1 oxygen atom, optionally substituted with at least one halogen, for example, the 4-6 membered non-aromatic heterocyclic ring is azetidinyl, piperidinyl, morpholinyl and isoxazolidinyl, optionally substituted with at least one F.

[0082] In yet another embodiment, the compound of formula (I) is selected from any one of the exemplary compounds of Example 1 to Example 21b; or a pharmaceutically acceptable salt thereof.

[0083] In certain embodiments, whenever C 1-6 Alkyl or C 1-6 When the alkoxy group is substituted by halogen, it is preferred that the C 1-6 Alkyl or C 1-6 The alkoxy group is substituted by 1 to 3 halogens (eg 1 to 3 F atoms), preferably CF3 and OCF3.

[0084] Each of the compounds described in the experimental section constitutes an embodiment of the present invention in any form (eg salt or free base) and rights may be claimed as such a compound or as a salt thereof.

[0085] In another embodiment, the compound of formula (I) is selected from a pharmaceutically acceptable acid salt of any one of the compounds of Example 1 to Example 21b.

[0086] Heart disease

[0087] 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 abnormal or variable heart rhythms and exercise-induced angina.

[0088] In more specific embodiments, the cardiac disease, disorder or condition is any disease, disorder or condition associated with abnormal or variable heart rhythms and exercise-induced angina.

[0089] In more specific embodiments, the cardiac disease, disorder or condition is any disease, disorder or condition associated with an abnormal rhythm of the heart.

[0090] In more specific embodiments, the cardiac disease, disorder or condition associated with abnormal cardiac rhythm is selected from arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia and bradyarrhythmia.

[0091] In another embodiment, the cardiac disease, disorder or condition of the invention is an abnormal rhythm caused by myocardial ischemia, myocardial infarction, cardiac hypertrophy or cardiomyopathy.

[0092] In another embodiment, the cardiac disease, disorder or condition of the present invention is an abnormal rhythm that occurs following cardiac surgery or cardiac ablation procedure.

[0093] In another specific embodiment, the cardiac disease, disorder or condition associated with abnormal heart rhythm is an arrhythmia caused by a genetic disease.

[0094] In another preferred embodiment, the cardiac disease, disorder or condition associated with abnormal heart rhythm is arrhythmia.

[0095] In a preferred embodiment, the cardiac disease, disorder or condition associated with an abnormal cardiac rhythm is atrial fibrillation.

[0096] In a specific embodiment, the compounds of formula (I) of the present invention are useful for treating atrial fibrillation by acute cardioversion to normal sinus rhythm.

[0097] In another specific embodiment, the compounds of formula (I) of the present invention are useful for treating atrial fibrillation by maintaining normal sinus rhythm and avoiding or reducing the occurrence of new episodes of atrial fibrillation.

[0098] Drug treatment of atrial fibrillation

[0099] In the context of the present invention, as understood by those skilled in the art, the treatment of atrial fibrillation is acute cardioversion or maintenance of sinus rhythm or both. Acute cardioversion is defined as the application of a compound capable of converting atrial fibrillation to normal cardiac sinus rhythm. Normal sinus rhythm is defined as a regular, stable heart beat at a frequency of 40 to 100 times at rest in an adult with a normal, regular p-wave 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 a period of time without recurrence to atrial fibrillation, or the ability of a compound to significantly reduce the incidence of recurrence from atrial fibrillation to normal sinus rhythm compared to an untreated control.

[0100] General method description

[0101] Schemes 1 to 9 outline a synthetic method that can be used to prepare compounds of general formula (I).

[0102] Scheme 1: Route for preparation of intermediate 8

[0103]

[0104] A large number of ketones and aldehydes (1) are commercially available or can be readily prepared by a number of routes described in the literature. Ketones and aldehydes (1) can be converted to hydantoin derivatives (2) by a variety of methods, such as reacting (1) with potassium cyanide under the action of an ammonium salt (e.g., ammonium carbonate) while heating a solvent such as water and an alcohol (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 heating in water. Many other well-established methods for preparing amino acids are described in the literature. Many amino acid derivatives are also readily commercially available. Amino acids (3) can be protected as N-(tert-butyloxy)carbonyl derivatives (4) by treatment with di-tert-butyl dicarbonate and a base (e.g., sodium bicarbonate) in a suitable solvent (e.g., tetrahydrofuran, water). Intermediates (4) can be reduced to alcohol derivatives (5) by a variety of methods, including by a hydride reducing agent (e.g., sodium borohydride or lithium aluminum hydride). This can be achieved by direct reduction of the acid group (e.g., with lithium aluminum hydride in tetrahydrofuran) or by first activating the acid group in (4) by converting it into a mixed anhydride (e.g., with isobutyl chloroformate and triethylamine in tetrahydrofuran) and then reducing it with sodium borohydride (e.g., in water). It may be necessary to protect the alcohol derivative (5), for example, by converting it into an ester (e.g., 2,2-dimethylpropionate) by reaction with 2,2-dimethylpropanoyl chloride and a base (e.g., triethylamine) in a solvent (e.g., dichloromethane). The intermediate (6) can be deprotected to the amine derivative (7) by treatment with an acid (e.g., hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g., dioxane or dichloromethane). The intermediate (7) can be converted to the isothiocyanate derivative (8) by reaction with thiophosgene in a suitable solvent (e.g., dichloromethane) in the presence of a base (e.g., sodium bicarbonate).

[0105] Scheme 2: Route for the preparation of intermediates 14 and 16

[0106]

[0107] Ketones and aldehydes (1) can be converted to sulfenamide derivatives (9) by reacting (1) with 2-methylpropane-2-sulfenamide under the action of a Lewis acid (e.g., titanium (IV) ethoxide) with heating in a suitable solvent (e.g., tetrahydrofuran). Sulfenamide derivatives (9) can be converted to β-amino acid esters (10) by reacting with methyl 2-bromoacetate under the action of zinc under heating in a solvent (e.g., tetrahydrofuran). Many other well-established methods for preparing β-amino acids are described in the literature. Some β-amino acid derivatives are also readily commercially available. β-Amino acid esters (10) can be reduced to alcohol derivatives (11) by various methods, including by hydride reducing agents (e.g., sodium borohydride, lithium aluminum hydride) in a suitable solvent (e.g., tetrahydrofuran). It may be necessary to protect the alcohol derivative (11), for example, by converting it to an ester (e.g., 2,2-dimethylpropionyl chloride) and a base (e.g., triethylamine) in a solvent (e.g., dichloromethane). Intermediate (12) can be deprotected to amine derivative (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 derivative (14) by reaction with thiophosgene in a suitable solvent (e.g., dichloromethane) under the action of a base (e.g., sodium bicarbonate).

[0108] 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 action of a base (e.g., sodium bicarbonate).

[0109] Scheme 3: Route for preparation of intermediate 19

[0110]

[0111] The alcohol derivative (5) can be alkylated on the alcohol oxygen atom by reacting with methyl iodide in a solvent (e.g. acetonitrile) under the action of a metal oxide (e.g. silver oxide) and converted into an intermediate (17). The intermediate (17) can be deprotected into an amine derivative (18) by treating with an acid (e.g. hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g. dioxane or dichloromethane). The intermediate (18) can be converted into an isothiocyanate derivative (19) by reacting with thiophosgene in a suitable solvent (e.g. dichloromethane) under the action of a base (e.g. sodium bicarbonate).

[0112] Scheme 4: Route for preparation of intermediate 21

[0113]

[0114] Various intermediates (20) are readily commercially available or can be prepared by methods described in the literature. Intermediate (20) can be converted to an isothiocyanate derivative (21) by reaction with thiophosgene in a suitable solvent (e.g., dichloromethane) under the action of a base (e.g., sodium bicarbonate).

[0115] Scheme 5: Route for preparation of intermediate 28

[0116]

[0117] Various benzene-1,2-diamine intermediates (22) 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 action of a free radical initiator (e.g., benzoyl peroxide) while heating. Intermediate (24) can be reacted with tert-butyl N-tert-butoxycarbonylcarbamate while heating in a solvent (e.g., acetonitrile) under the action of a base (e.g., potassium carbonate) 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). The intermediate (26) can be converted into a urea derivative (27) by reacting with various commercial carbamoyl chlorides in a suitable solvent (e.g., dichloromethane) in the presence of a base (e.g., triethylamine). The intermediate (27) can be converted into a benzene-1,2-diamine derivative (28) by desulfurization with hydrogen in a suitable solvent (e.g., methanol) in the presence of a metal catalyst (e.g., Raney nickel).

[0118] Scheme 6: Preparation of Route 1 of Example 1 and separation of enantiomers

[0119]

[0120] 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 variety of other benzene-1,2-diamine derivatives are commercially available or can be readily prepared by well-established methods described in the literature (e.g., by nitration and subsequent reduction of commercial substituted benzene starting materials). Thiourea derivatives (29) and (30) can be converted to 2-aminobenzimidazole derivatives (31) by a cyclization 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 a mercuric salt (e.g., mercuric oxide) and heating in a suitable solvent (e.g., acetonitrile). 2-Aminobenzimidazole ester derivatives (31) can be converted to compounds of formula (I) by deprotecting the ester under the influence of a base (e.g., sodium hydroxide) in a suitable solvent (e.g., methanol).

[0121] The 2-aminobenzimidazole derivatives of formula (I) may be a racemic mixture which may be separated into two enantiomers A and B by a range of methods including chromatography using a chiral stationary phase. This may be normal phase chromatography or reverse phase chromatography using a suitable solvent mixture as eluent (e.g. chloroform, dichloromethane, ethanol, ethyl acetate, methanol, ethanol), sometimes with additives (e.g. ammonia, triethylamine, trifluoroacetic acid, acetic acid).

[0122] Scheme 7: Route 2 of the preparation example and separation of enantiomers

[0123]

[0124] Benzene-1,2-diamine derivatives (28) can be reacted with isothiocyanates (16) in a suitable solvent (e.g., dichloromethane) to give a mixture of thiourea products (32) and (33). Many other benzene-1,2-diamine derivatives are commercially available or can be readily prepared by well-established methods described in the literature (e.g., by nitration of commercial substituted benzene starting materials and subsequent reduction). Thiourea derivatives (32) and (33) can be converted to derivatives (34) by cyclization reactions that occur under the influence of iodoacetic acid and heating in a suitable solvent (e.g., methanol or acetonitrile). Cyclization of (32) and (33) to give (34) can also occur under the influence of mercuric salts (e.g., mercuric oxide) and heating in a suitable solvent (e.g., acetonitrile, methanol). Derivatives (34) can be converted to compounds of formula (I) by reduction in a suitable solvent (e.g., tetrahydrofuran) under the influence of a hydride reducing agent (e.g., sodium borohydride) and heating.

[0125] The 2-aminobenzimidazole derivatives of formula (I) may be a racemic mixture which may be separated into two enantiomers A and B by a range of methods including chromatography using a chiral stationary phase. This may be normal phase chromatography or reverse phase chromatography using a suitable solvent mixture as eluent (e.g. chloroform, dichloromethane, ethanol, ethyl acetate, methanol, ethanol), sometimes with additives (e.g. ammonia, triethylamine, trifluoroacetic acid, acetic acid).

[0126] Scheme 8: Route 3 of the preparation example and separation of enantiomers

[0127]

[0128] The intermediate (25) can be converted to a benzene-1,2-diamine derivative (35) by desulfurization with hydrogen in a suitable solvent (e.g., methanol) in the presence of a metal catalyst (e.g., Raney nickel). The derivative (35) can be reacted with an isothiocyanate (8) in a suitable solvent (e.g., dichloromethane, acetonitrile) to give a mixture of thiourea products (36) and (37). The thiourea derivatives (36) and (37) can be converted to 2-aminobenzimidazole derivatives (38) by a cyclization reaction that occurs under the influence of iodoacetic acid and heating in a suitable solvent (e.g., methanol or acetonitrile). The cyclization of (36) and (37) to give the aminobenzimidazole derivative (38) can also be carried out under the influence of a mercuric salt (e.g., mercuric oxide) and heating in a suitable solvent (e.g., acetonitrile, methanol). The intermediate (38) can be deprotected to an amine derivative (39) by treatment with an acid (e.g., hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g., dioxane or dichloromethane). In a suitable solvent (e.g., dichloromethane), under the action of a base (e.g., triethylamine), the intermediate (39) can be converted into a urea derivative (40) by reacting with a variety of commercial carbamoyl chlorides or isocyanates. In a suitable solvent (e.g., ethanol), under the action of a base (e.g., sodium hydroxide), the 2-aminobenzimidazole ester derivative (40) can be converted into a compound of formula (I) by deprotecting the ester. The 2-aminobenzimidazole derivative of formula (I) can be a racemic mixture, which can be separated into two enantiomers A and B by a series of methods, including chromatography using a chiral stationary phase. This can be normal phase chromatography or reverse phase chromatography, which uses a suitable solvent mixture as an eluent (e.g., chloroform, dichloromethane, ethanol, ethyl acetate, methanol, ethanol), and sometimes uses additives (e.g., ammonia, triethylamine, trifluoroacetic acid, acetic acid).

[0129] Scheme 9: Route 4 of Example

[0130]

[0131] 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). Thiourea derivatives (41) and (42) can be converted to 2-aminobenzimidazole derivatives of formula (I) by a cyclization reaction which 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 derivatives of formula (I) can also occur under the influence of a mercuric salt (e.g., mercuric oxide) and heating in a suitable solvent (e.g., acetonitrile, methanol). The 2-aminobenzimidazole derivatives of formula (I) can be a racemic mixture which can be separated into two enantiomers A and B by a range of methods including chromatography using a chiral stationary phase. This can be normal phase or reverse phase chromatography using a suitable solvent mixture as eluent (eg chloroform, dichloromethane, ethanol, ethyl acetate, methanol, ethanol), sometimes with additives (eg ammonia, triethylamine, trifluoroacetic acid, acetic acid).

[0132] Those skilled in the art will appreciate that it may be necessary to adjust or change the order of the steps in the above-described methods, and that such changes in order are encompassed within the aspects of the methods in the above-described reaction schemes and accompanying process step descriptions.

[0133] Furthermore, it will be appreciated by those skilled in the art that the functional groups of the intermediate compounds in the above methods and hereinafter may need to be protected by protecting groups.

[0134] Functional groups that need to be protected include hydroxyl, amino and carboxylic acid. Suitable hydroxyl protecting groups include optionally substituted and / or unsaturated alkyl (e.g., methyl, allyl, benzyl or tert-butyl), trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), AcO (acetoxy), 2,2-dimethylpropionate, TBS (tert-butyldimethylsilyl), TMS (trimethylsilyl), PMB (p-methoxybenzyl) and tetrahydropyranyl. Suitable protecting groups for carboxylic acids include (C1-C6)-alkyl esters or benzyl esters. Suitable protecting groups for amino include tert-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy-methyl or 2-trimethylsilylethoxycarbonyl (Teoc). Suitable protecting groups for S include SC(=N)NH2, TIPS.

[0135] Protection and deprotection of functional groups can be carried out before or after any reaction in the above methods.

[0136] Furthermore, it will be appreciated by those skilled in the art that the various process steps mentioned above may be carried out in a different order, and / or the various reactions may be carried out at different stages of the overall route (i.e., substituents may be added to and / or chemically transformed to the various intermediates mentioned 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. This may negate the necessity of protecting groups, or make it necessary.

[0137] The compounds of formula (I) have at least one asymmetric center and may have other asymmetric centers, and any optical isomers (i.e., enantiomers or diastereomers) are intended to be included within the scope of the present invention in the form of separated, pure or partially purified optical isomers and any mixtures thereof (including racemic mixtures, i.e., mixtures of stereoisomers). In particular, the carbon atom of formula (I), wherein 4 valence bonds are connected to R7, R8, NH, phenyl, and is an asymmetric center, produces two kinds of optical isomers, R type and S type. 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 another embodiment, the compounds of the present invention are racemic mixtures.

[0138] In this document, it is understood that when an enantiomeric form is specified, the compound is in enantiomeric excess, such as a substantially pure single enantiomer. Therefore, 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%.

[0139] The racemic forms can be resolved into the optical antipodes by known methods, for example by separation of their diastereomeric salts with optically active acids and liberating the optically active amine compounds by treatment with bases. Another method for resolving the racemates into the optical antipodes is chromatography based on optically active matrices. The compounds of the invention can also be resolved by forming diastereomeric derivatives.

[0140] Additional methods known to those skilled in the art for the resolution of optical isomers may be used. These methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). Optically active compounds may also be prepared from optically active starting materials.

[0141] In addition, when there are double bonds or completely or partially saturated ring systems in the molecule, geometric isomers may be formed. Any geometric isomer, such as isolated, pure or partially purified geometric isomers or mixtures thereof, is intended to be included within the scope of the present invention. Similarly, molecules with restricted rotation bonds can form geometric isomers. These are also intended to be included within the scope of the present invention.

[0142] Furthermore, the compounds of the general formula I of the present invention have benzimidazole structures that exist in tautomeric forms, and as used herein, all tautomers are included in the compounds of the formula I even though only one is shown.

[0143] The tautomers of formula (I) are:

[0144]

[0145]

[0146] The benzimidazole tautomers of the above-mentioned formula I refer to that hydrogen switches back and forth from one nitrogen to another nitrogen, and the double bond is therefore switched back and forth between the nitrogen and the carbon and the point of attachment of the NH-group. In addition, when the structure is present as part of the general structure of benzimidazole or as a separate specific compound, it should be understood that benzimidazole encompasses all tautomers, so although only one tautomer is shown, it includes all tautomers.

[0147] Unless otherwise stated herein or clearly contradicted by the context, "a compound of formula (I)" as used herein refers to a compound of formula (I) in any form, including a free form or a salt thereof, such as a pharmaceutically acceptable salt thereof.

[0148] Whenever a substituent is disclosed as R1-R15, it is meant that every consecutive possibility is disclosed, for example, R2-R4 represents R2, R3 and R4, for example, R9-R13 represents R9, R10, R11, R12 and R13. In another embodiment, Compound I is in free form. In one embodiment, the free form is an anhydrous compound. In another embodiment, the free form is a solvate, such as a hydrate.

[0149] In another embodiment, the compound is in crystalline form. A skilled artisan may perform experiments to discover polymorphs, and such polymorphs are intended to be included in the term "crystalline form" as used herein.

[0150] When the compounds and pharmaceutical compositions disclosed herein are used in the above-mentioned treatments, a therapeutically effective amount of at least one compound is administered to a mammal in need of such treatment.

[0151] The term "free form" as used herein refers to the compound of formula (I), either as a free base or a free acid, as the case may be, and not in any salt form.

[0152] The term "C 1-x "Alkyl" refers to an alkyl group containing 1 to x carbon atoms, such as C 1-3 , C 1-4 , C 1-5 or C 1-6 , such as methyl, ethyl, propyl, butyl, pentyl or hexyl, and also includes branched C 3-6 Alkyl, for example isopropyl, isobutyl, tert-butyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl. 1-x Alkyl (e.g. C 1-6 When a (alkyl) group is substituted with a group (e.g. a halogen, such as F), this means that the F (e.g. 3F) is attached to one carbon (CF3) or two carbons (CF2-CF) or even three carbons (CF-CF-CF).

[0153] The term "C 1-x "Alkylene" refers to an alkylene group containing 1 to x carbon atoms, such as C 1-3 , C 1-4 , C 1-5 or C 1-6 , such as methylene, ethylene, propylene, butylene, pentylene or hexylene, and also includes branched C 3-6 Alkylene groups, for example, isopropylene, isobutylene, tert-butylene, isopentylene, 3-methylbutylene, 2,2-dimethylpropylene, n-hexylene, 2-methylpentylene, 2,2-dimethylbutylene, 2,3-dimethylbutylene.

[0154] The term "C 1-x Alkoxy" or "OC 1-x "alkyl" (used interchangeably) refers to an oxygen atom covalently attached to an alkyl group containing 1 to x carbon atoms (e.g., C 1-5 or C 1-6 ) on, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy or n-hexoxy.

[0155] The term "C 1-x "Alkylthio" or "SC 1-x "alkyl" (used interchangeably) refers to a sulfur atom covalently attached to an alkyl group containing 1 to x carbon atoms (e.g., C 1-5 or C 1-6 ), for example, methylthio, ethylthio, n-propylthio.

[0156] The term "C 3-4 "Cycloalkyl" refers to a cyclic alkyl group containing 3-4 carbon atoms, such as cyclopropyl or cyclobutyl.

[0157] The term "CN" as used herein refers to a cyano or nitrile group (C and N connected by a triple bond).

[0158] As used herein, the term "C 1-6 "Alkyl" means one or more halogen atoms as defined herein attached to a C 1-6 On one or more carbon atoms of an alkyl group, for example CHFCF3 or CF3.

[0159] As used herein, the term "C 1-6 "Alkoxy" refers to one or more halogen atoms, as defined herein, attached to a C 1-6 On one or more carbon atoms of an alkoxy group, for example OCH2CHF2 or OCF3.

[0160] As used herein, the term "C 1-4 "Alkyl" means an OH group attached to a C 1-4 On one or more carbon atoms of an alkyl group, for example, CH2OH, CH2CH2OH or CHOHCH3.

[0161] As used herein, the term “being 1-3 Alkyl substituted C 1-4 "Alkyl" refers to one or more OC 1-3 The alkyl group is linked to a C 1-4 On one or more carbon atoms of an alkyl group, for example, CH2OCH3 or CH2CH2OCH3.

[0162] As used herein, the term "halogen" refers to an atom selected from chlorine (Cl), fluorine (F), iodine (I) and bromine (Br).

[0163] The term "5- or 6-membered aromatic heterocycle containing at least one nitrogen atom and optionally 1 oxygen atom and optionally 1 sulfur atom" as used herein refers to a chemically stable single aromatic ring system which contains at least one nitrogen atom (preferably 1 to 3 N), not more than 5 carbon atoms, may contain 1 oxygen atom and / or 1 sulfur atom, for example, it includes but is not limited to pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyridyl, diazinyl, pyridazinyl, triazinyl and tetrazinyl.

[0164] 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 refers to a monocyclic ring system having 1 or 2 nitrogen atoms and optionally 1 oxygen atom and optionally 1 sulfur atom, forming a saturated or unsaturated 4-, 5- or 6-membered ring system, for example, the 4-6 membered non-aromatic heterocycle is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolidinyl, isothiazolidinyl and isoxazolidinyl.

