Novel potassium channel inhibitors

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to novel compounds, the use of said compounds as pharmaceuticals, and the manufacture of pharmaceuticals for the treatment of heart disease, disorder, or condition in mammals. The present invention also relates to pharmaceutical compositions comprising said novel compounds. [Background technology]

[0002] The heart is a muscle that contracts 1 to 3 times per second to circulate blood. A heartbeat is caused by the simultaneous contraction of individual cardiomyocytes (cardiac muscle cells). The synchronization of cell contractions is controlled by electrical cardiac impulses (cardiac action potentials). These impulses are generated in pacemaker cells in sinusoidal nodes and spread rapidly throughout the heart via specific conduction systems.

[0003] Impulse generation and impulse conduction can occur as a result of illness, medication, electrolyte imbalances, and other factors. Such impulse disturbances are called arrhythmias or rhythmic irregularities and can cause anxiety, embolism, syncope, and sudden death. In its simplest form, arrhythmia encompasses anything that deviates from the normal sinus rhythm of the heart. Disorders range from simple palpitations to catastrophic ventricular fibrillation, including bradycardia and tachycardia.

[0004] At the molecular level, a group of proteins called ion channels underpin electrical events in the heart by enabling electric currents to pass across cell membranes. Therefore, various types of ion channels are involved in the generation and conduction of cardiac action potentials, the regulation of heart rate by the autonomic nervous system, and the contraction process in individual cardiac cells. Thus, it is clear that various types of ion channels are targets for antiarrhythmic drugs, and many commercially available antiarrhythmic drugs exert their effects by interacting with ion channels.

[0005] Antiarrhythmic drugs are typically divided into four main classes according to the so-called Singh-Vaughan-Williams classification: all Class I compounds inhibit the voltage-gated sodium channels of the heart. Some Class I compounds have additional effects that affect the cardiac action potential, which is the basis for their further classification into three subclasses.

[0006] Class IA compounds, such as quinidine, procainamide, and disopyramide, are sodium channel inhibitors that prolong action potentials.

[0007] Class IB compounds, such as lidocaine, mexiletine, tokainide, and phenytoin, are sodium channel inhibitors that shorten action potentials.

[0008] Class IC compounds are sodium channel inhibitors such as flecainide, moriscidine, and propafenone, which do not alter the action potential duration.

[0009] Class I compounds interact with sodium channels when they are open or inactive, and dissociate from them when they are closed (diastole). The rate of dissociation determines whether or not they exhibit frequency-dependent channel inhibition. Some Class I compounds inhibit potassium or calcium-permeable channel subtypes in addition to inhibiting sodium channels.

[0010] Class II compounds are β-adrenergic receptor inhibitors, including drugs such as atenolol, metoprolol, timolol, and propranolol. β-adrenergic receptor inhibitors are either selective for cardiac β1 receptors or have affinity for both β1 and β2 receptors. Some compounds inherently possess β-stimulating effects.

[0011] Class III compounds, such as amiodarone, dolonedarone, sotalol, ibutilide, and dofetilide, are potassium channel inhibitors that prolong action potentials.

[0012] Class IV compounds are inhibitors of L-type calcium channels such as verapamil.

[0013] Small conductance calcium-activated potassium (SK) channels belong to the Ca 2+ activated K + channel family. Three subtypes of SK channels: SK1, SK2, and SK3 (corresponding to KCNN1-3 in genomic nomenclature) have been cloned. The activity of these channels is determined by the intracellular free calcium concentration ([Ca 2+ i) via calmodulin constitutively bound to the channel. SK channels are tightly regulated by [Ca 2+ i within the physiological range, being closed when [Ca 2+ i is about 0.1 μM, but fully activated when [Ca 2+ i reaches 1 μM. Since they are selective for potassium, open or activated SK channels hyperpolarize the cell's membrane potential. 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 regulating the firing pattern and excitability of excitatory cells. SK channel inhibitors such as apamin and N-methyl-vicurin enhance excitability, while 1-EBIO, an SK channel opener, has been demonstrated to be able to reduce electrical activity. In non-excitable cells where the Ca 2+ influx via a voltage-independent pathway is very sensitive to the membrane potential, activation of SK channels increases the driving force, while SK channel inhibitors have a depolarizing effect and thus reduce the calcium driving force.

[0015] SK channel inhibitors are pharmaceuticals that inhibit the conduction of potassium ions (K 2+ via small conductance calcium-activated K + channels. This impairment can result from, for example, direct inhibition of ion conduction to the essential condition for channel activation, Ca + ) to Ca 2+This can be achieved by reducing the current due to factors such as inhibition of binding and decreased calcium sensitivity.