[0165] The terms "treatment" and "treating" as used herein refer to the management and care of a patient in order to combat a condition, such as a disease or disorder. The term is intended to include all treatments for a given condition suffered by a patient, such as the administration of active compounds to alleviate symptoms or complications, slow the progression of a disease, disorder or condition, alleviate or relieve symptoms and complications, and / or cure or eliminate a disease, disorder or condition, as well as the prevention of a condition, wherein prevention is understood as the management and care of a patient in order to combat a disease, disorder or disorder, and includes the administration of active compounds to prevent the onset of symptoms or complications. Treatment may be performed in an acute or chronic manner. The patient to be treated is preferably a mammal; in particular, a human, but may also include animals such as dogs, cats, cattle, sheep and pigs.

[0166] The term "pharmaceutically acceptable salt" as used herein is used to indicate that the salt is suitable for use in the human or animal body. A list of examples of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use, PHStahl and CG Wermuth, editors, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutically acceptable salts of compounds of formula (I) include salts formed in the human or animal body after the compound is administered to the human or animal body.

[0167] The term "therapeutically effective amount" of the compound of formula (I) of the present invention used herein refers to an amount sufficient to cure, alleviate or partially inhibit the clinical manifestations of a given disease and its complications. An amount sufficient to achieve this purpose is defined as a "therapeutically effective amount". The effective amount for each purpose will depend on the severity of the disease or injury and the weight and general state of the subject. It should be understood that routine experiments can be used to determine the appropriate dosage by constructing a numerical matrix and testing different points in the matrix, which is within the ordinary skills of a trained physician or veterinarian.

[0168] In yet another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and optionally a pharmaceutically acceptable additive, such as a carrier or excipient. Generally, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable additive (such as a carrier or excipient).

[0169] As used herein, "pharmaceutically acceptable additives" are intended to include, but are not limited to, carriers, excipients, diluents, adjuvants, colorants, fragrances, preservatives, etc. A skilled artisan would consider using the compounds of the present invention when formulating them to prepare pharmaceutical compositions.

[0170] The adjuvants, diluents, excipients and / or carriers that can be used in the compositions of the present invention must be pharmaceutically acceptable, i.e., compatible with the compound of formula (1) and the other ingredients of the pharmaceutical composition, and harmless to the recipient. Preferably, the composition should not contain any substance that may cause adverse reactions (e.g., allergic reactions). The adjuvants, diluents, excipients and carriers that can be used in the pharmaceutical compositions of the present invention are well known to those skilled in the art.

[0171] As described above, in addition to the compounds disclosed herein, the compositions disclosed herein, in particular pharmaceutical compositions, may also include at least one pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier. In some embodiments, the pharmaceutical composition comprises 1% to 99% by weight of the at least one pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier and 1% to 99% by weight of the compounds disclosed herein. The total amount of active ingredient and pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier does not exceed 100% weight of the composition, in particular the pharmaceutical composition.

[0172] In some embodiments, only one compound disclosed herein is used for the above purposes.

[0173] In some embodiments, two or more compounds disclosed herein are combined for the above purposes.

[0174] The composition, in particular the pharmaceutical composition comprising the compound described herein, can be suitable for oral, intravenous, topical, intraperitoneal, intranasal, buccal, sublingual or subcutaneous administration, or suitable for administration through the respiratory tract in the form of, for example, an aerosol or air-suspended fine powder. Thus, the pharmaceutical composition can be in the form of, for example, a tablet, capsule, powder, nanoparticle, crystal, amorphous material, solution, transdermal patch or suppository.

[0175] Further embodiments of the process are described in the experimental part herein, and each individual process as well as each starting material constitutes an embodiment that can form part of an embodiment.

[0176] Unless it is specifically stated that an embodiment relates to a certain aspect or aspects of the invention, the above embodiments should be considered to relate to any aspect described herein (e.g., "a method of treatment", "a pharmaceutical composition", "a compound for use as a medicament" or "a compound for use in a method"), as well as any embodiment described herein.

[0177] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0178] All headings and sub-headings used herein are for convenience only and should not be construed as limiting the invention in any way.

[0179] 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.

[0180] The terms "a," "an," and "the" and similar referents used in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0181] Unless otherwise indicated herein, recitation of ranges of values ​​herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise indicated herein, all exact values ​​provided herein represent corresponding approximate values ​​(e.g., all exact exemplary values ​​provided with respect to a particular factor or measurement can be considered to also provide corresponding approximate measurements, modified by "about" where appropriate).

[0182] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0183] Unless otherwise specified, the use of any and all examples or exemplary language (e.g., "such as") provided herein is merely to better explain the present invention and does not limit the scope of the present invention. Unless otherwise expressly stated, no language in the specification should be construed as indicating that any element is essential to the practice of the present invention.

[0184] The citation and incorporation of patent documents herein is for convenience only and does not reflect any view of the validity, patentability, and / or enforceability of these patent documents.

[0185] Unless otherwise stated or clearly contradicted by context (for example, a composition described herein as comprising a particular element is to be understood to also describe a composition consisting of that element, unless otherwise stated or clearly contradicted by context), the description of any aspect or embodiment of the invention herein using terms such as "comprising," "having," "including," or "containing" with respect to one or more elements is intended to provide support for similar aspects or embodiments of the invention (i.e., "consisting of," "consisting essentially of," or "consisting essentially of" the particular element or elements).

[0186] To the maximum extent permitted by applicable law, this invention includes all modifications and equivalents of the subject matter recited in the aspects or claims set forth herein.

[0187] The present invention is further illustrated by the following examples, which, however, should not be construed as limiting the scope of protection. The features disclosed in the preceding description and in the following examples, either alone or in any combination, are important for realizing the present invention in various forms.

[0188] Experimental Procedure

[0189] Automatic patch clamp

[0190] The QPatch 16HT system and single-well Qplates (Biolin Scientific, Sophion, Denmark) were used to clone cells stably expressing the human SK3 channel (hK Ca 2.3) HEK-293 cells were cultured and prepared for the experiment using normal cell culture procedures. A total of 4-5 million cells were used for each experiment. Qpatch automatically generated gigaseals, whole-cell formation, composite application, and current recordings. + Recording hK in solution Ca 2.3 Current, the intracellular solution consisted of the following: 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, pH adjusted to pH = 7.2 with HCl. The free calcium concentration was calculated to be 400 nM. The extracellular solution consisted of the following: in mM: KCl 150; CaCl2 0.1; MgCl2 3; HEPES 10; Glucose 10, adjusted to pH = 7.4 with KOH. The cell was held at 0 mV, and a linear voltage ramp from -80 mV to +80 mV (duration 200 ms) was applied every 5 seconds to elicit hK Ca2.3 Currents. The compound application protocol consisted of 12 recording cycles lasting 50–200 s: 1) baseline recording in the extracellular solution; 2) application of the positive control N-methylbicuculline (100 μM), which is characterized by full efficacy and fast on and off rates; 3–4) washout; 5–9) increasing concentrations of the test compound to establish the IC 50 values; 10-11) washout; 12) positive control with compound NS8593 (N-[(1R)-1,2,3,4-tetrahydro-1-naphthyl]-1H-benzimidazol-2-amine) (1 μM). Data were sampled at 10 kHz, 4th order Bessel filter, cutoff frequency at 3 kHz. Currents were compensated for drops. Potency was quantified as the concentration required to inhibit SK channel activity by half and expressed as IC 50 All effects of compounds of the invention tested were normalized to the inhibition observed with N-methylbicuculline.

[0191] result

[0192] The examples are potent inhibitors of SK3 channels and exhibit the following IC in the automated patch clamp assay described above: 50 :

[0193] Embodiments: 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 of the IC 50 All were below 1μM.

[0194] Examples: ICs of 1a, 9a, 11b, 17b, 19b, 20b, 21 and 21a 50 All were lower than 3μM.

[0195] Materials and methods

[0196] Unless otherwise stated, commercial reagents were used without further purification. 254(Merck) and detected by fluorescence and immersion in KMnO4 solution (KMnO4 solution recipe: 1.5 g KMnO4, 10 g K2CO3 and 1.25 mL 10% NaOH dissolved in 200 mL water) followed by charring. The compounds were purified by column chromatography on silica gel (60-120 mesh, Swambe Chemicals, India). The NMR spectra were obtained at ambient temperature using a Bruker AV 400 MHz spectrometer (400 MHz for 1 H, 100MHz for 13 C) Recording of NMR spectra, e.g. 1 H. 1 3C and 2D COSY. Chemical shifts are reported in parts per million (ppm). ESI-MS was recorded on an Agilent LC1200 Series MS Single Quadrupole 6130 mass spectrometer.

[0197] Abbreviations used in the Experimental section:

[0198] BOP = (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0199] PyBOP = (Benzotriazol-1-yloxy)tripyrrolidine hexafluorophosphate

[0200] EDC.HCl = N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

[0201] HBTU = N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate

[0202] DCM = dichloromethane; DMF = N,N-dimethylformamide; TEA = triethylamine

[0203] 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 = isopropanol; Pd / C = palladium on carbon; RT = ambient temperature; MeOH = methanol.

[0204] Grace Flash Chromatography System:

[0205] Grace The Prep Purification System is used for sample purification by flash chromatography, using flash columns prepacked with silica gel:

[0206] Column used:

[0207] High-purity fast silica gel column (normal phase);

[0208] 12g, 60A, maximum pressure 350psi (24 bar),

[0209] 24g, 60A, maximum pressure 350psi (24 bar),

[0210] 40g, 60A, maximum pressure 350psi (24 bar),

[0211] 80g, 60A, max pressure 350psi (24 bar).

[0212] Solvents: hexane, EtOAc, CHCl3 and MeOH.

[0213] 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

[0214]

[0215] Example 1, Step 1: Preparation of 5-methyl-5-(3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione

[0216]

[0217] To a stirred solution of 3-trifluoromethylacetophenone (commercially available) (45.00 g, 239.00 mmol) in ethanol / water (1:1, 1000 mL) solvent mixture 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 h. The reaction mass was poured into ice-cold water (1500 mL) and stirred for 30 min, the formed solid was filtered 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.

[0218] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.78 (d, 1H, J = 7.70Hz), 7.72 (d, 2H, J = 8.90Hz), 7.65 (t, 1H, J = 7.70Hz), 1.69 (s, 3H);

[0219] MS: m / z 259 (M+1).

[0220] Example 1, Step 2: Preparation of 2-amino-2-(3-(trifluoromethyl)phenyl)propanoic acid

[0221]

[0222] 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 solution (600 mL), and the mixture was refluxed for 48 h. The reaction mixture was neutralized with 6.0 N HCl (250 mL) (adjusting pH = 7), and the formed solid 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.

[0223] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.85 (s, 1H), 7.79 (d, 1H, J = 8.00Hz), 7.65 (d, 1H, J = 7.60Hz), 7.60 (t, 1H, J = 7.60Hz), 1.68 (s, 3H);

[0224] MS: m / z 234.1 (M+1).

[0225] Example 1, Step 3: Preparation of 2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)propanoic acid

[0226]

[0227] 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 , 643.00mmol), and the whole mixture was stirred at ambient temperature for 72h. The reaction mixture was diluted with water (1000mL) and extracted with ethyl acetate (4×2000mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)propanoic acid (140.00g) as a light yellow jelly which was used in the next step without further purification.

[0228] 1H NMR (400MHz, DMSO-d6:D2O) δ7.64(s,1H),7.57(s,1H),7.47(d,2H,J=4.40Hz),1.47(s,3H),1.35(s,9H);

[0229] MS: m / z 234.1 [(M+1)-Boc].

[0230] Example 1, Step 4: Preparation of tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate

[0231]

[0232] 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 anhydrous tetrahydrofuran (1000 mL) at 0°C was added triethylamine (158.00 mL, d = 0.726 g / cm 3 , 1130.00mmol), then add isobutyl chloroformate (68.80mL, d = 1.053g / cm 3 , 529.00mmol), and stirred at the same temperature for 4h. The formed solid was filtered at 0°C, and the residue was washed with dry tetrahydrofuran (400mL). The combined filtrate was added to a cooling mixture of sodium borohydride (85.80g, 2270.00mmol) in water (200mL). The reaction mass was slowly warmed to ambient temperature and stirred for 30h. The reaction mass was quenched with ice-cold water (1000mL), extracted with ethyl acetate (4×2000mL), washed with brine (250mL) and dried over sodium sulfate, filtered and concentrated to obtain a pale yellow liquid crude product (200g). The liquid was purified by flash chromatography on 60-120 silica gel, and the product was eluted with a petroleum ether solution of 30-35% ethyl acetate to obtain tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2yl}carbamate (63.00g), which was a colorless liquid.

[0233] 1 H NMR(400MHz,DMSO-d6)δ7.61(t,2H,J=6.80Hz),7.57(s,1H),7.53(t,1H,J=7.20Hz),6 .92(bs,1H),4.98(t,1H,J=5.20Hz),3.50(d,2H,J=6.00Hz),1.59(s,3H),1.35(s,9H);

[0234] MS: m / z 221.2 [(M+1)-Boc].

[0235] Example 1, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate

[0236]

[0237] 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) was added triethylamine (96.2 mL, d = 0.726 g / cm2) dropwise at 0°C under nitrogen atmosphere. 3 , 691.00mmol), and then pivaloyl chloride (36.40mL, d = 0.985g / cm 3 , 296.00mmol), and then the entire reaction mixture was stirred at ambient temperature for 36h. The reaction mixture was quenched with ice-cold water (500mL) and extracted with dichloromethane (4×1000mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a brown liquid (110.00g), which was purified by flash chromatography on 60-120 silica gel, eluted with 20% ethyl acetate in hexane to give 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropionic acid propyl ester (70.00g), which was a light yellow liquid.

[0238] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.61 (d, 2H, J = 6.80Hz), 7.55 (t, 1H, J = 7.60Hz), 7.51(s,1H),4.26(q,2H,J=10.40Hz),1.52(s,3H),1.35(s,9H),1.05(s,9H);

[0239] MS: m / z 305.2 [(M+1)-Boc].

[0240] Example 1, Step 6: Preparation of 2-amino-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate hydrochloride

[0241]

[0242] To a solution of propyl 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 anhydrous dichloromethane (700 mL) was added dropwise 4M HCl in dioxane (127.00 mL, 521.00 mmol) at 0° C. under nitrogen atmosphere, 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 light yellow gum which was used in the next step without further purification.

[0243] 1 H NMR(400MHz, DMSO-d6:D2O)δ7.88(s,1H),7.84(d,1H,J=8.00Hz),7.79(d,1H,J=7.60Hz),7.71 (t,1H,J=7.60Hz),4.49(d,1H,J=12.00Hz),4.27(d,1H,J=12.00Hz),1.72(s,3H),1.01(s,9H);

[0244] MS: m / z 304.1 [(M+1)-HCl].

[0245] Example 1, Step 7: Preparation of 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropionate

[0246]

[0247] 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 anhydrous dichloromethane (500 mL) was added 10% aqueous sodium bicarbonate (500 mL) at 0°C. After 15 minutes, thiophosgene (14.40 mL, d = 1.5 g / cm 3 , 188.00mmol) and stirred at the same temperature for 1h. The reaction mass was extracted with dichloromethane (3×1000mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow liquid (75.00g), which was purified by column chromatography using 60-120 mesh silica gel and 5% ethyl acetate in hexane as eluent to obtain 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (44.00g) as a yellow liquid.

[0248] 1H NMR (400MHz, DMSO-d6) δ7..85(s,1H),7.81(d,1H,J=7.20Hz),7.76(d,1H,J=7.6 0Hz), 7.69 (t, 1H, J = 8.40Hz), 4.51 (q, 2H, J = 15.20Hz), 1.83 (s, 3H), 1.35 (s, 9H);

[0249] MS: m / z 344.0 (M-1).

[0250] Example 1, Step 8: Preparation of 4-methylbenzo[c][1,2,5]thiadiazole

[0251]

[0252] To a solution of 3-methylbenzene-1,2-diamine (commercially available) (330.00 g, 2700.00 mmol) in anhydrous pyridine (1800 mL) was added thionyl chloride (500.00 mL, d = 1.64 g / cm 3 , 6750.00mmol). During this addition, the internal temperature was maintained below 45°C and the reaction mass was then stirred at ambient temperature for 3h. The reaction mixture was quenched with concentrated hydrochloric acid (1300mL) by dropwise addition until the pH of the reaction was adjusted to 2-3, at this stage, the internal temperature was maintained below 65°C. The reaction mass was diluted with water (1500mL) and ethyl acetate (2000mL) and stirred for 2h. The organic layer was then separated by filtration through a celite bed and the aqueous layer was further extracted with ethyl acetate (3×1500mL). The combined organic layers were washed with brine solution (300mL), dried over sodium sulfate, filtered and concentrated to afford 4-methylbenzo[c][1,2,5]thiadiazole (380.00g) as a brown liquid which was used in the next step without any further purification.

[0253] 1 H NMR (400MHz, DMSO-d6) δ7.90 (d, 1H, J = 8.80Hz), 7.61 (t, 1H, J = 8.80Hz), 7.51 (d, 1H, J = 6.80Hz), 2.69 (s, 3H);

[0254] MS: m / z 151.2 (M+1).

[0255] Example 1, Step 9: Preparation of 4-(bromomethyl)benzo[c][1,2,5]thiadiazole

[0256]

[0257] To a stirred solution of 4-methylbenzo[c][1,2,5]thiadiazole (from Example 1, Step 8) (100.00 g, 666.00 mmol) in anhydrous 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, the succinimide precipitate was removed by filtration and the filtrate was concentrated to give a brown semisolid (170.00 g), which was dissolved in methanol (1000 mL) and stirred for 30 minutes. 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.

[0258] 1 H NMR (400MHz, DMSO-d6) δ8.09 (d, 1H, J = 8.60Hz), 7.87 (d, 1H, J = 8.80Hz), 7.71 (t, 1H, J = 8.40Hz), 5.13 (s, 2H);

[0259] MS: No molecular ions were observed.

[0260] Example 1, Step 10: tert-Butyl N-(2,1,3-benzothiadiazol-4-yl)methyl-N-(tert-butyloxy)carbonyl]carbamate

[0261] Preparation

[0262]

[0263] To a solution of 4-(bromomethyl)benzo[c][1,2,5]thiadiazole (from Example 1, Step 9) (300.00 g, 1310.00 mmol) in anhydrous tetrahydrofuran (2500 mL) was added potassium carbonate (543.00 g, 3930.00 mmol) and then tert-butyl N-tert-butoxycarbonylcarbamate (427.00 g, 1960 mmol) under nitrogen atmosphere and the mixture was stirred at 70°C for 48 h. The reaction mass was filtered to remove the inorganic solids and the filtrate was concentrated. The residue was dissolved in water (1500 mL) and then extracted with ethyl acetate (5×3000 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 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.

[0264] 1H NMR (400MHz, DMSO-d6) δ7.99 (d, 1H, J = 8.80Hz), 7.31 (t, 1H, J = 8.00Hz), 7.34 (d, 1H, J = 6.80Hz), 5.21 (s, 2H), 1.39 (s, 18H);

[0265] MS: m / z 166.2 [(M+1)-2xBoc].

[0266] Example 1, Step 11: Preparation of 2,1,3-benzothiadiazole-4-ylmethylamine hydrochloride

[0267]

[0268] 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 4M hydrochloric acid in 1,4-dioxane (2223.00 mL, 8890.00 mmol) at 0°C and stirred at ambient temperature for 75 h. The reaction mass was concentrated under reduced pressure to give a yellow solid (370.00 g), which was triturated with hexanes (2×1000 mL), filtered and dried to give 2,1,3-benzothiadiazol-4-ylmethylamine hydrochloride (340.00 g) as a white solid which was used in the next step without further purification.

[0269] 1 H NMR (400MHz, DMSO-d6) δ8.94 (bs, 3H), 8.10 (d, 1H, J = 8.80Hz), 7.91 (t, 1H, J = 6.40Hz), 7.79 (d, 1H, J = 6.80Hz), 4.52 (s, 2H);

[0270] MS: m / z 166.1 [(M+1)-HCl].

[0271] Example 1, Step 12: Preparation of 1-(Benzo[c][1,2,5]thiadiazol-4-ylmethyl)-3-methylurea

[0272]

[0273] To a solution of 2,1,3-benzothiadiazol-4-ylmethylamine hydrochloride (from Example 1, Step 11) (6.00 g, 29.80 mmol) in anhydrous dichloromethane (100 mL) was added triethylamine (12.40 mL, d: 0.726 g / cm 3, 89.30mmol), then N-methylcarbamoyl chloride (4.17g, 44.60mmol) was added at 0°C, and then stirred at room temperature for 1h. The reaction mass was quenched with ice-cold water (75mL), and the aqueous layer was extracted with dichloromethane (4×500mL). 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 (4.20g) as a yellow gum, which was used in the next step without further purification.

[0274] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.94(d,1H,J=8.80Hz),7.68(t,1H,J=7.84Hz),7.47(d,1H,J=6.84Hz),4.68(s,2H),2.57(s,3H);

[0275] MS: m / z 223.0 (M+1).

[0276] Example 1, Step 13: Preparation of 1-(2,3-diaminobenzyl)-3-methylurea

[0277]

[0278] 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 anhydrous methanol (150 mL) was added Raney nickel (10.00 g, 200% w / w, pre-washed five times with anhydrous methanol) and the resulting reaction mixture was heated at ambient temperature under a bladder pressure (approximately 1.5 kg / cm 2 ), stirred under hydrogen atmosphere for 24 h. The reaction mixture was filtered through a celite bed and the bed was washed with methanol (3×1000 mL). The combined filtrates were 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.

[0279] 1 H NMR (400MHz, DMSO-d6:D2O) δ6.48(d,1H,J=7.20Hz), 6.37(t,1H,J=7.20Hz), 6.32(d,1H,J=7.32Hz), 4.03(s,2H), 2.54(s,3H);

[0280] MS: m / z 195.1 (M+1).

[0281] Example 1, Step 14: Preparation 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)phenylphenyl]propyl 2,2-dimethylpropanoate (mixture of regio isomers)

[0282]

[0283] To a solution of 1-(2,3-diaminobenzyl)-3-methylurea (from Example 1, Step 13) (7.00 g, 36.00 mmol) in a solvent mixture of 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 h. The reaction was concentrated to give a brown gum (20.00 g). Purification by flash column chromatography on 230-300 silica gel and eluting the product with 40-45% ethyl acetate in hexanes gave 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) as a brown solid which was used in the next step without further purification.

[0284] MS: m / z 540.1 (M+1).

[0285] 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

[0286]

[0287] 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, 36.60 mmol) and the mixture was stirred at 65° C. for 2 h. 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). Purification by Grace chromatography using 120.00 g of a pre-packed flash column packed with normal phase silica gel (60°A, 40-63 μm) 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.

[0288] 1 H NMR (400MHz, AcOH-d4) δ7.92(s,1H),7.90(d,1H,J=7.60Hz),7.72(d,1H,J=8.00Hz),7.65(t,1H,J=7.60Hz),7.35(d,1H,J=8.00Hz),7.18(t,1H,J= 8.00Hz), 7.10 (d, 1H, J = 7.60Hz), 4.65 (d, 1H, J = 11.60Hz), 4.56 (d, 1H, J = 11.60Hz), 4.41 (d, 2H, J = 6.80Hz), 2.70 (s, 3H), 2.05 (s, 3H), 1.16 (s, 9H);

[0289] MS: m / z 506.2 (M+1).

[0290] 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

[0291]

[0292] 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 h. The reaction mass was concentrated and the residue was diluted with 10% aqueous sodium bicarbonate solution (15 mL) and extracted with ethyl acetate (3×50 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) eluting the product 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.

[0293] 1 H NMR (400MHz, AcOH-d4) δ7.87(s,1H),7.84(d,1H,J=8.40Hz),7.68(d,1H,J=8.00Hz),7.60(t,1H,J=8.00Hz),7.31(d,1H,J=7.20Hz),7.17(t, 1H,J=7.60Hz),7.12(d,1H,J=6.80Hz),4.46(q,2H,J=15.20Hz),4.29(d,1H,J=12.00Hz),4.07(d,1H,J=12.00Hz),2.69(s,3H),1.88(s,3H);

[0294] MS: m / z 422.1(M+1).

[0295] 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

[0296] 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 method: column: Chiral Pak OX-H; flow rate: 3.0 mL / min; co-solvent: 20%; co-solvent name: 0.5% diethylamine in isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 15a and 15b were obtained.

[0297] The (+) enantiomer 15a eluted first from the column.

[0298]

[0299] Fraction-1 was eluted first from the SFC column and concentrated to give (+) 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 with 100% ee.

[0300] The (-) enantiomer 15b was the second to elute from the column.

[0301]

[0302] Fraction-2 was eluted second from the SFC column and concentrated to give (-)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 with 100% ee.

[0303] 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

[0304]

[0305] 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 step 15, compound 15a, fraction 1) (0.300 g, 0.593 mmol) in ethanol (15 mL) was added sodium hydroxide (0.071 g, 2.00 mmol) pellets and stirred at ambient temperature for 2 h. 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.

[0306] 1 H NMR (400MHz, AcOH-d4): δ7.86 (s, 1H), 7.83 (d, 1H, J = 8.00Hz), 7.67 (d, 1H, J = 7.76Hz), 7.59 (t, 1H, J = 7.76Hz), 7.30 (d, 1H, J = 7.76Hz), 7.17 (t ,1H,J=7.80Hz),7.11(d,1H,J=7.36Hz),4.45(q,2H,J=15.24Hz),4.28(d,1H,J=12.00Hz),4.06(d,1H,J=11.96Hz),2.68(s,3H),1.87(s,3H);

[0307] MS: m / z 422.2 (M+1);

[0308] [α] D 22.3 (+) 12.00 (MeOH, c = 0.1).

[0309] 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

[0310]

[0311] 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 step 15, compound 15b, fraction 2) (0.270 g, 0.534 mmol) in ethanol (15 mL) was added sodium hydroxide pellets (0.071 g, 2.00 mmol) and stirred at ambient temperature for 2 h. 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 afford (-)-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.

[0312] 1 H NMR (400MHz, AcOH-d4) δ7.86 (s, 1H), 7.83 (d, 1H, J = 7.96Hz), 7.67 (d, 1H, J = 7.64Hz), 7.59 (t, 1H, J = 7.72Hz), 7.30 (d, 1H, J = 7.88Hz), 7.16 (t, 1H,J=7.84Hz),7.11(d,1H,J=7.52Hz),4.45(q,2H,J=15.20Hz),4.28(d,1H,J=11.92Hz),4.06(d,1H,J=11.92Hz),2.68(s,3H),1.87(s,3H);

[0313] MS: m / z 422.2 (M+1);

[0314] [α] D 22.5 (-)12.00 (MeOH, c=0.1).

[0315] 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

[0316]

[0317] Example 2, Step 1: Preparation of 3-(Benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1,1-dimethylurea

[0318]

[0319] To a solution of 2,1,3-benzothiadiazol-4-ylmethylamine hydrochloride (from Example 1, Step 11) (10.00 g, 49.6 mmol) in anhydrous dichloromethane (100 mL) cooled to 0°C under nitrogen atmosphere was added triethylamine (17.30 mL, d: 0.726 g / cm 3 , 124.00mmol), and then N,N-dimethylcarbamoyl chloride (6.85mL, d: 1.168g / cm 3 , 74.40mmol), and then the mixture was stirred at room temperature for 2h. The above reaction mass was quenched with ice-cold water (50mL), and the aqueous layer was extracted with dichloromethane (3×50mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow gum (12.00g). Chromatographic purification was performed on a Grace instrument using 120.0g of a pre-packed column filled 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 (6.00g) as a colorless gum, which was used in the next step without further purification.

[0320] 1 H NMR (400MHz, DMSO-d6) δ7.95 (d, 1H, J = 8.70Hz), 7.70 (t, 1H, J = 7.58Hz), 7.47 ( d,1H,J=6.80Hz),7.01(t,1H,J=5.44Hz),4.74(d,2H,J=5.60Hz),2.87(s,6H);

[0321] MS: m / z 237.2 (M+1).

[0322] Example 2, Step 2: Preparation of 3-(2,3-diaminobenzyl)-1,1-dimethylurea

[0323]

[0324] To a degassed solution of 3-(2,1,3-benzothiadiazol-4-ylmethyl)-1,1-dimethylurea (from Example 2, Step 1) (9.00 g, 38.1 mmol) in anhydrous methanol (1000 mL) was added Raney nickel (18.00 g, 200% w / w, pre-washed five times with anhydrous methanol) and the resulting reaction mixture was heated at ambient temperature under balloon pressure (about 1.5 kg / cm 2), stirred under hydrogen atmosphere for 24 h. The reaction mixture was filtered through a celite bed 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.

[0325] 1 H NMR (400MHz, DMSO-d6) δ6.63(bs,1H),6.45(s,1H),6.40(s,1H),6.34(d,1H,J=6.40Hz),4.62(bs,2H),4.37(bs,2H),4.09(bs,2H),2.80(s,6H);

[0326] MS: m / z 209.2 (M+1).

[0327] 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)

[0328]

[0329] 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 h. 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 (1:1 mixture as regioisomers) as a light yellow gum (1.50 g) which was used in the next step without further purification.

[0330] MS: m / z 554.3 (M+1).

[0331] 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

[0332]

[0333] To a mixture 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 (1:1 mixture as 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 solution (2×10 mL), the organic layer was dried over sodium sulfate, filtered and concentrated to give a light red gum (1.40 g). Purification by flash column chromatography on 230-400 silica gel, 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.

[0334] 1 H NMR(400MHz,DMSO-d6)δ10.57(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);

[0335] MS: m / z 520.2 (M+1).

[0336] 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

[0337]

[0338] 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 and the residue was dissolved in water (30 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude product as a 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.

[0339] 1 H NMR (400MHz, AcOH-d4) δ7.85 (t, 2H, J = 7.60Hz), 7.67 (d, 1H, J = 7.60Hz), 7.60 (t, 1H, J = 7.60Hz), 7.34 (d, 1H, J = 7.20Hz), 7.17 (t, 1H, J = 8.00Hz), 7.1 0(d,1H,J=6.80Hz),4.51(d,1H,J=14.80Hz),4.40(d,1H,J=15.20Hz),4. 25(d,1H,J=11.60Hz), 4.06(d,1H,J=11.60Hz), 2.86(s,6H), 1.90(s,3H);

[0340] MS: m / z 436.2 (M+1).

[0341] The above product was separated into its two enantiomers by chiral SFC using the following method; column: Chiral PakOX-H; flow rate: 3.0 mL / min, co-solvent: 30%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 2a and bb were obtained.

[0342] Example 2a: (+)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea

[0343] The (+) enantiomer elutes from the column first.

[0344] 1 H NMR (400MHz, AcOH-d4) δ7.85 (t, 2H, J = 7.60Hz), 7.67 (d, 1H, J = 7.60Hz), 7.60 (t, 1H, J = 7.60Hz), 7.34 (d, 1H, J = 7.20Hz), 7.17 (t, 1H, J = 8.00Hz), 7.1 0(d,1H,J=6.80Hz),4.51(d,1H,J=14.80Hz),4.40(d,1H,J=15.20Hz),4. 25(d,1H,J=11.60Hz), 4.06(d,1H,J=11.60Hz), 2.86(s,6H), 1.90(s,3H);

[0345] MS: m / z 436.2 (M+1);

[0346] [α]D 22.4 (+) 44.0 (MeOH, c = 0.1).

[0347] Example 2b: (-)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea

[0348] The (-) enantiomer is the second to elute from the column.

[0349] 1 H NMR (400MHz, AcOH-d4) δ7.85 (t, 2H, J = 7.60Hz), 7.67 (d, 1H, J = 7.60Hz), 7.60 (t, 1H, J = 7.60Hz), 7.34 (d, 1H, J = 7.20Hz), 7.17 (t, 1H, J = 8.00Hz), 7.1 0(d,1H,J=6.80Hz),4.51(d,1H,J=14.80Hz),4.40(d,1H,J=15.20Hz),4. 25(d,1H,J=11.60Hz), 4.06(d,1H,J=11.60Hz), 2.86(s,6H), 1.90(s,3H);

[0350] MS: m / z 436.2 (M+1);

[0351] [α]D 22.5 (-)20.0 (MeOH, c=0.1).

[0352] 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

[0353]

[0354] Example 3, Step 1: Preparation of tert-butyl N-{1-methoxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate

[0355]

[0356] 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 iodomethane (6.00 mL, 95 mmol) and stirred at room temperature in the dark 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 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.

[0357] 1 H NMR (400MHz, DMSO-d6) δ7.65-7.53(m,4H),7.12(s,1H),3.55-3.47(m,2H),3.23(s,3H),1.58(s,3H),1.34(s,9H);

[0358] MS: m / z 234.1 [(M+1)-Boc].

[0359] Example 3, Step 2: 1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-amine hydrochloride

[0360]

[0361] 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 slowly warmed 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.

[0362] 1 H NMR (400MHz, DMSO-d6) δ8.74 (s, 2H), 7.87-7.71 (m, 3H), 3.76 (d, 1H, J = 10.00H z), 3.65 (d, 1H, J = 10.00Hz), 3.57 (d, 2H, J = 2.40Hz), 3.35 (s, 3H), 1.62 (s, 3H);

[0363] MS: m / z 234.1 (M+1).

[0364] Example 3, Step 3: 1-(2-isothiocyanato-1-methoxypropan-2-yl)-3-(trifluoromethyl)benzene

[0365]

[0366] 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) at 0°C was added 10% sodium bicarbonate solution followed by thiophosgene (0.55 mL, 7.29 mmol) and the reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with dichloromethane (100 mL), 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, eluting the product 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.

[0367] 1 H NMR (400MHz, DMSO-d6) δ7.82-7.74(m,3H),7.70-7.67(m,1H),3.76(s,2H),3.33(s,3H),1.77(s,3H).

[0368] 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)

[0369]

[0370] 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 h. 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 (1:1 mixture as regioisomers) (1.00 g) as a brown gum which was used in the next step without further purification.

[0371] MS: m / z 470.2 (M+1).

[0372] 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

[0373]

[0374] 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 (1:1 mixture as 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 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (100 mL), washed with 10% aqueous sodium bicarbonate solution (2 x 20 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.900 g). It was purified by flash column chromatography on 230-400 silica gel eluting the product 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.

[0375] 1 H NMR (400MHz, AcOH-d4) δ7.85-7.82(m,2H),7.69(d,1H,J=7.20Hz),7.61(t,1H,J=7.60Hz,1H),7.30(d,1H,J=7.60Hz),7.20-7 .14(m,2H),4.47(d,2H,J=10.00Hz),4.02(d,1H,J=10.40Hz),3.84(d,1H,J=10.00Hz),3.48(s,3H),2.71(s,3H),1.91(s,3H);

[0376] MS: m / z 436.2 (M+1).

[0377] The above product was separated into its two enantiomers by chiral SFC using the following method; column: Chiral PakOX-H; flow rate: 3.0 mL / min, co-solvent: 40%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 10.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 3a and 3b were obtained.

[0378] Example 3a: (+)-1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[0379] The (+) enantiomer elutes from the column first.

[0380] 1 H NMR(400MHz,AcOH-d4)δ7.85-7.82(m,2H),7.69(d,1H,J=7.20Hz),7.61(t,1H,J=7.60Hz),7.30(d,1H,J=7.60Hz),7.20-7.1 4(m,2H),4.47(d,2H,J=10.00Hz),4.02(d,1H,J=10.40Hz),3.84(d,1H,J=10.00Hz),3.48(s,3H),2.71(s,3H),1.91(s,3H);

[0381] MS: m / z 436.2 (M+1);

[0382] [α]D 22.4 (+) 13.59 (MeOH, c = 0.1).

[0383] Example 3b: (-)-1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[0384] The (-) enantiomer is the second to elute from the column.

[0385] 1 H NMR(400MHz,AcOH-d4)δ7.85-7.82(m,2H),7.69(d,1H,J=7.20Hz),7.61(t,1H,J=7.60Hz),7.30(d,1H,J=7.60Hz),7.20-7.1 4(m,2H),4.47(d,2H,J=10.00Hz),4.02(d,1H,J=10.40Hz),3.84(d,1H,J=10.00Hz),3.48(s,3H),2.71(s,3H),1.91(s,3H);

[0386] MS: m / z 436.2 (M+1);

[0387] [α]D 23.5 (-)12.60 (MeOH, c=0.1).

[0388] 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

[0389]

[0390] Example 4, Step 1: Preparation of 3-(Benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1-methoxy-1-methylurea

[0391]

[0392] To a stirred solution of benzo[c][1,2,5]thiadiazol-4-ylmethylamine hydrochloride (from Example 1, Step 11) (20.00 g, 99.20

[0393] mmol) in dichloromethane (200 mL) was added trimethylamine (42.5 mL, d = 0.724 gm / cm 3 , 305.00mmol), and the reaction mixture was stirred for 5min. Then, N-methoxy-N-methyl-carbamoyl chloride (12.91mL, 129.00mmol) was added dropwise to the reaction mixture at 0°C over 5min, and the mixture was slowly warmed to room temperature and stirred for 2h.

[0394] The reaction was quenched with ice-cold water (100 mL), the organic phase was separated, and the aqueous phase was further extracted with dichloromethane (3×500 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, eluting the product with 45% ethyl acetate in petroleum ether to give 3-(benzo[c][1,2,5]

[0395] Thiadiazol-4-ylmethyl)-1-methoxy-1-methylurea (15.00 g) as a colorless gum.

[0396] 1 H NMR (400MHz, DMSO-d6) δ7.98 (dd, 1H, J = 8.80, 0.80Hz), 7.89 (t, 1H, J = 6.00Hz), 7.72 (q, 1H, J =6.80Hz),7.47(dd,1H,J=7.00,0.80Hz),4.77(d,2H,J=6.00Hz),3.67(s,3H),3.00(s,3H);

[0397] MS: m / z 253.0 (M+1).

[0398] Example 4, Step 2: Preparation of 3-(2,3-diaminobenzyl)-1-methoxy-1-methylurea

[0399]

[0400] To a stirred solution of 3-(2,1,3-benzothiadiazol-4-ylmethyl)-1-methoxy-1-methylurea (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 at 1.5 kg / cm using a balloon. 2 The reaction mixture was filtered through a bed of celite and the filtrate was concentrated to give a yellow solid (13.00 g). This was purified by flash column chromatography on 230-400 silica gel, eluting the product with 100% ethyl acetate to give 3-(2,3-diaminobenzyl)-1-methoxy-1-methylurea (7.00 g) as a yellow solid.

[0401] 1 H NMR (400MHz, DMSO-d6) δ7.53-7.49(m,1H),6.47(dd,1H,J=7.40,1.60Hz),6.42(dd,1H,J=7.40,1.20H z), 6.34 (t, 1H, J = 7.60Hz), 4.52 (s, 2H), 4.42 (s, 2H), 4.09 (d, 2H, J = 6.4Hz), 3.58 (s, 3H), 2.95 (s, 3H);

[0402] MS: m / z 225.2 (M+1).

[0403] Example 4, Step 3: Preparation of 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 (mixture of regioisomers)

[0404]

[0405] To a stirred solution of 3-[(2,3-diaminophenyl)methyl]-1-methoxy-1-methyl-urea (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 h. 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 (1:1 mixture as regioisomers) (0.980 g) as a light yellow gum which was used in the next step without further purification.

[0406] MS: m / z 570.2 (M+1).

[0407] 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

[0408]

[0409] To a solution of 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 (1:1 mixture as 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 light red gum (0.90 g). This was purified by flash column chromatography on 230-400 silica gel, eluting the product 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 light red gum.

[0410] 1 H NMR(400MHz, DMSO-d6:D2O)δ7.76(s,2H),7.58(t,2H,J=7.60Hz),7.03(s,1H),6.90-6.8 0(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);

[0411] MS: m / z 536.6 (M+1).

[0412] 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

[0413]

[0414] 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 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 hydrochloric acid solution (3 mL) and concentrated under reduced pressure at 30° C. to give a brown gum (0.600 g). Purification by preparative HPLC using 0.1% TFA in acetonitrile:water gave 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.

[0415] 1 H NMR (400MHz, AcOH-d4) δ7.87(s,1H),7.84(d,1H,J=7.60Hz),7.67(d,1H,J=8.00Hz),7.60(t,1H,J=7.60Hz),7.36(d,1H,J=8.00Hz),7.19(t,1H,J= 7.60Hz),7.13(d,1H,J=7.20Hz),4.45(q,2H,J=15.20Hz),4.26(d,1H,J=1 2.00Hz), 4.06 (d, 1H, J = 11.60Hz), 3.60 (s, 3H), 3.02 (s, 3H), 1.89 (s, 3H);

[0416] MS: m / z 452.2 (M+1).

[0417] The above product was separated into its two enantiomers by chiral SFC using the following method; column: chiral LuxC4; flow rate: 3.0 mL / min, co-solvent: 30%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 4a and 4b were obtained.

[0418] 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

[0419] The (+) enantiomer elutes from the column first.

[0420] 1H NMR (400MHz, AcOH-d4) δ7.87(s,1H),7.84(d,1H,J=7.60Hz),7.67(d,1H,J=8.00Hz),7.60(t,1H,J=7.60Hz),7.36(d,1H,J=8.00Hz),7.19(t,1H,J= 7.60Hz),7.13(d,1H,J=7.20Hz),4.45(q,2H,J=15.20Hz),4.26(d,1H,J=1 2.00Hz), 4.06 (d, 1H, J = 11.60Hz), 3.60 (s, 3H), 3.02 (s, 3H), 1.89 (s, 3H);

[0421] MS: m / z 452.2 (M+1);

[0422] [α] D 25.0 (+) 15.40 (MeOH, c = 1.0).

[0423] 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

[0424] The (-) enantiomer is the second to elute from the column.

[0425] 1 H NMR (400MHz, AcOH-d4) δ7.87(s,1H),7.84(d,1H,J=7.60Hz),7.67(d,1H,J=8.00Hz),7.60(t,1H,J=7.60Hz),7.36(d,1H,J=8.00Hz),7.19(t,1H,J= 7.60Hz),7.13(d,1H,J=7.20Hz),4.45(q,2H,J=15.20Hz),4.26(d,1H,J=1 2.00Hz), 4.06 (d, 1H, J = 11.60Hz), 3.60 (s, 3H), 3.02 (s, 3H), 1.89 (s, 3H);

[0426] MS: m / z 452.2 (M+1);

[0427] [α] D 25.2 (-)16.20 (MeOH, c=1.0).

[0428] 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

[0429]

[0430] Example 5, Step 1: Preparation of 3-(Benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1-ethyl-1-methylurea

[0431]

[0432] To a solution of 2,1,3-benzothiadiazol-4-ylmethylamine hydrochloride (from Example 1, Step 11) (25.00 g, 124.00 mmol) in anhydrous dichloromethane (800 mL) cooled to 0°C was added triethylamine (52.00 mL, d: 0.726 g / cm3) under nitrogen atmosphere. 3 , 372.00mmol), then N-ethyl-N-methyl-carbamoyl chloride (20.50mL, d: 1.11g / cm 3 , 186.00mmol), and then the mixture was stirred at room temperature for 2h. The above reaction mixture was quenched with ice-cold water (200mL), and the aqueous layer was extracted with dichloromethane (3×1000mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow gum (31.00g). Chromatographic purification was performed using a Grace instrument using 220.0g pre-loaded flash column filled with normal phase silica gel (60°A, 40-63μm), and the product was eluted with 26% ethyl acetate in petroleum ether to give 3-(benzo[c][1,2,5]thiadiazole-4-ylmethyl)-1-ethyl-1-methylurea (27.00g) as a yellow gum.

[0433] 1 H NMR (400MHz, DMSO-d6; D2O) δ7.94(d,1H,J=8.80Hz),7.67(d,1H,J=6.80Hz),7.42(dd,1H,J =7.20,1.20Hz),4.72(s,2H),3.25(d,2H,J=7.20Hz),2.83(s,3H),1.02(t,3H,J=7.20Hz);

[0434] MS: m / z 251.1 (M+1).

[0435] Example 5, Step 2: Preparation of 3-(2,3-diaminobenzyl)-1-ethyl-1-methylurea

[0436]

[0437] 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 anhydrous methanol (1500 mL) was added Raney nickel (54.00 g, 200% w / w, pre-washed five times with anhydrous methanol) and the resulting reaction mixture was heated at ambient temperature under balloon pressure (approximately 1.5 kg / cm 2 ), stirred for 24 h under hydrogen atmosphere. The reaction mixture was filtered through a celite bed and the bed was washed with methanol (3×2500 mL). The combined filtrates were 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.