[0016] Reviews on SK channels and SK channel modulators can be found in Wulff H et al: "Modulators of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels and their Therapeutic Indications," Current Medicinal Chemistry 2007 14 1437-1457; and Liegeois J-F 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] [Ca 2+ Based on the important role of SK channels in linking ]i with membrane potential, SK channels are an interesting target for the development of novel therapeutic agents, and the potential of SK channel inhibitors for use in antiarrhythmic therapy has been established. For example, Nattel S; J. Physiol. 2009 587 1385-1386 (doi: 10.1113 / jphysiol. 2009. 170621), Xiao-Yan Qi et al, Circulation 2014 28 430-440 (doi: 10.1161 / CIRCULATIONAHA. 113. 003019), and Diness et al; Circ. Arrhythm. Electrophysiol. 2017 10 1-13 (see doi: 10.1161 / CIRCEP. 117. 005125).

[0018] WO2006 / 013210 describes certain 2-aminobenzimidazole derivatives and their use as modulators of small conductance calcium-activated potassium channels. [Overview of the project]

[0019] The exemplified compounds of the present invention are inhibitors or negative modulators of small conductance calcium-activated potassium (SK) channels (particularly (SK3)), possessing IC50 values ​​less than 30 μM, as demonstrated by the automated patch-clamp system described herein, and are considered potent drug candidates. Certain selections of these compounds have significantly improved IC50 values ​​less than 1 μM. Furthermore, some of these compounds possess physicochemical properties suitable for pharmaceutical substances, which are important for the manufacture of pharmaceutical formulations, and may have beneficial properties in terms of pharmacological selectivity profiles, in vivo absorption / bioavailability, toxicity and safety profiles, and manufacturability. In addition, some of these compounds possess pharmacokinetic properties suitable for use as pharmaceuticals.

[0020] In a broader embodiment, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof. [ka] Here A is halogen, C 1‐6 Alkyl, C substituted with at least one halogen 1‐6 Alkyl, C 1‐6 alkoxy, C substituted with at least one halogen 1‐6 Alkoxy, C 1‐6 A five- or six-membered aromatic heterocycle containing at least one nitrogen atom, optionally one sulfur atom, and optionally one oxygen atom, optionally substituted with at least one group selected from alkylthio and cyano; R1 is hydrogen and C 1‐6 Selected from alkyl groups; Alternatively, A and R1, together with the nitrogen atoms they are linked to, contain 1 to 2 nitrogen atoms, optionally 1 oxygen atom, and optionally 1 sulfur atom, and halogens, C 1‐6 C substituted with alkyl or halogen 1‐6 Alkyl, C 1‐6 C substituted with alkoxy and halogens 1‐6 Alkoxy, C 1‐6 Forms a 5-6 member aromatic or aromatic heterocycle optionally substituted with groups selected from alkylthio, =NH, =O, -OH, and cyano; R2~R3 independently contain hydrogen and C 1‐6 It is a group selected from alkyl groups; Alternatively, R2 and R3, together with the carbon atoms they are linked to, become C 3‐4 Forms a cycloalkyl group; R4~R6 are independently hydrogen, halogen, and C 1‐4 It is a group selected from alkyl groups; R7~R8 are independently hydrogen, C 1‐4 Alkyl, C substituted with one OH group 1‐4 Alkyl, 1 OC 1‐3 C substituted with alkyl 1‐4 Alkyl, C substituted with at least one halogen 1‐4 A group selected from alkyl groups, Alternatively, R7 and R8, together with the carbon atoms they are linked to, become C 3‐4 Forms a cycloalkyl group; R9~R13 are independently hydrogen, halogen, and C substituted with at least one halogen. 1‐6 Alkyl, C 1‐6 alkoxy, C substituted with at least one halogen 1‐6 Alkoxy, C 1‐6 The group is selected from alkylthio and cyano.

[0021] In the embodiment, A is a 5-membered aromatic heterocycle containing 1 to 3 nitrogen atoms and optionally 1 oxygen atom, and is a halogen, C 1‐6 Alkyl, C substituted with at least one halogen1‐6 Alkyl, C 1‐6 alkoxy, C substituted with at least one halogen 1‐6 Alkoxy, C 1‐6 It is optionally substituted with at least one group selected from alkylthio and cyano.