[0438] 1 H NMR(400MHz, DMSO-d6:D2O)δ6.45(d,1H,J=7.42Hz),6.40(d,1H,J=7.24Hz),7.33(t,1H ,J=7.50Hz),4.07(s,2H),3.20(d,2H,J=7.00Hz),2.75(s,3H),0.97(t,3H,J=7.00Hz);

[0439] MS: m / z 223.3 (M+1).

[0440] Example 5, Step 3: Preparation of 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 (mixture of regioisomers)

[0441]

[0442] 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 solvent mixture of 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 h. The reaction mass was concentrated to afford a brown gum (23.00 g) which was purified by chromatography on Grace instrument using 120.0 g of pre-packed flash column packed with normal phase silica gel (60°A, 40-63 μm) and eluting the product with 5% methanol in chloroform to afford 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 (4:1 mixture as regioisomers) (17.00 g) as yellow solid.

[0443] MS: m / z 568.3 (M+1).

[0444] 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

[0445]

[0446] Starting with 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 (4:1 mixture as regioisomers) (from Example 5, Step 3), using the procedure described in Example 1, Step 15, 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.

[0447] 1H NMR(400MHz, DMSO-d6:D2O)δ7.82(s,1H),7.77(d,1H,J=8.00Hz),7.57(d,2H, J=11.20Hz),6.97(d,1H,J=10.40Hz),6.79(t,1H,J=9.60Hz),6.73(t,1H,J=11 .60Hz),4.49(d,2H,J=11.20Hz),4.28(s,2H),3.23(t,1H,J=9.60Hz),3.14(t, 1H,J=4.80Hz),2.77(s,3H),1.89(s,3H),1.01(s,9H),0.96(t,3H,J=9.20Hz);

[0448] MS: m / z 534.2 (M+1).

[0449] 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

[0450]

[0451] 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 was added sodium hydroxide pellets (2.25 g, 56.20 mmol) and the mixture was stirred at ambient temperature for 2 h. The reaction mass was concentrated to remove the solvent methanol and the residue was dissolved with 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). Purification by chromatography on a Grace instrument using a 220.0 g prepacked flash column packed with normal phase silica gel (60°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.

[0452] 1H NMR(400MHz,AcOH-d4)δ7.87(s,1H),7.84(d,1H,J=8.00Hz),7.67(d,1H,J=7.60Hz ),7.60(t,1H,J=8.00Hz),7.33(d,1H,J=8.00Hz),7.17(t,1H,J=8.00Hz),7.11(d, 1H, J=7.20Hz), 4.46 (q, 2H, J=15.20Hz), 4.25 (d, 1H, J=12.00Hz), 4.06 (d, 1H, J=12 .00Hz), 3.27 (d, 2H, J = 7.20Hz), 2.87 (s, 3H), 1.91 (s, 3H), 1.08 (t, 3H, J = 6.80Hz);

[0453] MS: m / z 450.1 (M+1).

[0454] The above product was separated into its two enantiomers by chiral SFC using the following method; column: ChiralcelOX-H; flow rate: 3.0 mL / min, co-solvent: 30%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 5a and 5b were obtained.

[0455] 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

[0456] The (+) enantiomer is the first to elute from the column.

[0457] 1 H NMR(400MHz,AcOH-d4)δ7.87(s,1H),7.82(d,1H,J=8.00Hz),7.67(d,1H,J=7.60Hz ),7.60(t,1H,J=7.60Hz),7.33(d,1H,J=7.60Hz),7.17(t,1H,J=7.60Hz),7.10(d, 1H, J=7.20Hz), 4.48 (q, 2H, J=15.20Hz), 4.24 (d, 1H, J=12.00Hz), 4.06 (d, 1H, J=11 .60Hz), 3.27 (d, 2H, J = 7.20Hz), 2.84 (s, 3H), 1.90 (s, 3H), 1.08 (t, 3H, J = 7.20Hz);

[0458] MS: m / z 450.3 (M+1);

[0459] [α] D 23.8 (+) 71.16 (MeOH, c = 1.0).

[0460] 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

[0461] The (-) enantiomer is the second to elute from the column.

[0462] 1 H NMR(400MHz,AcOH-d4)δ7.87(s,1H),7.84(d,1H,J=7.60Hz),7.67(d,1H,J=7.60Hz ),7.58(t,1H,J=7.60Hz),7.33(d,1H,J=7.60Hz),7.17(t,1H,J=7.60Hz),7.10(d, 1H, J=7.60Hz), 4.50 (q, 2H, J=14.80Hz), 4.23 (d, 1H, J=12.00Hz), 4.06 (d, 1H, J=11 .60Hz), 3.27 (d, 2H, J = 6.80Hz), 2.84 (s, 3H), 1.90 (s, 3H), 1.08 (t, 3H, J = 7.20Hz);

[0463] MS: m / z 450.3 (M+1);

[0464] [α] D 23.7 (-)61.12 (MeOH, c=1.0).

[0465] 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

[0466]

[0467] Example 6, Step 1: Preparation of 5-fluoro-4-methylbenzo[c][1,2,5]thiadiazole

[0468]

[0469] To a solution of 4-fluoro-3-methylbenzene-1,2-diamine (commercially available) (4.00 g, 28.50 mmol) in anhydrous pyridine (24 mL) was added thionyl chloride (5.00 mL, d = 1.64 g / cm 3 , 68.50mmol), during this addition, the internal temperature was maintained below 45°C, and the reaction mixture was then stirred at ambient temperature for 3h. The reaction mixture was quenched by the dropwise addition of concentrated hydrochloric acid (30mL) until the pH of the reaction was adjusted to 2-3, at this stage, the internal temperature was maintained below 65°C. The reaction mixture was diluted with water (100mL) and ethyl acetate (200mL) and stirred for 2h. The organic layer was then separated by filtration through a celite bed, and the aqueous layer was further extracted with ethyl acetate (3×500mL). The combined organic layers were washed with brine solution (50mL), dried over sodium sulfate, filtered and concentrated to give 5-fluoro-4-methylbenzo[c][1,2,5]thiadiazole (4.50g) as a brown liquid, which was used in the next step without further purification.

[0470] 1 H NMR (400MHz, DMSO-d6) δ7.82 (d, 1H, J = 4.80Hz), 7.43 (t, 1H, J = 9.60Hz), 2.65 (s, 3H);

[0471] MS: m / z 169.0 (M+1).

[0472] Example 6, Step 2: Preparation of 4-(bromomethyl)-5-fluorobenzo[c][1,2,5]thiadiazole

[0473]

[0474] 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 anhydrous 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 h. The reaction mass was cooled and the succinimide solids were removed by filtration. The filtrate was concentrated to give a brown semisolid (7.00 g). Crystallization was carried out in ethyl acetate (50 mL), 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.

[0475] 1H NMR (400MHz, DMSO-d6) δ 8.00 (d, 1H, J = 9.52Hz), 7.47 (t, 1H, J = 9.40Hz), 5.00 (s, 2H).

[0476] Example 6, Step 3: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(5-fluoro-2,1,3-benzothiadiazol-4-yl)methyl]carbamate

[0477]

[0478] Under nitrogen atmosphere, potassium carbonate (7.00 g, 50.60 mmol) was added 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 anhydrous tetrahydrofuran (50 mL), 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 h. The reaction mass was filtered to remove the 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). Chromatographic purification was performed on a Grace instrument using a 40.0 g pre-packed flash column packed with normal phase silica gel (60°A, 40-63 μm) and eluting the product with 1-2% ethyl acetate in hexanes to afford 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.

[0479] 1 H NMR (400MHz, DMSO-d6) δ8.10 (d, 1H, J = 9.52Hz), 7.72 (t, 1H, J = 10.32Hz), 5.22 (s, 2H), 1.35 (s, 18H);

[0480] MS: m / z 283.0 [(M+1)-Boc].

[0481] Example 6, Step 4: Preparation of (5-fluorobenzo[c][1,2,5]thiadiazol-4-yl)methylamine hydrochloride

[0482]

[0483] 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 h. The reaction mass was concentrated under reduced pressure to obtain a yellow solid (3.00 g). It was triturated with hexanes (2×100 mL) and the supernatant layer was decanted and dried to obtain (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.

[0484] 1 H NMR (400MHz, DMSO-d6:D2O) δ8.20 (d, 1H, J = 12.00Hz), 7.77 (t, 1H, J = 8.00Hz), 4.47 (s, 2H);

[0485] MS: m / z 184.1 [(M+1)-HCl].

[0486] Example 6, Step 5: Preparation of 3-((5-fluorobenzo[c][1,2,5]thiadiazol-4-yl)methyl)-1,1-dimethylurea

[0487]

[0488] 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 anhydrous dichloromethane (50 mL) was added triethylamine (3.81 mL, d: 0.726 g / cm2) at 0°C under nitrogen atmosphere. 3 , 27.30 mmol), and then N,N-dimethylcarbamoyl chloride (commercially available) (1.26 mL, d: 1.168 g / cm 3 , 13.70mmol), and then the mixture was stirred at room temperature for 2h. The reaction mass was quenched with ice-cold water (50mL), and the aqueous layer was extracted with dichloromethane (3×200mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow gum (2.50g). Purification was performed by chromatography on a Grace instrument using 40.0g of a pre-loaded flash column filled with normal phase silica gel (60°A, 40-63μm), 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 (1.50g) as a light yellow liquid.

[0489] 1 H NMR (400MHz, DMSO-d6:D2O) δ8.04 (d, 1H, J = 9.60Hz), 7.66 (t, 1H, J = 9.60Hz), 4.68 (s, 2H), 2.74 (s, 6H);

[0490] MS: m / z 255.0 (M+1).

[0491] Example 6, Step 6: Preparation of 3-(2,3-diamino-6-fluorobenzyl)-1,1-dimethylurea

[0492]

[0493] 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 anhydrous methanol (60 mL) was added Raney nickel (3.00 g, 200% w / w, pre-washed five times with anhydrous methanol) and the resulting reaction mixture was heated at ambient temperature under balloon pressure (approximately 1.5 kg / cm 2 ), stirred under hydrogen atmosphere for 16 h. The reaction mixture was then filtered through a celite bed and the bed was washed with methanol (3×200 mL). The combined filtrates were 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.

[0494] 1 H NMR (400MHz, CD3OD) δ6.59 (t, 1H, J = 7.80Hz), 6.27 (t, 1H, J = 9.20Hz), 4.36 (s, 2H), 2.85 (s, 6H);

[0495] MS: m / z 227.2 (M+1).

[0496] 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)

[0497]

[0498] 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 dichloromethane:methanol (4:1, 20 mL) solvent mixture 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 h. The reaction mass was concentrated to give a brown gum (0.682). Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash column packed with normal phase silica gel (60°A, 40-63 μm) eluting the product with 80-85% ethyl acetate in hexanes 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 (1:1 mixture as regioisomers) (0.460 g) as a yellow solid.

[0499] MS: m / z 572.2 (M+1).

[0500] 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

[0501]

[0502] 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 (1:1 mixture as regioisomers) (from Example 6, Step 7) (0.460 g, 0.805 mmol) in anhydrous methanol (20 mL) was added iodoacetic acid (0.195 g, 1.05 mmol) under nitrogen atmosphere and the reaction mixture was heated at 70° C. for 1 h. The reaction mass was concentrated to remove the 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 (30 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.450 g). Purification by chromatography on a Grace instrument using 24.0 g of a pre-packed flash column packed with normal phase silica gel (60°A, 40-63 μm) 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.

[0503] 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),7.78(s,2H),7.61(t,1H,J=10.80Hz),7.54(d,1H,J=10.00Hz),7.50(s,1H),7.00(d,1H,J=10.80Hz) ,6.92(d,1H,J=6.00Hz),6.65(t,1H,J=15.20Hz),4.57(q,2H,J=8.00Hz),4.35(t,2H,J=13.20Hz),2.82(s,6H),1.83(s,3H),1.02(s,9H);

[0504] MS: m / z 538.3 (M+1).

[0505] 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

[0506]

[0507] 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 mass was concentrated to remove the solvent methanol and the residue was dissolved with water (20 mL) and extracted with ethyl acetate (4 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to get a brown gum (0.140 g). Purification by chromatography on a Grace instrument using a 12.0 g prepacked flash column packed with normal phase silica gel (60°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.

[0508] 1 H NMR (400MHz, AcOH-d4) δ7.88(s,1H),7.83(d,1H,J=7.84Hz),7.67(d,1H,J=7.72Hz),7.61(d,1H,J=7.76Hz),7.34(d,1H,J= 7.32Hz), 6.98 (t, 1H, J = 9.92Hz), 4.48 (s, 2H), 4.22 (d, 1H, J = 11.84Hz), 4.03 (d, 1H, J = 11.90Hz), 2.85 (s, 6H), 1.91 (s, 3H);

[0509] MS: m / z 454.1 (M+1).

[0510] The above product was separated into its two enantiomers by chiral SFC using the following method; column: RR-Whelk-01; flow rate: 3.0 mL / min, co-solvent: 40%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 7.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 6a and 6b were obtained.

[0511] 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

[0512] The (+) enantiomer is the first to elute from the column.

[0513] 1 H NMR (400MHz, AcOH-d4) δ7.88(s,1H),7.83(d,1H,J=8.08Hz),7.67(d,1H,J=7.72Hz),7.60(d,1H,J=8.00Hz),7.32(d,1H,J= 8.00Hz), 6.98 (t, 1H, J = 10.24Hz), 4.48 (s, 2H), 4.23 (d, 1H, J = 12.04Hz), 4.03 (d, 1H, J = 11.90Hz), 2.84 (s, 6H), 1.91 (s, 3H);

[0514] MS: m / z 454.2 (M+1);

[0515] [α] D 21.2 (+) 18.40 (MeOH, c = 0.5).

[0516] 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

[0517] The (-) enantiomer is the second to elute from the column.

[0518] 1 H NMR (400MHz, AcOH-d4) δ7.88(s,1H),7.83(d,1H,J=8.04Hz),7.67(d,1H,J=7.84Hz),7.60(t,1H,J=7.90Hz),7.34(d,1H,J= 8.80Hz), 6.98 (t, 1H, J = 10.28Hz), 4.48 (s, 2H), 4.22 (d, 1H, J = 11.90Hz), 4.04 (d, 1H, J = 11.80Hz), 2.85 (s, 6H), 1.91 (s, 3H);

[0519] MS: m / z 454.2 (M+1);

[0520] [α] D 21.3 (-)14.80 (MeOH, c=0.5).

[0521] 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

[0522]

[0523] Example 7, Step 1: Preparation of 1-(Benzo[c][1,2,5]thiadiazol-4-ylmethyl)-3-cyclopropylurea

[0524]

[0525] To a solution of 2,1,3-benzothiadiazol-4-ylmethylamine hydrochloride (from Example 1, Step 11) (5.00 g, 24.80 mmol) in anhydrous dichloromethane (100 mL) cooled to 0°C under nitrogen atmosphere was added triethylamine (10.40 mL, d: 0.726 g / cm 3 , 74.40mmol), then add isocyanatocyclopropane (2.90g, 34.80mmol), then the mixture is stirred at room temperature for 1h. The reaction mass is diluted with ice-cold water (50mL), the precipitate formed is filtered, and washed with dichloromethane (50mL). The solid is dried under vacuum to obtain 1-(benzo[c][1,2,5]thiadiazole-4-ylmethyl)-3-cyclopropylurea (3.80g), which is an off-white solid that can be used in the next step without further purification.

[0526] 1 H NMR (400MHz, DMSO-d6) δ7.96 (d, 1H, J = 8.80Hz), 7.70 (t, 1H, J = 8.80Hz), 7.48 (d, 1H, J = 6.80Hz), 6.59 (s, 1H), 6.40 (s, 1H), 4.72 (d, 2H, J = 5.60Hz), 2.46 (q, 1H, J = 3.60Hz), 0.59 (q, 2H, J = 6.40Hz), 0.37 (t, 2H, J = 7.60Hz);

[0527] MS: m / z 249.1 (M+1).

[0528] Example 7, Step 2: Preparation of 1-cyclopropyl-3-(2,3-diaminobenzyl)urea

[0529]

[0530] 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 anhydrous methanol (150 mL) was added Raney nickel (7.60 g, 200% w / w, pre-washed five times with anhydrous methanol) and the resulting reaction mixture was heated at ambient temperature under balloon pressure (about 1.5 kg / cm 2 ), stirred under hydrogen atmosphere for 24 h. The reaction mixture was then filtered over a celite bed 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.

[0531] 1 H NMR (400MHz, CD3OD) δ6.69 (d, 1H, J = 7.28Hz), 6.63 (t, 1H, J = 6.60Hz), 6.57 (d, 1H,J=7.48Hz),4.29(s,2H),2.47(s,1H),0.69(d,2H,J=5.20Hz),0.46(s,2H);

[0532] MS: m / z 221.2 (M+1).

[0533] 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-dimethylpropanoic acid (mixture of regioisomers)

[0534]

[0535] 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 solvent mixture of dichloromethane:methanol (4:1, 10.0 mL) was stirred at ambient temperature for 16 h. The reaction mass was concentrated to afford 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-dimethylpropanoic acid (1:1 mixture as regioisomers) (0.700 g) as brown gum which was used in the next step without further purification.

[0536] MS: m / z 566.2 (M+1).

[0537] 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

[0538]

[0539] 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-dimethylpropanoic acid (1:1 mixture as regioisomers) (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 h. The reaction was concentrated and the residue was diluted with 10% aqueous sodium bicarbonate solution (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.

[0540] MS: m / z 532.1(M+1).

[0541] 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

[0542]

[0543] 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 afford (0.350 g) of a dark brown gum. Purification by preparative HPLC gave 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.

[0544] 1 H NMR (400MHz, AcOH-d4) δ7.84(t,2H,J=8.08Hz),7.68(d,1H,J=7.80Hz),7.61(t,1H,J=7.64Hz),7.35(d,1H,J=8.00Hz),7.21-7.15(m,2H),4.52(d, 2H,J=15.44Hz),4.31(d,1H,J=11.96Hz),4.09(d,1H,J=12.00Hz),2.41( d,1H,J=3.28Hz),1.88(s,3H),0.72(t,2H,J=1.72Hz),0.53-0.50(m,2H);

[0545] MS: m / z 448.1(M+1).

[0546] The above product was separated 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 isopropanol; injection volume: 12.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 7a and 7b were obtained.

[0547] Example 7a: (-)-1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea

[0548] The (-) enantiomer elutes from the column first.

[0549] 1 H NMR (400MHz, AcOH-d4) δ7.81 (s, 1H), 7.82 (d, 1H, J = 8.00Hz), 7.67 (d, 1H, J = 7. 60Hz),7.60(t,1H,J=8.00Hz),7.33(d,1H,J=8.00Hz),7.21-7.13(m,2H),4.5 1(t,2H,J=16.80Hz),4.29(d,1H,J=12.00Hz),4.08(d,1H,J=12.00Hz),2.41( t,1H,J=3.20Hz),1.87(s,3H),0.71(q,2H,J=4.80Hz),0.51(q,2H,J=7.20Hz);

[0550] MS: m / z 448.2 (M+1);

[0551] [α] D 22.5 (-)16.80 (MeOH, c=1.0).

[0552] Example 7b: (+)-1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea

[0553] The (+) enantiomer eluted second on the column.

[0554] 1H NMR (400MHz, AcOH-d4) δ7.86 (s, 1H), 7.82 (d, 1H, J = 7.60Hz), 7.67 (d, 1H, J = 7. 60Hz),7.60(t,1H,J=7.60Hz),7.32(d,1H,J=8.00Hz),7.21-7.13(m,2H),4.5 1(d,2H,J=1.60Hz),4.29(d,1H,J=12.00Hz),4.08(d,1H,J=12.00Hz),2.41(q ,1H,J=3.60Hz),1.87(s,3H),0.72(q,2H,J=2.00Hz),0.52(t,2H,J=2.40Hz);

[0555] MS: m / z 448.2 (M+1);

[0556] [α] D 22.5 (+) 15.47 (MeOH, c = 1.0).

[0557] 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

[0558]

[0559] Example 8, Step 1: Preparation of N-(Benzo[c][1,2,5]thiadiazol-4-ylmethyl)azetidine-1-carboxamide

[0560]

[0561] To a solution of benzo[c][1,2,5]thiadiazol-4-ylmethylamine (from Example 1, Step 11, free base) (50.00 g, 303.00 mmol) in anhydrous dichloromethane (850 mL) was added triethylamine (127.00 mL, d = 0.726 g / cm 2 , 908.00mmol), and then stirred for 15min. 4-Nitrophenyl chloroformate (90.00g, 272.00mmol) was added, and the reaction was stirred at the same temperature for 2h. The complete consumption of the starting material and the formation of a new non-polar intermediate point were confirmed by TLC. Azetidine hydrochloride (28.00g, 300.00mmol) was then added, followed by triethylamine (38.00mL, d = 0.726g / cm 2, 272.00mmol) and then stirred the reaction at ambient temperature for 16h. The reaction mixture was diluted with aqueous sodium hydroxide (300mL) and extracted with dichloromethane (5×1000mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to give a yellow solid (68.00g). Purification was performed by chromatography on a Grace instrument using 330.0g of a pre-packed flash column filled with normal phase silica gel (60°A, 40-63μm) and eluting the product with 10% ethyl acetate in petroleum ether to give a yellow solid. The solid was washed with 15% ethyl acetate in petroleum ether (3×300mL) (to remove the by-product 4-nitrophenol), stirred for 30 minutes, filtered and dried in vacuo to give N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)azetidine-1-carboxamide (15.0gm) as an off-white solid.

[0562] 1 H NMR(400MHz, DMSO-d6:D2O)δ7.94(d,1H,J=6.80Hz),7.70(t,1H,J=7.60Hz),7.48(d ,1H,J=7.20Hz),4.68(d,2H,J=5.20Hz),3.87(t,4H,J=7.60Hz),2.20-2.13(m,2H);

[0563] MS: m / z 249.0 (M+1).

[0564] Example 8, Step 2: Preparation of N-(2,3-diaminobenzyl)azetidine-1-carboxamide

[0565]

[0566] 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 anhydrous methanol (1200 mL) was added Raney nickel (30.0 g, 200% w / w, pre-washed five times with anhydrous methanol) and the resulting reaction mixture was heated at ambient temperature under balloon pressure (approximately 1.5 kg / cm 2 ), stirred under hydrogen atmosphere for 48 h. The reaction mixture was filtered through a celite bed 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.

[0567] 1H NMR(400MHz, DMSO-d6:D2O)δ6.46(d,1H,J=7.24Hz),6.38(d,1H,J=6.84Hz),6.34(t ,1H,J=7.40Hz),4.02(d,2H,J=4.52Hz),3.77(t,4H,J=7.40Hz),2.14-2.07(m,2H);

[0568] MS: m / z 221.1 (M+1).

[0569] 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)

[0570]

[0571] To a solution of N-(2,3-diaminobenzyl)azetidine-1-carboxamide (from Example 8, Step 2) (0.500 g, 2.00 mmol) in dichloromethane / methanol (4:1; 40 mL) solvent mixture 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 obtain a brown gum (1.300 g). Purification by chromatography on a Grace instrument using a 40.0 g prepacked flash column packed with normal phase silica gel (60°A, 40-63 μm) and eluting 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 (1:1 mixture as regioisomers) (0.200 g) as a yellow solid.

[0572] MS: m / z 566.3 (M+1).

[0573] 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

[0574]

[0575] 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 (1:1 mixture as regioisomers) (from Example 8, Step 3) (0.900 g, 0.999 mmol) in anhydrous methanol (30 mL) was added iodoacetic acid (0.372 g, 2.00 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 70° C. for 1 h. The reaction mass was concentrated to remove the methanol solvent and the residue was washed 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). Purification by chromatography on a Grace instrument using 24.0 g pre-packed flash column packed with normal phase silica gel (60°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.

[0576] 1 H NMR(400MHz,AcOH-d4)δ7.92(s,1H),7.89(d,1H,J=7.72Hz),7.72(d,1H,J=7.48Hz ),7.64(t,1H,J=7.68Hz),7.31(d,1H,J=7.80Hz),7.17(t,1H,J=7.84Hz),7.10(d, 1H, J=7.32Hz), 4.65 (d, 1H, J=11.52Hz), 4.57 (d, 1H, J=11.52Hz), 4.40 (q, 2H, J=15 .04Hz), 3.96 (t, 4H, J = 7.28Hz), 2.25 (q, 2H, J = 7.44Hz), 2.05 (s, 3H), 1.16 (s, 9H);

[0577] MS: m / z 532.3 (M+1).

[0578] 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

[0579]

[0580] 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 was added sodium hydroxide pellets (0.756 g, 19.00 mmol) and the mixture was stirred at ambient temperature for 3 h. The reaction mass was concentrated to remove the solvent methanol and the residue was dissolved with 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). Purification was performed by chromatography on a Grace instrument using a 24.0 g pre-packed flash column packed with normal phase silica gel (60°A, 40-63 μm) and eluting the product at 8% methanol in chloroform to afford 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.

[0581] 1 H NMR (400MHz, CD3OD) δ7.82 (s, 1H), 7.79 (d, 1H, J = 7.88Hz), 7.69 (d, 1H, J = 7.76Hz), 7.64 (t, 1H, J = 7.56Hz), 7.27 (d, 1H, J = 7. 84Hz), 7.21 (t, 1H, J = 7.88Hz), 7.14 (d, 1H, J = 7.40Hz), 4.35 (s, 2H), 4.01-3.88 (m, 6H), 2.25 (q, 2H, J = 7.44Hz), 1.90 (s, 3H);

[0582] MS: m / z 448.2 (M+1).

[0583] The above product was separated 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 isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 8a and 8b were obtained.

[0584] Example 8a: (-)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide

[0585] The (-) enantiomer elutes from the column first.

[0586] 1 H NMR (400MHz, AcOH-d4) δ7.87 (s, 1H), 7.84 (d, 1H, J = 8.00Hz), 7.68 (d, 1H, J = 7. 60Hz),7.61(t,1H,J=7.60Hz),7.33(d,1H,J=8.00Hz),7.17(t,1H,J=8.00Hz) ,7.11(d,1H,J=7.20Hz),4.45(q,2H,J=15.20Hz),4.33(d,1H,J=12.00Hz),4. 09(d,1H,J=12.00Hz),4.00-3.91(m,4H),2.24(t,2H,J=7.20Hz),1.87(s,3H);

[0587] MS: m / z 448.2 (M+1);

[0588] [α] D 22.0 (-)38.46 (MeOH, c=0.104).

[0589] Example 8b: (+)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide

[0590] The (+) enantiomer is the second to elute from the column.

[0591] 1H NMR (400MHz, AcOH-d4) δ7.87 (s, 1H), 7.84 (d, 1H, J = 8.40Hz), 7.68 (d, 1H, J = 8. 00Hz),7.61(t,1H,J=7.60Hz),7.33(d,1H,J=8.40Hz),7.17(t,1H,J=7.60Hz), 7.11(d,1H,J=7.60Hz,),4.45(q,2H,J=15.20Hz),4.33(d,1H,J=12.40Hz),4. 09(d,1H,J=12.00Hz),4.00-3.93(m,4H),2.24(t,2H,J=7.20Hz),1.87(s,3H);

[0592] MS: m / z 448.2 (M+1);

[0593] [α] D 22.3 (+) 34.62 (MeOH, c = 0.104).

[0594] 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

[0595]

[0596] Example 9, Step 1: Preparation of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2,3-diaminophenyl)methyl]]carbamate

[0597]

[0598] To a stirred solution of tert-butyl N-[(2,1,3-benzothiadiazole-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 five times with anhydrous methanol), and the mixture was hydrogenated at ambient temperature using balloon pressure for 24 h. The above reaction mass was filtered through a diatomaceous earth bed 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.

[0599] 1H NMR (400MHz, DMSO-d6:D2O) δ6.46(d,1H,J=7.20Hz), 6.36(t,1H,J=7.60Hz), 6.25(d,1H,J=7.20Hz), 4.51(s,2H), 1.39(s,18H);

[0600] MS: m / z 238.2 [(M+1)-Boc].

[0601] Example 9, Step 2: Preparation of 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 (mixture of regioisomers)

[0602]

[0603] 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 solvent mixture of acetonitrile:methanol (4:1, 16 mL) was added 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (from Example 1, Step 7) (2.50 g, 7.00 mmol), and the mixture was stirred at ambient temperature for 48 h. The reaction mass was concentrated to afford 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 (3:2 mixture as regioisomers) (4.90 g) as brown gum which was used in the next step without further purification.

[0604] MS: m / z 683.3 (M+1).

[0605] 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

[0606]

[0607] To a solution of 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 (3:2 mixture as regioisomers) (from step 2 of example 9) (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 h. The reaction mass was filtered through a celite bed and washed with methanol (3 x 500 mL). The combined filtrates were concentrated to give a brown liquid (4.70 g), which was purified by gravity column chromatography using 60-120 silica gel and eluting the product with 5-8% ethyl acetate in hexanes 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.

[0608] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.75 (d, 2H, J = 5.20Hz), 7.56 (dd, 2H, J = 7.60, 1.60Hz), 6.98 (d, 1H, J = 8.00Hz), 6.82 (t, 1H,J=7.60Hz),6.59(t,1H,J=7.60Hz),4.75(s,2H),4.57(d,2H,J=7.60Hz),1.82(s,3H),1.39(s,18H),1.02(s,9H);

[0609] MS: m / z 649.3 (M+1).

[0610] Example 9, Step 4: Preparation of 2-{[4-aminomethyl-1H-1,3-benzodiazol-2-yl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate

[0611]

[0612] 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 h. 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 get a brown gum (0.70 g). Purification by preparative HPLC gave 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.

[0613] 1 H NMR(400MHz,AcOH-d4)δ7.87(d,2H,J=8.40Hz),7.73(d,1H,J=8.00Hz),7.65(t,1H,J=8.00Hz),7.44(dd,1H,J =2.00Hz),7.28(d,1H,J=1.60Hz),7.27(s,1H),4.57(s,2H),4.54(t,2H,J=5.20Hz),1.82(s,3H),1.18(s,9H);

[0614] MS: m / z 449.2[(M+1)].

[0615] 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

[0616]

[0617] 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 anhydrous dichloromethane (30 mL) was added triethylamine (7.97 mL, d = 0.724 g / cm 3, 6.00mmol), then ethyl isocyanate (0.154g, 2.00mmol) was added, and the mixture was stirred at ambient temperature for 16h. The reaction mass was concentrated, the residue was diluted with 10% aqueous sodium bicarbonate solution (30mL), and extracted with ethyl acetate (3×100mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown gum (0.915g), 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, which was isolated as a trifluoroacetate salt (0.350g) as a yellow solid.

[0618] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.81 (d, 2H, J = 10.40Hz), 7.73 (d, 1H, J = 7.60Hz), 7.65 (t, 1H, J = 8.00Hz), 7.27 (d, 1H, J = 8.00Hz), 7.18 (t, 1H, J = 7. 60Hz),7.10(d,1H,J=7.20Hz),4.48(q,2H,J=12.00Hz),4.21(s,2H),2.97(q,2H,J=7.20Hz),1.91(s,3H),1.02(s,9H),0.96(t,3H,J=7.20Hz);

[0619] MS: m / z 520.1[(M+1)].

[0620] 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

[0621]

[0622] To a solution of propyl 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 h. The reaction mass was concentrated and the residue was diluted with 10% aqueous sodium bicarbonate solution (15 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown gum (0.320 g). Purification by preparative HPLC gave 3-ethyl-1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazol-4-yl]methyl}urea which was isolated as a trifluoroacetate salt (0.040 g) as a yellow solid.

[0623] 1 H NMR(400MHz,AcOH-d4)δ7.87(s,1H),7.84(d,1H,J=7.60Hz),7.68(d,1H,J=7.6 0Hz),7.61(t,1H,J=8.00Hz),7.30(d,1H,J=7.60Hz),7.19(d,1H,J=7.60Hz),7 .15(t,1H,J=6.40Hz),4.47(q,2H,J=15.20Hz); 4.29(d,1H,J=12.00Hz),4.08( d,1H,J=11.60Hz),3.13(q,2H,J=6.80Hz),1.90(s,3H),1.11(t,3H,J=7.20Hz);

[0624] MS: m / z 436.3[(M+1)].

[0625] 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 separated 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 isopropanol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 40°C to obtain the two enantiomers shown in Steps 5a and 5b.

[0626] 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.

[0627]

[0628] Fraction-1 was eluted first from the SFC column and then concentrated to afford 100% ee of enantiomer 1 (0.120 g) which was isolated as trifluoroacetate salt as a yellow solid.

[0629] 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.

[0630]

[0631] Fraction-2 eluted second from the SFC column and it was concentrated to give enantiomer 2 (0.120 g) with 100% ee, isolated as trifluoroacetate salt as a yellow solid.

[0632] 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

[0633]

[0634] 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 and it was stirred at ambient temperature for 2 h. The reaction mass was concentrated and the residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford (+)-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.

[0635] 1H NMR(400MHz,AcOH-d4)δ7.87(s,1H),7.83(d,1H,J=8.00Hz),7.68(d,1H,J=7.6 0Hz),7.60(t,1H,J=7.60Hz),7.31(d,1H,J=7.20Hz),7.17(t,1H,J=7.60Hz),7 .12(d,1H,J=6.80Hz),4.46(q,2H,J=15.20Hz),4.27(d,1H,J=12.00Hz),4.07( d,1H,J=12.00Hz),3.12(q,2H,J=7.20Hz),1.89(s,3H),1.10(t,3H,J=7.20Hz);

[0636] MS: m / z 436.3 (M+1);

[0637] [α] D 22.5 (+)57.48, (MeOH, c=1.0).

[0638] 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

[0639]

[0640] 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 and it was stirred at ambient temperature for 2 h. The reaction mass was concentrated and the residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford (-)-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.

[0641] 1H NMR(400MHz,AcOH-d4)δ7.87(s,1H),7.83(d,1H,J=8.00Hz),7.68(d,1H,J=7.6 0Hz),7.60(t,1H,J=7.60Hz),7.31(d,1H,J=8.00Hz),7.18(d,1H,J=7.60Hz),7 .13(t,1H,J=6.80Hz),4.46(q,2H,J=15.20Hz),4.27(d,1H,J=12.00Hz),4.07( d,1H,J=12.00Hz),3.12(q,2H,J=7.20Hz),1.89(s,3H),1.11(t,3H,J=7.20Hz);

[0642] MS: m / z 436.3 (M+1);

[0643] [α] D 22.6 (-)59.68 (MeOH, c=1.0).

[0644] 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

[0645]

[0646] Example 10, Step 1: Preparation of 5-ethyl-5-(3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione

[0647]

[0648] To a stirred solution of 1-(3-(trifluoromethyl)phenyl)propan-1-one (commercially available) (45.00 g, 223.00 mmol) in ethanol / water (1:1, 1000 mL) solvent mixture was added ammonium carbonate (107.00 g, 1110.00 mmol) followed by potassium cyanide (17.10 g, 263.00 mmol) and the mixture was stirred at 60 °C for 16 h. The reaction mass was poured into ice-cold water (1500 mL) and stirred for 30 min. 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.

[0649] 1H NMR (400MHz, DMSO-d6:D2O) δ7.78(d,1H,J=7.68Hz),7.75(s,1H),7.68(d,1H,J=7.84Hz),7. 63(t,1H,J=7.76Hz), 2.08(q,1H,J=7.20Hz), 1.90(q,1H,J=7.32Hz), 0.78(t,3H,J=7.24Hz);

[0650] MS: m / z 271.1 (M-1).

[0651] Example 10, Step 2: Preparation of 2-amino-2-(3-(trifluoromethyl)phenyl)butyric acid

[0652]

[0653] 5-Ethyl-5-(3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione (from Example 10, Step 1) (55.00 g, 202.00 mmol) was taken up in 10% aqueous sodium hydroxide solution (350 mL), and the mixture was refluxed for 48 h. The reaction mixture was neutralized with 6.0 N HCl (200 mL) (adjusting 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.

[0654] 1 H NMR(400MHz, DMSO-d6:D2O)δ7.86(s,1H),7.80(d,1H,J=7.60Hz),7.62(d,1H, J=7.60Hz),7.57(t,1H,J=7.60Hz),2.14-2.08(m,2H),0.81(t,3H,J=7.60Hz);

[0655] MS: m / z 248.2 (M+1).

[0656] Example 10, Step 3: Preparation of 2-amino-2-(3-(trifluoromethyl)phenyl)butan-1-ol

[0657]

[0658] To a solution of 2-amino-2-(3-(trifluoromethyl)phenyl)butanoic acid (from Example 10, Step 2) (40.00 g, 162.00 mmol) in anhydrous tetrahydrofuran (1200 mL) was added 2M lithium aluminum hydride in tetrahydrofuran (202.00 mL, 405.00 mmol) at 0°C and the reaction mass was slowly warmed to ambient temperature and stirred for 3 h. The reaction mixture was cooled to 0°C and quenched by the dropwise addition of ethyl acetate (120 mL) and stirred for 30 min. A saturated solution of ammonium chloride (150 mL) was then added dropwise for final quenching and stirred at 0°C for 15 min. The precipitate obtained was separated by filtration and the filtrate was concentrated under reduced pressure to give a yellow gum (40.00 g). It 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.

[0659] 1 H NMR (400MHz, DMSO-d6) δ7.85 (s, 1H), 7.75 (d, 1H, J = 6.00Hz), 7.53 (d, 2H, J = 6.40Hz), 4.76 (t, 1H, J = 5.60Hz), 3.5 4(dd,2H,J=10.20,5.60Hz),1.84(s,2H),1.75(q,1H,J=7.60Hz),1.62(q,1H,J=6.80Hz),0.61(t,3H,J=7.60Hz);

[0660] MS: m / z 234.1 (M+1).

[0661] Example 10, Step 4: Preparation of tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]butan-2-yl}carbamate

[0662]

[0663] To 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 solvent mixture of dichloromethane:1,4-dioxane (4:1, 500 mL) was added di-tert-butyl dicarbonate (13.50 mL, d: 0.950 g / cm 3, 61.90mmol), and the mixture was stirred at ambient temperature for 48h. The reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (4×1000mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow jelly (18.00g). Chromatographic purification was performed by using 220.0g pre-loaded flash columns filled with normal phase silica gel (60°A, 40-63μm) on a Grace instrument, and the product was eluted with a hexane solution of 25-30% ethyl acetate to give tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]butan-2-yl}carbamate (11.50g), which was a colorless jelly.

[0664] 1 H NMR(400MHz, DMSO-d6:D2O)δ7.58(s,1H),7.56(d,2H,J=2.16Hz),7.53(t,1H,J=6.32Hz ), 3.61 (t, 2H, J = 12.40Hz), 1.97 (q, 2H, J = 7.64Hz), 1.46 (s, 9H), 0.61 (t, 3H, J = 7.60Hz);

[0665] MS: m / z 234.2 [(M+1)-Boc].

[0666] Example 10, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate

[0667]

[0668] 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 anhydrous dichloromethane (300 mL) was added triethylamine (31.30 mL, d = 0.726 g / cm2) dropwise at 0°C under nitrogen atmosphere. 3 , 224.00mmol), and then pivaloyl chloride (12.70mL, d = 0.985g / cm 3, 103.00mmol), and then the entire reaction mixture was stirred at ambient temperature for 48h. The reaction mixture was quenched with ice-cold water (100mL) and extracted with dichloromethane (4×500mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a brown gum (15.00g). Chromatographic purification was performed using 120.0g of pre-loaded flash columns filled with normal phase silica gel (60°A, 40-63μm) on a Grace instrument, and the product was eluted with 15-20% ethyl acetate in hexane to give 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (10.00g) as a colorless gum.

[0669] 1 H NMR(400MHz, DMSO-d6:D2O)δ7.61(s,1H),7.59(d,2H,J=7.52Hz),7.58(t,1H,J=7.00Hz),4.38 (q,2H,J=14.40Hz),1.95(q,2H,J=7.28Hz),1.39(s,9H),1.11(s,9H),1.09(t,3H,J=6.08Hz);

[0670] MS: m / z 318.2 [(M+1)-Boc].

[0671] Example 10, Step 6: Preparation of 2-amino-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate hydrochloride

[0672]

[0673] 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 anhydrous dichloromethane (300 mL) was added dropwise 4M HCl in dioxane (15.00 mL, 59.90 mmol) at 0°C under nitrogen atmosphere, and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated and triturated with hexanes (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.

[0674] 1H NMR (400MHz, DMSO-d6:D2O) δ7.74(s,1H),7.68(d,2H,J=13.60Hz),7.56(t,1H,J=8.84Hz),4.56(d ,1H,J=12.08Hz),4.22(d,1H,J=12.12Hz),2.17-1.97(m,2H),1.02(s,9H),0.78(t,3H,J=7.36Hz);

[0675] MS: m / z 318.2 [(M+1)-HCl].

[0676] Example 10, Step 7: Preparation of 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate

[0677]

[0678] 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 anhydrous dichloromethane (300 mL) was added 10% aqueous sodium bicarbonate (300 mL) at 0°C. After 30 minutes, thiophosgene (11.00 mL, d = 1.5 g / cm 3 , 144.00mmol), and stirred at the same temperature for 1h. The reaction mass was extracted with dichloromethane (3×500mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude yellow liquid (9.00g). Chromatographic purification was performed on a Grace instrument using 60.0g of a pre-loaded flash column filled with normal phase silica gel (60°A, 40-63μm), and the product was eluted with 5-10% ethyl acetate in hexane to give 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (6.50g) as a yellow liquid.

[0679] 1 H NMR (400MHz, DMSO-d6) δ7.62 (s, 1H), 7.59 (d, 2H, J = 7.16Hz), 7.56 (t, 1H, J = 7.76Hz), 4.39 (d, 2H, J=4.04Hz), 2.21(q,1H,J=7.20Hz), 2.07(q,1H,J=6.96Hz), 1.16(s,9H), 0.91(t,3H,J=7.12Hz).

[0680] 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)

[0681]

[0682] To a solution of 1-(2,3-diaminobenzyl)-3-methylurea (from Example 1, Step 13) (0.200 g, 10.00 mmol) in a dichloromethane / methanol (4:1, 20 mL) solvent mixture 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 h. The reaction was concentrated to give a brown gum (0.600 g). Purification by chromatography on a Grace instrument using a prepacked flash column packed with normal phase silica gel (60°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 (4:1 mixture as regioisomers) (0.200 g) as a yellow solid.

[0683] MS: m / z 554.3 (M+1).

[0684] 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

[0685]

[0686] 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 (4:1 mixture as regioisomers) (from Example 10, Step 8) (0.550 g, 0.993 mmol) in anhydrous methanol (30 mL) was added iodoacetic acid (0.369 g, 1.99 mmol) under nitrogen atmosphere and refluxed for 1 h. The reaction mass was concentrated to remove the 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 a brown gum (0.550 g). Purification by chromatography on a Grace instrument using 24.0 g pre-packed flash column packed with normal phase silica gel (60°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.

[0687] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.72(s,2H),7.57(d,2H,J=11.32Hz),6.98(s,1H),6.83(d,1H,J=7.44Hz),6.76(t,1H,J=7.32Hz ), 4.66 (t, 2H, J = 7.52Hz), 4.25 (q, 2H, J = 12.88Hz), 2.58 (d, 2H, J = 16.04Hz), 2.22 (s, 3H), 1.00 (s, 9H), 0.77 (t, 3H, J = 4.40Hz);

[0688] MS: m / z 520.1 (M+1).

[0689] 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

[0690]

[0691] 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 was added sodium hydroxide pellets (0.948 g, 24.00 mmol) and the mixture was stirred at ambient temperature for 3 h. The reaction mass was concentrated to remove the solvent methanol and the residue was dissolved with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated to get a brown gum (0.420 g). Purification by chromatography on a Grace instrument using a 24.0 g pre-packed flash column packed with normal phase silica gel (60°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.

[0692] 1 H NMR(400MHz,AcOH-d4)δ7.81(s,1H),7.77(d,1H,J=7.80Hz,1H),7.67(d,1H,J= 7.92Hz),7.60(t,1H,J=7.84Hz),7.28(d,1H,J=7.48Hz),7.16(t,1H,J=7.56Hz ),7.12(d,1H,J=6.24Hz),4.54(q,2H,J=15.36Hz),4.42(d,1H,J=15.28Hz),4. 27(d,1H,J=12.24Hz),2.70(s,3H),2.21-2.05(m,2H),0.90(t,3H,J=8.32Hz);

[0693] MS: m / z 436.2 (M+1).

[0694] The above product was separated 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% diethylamine in isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 40°C; two enantiomers 10a and 10b were obtained.

[0695] Example 10a: (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[0696] The (-) enantiomer elutes from the column first.

[0697] 1 H NMR (400MHz, AcOH-d4) δ7.81 (s, 1H), 7.77 (d, 1H, J = 7.88Hz), 7.67 (d, 1H, J = 7. 88Hz),7.60(t,1H,J=7.76Hz),7.27(d,1H,J=7.60Hz),7.16(t,1H,J=7.60Hz) ,7.12(d,1H,J=7.52Hz),4.54(q,2H,J=15.28Hz),4.42(d,1H,J=15.32Hz),4. 27(d,1H,J=12.24Hz),2.70(s,3H),2.20-2.11(m,2H),0.91(t,3H,J=8.32Hz);

[0698] MS: m / z 436.3 (M+1);

[0699] [α] D 24.6 (-)29.60 (MeOH, c=0.5).

[0700] Example 10b: (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[0701] The (+) enantiomer is the second to elute from the column.

[0702] 1 H NMR (400MHz, AcOH-d4) δ7.81 (s, 1H), 7.77 (d, 1H, J = 8.04Hz), 7.67 (d, 1H, J = 7. 24Hz),7.60(t,1H,J=7.44Hz),7.27(d,1H,J=7.36Hz),7.17(t,1H,J=7.52Hz) ,7.12(d,1H,J=7.52Hz),4.54(q,2H,J=15.64Hz),4.42(d,1H,J=15.32Hz),4. 27(d,1H,J=12.00Hz),2.70(s,3H),2.19-2.11(m,2H),0.91(t,3H,J=8.32Hz);

[0703] MS: m / z 436.1 (M+1);

[0704] [α] D24.6 (+) 24.80 (MeOH, c = 0.5).

[0705] Example 11: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropyl-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea

[0706]

[0707] Example 11, Step 1: Preparation of 5-(3-chlorophenyl)-5-methylimidazolidine-○2,4-dione

[0708]

[0709] To a stirred solution of 1-(3-chlorophenyl)ethan-1-one (commercially available) (120.00 g, 776.00 mmol) in ethanol / water (1:1, 2400 mL) solvent mixture was added ammonium carbonate (448.00 g, 4660.00 mmol) followed by potassium cyanide (45.60 g, 931.00 mmol) and the mixture was stirred at 60 °C for 16 h. The reaction mass was poured into ice-cold water (1500 mL) and stirred for 30 min. 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.

[0710] 1 H NMR (400MHz, DMSO-d6) δ10.87 (bs, 1H), 8.63 (s, 1H), 7.50 (d, 1H, J = 1.60Hz), 7.47 (d,1H,J=4.80Hz),7.45(t,1H,J=2.40Hz),7.42(dd,1H,J=2.40Hz),1.65(s,3H);

[0711] MS: m / z 225.2 (M+1).

[0712] Example 11, Step 2: Preparation of 2-amino-2-(3-chlorophenyl)propionic acid

[0713]

[0714] 5-(3-Chlorophenyl)-5-methylimidazolidine-2,4-dione (from Example 11, step 1) (160.00 g, 712.00 mmol) was added to 10% aqueous sodium hydroxide solution (1200 mL), and the mixture was stirred at 110° C. for 72 h. The reaction mixture was neutralized with 6.0 N HCl (500 mL) (adjusting pH=7), and the solid formed was filtered off 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.

[0715] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.56 (s, 1H), 7.46 (d, 1H, J = 7.60Hz), 7.37 (t, 1H, J = 7.60Hz), 7.35 (d, 1H, J = 7.60Hz), 1.65 (s, 3H);

[0716] MS: m / z 200.1 (M+1).

[0717] Example 11, Step 3: Preparation of 2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)propanoic acid

[0718]

[0719] To a suspension of 2-amino-2-(3-chlorophenyl)propanoic acid (from Example 11, Step 2) (286.00 g, 1430.00 mmol) in a solvent mixture of 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 , 2870.00mmol), and the whole mixture was stirred at ambient temperature for 15 days. The reaction mixture was diluted with water (2000mL) and extracted with ethyl acetate (4×5000mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)propanoic acid (410.00g) as a colorless gum which was used in the next step without further purification.

[0720] 1 H NMR (400MHz, DMSO-d6) δ7.23 (dd, 2H, J = 6.40Hz), 7.16 (t, 2H, J = 6.40Hz), 1.70 (s, 3H), 1.34 (s, 9H);

[0721] MS: m / z 199.9 [(M+1)-Boc].

[0722] Example 11, Step 4: Preparation of tert-butyl N-[2-(3-chlorophenyl)-1-hydroxypropan-2-yl]carbamate

[0723]

[0724] 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 anhydrous tetrahydrofuran (2000 mL) at 0°C was added triethylamine (349.00 mL, d = 0.726 g / cm 3 , 2500.00mmol), then add isobutyl chloroformate (130.00mL, d = 1.053g / cm 3 , 1080mmol), and stirred at the same temperature for 4h. The solid formed was filtered out at 0°C, and the residue was washed with tetrahydrofuran (400mL). The combined filtrate was added to a cooling mixture of water (500mL) of sodium borohydride (221.00g, 5840.00mmol). The reaction mass was slowly warmed to ambient temperature and stirred for 48h. The reaction mass was quenched with ice-cold water (1000mL) and extracted with ethyl acetate (4×5000mL). The combined organic layer was washed with brine (300mL), dried over sodium sulfate, filtered and concentrated to obtain a light yellow liquid (250.00g), which was purified by gravity column chromatography with 60-120 silica gel, and the product was eluted with a petroleum ether solution of 30-35% ethyl acetate to obtain tert-butyl (2-(3-chlorophenyl)-1-hydroxypropyl-2-yl)carbamate (95.00g), which is a colorless liquid.

[0725] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.34(s,1H),7.32(d,1H,J=7.60Hz),7.28(t,1H,J=7 .40Hz),7.25(d,1H,J=7.20Hz),3.57(d,2H,J=6.40Hz),1.52(s,3H),1.34(s,9H);

[0726] MS: m / z 186.1 [(M+1)-Boc].

[0727] Example 11, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate

[0728]

[0729] To 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 added triethylamine (250.00 mL, d = 0.726 g / cm2) dropwise at 0°C under nitrogen atmosphere. 3 , 1780.00mmol), and then pivaloyl chloride (145.50mL, d = 0.985g / cm 3 , 1190.00mmol), and the entire reaction mixture was stirred at ambient temperature for 48h. The reaction mixture was quenched with ice-cold water (1000mL) and extracted with dichloromethane (4×2500mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a brown liquid (200.00g). Chromatographic purification was performed using 330.0g pre-loaded flash columns with 60-120 silica gel on a Grace instrument, 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 (218.00g) as a light yellow liquid.

[0730] 1 H NMR(400MHz, DMSO-d6:D2O)δ7.35(d,1H,J=8.00Hz),7.32(s,1H),7.30(d,1H,J=7.20Hz),7.28(t,1H, J=6.80Hz),4.30(d,1H,J=10.40Hz),4.21(d,1H,J=10.80Hz),1.50(s,3H),1.31(s,9H),1.10(s,9H);

[0731] MS: m / z 271.8 [(M+1)-Boc].

[0732] Example 11, Step 6: Preparation of 2-amino-2 (3-chlorophenyl) propyl 2,2-dimethylpropanoate hydrochloride

[0733]

[0734] To a solution of 2-{[(tert-butoxy)carbonyl]amino}-2(3-chlorophenyl)2,2-dimethylpropanoic acid propyl ester (from Example 11, Step 5) (218.00 g, 589.00 mmol) in anhydrous dichloromethane (1200 mL) was added dropwise 4M HCl in dioxane (442.00 mL, 1770.00 mmol) at 0°C under nitrogen atmosphere, and the reaction mixture was then stirred at ambient temperature for 16 h. The reaction mixture was concentrated under high pressure to give 2-amino-2(3-chlorophenyl)propyl 2,2-dimethylpropanoate hydrochloride (180.00 g) as a light yellow gum, which was used in the next step without further purification.

[0735] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.64 (s, 1H), 7.51-7.47 (m, 3H), 4.44 (d, 1H, J = 11.60Hz), 4.26 (d, 1H, J = 11.60Hz), 1.69 (s, 3H), 1.04 (s, 9H);

[0736] MS: m / z 270.1 [(M+1)-HCl].

[0737] Example 11, Step 7: Preparation of 2-(3-chlorophenyl)-2-isothiocyanate propyl 2,2-dimethylpropionate

[0738]

[0739] 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 anhydrous dichloromethane (900 mL) was added 10% aqueous sodium bicarbonate (900 mL) at 0°C. After 30 minutes, thiophosgene (33.80 mL, d = 1.5 g / cm 3 , 441.00mmol) and stirred at the same temperature for 1h. The reaction mass was extracted with dichloromethane (3×2000mL), the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow liquid (95.00g), which was purified by gravity column chromatography on 60-120 mesh silica gel using 3-5% ethyl acetate in hexane as eluent to give 2-(3-chlorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate (75.00g) as a yellow liquid.

[0740] 1H NMR (400MHz, DMSO-d6) δ7.55 (s, 1H), 7.55-7.45 (m, 3H), 4.45 (dd, 2H, J = 11.20Hz), 1.79 (s, 3H), 1.11 (s, 9H).

[0741] 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)

[0742]

[0743] 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 h. 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 (4:1 mixture as regioisomers) (0.560 g) as a brown gum which was used in the next step without further purification.

[0744] MS: m / z 537.2 (M+1).

[0745] 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

[0746]

[0747] 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 (4:1 mixture as 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 light red gum (0.500 g), which was purified by flash column chromatography on 230-400 silica gel using 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.

[0748] 1 H NMR (400 MHz, DMSO-d 6: D2O)δ7.51(s,1H),7.42(s,3H),7.26(d,1H,J=7.84Hz),7.20(t,1H,J=7.80Hz),7.13(d,1H,J=7.04Hz),4.49( d,1H,J=11.44Hz),4.39(d,1H,J=11.44Hz),4.30(s,2H),3.53(s,3H),2.92(s,3H),1.83(s,3H),1.04(s,9H);

[0749] MS: m / z 502.3 / 504.2 (M+1).

[0750] Example 11: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropyl-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea

[0751]

[0752] 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 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 hydrochloric acid solution (2 mL) and concentrated under reduced pressure at 30 ° C to give a brown gum (0.300 g). Purification by preparative HPLC with 0.1% TFA in acetonitrile:water gave 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.

[0753] 1 H NMR(400MHz,AcOH-d4)δ7.58(s,1H),7.49(d,1H,J=7.32Hz),7.41-7.35(m,3H),7.20-7.12(m,2H),4.48(d ,2H,J=5.88Hz),4.22(d,1H,J=11.92Hz),4.02(d,1H,J=12.00Hz),3.61(s,3H),3.05(s,3H),1.85(s,3H);

[0754] MS: m / z 418.1 / 420.2 (M+1).

[0755] The above product was separated into its two enantiomers by chiral SFC using the following method; column: Lux C4; flow rate: 3.0 mL / min, co-solvent: 30%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 11a and 11b were obtained.

[0756] Example 11a: (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea

[0757] The (-) enantiomer elutes from the column first.

[0758] 1H NMR(400MHz,AcOH-d4)δ7.58(s,1H),7.49(d,1H,J=7.32Hz),7.41-7.35(m,3H),7.20-7.12(m,2H),4.48(d ,2H,J=5.88Hz),4.22(d,1H,J=11.92Hz),4.02(d,1H,J=12.00Hz),3.61(s,3H),3.05(s,3H),1.85(s,3H);

[0759] MS: m / z 418.1 / 420.2 (M+1);

[0760] [α]D 23.2 (-)11.52 (MeOH, c=1.0).

[0761] Example 11b: (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea

[0762] The (+) enantiomer is the second to elute from the column.

[0763] 1 H NMR(400MHz,AcOH-d4)δ7.58(s,1H),7.49(d,1H,J=7.32Hz),7.41-7.35(m,3H),7.20-7.12(m,2H),4.48(d ,2H,J=5.88Hz),4.22(d,1H,J=11.92Hz),4.02(d,1H,J=12.00Hz),3.61(s,3H),3.05(s,3H),1.85(s,3H);

[0764] MS: m / z 418.1 / 420.2 (M+1);

[0765] [α]D 25.9 (+) 11.04 (MeOH, c = 1.0).

[0766] 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

[0767]

[0768] 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

[0769]

[0770] 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 Step 1 to Step 15 of Example 1, [2-(3-chloro-4-fluoro-phenyl)-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.

[0771] 1 H NMR(400MHz,DMSO-d6)δ7.68(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=10.80Hz),4.25(t,2H,J=8.40Hz),3.74(s,3H),1.83(s,3H),1.06(s,9H);

[0772] MS: m / z 490.2 (M+1).

[0773] 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

[0774]

[0775] 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 x 70 mL), and the combined organic layers were washed with water (30 mL), then with 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-benzoimidazol-4-yl]methyl]-3-methyl-urea (0.49 g) as a light yellow solid.

[0776] 1 H NMR(400MHz,DMSO-d6)δ10.62(s,1H),7.69-7.67(m,1H),7.53-7.50(m,1H),7.33(d,1H, J=7.80Hz),7.25(t,1H,J=8.80Hz),7.18(t,1H,J=7.80Hz),7.11(d,1H,J=7.48Hz),6.47 (bs,1H),6.13(d,1H,J=5.40Hz),5.87(d,1H,J=4.56Hz),4.51(d,1H,J=15.24Hz),4.42( d,1H,J=15.24Hz),4.18-4.12(m,1H),4.01(d,1H,J=11.92Hz),2.72(s,3H),1.84(s,3H);

[0777] MS: m / z 406.1 (M+1).

[0778] The above product was separated 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 isopropanol; injection volume: 10.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 12a and 12b were obtained.

[0779] Example 12a: (-)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[0780] The (-) enantiomer elutes from the column first.

[0781] 1 H NMR (400MHz, AcOH-d4) δ7.69-7.67(m,1H),7.54-7.50(m,1H),7.33(d,1H,J=7.84Hz),7.25(t,1H,J=8.80Hz),7.18(t,1H,J=7.84Hz),7.12(d, 1H,J=7.24Hz), 4.51(d,1H,J=15.28Hz), 4.42(d,1H,J=15.32Hz), 4.19(d,1H,J=11.92Hz), 4.01(d,1H,J=11.92Hz), 2.72(s,3H), 1.84(s,3H);

[0782] MS: m / z 406.1 (M+1);

[0783] [α] D 22.5 (-)7.31 (MeOH, c=1.0).

[0784] Example 12b: (+)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[0785] The (+) enantiomer was the second to elute from the column.

[0786] 1 H NMR (400MHz, AcOH-d4) δ7.69-7.67(m,1H),7.54-7.50(m,1H),7.33(d,1H,J=7.88Hz),7.25(t,1H,J=8.80Hz),7.18(t,1H,J=7.84Hz),7.12(d, 1H, J=7.36Hz), 4.51 (d, 1H, J=15.28Hz), 4.42 (d, 1H, J=15.16Hz), 4.19 (d, 1H, J=11.92Hz), 4.01 (d, 1H, J=11.92Hz), 2.72 (s, 3H), 1.84 (s, 3H);

[0787] MS: m / z 406.2 (M+1);

[0788] [α] D 22.5 (+) 6.46 (MeOH, c = 1.0).

[0789] Example 13: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropyl-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea

[0790]

[0791] 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)

[0792]

[0793] To a solution of 3-(2,3-diaminobenzyl)-1,1-dimethylurea (Example 2, Step 2) (9.35 g, 44.90 mmol) in a solvent mixture of dichloromethane:methanol (4:1; 200 mL) was added 2-(3-chlorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate (Example 11, Step 7) (14.00 g, 44.90 mmol) and the mixture was stirred at ambient temperature for 48 h. The reaction mass was concentrated to obtain a brown gum (23.00 g). Purification by chromatography on a Grace instrument using a 120.0 g pre-packed column with 60-120 silica gel eluting the product with 75% ethyl acetate in hexanes gave 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 (4:1 mixture as regioisomers) (17.00 g) as a yellow solid which was used in the next step without further purification.

[0794] MS: m / z 521.2 (M+1).

[0795] 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

[0796]

[0797] 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 (4:1 mixture as regioisomers) (Example 13, Step 1) (17.00 g, 32.70 mmol) in methanol (200 mL) was added iodoacetic acid (6.08 g, 32.70 mmol) under nitrogen atmosphere, and the mixture was stirred at 70° C. for 1 h. The reaction mass was concentrated to remove the 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). This was chromatographed on a Grace instrument using 80.0 g of a pre-packed column filled 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.

[0798] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),7.59(s,1H),7.43(d,1H,J=7.60Hz),7. 35(t,1H,J=7.60Hz),7.28(d,1H,J=7.60Hz),7.25(s,1H),7.05(bs,1H),6.97 b(d,1H,J=7.20Hz),6.79(t,1H,J=7.60Hz),6.73(d,1H,J=7.20Hz),4.52(q,2 H, J=10.80Hz), 4.29 (d, 2H, J=4.80Hz), 2.82 (s, 6H), 1.80 (s, 3H), 1.02 (s, 9H);

[0799] MS: m / z 487.2 (M+1).

[0800] Example 13: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropyl-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea

[0801]

[0802] 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 was added sodium hydroxide pellets (3.70 g, 92.60 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 with water (50 mL) and extracted with ethyl acetate (4 x 300 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to get a brown gum (12.40 g). Purification by chromatography on a Grace instrument using a 80.0 g prepacked column packed with 60-120 silica gel and eluting the product with 8% methanol in chloroform gave 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.

[0803] 1 H NMR (400MHz, AcOH-d4) δ7.59(s,1H),7.50(d,1H,J=7.16Hz),7.38(t,1H,J=7.60Hz),7.33(d,2H,J=8.10Hz),7.18(t,1H,J=7.70H z), 7.11 (d, 1H, J = 7.50Hz), 4.47 (q, 2H, J = 15.04Hz), 4.20 (d, 1H, J = 11.80Hz), 4.00 (d, 1H, J = 11.80Hz), 2.87 (s, 6H), 1.85 (s, 3H);

[0804] MS: m / z 402.2 (M+1).

[0805] The above product was separated into its two enantiomers by chiral SFC using the following method; column: ChiralcelOX-H; flow rate: 3 mL / min, co-solvent: 30%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 2.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 13a and 13b were obtained.

[0806] Example 13a: (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea

[0807] The (-) enantiomer elutes from the column first.

[0808] 1 H NMR(400MHz,AcOH-d4)δ7.57(s,1H),7.47(d,1H,J=7.60Hz),7.36(t,1H,J=7.60Hz),7.32(d,2H,J=7.20Hz),7.15(t,1H,J=8.00H z), 7.09 (d, 1H, J = 7.20Hz), 4.46 (q, 2H, J = 14.80Hz), 4.18 (d, 1H, J = 12.00Hz), 4.00 (d, 1H, J = 12.00Hz), 2.86 (s, 6H), 1.83 (s, 3H);

[0809] MS: m / z 402.2 (M+1);

[0810] [α] D 24.4 (-)11.60 (MeOH, c=1.0).

[0811] Example 13b: (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea

[0812] The (+) enantiomer is the second to elute from the column.

[0813] 1 H NMR (400MHz, AcOH-d4) δ7.57(s,1H),7.47(d,1H,J=7.60Hz),7.36(t,1H,J=7.60Hz),7.31(d,2H,J=7.20Hz),7.15(t,1H,J=8.00H z), 7.09 (d, 1H, J = 6.80Hz), 4.46 (q, 2H, J = 15.20Hz), 4.18 (d, 1H, J = 11.60Hz), 4.00 (d, 1H, J = 11.80Hz), 2.85 (s, 6H), 1.83 (s, 3H);

[0814] MS: m / z 402.2 (M+1);

[0815] [α] D 24.3 (+) 12.60 (MeOH, c = 1.0).

[0816] 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

[0817]

[0818] 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

[0819]

[0820] 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) (1.00 g, 2.00 mmol) in dichloromethane (50 mL) was added triethylamine (0.56 mL, d = 0.726 g / cm 3 , 4.00mmol), and the mixture was cooled to -78°C. 1,1,1-trifluoro-3-isocyanatopropane (0.310g, 2.00mmol) was then added, and the reaction was stirred at the same temperature for 30min. The reaction mixture was diluted with water (50mL) and extracted with dichloromethane (3×150mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to give a brown gum (1.00g). Purification by preparative HPLC gave 2-[3-(trifluoromethyl)phenyl]-2-{[4-({[(3,3,3-trifluoropropyl)carbamoyl]amino}methyl)-1H-1,3-benzodiazol-2-yl]amino}propyl 2,2-dimethylpropanoate (0.650g) as an off-white solid.

[0821] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.79(s,1H),7.73(d,2H,J=7.70Hz),7.64(t,1H,J=8.00Hz),7.27(d,1H,J=7.84Hz),7.18(t,1H,J=7.70Hz),7.10 (d,1H,J=7.52Hz),4.48(q,2H,J=11.40Hz),4.19(d,2H,J=5.04Hz),3.24(dd,2H,J=6.90Hz),2.35(d,2H,J=4.72Hz),1.89(s,3H),1.03(s,9H);

[0822] MS: m / z 588.1 (M+1).

[0823] The above product was separated into its two enantiomers by chiral SFC using the following method; column: ChiralcelOX-H; flow rate: 3.0 mL / min, co-solvent: 20%; co-solvent d name: 0.5% isopropylamine in isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 14-1a and 14-1b were obtained.

[0824] 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

[0825] The (+) enantiomer eluted from the column first (fraction 1).

[0826] MS: M / z 588.1 (M+1);

[0827] [α] D 26.0 (+) 14.00 (MeOH, c = 1.0).

[0828] 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

[0829] The (-) enantiomer was the second to elute from the column (fraction 2).

[0830] MS: M / z 588.1 (M+1);

[0831] [α] D 26.0 (-)14.44 (MeOH, c=1.0).

[0832] 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

[0833]

[0834] 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 h. The reaction mass was concentrated and the residue was diluted with 10% aqueous sodium bicarbonate solution (15 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a brown gum (0.130 g). Purification by chromatography on a Grace instrument using a 12.00 g pre-packed flash column packed with normal phase silica gel (60°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.

[0835] 1 H NMR (400MHz, AcOH-d4) δ7.89 (s, 1H), 7.84 (d, 1H, J = 8.00Hz), 7.69 (d, 1H, J = 7. 80Hz),7.61(t,1H,J=7.90Hz),7.28(d,1H,J=7.52Hz),7.19(t,1H,J=7.60Hz) ,7.15(d,1H,J=7.52Hz),4.47(q,2H,J=15.32Hz),4.29(d,1H,J=12.00Hz),4. 08(d,1H,J=12.00Hz),3.42(d,2H,J=4.40Hz),2.45-2.40(m,2H),1.89(s,3H);

[0836] MS: m / z 504.2 (M+1).

[0837] 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

[0838]

[0839] 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 h. 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). Purification by preparative HPLC 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 (0.140 g) as an off-white solid.

[0840] 1 H NMR (400MHz, AcOH-d4) δ7.88 (s, 1H), 7.84 (d, 1H, J = 7.90Hz), 7.68 (d, 1H, J = 7. 90Hz),7.61(t,1H,J=7.80Hz),7.29(d,1H,J=7.00Hz),7.17(t,1H,J=7.64Hz) ,7.12(d,1H,J=6.72Hz),4.43(q,2H,J=15.40Hz),4.29(d,1H,J=11.92Hz),4. 07(d,1H,J=12.00Hz),3.41(t,2H,J=7.00Hz),2.44-2.36(m,2H),1.89(s,3H);

[0841] MS: m / z 504.2 (M+1);

[0842] [α] D 25.1 (-)12.03 (MeOH, c=1.15).

[0843] 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

[0844]

[0845] 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 h. 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). Purification by preparative HPLC 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 (0.160 g) as an off-white solid.

[0846] 1 H NMR (400MHz, AcOH-d4) δ7.89 (s, 1H), 7.84 (d, 1H, J = 7.80Hz), 7.68 (d, 1H, J = 8. 00Hz),7.61(t,1H,J=7.80Hz),7.29(d,1H,J=7.70Hz),7.18(t,1H,J=7.64Hz) ,7.12(d,1H,J=6.84Hz),4.43(q,2H,J=15.32Hz),4.28(d,1H,J=11.92Hz),4. 07(d,1H,J=12.00Hz),3.41(t,2H,J=7.12Hz),2.43-2.36(m,2H),1.89(s,3H);

[0847] MS: m / z 504.2 (M+1);

[0848] [α] D 25.2 (+) 14.73 (MeOH, c = 1.20).

[0849] Example 15: Preparation of N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide

[0850]

[0851] 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)

[0852]

[0853] 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 h. The reaction mass was concentrated to give a brown gum (1.5 g). Purification by chromatography on a Grace instrument using a 24.0 g prepacked flash column packed with normal phase silica gel (60°A, 40-63 μm) eluting the product with 65% ethyl acetate in hexanes 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 (3:2 mixture as regioisomers) (0.90 g) as a yellow solid which was used in the next step without further purification.

[0854] MS: m / z 533.2 (M+1).

[0855] 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

[0856]

[0857] 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 (3:2 mixture as regioisomers) (from Example 15, step 1) (0.90 g, 1.69 mmol) in anhydrous methanol (20 mL) was added iodoacetic acid (0.799 g, 4.23 mmol) under nitrogen atmosphere and the mixture was stirred at 70° C. for 1 h. The reaction mass was concentrated to remove the 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). Purification by chromatography on a Grace instrument using 24.0 g of a pre-packed flash column filled with normal phase silica gel (60°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.

[0858] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.45 (s, 1H), 7.40 (d, 1H, J = 7.60Hz), 7.34 (t, 1H, J = 7. 80Hz),7.27(d,1H,J=7.70Hz),6.97(d,1H,J=7.32Hz),6.81(t,1H,J=7.50Hz),6.73 (d,1H,J=7.40Hz),4.50(d,2H,J=10.60Hz),4.43(d,2H,J=6.90Hz),4.02(d,2H,J= 4.64Hz), 3.78 (t, 2H, J = 7.12Hz), 2.11 (d, 2H, J = 6.60Hz), 1.81 (s, 3H), 1.02 (s, 9H);

[0859] MS: m / z 499.2 (M+1).

[0860] Example 15: Preparation of N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide

[0861]

[0862] 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 was added sodium hydroxide pellets (0.667 g, 1.67 mmol) and the mixture was stirred at ambient temperature for 3 h. The reaction mass was concentrated to remove the solvent methanol and the residue was dissolved with 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). Purification by chromatography on a Grace instrument using a 24.0 g pre-packed flash column packed with normal phase silica gel (60°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.

[0863] 1 H NMR (400MHz, AcOH-d4) δ7.57 (s, 1H), 7.48 (d, 1H, J = 7.20Hz), 7.39 (d, 1H, J = 8.00Hz), 7.36(d,1H,J=1.20Hz),7.32(t,1H,J=6.00Hz),7.16(t,1H,J=7.60Hz),7.10(d,1H,J= 7.40Hz), 4.52(d,1H,J=15.10Hz), 4.38(d,1H,J=15.12Hz), 4.27(d,1H,J=12.00Hz), 4.02(d,1H,J=12.00Hz), 3.96(d,4H,J=7.04Hz), 2.24(t,2H,J=7.30Hz), 1.85(s,3H);

[0864] MS: m / z 414.2 (M+1).

[0865] The above product was separated into its two enantiomers by chiral SFC using the following method; column: Chiral PakOX-H; flow rate: 3.0 mL / min, co-solvent: 30%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 7.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 15a and 15b were obtained.

[0866] Example 15a: (-)-(N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide

[0867] The (-) enantiomer elutes from the column first.

[0868] 1 H NMR (400MHz, AcOH-d4) δ7.56 (s, 1H), 7.46 (d, 1H, J = 7.20Hz), 7.39 (d, 1H, J = 8.00Hz), 7.36(d,1H,J=1.20Hz),7.32(t,1H,J=6.00Hz),7.14(t,1H,J=7.60Hz),7.08(d,1H,J= 7.20Hz), 4.48 (d, 1H, J = 15.20Hz), 4.37 (d, 1H, J = 15.20Hz), 4.26 (d, 1H, J = 11.20Hz), 4.02(d,1H,J=12.00Hz), 3.96(d,4H,J=7.04Hz), 2.21(t,2H,J=7.30Hz), 1.79(s,3H);

[0869] MS: m / z 414.2 (M+1);

[0870] [α] D 22.2 (-)18.40 (MeOH, c=1.0).

[0871] Example 15b: (+)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide

[0872] The (+) enantiomer is the second to elute from the column.

[0873] 1H NMR (400MHz, AcOH-d4) δ7.56 (s, 1H), 7.46 (d, 1H, J = 7.20Hz), 7.39 (d, 1H, J = 8.00Hz), 7.37(t,1H,J=8.40Hz),7.30(d,1H,J=7.60Hz),7.13(t,1H,J=7.60Hz),7.08(d,1H,J= 7.60Hz), 4.48(d,1H,J=15.20Hz), 4.38(d,1H,J=15.60Hz), 4.27(d,1H,J=12.40Hz), 4.02(d,1H,J=12.40Hz), 3.96(d,4H,J=7.04Hz), 2.22(t,2H,J=7.60Hz), 1.79(s,3H);

[0874] MS: m / z 414.2 (M+1);

[0875] [α] D 22.6 (+) 15.40 (MeOH, c = 1.0).

[0876] 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

[0877]

[0878] 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

[0879]

[0880] Starting with 1-[3-(trifluoromethoxy)phenyl]ethan-1-one instead of 1-[3-(trifluoromethyl)phenyl]ethan-1-one and using the method described in Step 1 to Step 15 of Example 1, 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.

[0881] MS: m / z 522.1 (M+1).

[0882] 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

[0883]

[0884] 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 with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to get a brown gum (0.110 g). Purification by chromatography on a Grace instrument using a 12.0 g pre-packed flash column packed with normal phase silica gel (60°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.

[0885] 1 H NMR (400MHz, CD3OD) δ7.55(d,1H,J=7.60Hz),7.54(s,1H),7.41(s,1H),7.29(t,1H,J=7.20Hz),7.27(d,1H,J=7.80Hz),7.22(t, 1H,J=7.60Hz),7.15(d,1H,J=7.60Hz),4.37(s,2H),4.00(d,1H,J=11.20Hz),3.88(d,1H,J=11.60Hz),2.70(s,3H),1.89(s,3H);

[0886] MS: m / z 438.1 (M+1).

[0887] The above product was separated 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 isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 16a and 16b were obtained.

[0888] Example 16a: (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[0889] The (-) enantiomer elutes from the column first.

[0890] 1 H NMR (400MHz, CD3OD) δ7.54(d,1H,J=7.32Hz),7.53(s,1H),7.41(s,1H),7.29(dd,1H,J=7.20Hz),7.26(d,1H),7.21(t,1H,J =7.40Hz),7.14(d,1H,J=7.40Hz),4.36(s,2H),3.98(d,1H,J=11.44Hz),3.87(d,1H,J=11.40Hz),2.69(s,3H),1.88(s,3H);

[0891] MS: m / z 438.1 (M+1);

[0892] [α] D 20.5 (-)16.67 (MeOH, c=0.60).

[0893] Example 16b: (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[0894] The (+) enantiomer is the second to elute from the column.

[0895] 1 H NMR (400MHz, CD3OD) δ7.55(d,1H,J=7.20Hz),7.53(s,1H),7.40(s,1H),7.29(t,1H,J=7.20Hz),7.27(d,1H,J=8.32Hz),7.16(t, 1H,J=7.64Hz),7.10(d,1H,J=7.32Hz),4.37(s,2H),3.98(d,1H,J=11.50Hz),3.87(d,1H,J=11.32Hz),2.70(s,3H),1.86(s,3H);

[0896] MS: m / z 438.1 (M+1);

[0897] [α] D 21.0(+)17.23, (MeOH, c=0.65).

[0898] 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

[0899]

[0900] Example 17, Step 1: Preparation of 2-chloro-1-fluoro-4-(2-isothiocyanato-1-methoxyprop-2-yl)benzene

[0901]

[0902] 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 Step 1 to Step 4 of Example 1 and Step 1 to Step 3 of Example 3, 2-chloro-1-fluoro-4-(2-isothiocyanato-1-methoxyprop-2-yl)benzene (3.50 g) was obtained as a yellow liquid.

[0903] 1 H NMR (400MHz, DMSO-d6) δ7.68-7.65(m,1H),7.50(d,1H,J=7.50Hz),7.48-7.46(m,1H),3.69(s,2H),3.32(s,3H),1.72(s,3H).

[0904] 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)

[0905]

[0906] 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 h. The reaction mass was concentrated to afford brown gum (0.440 g) which was purified by chromatography on Grace instrument using 24.0 g pre-packed flash column packed with normal phase silica gel (60°A, 40-63 μm) and eluted with 75% ethyl acetate in hexanes to afford 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 (4:1 mixture as regioisomers) (0.350 g) as yellow solid.

[0907] MS: m / z 454.1 (M+1).

[0908] 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

[0909]

[0910] To a solution 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 (4:1 mixture as regioisomers) (from Example 17, step 2) (0.350 g, 7.71 mmol) in anhydrous methanol (30 mL) was added iodoacetic acid (0.143 g, 7.71 mmol) under nitrogen atmosphere and the mixture was stirred at 70° C. for 1 h. The reaction mass was concentrated to remove the 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 a brown gum (0.350 g). Purification was performed by chromatography on a Grace instrument using 24.0 g of a pre-packed flash column filled with normal phase silica gel (60°A, 40-63 μm) and eluting the product with 5% methanol in chloroform to give 1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropyl-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea (0.240 g) as a yellow solid.

[0911] 1 H NMR (400MHz, AcOH-d4) δ7.67 (d, 1H, J = 6.84Hz), 7.53-7.49 (m, 1H), 7.32 (d, 1H, J = 7.72Hz), 7.25 (t, 1H, J = 8.84Hz), 7.18 (t, 1H, J = 7.70Hz), 7.12(d,1H,J=7.12Hz),4.46(q,2H,J=15.32Hz),3.96(d,1H,J=10.00Hz),3.77(d,1H,J=10.00Hz),3.46(s,3H),2.72(s,3H),1.85(s,3H);

[0912] MS: m / z 420.2 (M+1).

[0913] The above product was separated into its two enantiomers by chiral SFC using the following method; column: Lux C4; flow rate: 3.0 mL / min, co-solvent: 40%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 4.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 17a and 17b were obtained.

[0914] Example 17a: (+)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[0915] The (+) enantiomer elutes from the column first.

[0916] 1 H NMR (400MHz, AcOH-d4) δ7.66(d,1H,J=6.52Hz),7.52(t,1H,J=4.40Hz),7.31(d,1H,J=7.80Hz),7.25(t,1H,J=8.80Hz),7.17(t,1H,J=7.60Hz ),7.12(d,1H,J=7.50Hz),4.46(q,2H,J=15.30Hz),3.96(d,1H,J=10.00Hz),3.77(d,1H,J=10.00Hz),3.47(s,3H),2.73(s,3H),1.86(s,3H);

[0917] MS: m / z 420.1 (M+1);

[0918] [α] D 23.8 (+) 13.20 (MeOH, c = 1.0).

[0919] Example 17b: (-)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[0920] The (-) enantiomer is the second to elute from the column.

[0921] 1 H NMR (400MHz, AcOH-d4) δ7.66(d,1H,J=6.60Hz),7.52(t,1H,J=4.60Hz),7.32(d,1H,J=7.72Hz),7.25(t,1H,J=8.80Hz),7.18(t,1H,J=7.60Hz ),7.12(d,1H,J=7.44Hz),4.47(q,2H,J=15.36Hz),3.97(d,1H,J=10.00Hz),3.77(d,1H,J=10.00Hz),3.47(s,3H),2.73(s,3H),1.86(s,3H);

[0922] MS: m / z 420.1 (M+1);

[0923] [α] D 23.8 (-)11.36 (MeOH, c=1.0).

[0924] Example 18: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropyl-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea

[0925]

[0926] 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)

[0927]

[0928] 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 solvent mixture of 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 h. The reaction mass was concentrated to afford a brown gum (2.40 g) which was purified by chromatography on Grace instrument using 40.0 g of pre-packed flash column packed with normal phase silica gel (60°A, 40-63 μm) and eluting the product with 60-65% ethyl acetate in hexanes to afford 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 (4:1 mixture as regioisomers) (2.00 g) as brown solid.

[0929] MS: m / z 535.1 (M+1).

[0930] 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

[0931]

[0932] 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 (4:1 mixture as regioisomers) (from Example 18, Step 1) (2.00 g, 3.74 mmol) in anhydrous methanol (30 mL) was added iodoacetic acid (1.39 g, 7.49 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 70° C. for 1 h. The reaction mass was concentrated to remove the 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.

[0933] MS: m / z 501.2 (M+1).

[0934] Example 18: Preparation of 3-((2-((2-(3-chlorophenyl)-1-hydroxypropyl-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea

[0935]

[0936] 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 step 2 of Example 18) (2.10 g, 4.20 mmol) in methanol (50 mL) solvent was added sodium hydroxide pellets (1.34 g, 3.36 mmol) and the mixture was stirred at ambient temperature for 1.5 h. The reaction mass was concentrated to 5% by volume. The solvent methanol was removed 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-hydroxypropyl-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.

[0937] 1 H NMR(400MHz,AcOH-d4)δ7.59(s,1H),7.49(t,1H,J=7.34Hz),7.40(d,1H,J=8.00H z),7.36(d,1H,J=7.60Hz),7.31(d,1H,=7.20Hz),7.18(t,1H,J=7.60Hz),7.14(d, 1H, J=7.20Hz), 4.50 (q, 2H, J=15.20Hz), 4.22 (d, 1H, J=12.00Hz), 4.03 (d, 1H, J=12 .00Hz), 3.30 (q, 2H, J = 7.20Hz), 2.85 (s, 3H), 1.86 (s, 3H), 1.10 (t, 3H, J = 7.20Hz);

[0938] MS: m / z 416.2 (M+1).

[0939] The above product was separated into its two enantiomers by chiral SFC using the following method; column: Chiral PakOX-H; flow rate: 3.0 mL / min, co-solvent: 30%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 18a and 18b were obtained.

[0940] Example 18a: (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea

[0941] The (-) enantiomer elutes from the column first.

[0942] 1 H NMR (400MHz, AcOH-d4) δ7.58 (s, 1H), 7.48 (t, 1H, J = 7.40Hz), 7.38 (d, 1H, J = 8.00Hz), 7.3 5(d,1H,J=7.40Hz),7.31(d,1H,J=8.40Hz),7.16(t,1H,J=7.60Hz),7.10(d,1H,J=7.20H z),4.52(d,1H,J=14.80Hz),4.44(d,1H,J=14.80Hz),4.20(d,1H,J=12.00Hz),4.00(d,1 H,J=12.00Hz),3.29(q,2H,J=7.20Hz),2.84(s,3H),1.84(s,3H),1.08(t,3H,J=7.20Hz);

[0943] MS: m / z 416.2 (M+1);

[0944] [α] D 25.5 (-)30.88 (MeOH, c=1.0).

[0945] Example 18b: (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea

[0946] The (+) enantiomer is the second to elute from the column.

[0947] 1 H NMR (400MHz, AcOH-d4) δ7.59 (s, 1H), 7.49 (t, 1H, J = 7.60Hz), 7.39 (d, 1H, J = 8.00Hz), 7.3 6(d,1H,J=7.30Hz),7.34(d,1H,J=7.60Hz),7.16(t,1H,J=8.00Hz),7.11(d,1H,J=7.20H z),4.53(d,1H,J=14.80Hz),4.43(d,1H,J=15.20Hz),4.20(d,1H,J=12.00Hz),4.00(d,1 H, J=12.00Hz), 3.30 (q, 2H, J=7.20Hz), 2.85 (s, 3H), 1.86 (s, 3H), 1.09 (t, 3H, J=7.20Hz);

[0948] MS: m / z 416.2 (M+1);

[0949] [α]D 25.6 (+) 22.92 (MeOH, c = 1.0).

[0950] Example 19: Preparation of N-[[2-[[1-(3-chlorophenyl)-2-hydroxy-1-methyl-ethyl]amino]-3H-benzimidazol-4-yl]methyl]isoxazolidine-2-carboxamide

[0951]

[0952] 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)

[0953]

[0954] 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 methanol:dichloromethane (1:4; 5.00 ml) solvent mixture 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 h. The reaction mass was concentrated to remove methanol and the crude product was purified by chromatography on Grace instrument using 24.0 g pre-packed flash column packed with normal phase silica gel (60°A, 40-63 μm) and eluted with 40-45% ethyl acetate in hexanes to afford 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 mixture of regioisomers) (1.30 g) as brown solid.

[0955] MS: m / z 649.3 (M+1).

[0956] 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

[0957]

[0958] 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 h. The reaction mass was concentrated to remove methanol and the residue was diluted with dichloromethane (100 mL) and washed with 10% aqueous sodium bicarbonate solution (2 x 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). Purification by chromatography on a Grace instrument using 40.0 g of a pre-packed flash column filled with normal phase silica gel (60°A, 40-63 μm) and eluting the product with 50-55% ethyl acetate in hexanes 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.

[0959] MS: m / z 615.2 (M+1).

[0960] 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

[0961]

[0962] 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 step 2 of Example 19) (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 h. 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.

[0963] MS: m / z 415.1 (M+1).

[0964] 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

[0965]

[0966] To 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 added triethylamine (1.05 mL, d = 0.724 gm / cm 3 , 7.52mmol), and the mixture was stirred at ambient temperature for 1h. Carbonyldiimidazole (0.610g, 0.376mmol) was then added in portions at 0°C, and the reaction mixture was stirred at ambient temperature for 16h. The reaction mixture was quenched with water (30mL) and extracted with ethyl acetate (2×100mL). 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 (0.70g) as a brown gum which was used in the next step without further purification.

[0967] MS: m / z 509.2 (M+1).

[0968] 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

[0969]

[0970] 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 step 4 of Example 19) (1.0 g, 1.97 mmol) in anhydrous 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 h. The reaction mixture was 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.

[0971] MS: m / z 514 (M+1).

[0972] Example 19: Preparation of N-[[2-[[1-(3-chlorophenyl)-2-hydroxy-1-methyl-ethyl]amino]-3H-benzimidazol-4-yl]methyl]isoxazolidine-2-carboxamide

[0973]

[0974] 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 Step 5 of Example 19) (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 h. The reaction mixture was concentrated to remove methanol and the residue was diluted with dichloromethane (200 mL) and washed with water (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a brown gum (0.580 g). Purification by preparative HPLC (ammonium acetate method) gave N-[[2-[[1-(3-chlorophenyl)-2-hydroxy-1-methyl-ethyl]amino]-3H-benzoimidazol-4-yl]methyl]isoxazolidine-2-carboxamide (0.450 g) as an off-white solid.

[0975] 1 H NMR (400MHz, AcOH-d4) δ7.59(s,1H),7.50(d,1H,J=7.08Hz),7.40(d,1H,J=4.30Hz),7.36(d,1H,J=8.92Hz),7.34(t,1H,J=2.12Hz),7.18(t,1H J=7.52Hz),7.14(d,1H,J=1.00Hz),4.48(d,2H,J=4.32Hz),4.24(d,1H,J=11.96Hz),4.02(d,1H J=11.96Hz),3.85(t,2H,J=7.40Hz),3.60-3.56(m,2H),2.24-2.16(m,2H),1.84(s,3H);

[0976] MS: m / z 430.2 (M+1).

[0977] The above product was separated 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 isopropanol; injection volume: 7.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 19a and 19b were obtained.

[0978] Example 19a: (-)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-7-yl)methyl)isoxazolidine-2-carboxamide

[0979] The (-) enantiomer elutes from the column first.

[0980] 1 H NMR (400MHz, AcOH-d4) δ7.59 (s, 1H), 7.50 (d, 1H, J = 7.08Hz), 7.40 (d, 1H, J = 4.30Hz) ,7.37(t,1H,J=8.92Hz),7.34(d,1H,J=4.20Hz),7.19(t,1H,J=7.52Hz),7.14(d,1H ,J=7.56Hz),4.47(d,2H,J=4.32Hz),4.24(d,1H,J=11.96Hz),4.02(d,1H,J=11.92H z),3.85(t,2H,J=7.04Hz),3.56-3.60(m,2H),2.20(t,2H,J=7.28Hz),1.84(s,3H);

[0981] MS: m / z 430.2 (M+1);

[0982] [α] D 22.2 (-)14.40 (MeOH, c=1.0).

[0983] Example 19b: (+)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-7-yl)methyl)isoxazolidine-2-carboxamide

[0984] The (+) enantiomer is the second to elute from the column.

[0985] 1 H NMR (400MHz, AcOH-d4) δ7.59 (d, 1H, J = 1.00Hz), 7.50 (t, 1H, J = 5.40Hz), 7.39 (s, 1H) ,7.37(d,1H,J=1.44Hz),7.34(d,1H,J=4.60Hz),7.19(d,1H,J=7.64Hz),7.15(t,1H ,J=7.72Hz),4.47(d,2H,J=4.32Hz),4.24(d,1H,J=11.92Hz),4.02(d,1H,J=11.92H z),3.85(t,2H,J=7.04Hz),3.56-3.60(m,2H),2.20(t,2H,J=7.36Hz),1.84(s,3H);

[0986] MS: m / z 430.2 (M+1);

[0987] [α] D 22.3(+) 17.0 (MeOH, c = 1.0).

[0988] 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

[0989]

[0990] Example 20, Step 1: Preparation of (E)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfenamide

[0991]

[0992] To a solution of 1-(3-(trifluoromethyl)phenyl)ethan-1-one (commercially available) (125.00 g, 664.00 mmol) in anhydrous tetrahydrofuran (1500 mL) was added 2-methylpropane-2-sulfenamide (80.52 g, 664.00 mmol) and then ethyl titanate (IV) (278.60 mL, d = 1.008 gm / mL, 1328.00 mmol) under nitrogen atmosphere and the mixture was heated to 70°C for 17 h. The reaction mass was diluted with brine solution (200 mL), filtered and the filtrate was evaporated to give a light yellow gum (200.00 g). Purification by gravity column chromatography using silica gel (60-120 mesh) and eluting the product with 10% ethyl acetate in hexanes gave (E)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfenamide (150.00 g) as a light yellow gum.

[0993] 1 H NMR (400MHz, CD3OD) δ8.25 (s, 1H), 8.23 ​​(d, 1H, J = 7.60Hz), 7.88 (d, 1H, J = 7.60Hz), 7.72 (t, 1H, J = 8.00Hz), 2.84 (s, 3H), 1.35 (s, 9H);

[0994] MS: m / z 292.3 (M+1).

[0995] Example 20, Step 2: Preparation of methyl 3-[(2-methylpropane-2-sulfinyl)amino]-3-[3-(trifluoromethyl)phenyl]butanoate

[0996]

[0997] To a suspension of zinc powder (269.30 g, 4.120 gm atoms) in anhydrous tetrahydrofuran (750 mL) was added copper (I) chloride (51.00, 515.00 mmol), and the mixture was stirred at 60° C. After 30 min, a solution of methyl 2-bromoacetate (122.00 mL, d=1.616 gm / mL, 1287.00 mmol) in anhydrous tetrahydrofuran (500 mL) was added dropwise, followed by stirring at the same temperature for 30 min. A solution of (E)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfenamide (from Example 20, Step 1) (150.00 g, 515.00 mmol) in anhydrous tetrahydrofuran (500 mL) was added dropwise at 0 to 5° C., and stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL), the solid formed was filtered out, and the filtrate was extracted with ethyl acetate (3 × 1000 mL). The organic extracts combined were dried over anhydrous sodium sulfate, filtered and evaporated to give a light brown jelly (250.00 g). Purified by gravity column chromatography on 60-120 silica gel, eluted with 70-75% ethyl acetate in hexane to give 3-[(2-methylpropane-2-sulfinyl)amino]-3-[3-(trifluoromethyl)phenyl]butyric acid methyl ester (135.00 g), which was a light yellow jelly.

[0998] 1 H NMR(400MHz,AcOH-d4)δ7.81(d,1H,J=7.6Hz),7.74(d,1H,J=8.00Hz),7.62(d,1H,J=7.60H z),7.56(t,1H,J=8.00Hz),3.62(s,3H),3.20(q,2H,J=16.40Hz),1.87(s,3H),1.35(s,9H);

[0999] MS: m / z 366.2 (M+1).

[1000] Example 20, Step 3: Preparation of methyl 3-amino-3-(3-(trifluoromethyl)phenyl)butyrate hydrochloride

[1001]

[1002] To a solution of methyl 3-[(2-methylpropane-2-sulfinyl)amino]-3-[3-(trifluoromethyl)phenyl]butanoate (from step 2 of Example 20) (135.00 g, 369.00 mmol) was added 4M 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 light brown gum which was used in the next step without further purification.

[1003] 1 H NMR (400MHz, AcOH-d4) δ7.94(s,1H),7.91(d,J=8.80Hz,1H),7.74(d,J=7.60Hz,1H),7.70(t,J=7.60Hz,1H),3.69(s,3H),3.48(s,2H),2.02(s,3H);

[1004] MS: m / z 262.2 [(M+1)-HCl].

[1005] Example 20, Step 4: Preparation of methyl 3-isothiocyanato-3-(3-(trifluoromethyl)phenyl)butyrate

[1006]

[1007] 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 anhydrous 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 , 75.00mmol) and stirred at the same temperature for 1h. The reaction mass was extracted with dichloromethane (3×250mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow liquid (30.00g). Purification was performed by chromatography on a Grace instrument using 80.00g of a pre-loaded flash column filled with normal phase silica gel (60°A, 40-63μm), eluting the product with 3-5% methanol in chloroform to give methyl 3-isothiocyanato-3-(3-(trifluoromethyl)phenyl)butanoate (15.00g) as a yellow liquid.

[1008] 1H NMR (400MHz, DMSO-d6) δ7.83 (s, 1H), 7.81 (d, J = 7.20Hz, 1H), 7.72 (d, J = 8.00Hz, 1H),7.66(t,J=7.60Hz,1H),3.53(s,3H),3.30(d,J=13.60Hz,2H),1.86(s,3H);

[1009] MS: m / z 304.1 (M+1).

[1010] 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 (Regioisomer Mixture)

[1011]

[1012] To a solution of 1-(2,3-diaminobenzyl)-3-methylurea (from Example 1, Step 13) (0.800 g, 4.00 mmol) in a solvent mixture of 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 h. The reaction mass was concentrated to afford a yellow gum (2.05 g) which was purified by chromatography on Grace instrument using 40.00 g of pre-packed flash column packed with normal phase silica gel (60°A, 40-63 μm) and eluting the product with 40-45% ethyl acetate in hexane to afford 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 7:3 mixture of regioisomers) (1.70 g) as brown gum.

[1013] MS: m / z 498.2 (M+1).

[1014] 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

[1015]

[1016] 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 celite bed and washed with methanol (3×250 mL). The combined filtrate was concentrated to obtain a brown liquid (1.91 g). Purification by chromatography on a Grace instrument using 80.00 g of a prepacked flash column packed with normal phase silica gel (60°A, 40-63 μm) and eluting the product with 2-4% methanol in chloroform gave 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.

[1017] 1 H NMR(400MHz, DMSO-d6:D2O)δ7.92(s,1H),7.82(d,1H,J=7.20Hz),7.63(d,2H,J=7.60Hz),7.60(t,1H,J=7.20Hz),7.05(d,1H, J=6.80Hz),6.96(t,1H,J=8.00Hz),4.41(s,2H),3.58(d,1H,J=16.40Hz),3.37(d,1H,J=12.40Hz),2.54(s,3H),1.91(s,3H);

[1018] MS: m / z 432.2 (M+1).

[1019] 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

[1020]

[1021] 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 anhydrous tetrahydrofuran at 0°C under nitrogen atmosphere was added sodium borohydride (0.395 g, 10.00 mmol), which was then stirred at 50°C for 12 h. The reaction mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (50 mL) and extracted with ethyl acetate (4 x 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). Purification by preparative HPLC gave 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.

[1022] 1 H NMR (400MHz, AcOH-d4) δ7.88(s,1H),7.85(d,1H,J=7.60Hz),7.68(d,1H,J=7.56Hz),7.61(t,1H,J=7.76Hz),7.28(d,1H,J=7.96H z),7.17(t,1H,J=8.00Hz),7.11(d,1H,J=7.44Hz),4.42(s,2H),3.88-3.78(m,2H),2.69(s,3H),2.48-2.41(m,2H),2.03(s,3H);

[1023] MS: m / z 436.2 (M+1).

[1024] The above product was separated into its two enantiomers by chiral SFC using the following method; column: Chiral PakOX-H; flow rate: 3.0 mL / min, co-solvent: 30%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 40°C; two enantiomers 20a and 20b were obtained.

[1025] Example 20a: (-)-1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[1026] The (-) enantiomer elutes from the column first.

[1027] 1H NMR (400MHz, AcOH-d4) δ7.89 (s, 1H), 7.86 (d, 1H, J = 7.60Hz), 7.68 (d, 1H, J = 8.00Hz), 7.62 (t, 1H, J = 7.60Hz), 7.30 (d, 1H, J = 8.00H z),7.18(t,1H,J=7.60Hz),7.11(d,1H,J=7.20Hz),4.42(s,2H),3.88-3.79(m,2H),2.70(s,3H),2.51-2.40(m,2H),2.03(s,3H);

[1028] MS: m / z 436.2 (M+1);

[1029] [α] D 22.4 (-)26.40 (MeOH, c=0.1).

[1030] Example 20b: (+)-1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea

[1031] The (+) enantiomer is the second to elute from the column.

[1032] 1 H NMR (400MHz, AcOH-d4) δ7.89 (s, 1H), 7.86 (d, 1H, J = 8.00Hz), 7.68 (d, 1H, J = 8.00Hz), 7.62 (t, 1H, J = 7.60Hz), 7.31 (d, 1H, J = 8.00H z),7.17(t,1H,J=8.00Hz),7.10(d,1H,J=7.60Hz),4.41(s,2H),3.88-3.79(m,2H),2.70(s,3H),2.51-2.40(m,2H),2.02(s,3H);

[1033] MS: m / z 436.2 (M+1);

[1034] [α] D 22.0 (+) 24.00 (MeOH, c = 0.1).

[1035] 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

[1036]

[1037] Example 21, Step 1: Preparation of N-(Benzo[c][1,2,5]thiadiazol-4-ylmethyl)morpholine-4-carboxamide

[1038]

[1039] To a stirred solution of 2,1,3-benzothiadiazol-4-ylmethylamine; hydrochloride (from Example 1, Step 11) (13.00 g, 64.50 mmol) in dichloromethane (500 mL) was added triethylamine (27.00 mL, d: 0.726 g / cm 3 , 193.00mmol), then add morpholine-4-carbonyl chloride (9.05mL, d=1.282g / mL, 77.40mmol) dropwise, and stir the reaction mixture at ambient temperature for 2h. The reaction mixture is quenched with ice-cold water (100mL), and the aqueous layer is extracted with dichloromethane (4×750mL). The combined organic layer is washed with brine (50mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid (18.00g). The solid is ground with n-hexane (300mL), the supernatant is discarded, and the solid is dried to give N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)morpholine-4-carboxamide (14.5g), which is an off-white solid that can be used in the next step without further purification.

[1040] 1 H NMR(400MHz, DMSO-d6:D2O)δ7.95(d,1H,J=8.76Hz),7.70(t,1H,J=8.72Hz),7.4 7(d,1H,J=6.72Hz), 4.75(s,2H), 3.58(t,4H,J=4.92Hz), 3.34(t,4H,J=4.60Hz);

[1041] MS: m / z 279.1 (M+1).

[1042] Example 21, Step 2: Preparation of N-(2,3-diaminobenzyl)morpholine-4-carboxamide.

[1043]

[1044] 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 anhydrous methanol (1000 mL) was added Raney nickel (22.00 g, 200% w / w, pre-washed five times with anhydrous methanol) and the resulting reaction mixture was heated under balloon pressure (about 1.5 kg / cm2 ) and stirred under hydrogen atmosphere at ambient temperature for 48 h. The reaction mixture was filtered through a celite bed and the bed was washed with methanol (3×2000 mL). The combined filtrates were 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.

[1045] 1 H NMR (400MHz, DMSO-d6) δ6.94(t,1H,J=5.20Hz),6.47(d,1H,J=7.20Hz),6.39(t,1H,J=12.00Hz),6.33(d,1H, J=7.20Hz),4.60(s,2H),4.42(s,2H),4.11(d,2H,J=5.20Hz),3.54(t,4H,J=4.00Hz),3.31(t,4H,J=4.40Hz);

[1046] MS: m / z 251.2 (M+1).

[1047] 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)

[1048]

[1049] To a solution of N-(2,3-diaminobenzyl)morpholine-4-carboxamide (from Example 21, Step 2) (0.22 g, 0.87 mmol) in a solvent mixture of 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 h. The reaction mass was concentrated to obtain a brown gum (0.53 g). Purification by chromatography on a Grace apparatus using a 24.0 g prepacked flash column packed with normal phase silica gel (60°A, 40-63 μm) and eluting the product with 60-70% ethyl acetate in hexanes 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 (1:1 mixture as regioisomers) (0.25 g) as a brown gum.

[1050] MS: m / z 596.2 (M+1).

[1051] 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

[1052]

[1053] 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 (1:1 mixture as regioisomers) (from Example 21, step 3) (1.60 g, 2.69 mmol) in anhydrous methanol (20 mL) was added iodoacetic acid (0.50 g, 2.69 mmol) under nitrogen atmosphere and the reaction 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), then with 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.

[1054] 1 H NMR (400MHz, DMSO-d6:D2O) δ7.87 (d, 2H, J = 12.80Hz), 7.72 (d, 1H, J = 8.00Hz), 7.66 (t,1H,J=7.60Hz),7.29(d,1H,J=8.00Hz),7.20(t,1H,J=7.60Hz),7.13(d,1H,J=7 .60Hz), 4.70(d,1H,J=11.60Hz), 4.57(d,1H,J=11.60Hz), 4.36(d,2H,J=6.40Hz), 3.65(s,2H),3.64-3.62(m,4H),3.36(d,2H,J=5.20Hz),1.98(s,3H),1.16(s,9H);

[1055] MS: m / z 562.2 (M+1).

[1056] 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

[1057]

[1058] 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 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), then brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a brown gum (0.650 g). Purification by preparative HPLC gave N-((2-((l-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-lH-benzo[d]imidazol-4-yl)methyl)morpholine-4-carboxamide (0.450 g) as an off-white solid.

[1059] 1 H NMR(400MHz,AcOH-d4)δ7.88(s,1H),7.85(d,1H,J=8.00Hz),7.68(d,1H,J=7.6 0Hz),7.61(d,1H,J=7.60Hz),7.34(d,1H,J=8.00Hz),7.17(t,1H,J=8.00Hz),7 .11(d,1H,J=7.60Hz),4.45(q,2H,J=14.80Hz),4.23(d,1H,J=12.00Hz),4.06( d,1H,J=11.60Hz),3.69(t,4H,J=4.80Hz),3.35(t,4H,J=3.60Hz),1.90(s,3H);

[1060] MS: m / z 478.2 (M+1).

[1061] The above product was separated into its two enantiomers by chiral SFC using the following method; column: ChiralcelOX-H; flow rate: 3.0 mL / min; co-solvent: 30%; co-solvent name: 0.5% isopropylamine in isopropanol; injection volume: 15.0 μL; outlet pressure: 100 bar; temperature: 35°C; two enantiomers 21a and 21b were obtained.

[1062] Example 21a: (+)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)morpholine-4-carboxamide

[1063] The (+) enantiomer elutes from the column first.

[1064] 1 H NMR (400MHz, CD3OD): δ7.78(d,2H,J=12.80Hz),7.58-7.52(m,2H),7.11(d,1H,J=7.60Hz),6.96-6.88(m,2H),4.47(s ,2H),3.99(d,1H,J=11.60Hz),3.85(d,1H,J=11.20Hz),3.64(t,4H,J=5.20Hz),3.36(t,4H,J=5.20Hz),1.78(s,3H);

[1065] MS: m / z 478.2 (M+1);

[1066] [α] D 22.5 (+) 19.8 (MeOH, c = 1.0).

[1067] Example 21b: (-)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)morpholine-4-carboxamide

[1068] The (-) enantiomer is the second to elute from the column.

[1069] 1 H NMR (400MHz, CD3OD): δ7.78(t,2H,J=7.20Hz), 7.55(t,2H,J=7.20Hz), 7.11(d,1H,J=7.60Hz), 6.94(t,1H,J=8.00Hz), 6.89(d,1H,J= 7.20Hz), 4.47 (s, 2H), 3.99 (d, 1H, J = 11.60Hz), 3.85 (d, 1H, J = 11.20Hz), 3.64 (t, 4H, J = 4.80Hz), 3.36 (t, 4H, J = 4.80Hz), 1.78 (s, 3H);

[1070] MS: m / z 478.2 (M+1);

[1071] [α] D 22.5 (-)19.12 (MeOH, c=1.0).

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, in R1 is selected from hydrogen and C 1-6 alkyl; R2-R3 are independently selected from hydrogen and C 1-6 Alkyl groups; or R2 and R3 together with the carbon atom to which they are attached form C 3-4 Cycloalkyl; R4-R6 are independently selected from hydrogen, halogen and C 1-4 Alkyl groups; R7 is selected from hydrogen and C 1-4 The group consisting of alkyl groups, R8 choose free C 1-6 Alkyl, C substituted with one OH 1-6 Alkyl and an OC 1-3 Alkyl substituted C 1-6 The group consisting of alkyl groups, or R7 and R8 together with the carbon atom to which they are attached form C 3-4 Cycloalkyl; R9-R13 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 Alkoxy, C 1-6 Alkylthio, and cyano groups; R14 is selected from H, C 1-6 Alkyl or C 1-6 Alkoxy; R15 is selected from H, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted by 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 form a 4-6 membered non-aromatic heterocyclic ring containing 1-2 nitrogen atoms, optionally 1 oxygen atom and optionally 1 sulfur atom, optionally substituted by at least one selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 Alkoxy groups are substituted.

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

3. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein R2-R3 are independently selected from H and C 1-3 Alkyl groups are, for example, independently selected from H and methyl groups.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2-R3 are all H.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R4 to R6 are independently a group selected from H, F and methyl.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R7 is selected from H and C 1-3 The alkyl group is, for example, selected from methyl and ethyl.

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R8 is selected from C substituted with one OH 1-4 Alkyl and an OC 1-3 Alkyl substituted C 1-4 The alkyl group is, for example, a group selected from CH2OH, CH2CH2OH, CH2OCH3 and CH2CH2O-CH3.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R9-R13 are independently selected from H, halogen, C substituted with at least one halogen, 1-6 Alkyl and C substituted by at least one halogen 1-6 Alkoxy group.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R9, R12 and R13 are all H, and R10-R11 are independently selected from H, halogen, C substituted with at least one halogen. 1-6 Alkyl and C substituted by at least one halogen 1-6 an alkoxy group; provided that R10 and R11 are not both H.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R14 is selected from H and C 1-6 Alkyl is, for example, selected from H, methyl and ethyl.

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R15 is selected from H, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 1-6 Alkoxy, C substituted by at least one halogen 1-6 Alkoxy, or C 3-4 Cycloalkyl is, for example, selected from methyl, ethyl, methoxy, cyclopropyl, CH2CH2CF3 or CH2CH2OCF3.

12. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R14 and R15 together with the nitrogen atom to which they are attached form a 4-6 membered non-aromatic heterocycle containing 1 nitrogen atom and optionally 1 oxygen atom, optionally substituted with at least one halogen, for example, the 4-6 membered non-aromatic heterocycle is azetidinyl, piperidinyl, morpholinyl and isoxazolidinyl, optionally substituted with at least one F.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from any one of the following: 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, 3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea, (+)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea, (-)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea, 1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (+)-1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (-)-1-((2-((1-methoxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, 1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazol-4-yl]methyl}-3-methoxy-3-methylurea, (+)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea, (-)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea, 1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methylurea, (+)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methylurea, (-)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methylurea, 3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea, (+)-3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea, (-)-3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea, 1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea, (-)-1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea, (+)-1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea, N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide, (-)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide, (+)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide, 3-ethyl-1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazol-4-yl]methyl}urea, (+)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea, (-)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea, 1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea, (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea, (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropyl-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea, 1-[[2-[[1-(3-chloro-4-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]amino]-1H-benzimidazol-4-yl]methyl]-3-methyl-urea, (-)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (+)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea, (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea, (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1,1-dimethylurea, 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, (-)-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, (+)-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, N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide, (-)-(N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide, (+)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)azetidine-1-carboxamide, 1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, 1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (+)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxyprop-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (-)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxyprop-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, 3-((2-((2-(3-chlorophenyl)-1-hydroxyprop-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea, (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea, (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-ethyl-1-methylurea, N-[[2-[[1-(3-chlorophenyl)-2-hydroxy-1-methyl-ethyl]amino]-3H-benzimidazol-4-yl]methyl]isoxazolidine-2-carboxamide, (-)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-7-yl)methyl)isoxazolidine-2-carboxamide, (+)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-7-yl)methyl)isoxazolidine-2-carboxamide, 1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (-)-1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (+)-1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)morpholine-4-carboxamide, (+)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)morpholine-4-carboxamide, and (-)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)morpholine-4-carboxamide.

14. A compound according to any one of claims 1 to 13 for use as a medicament.

15. A pharmaceutical composition comprising a compound according to any one of the preceding claims and optionally a pharmaceutically acceptable additive, such as a carrier or excipient.

16. A compound according to any one of claims 1 to 14 for use in a method of treating a cardiac disease, disorder or condition in a mammal, such as a human.

17. A compound according to any one of claims 1 to 14 for use in a method of treating a cardiac disease, disorder or condition, wherein the disease, disorder or condition is associated with abnormal rhythm or variability of the heart and exercise-induced angina.

18. A compound according to any one of claims 1-14 for use in a method of treating a cardiac disease, disorder or condition selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal heart rhythms occurring following cardiac surgery or cardiac ablation procedures.

19. A method for treating a cardiac disease, disorder or condition in a mammal, such as a human, wherein a therapeutically effective amount of at least one compound according to any one of claims 1 to 14 is administered to a mammal in need of such treatment.

20. The method of claim 19, wherein the mammal's cardiac disease, disorder or condition is selected from the group consisting of arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal heart rhythms occurring after cardiac surgery or cardiac ablation procedures.

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