[0022] In another embodiment, A is a six-membered aromatic heterocycle containing 1 to 3 nitrogen atoms, and is a halogen, C 1‐6 Alkyl, C substituted with at least one halogen 1‐6 Alkyl, C 1‐6 alkoxy, C substituted with at least one halogen 1‐6 Alkoxy, C 1‐6 It is optionally substituted with at least one group selected from alkylthio and cyano.

[0023] In further embodiments, A is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, and pyrimidinyl, and halogen, C 1‐6 Alkyl, C substituted with at least one halogen 1‐6 Alkyl, C 1‐6 alkoxy, C substituted with at least one halogen 1‐6 Alkoxy, C 1‐6 It is optionally substituted with at least one group selected from alkylthio and cyano.

[0024] In certain embodiments of the A-N bond in the compound of formula I, A includes the carbon atom to which the N atom is bonded. Therefore, the situation in which A includes nitrogen, oxygen, or sulfur bonded to N is excluded.

[0025] Furthermore, if the halogen is a substituent on the A ring, it bonds to the carbon atom of the A ring. In particular, halogen substituents do not bond to the nitrogen atom of the A ring.

[0026] In further embodiments, R1 is selected from hydrogen (H) and methyl, and is typically H.

[0027] In a further embodiment, A and R1, together with the nitrogen atom they are linked to, form a five-membered aromatic or non-aromatic heterocycle containing one or two nitrogen atoms, optionally one oxygen atom, and optionally one sulfur atom, and optionally a halogen, C 1‐6 C substituted with alkyl or halogen 1‐6 Alkyl, C 1‐6 C substituted with alkoxy and halogens 1‐6 Alkoxy, C 1‐6 It is substituted with a group selected from alkylthio, =NH, OH, =O, and cyano.

[0028] In a further embodiment, A and R1, together with the nitrogen atom to which they are linked, form a halogen, C 1‐6 C substituted with alkyl or halogen 1‐6 Alkyl, C 1‐6 C substituted with alkoxy and halogens 1‐6 Alkoxy, C 1‐6 It forms a five-membered non-aromatic heterocycle containing one nitrogen atom and one oxygen atom, optionally substituted with groups selected from alkylthio, =NH, -OH, =O, and cyano. Typically, the five-membered non-aromatic heterocycle is substituted with one, two, or three groups selected from methyl and =NH, for example, a 2,3-dihydro-1,3-oxazole-2-imine optionally substituted with one or two methyl groups.

[0029] In a further embodiment, R2 to R3 are independently H and C 1‐3 The group is selected from alkyl groups, and typically, both R2 and R3 are H. In further embodiments, R2 is H and R3 is C 1‐3 Alkyl, for example, methyl.

[0030] In a further embodiment, R2 and R3, together with the carbon atoms to which they are linked, form a cyclopropyl group.

[0031] In a further embodiment, R4 to R6 are independently selected groups from H, F, Cl, and methyl, for example, R4 to R6 are all H.

[0032] In a further embodiment, R7 is H and C 1‐3 The group is selected from alkyl groups. Typically, R7 is H. In another embodiment, R7 is methyl.

[0033] In a further embodiment, R8 is C 1‐4 Alkyl, C substituted with one OH group 1‐4 Alkyl and one OC 1‐3 C substituted with alkyl 1‐4 The group is selected from alkyl groups. In one embodiment, R8 is CH2OH.

[0034] In a further embodiment, R7 and R8, together with the carbon atoms to which they are linked, form a cyclopropyl group.

[0035] In a further embodiment, R9 to R13 are independently H, halogen, and C substituted with at least one halogen. 1‐6 C substituted with alkyl and at least one halogen 1‐6 It is a group selected from alkoxy groups.

[0036] In a further embodiment, R9, R12, and R13 are all H, and R10 to R11 are independently H, halogen, and C substituted with at least one halogen. 1‐6 C substituted with alkyl and at least one halogen 1‐6 The group is selected from alkoxy groups; however, neither R10 nor R11 is H.

[0037] In further embodiments, the compound of formula (I) is selected from any one of the illustrated compounds in Examples 1 to 30b; or a pharmaceutically acceptable salt thereof.

[0038] In further embodiments, the compound of formula (I) is selected from any one of the exemplary compounds of Examples 1 to 49b; or is a pharmaceutically acceptable salt thereof.

[0039] In a further embodiment, the present invention relates to a compound of formula (I) as defined above for use as a pharmaceutical.

[0040] In a further embodiment, 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.

[0041] In a further embodiment, the present invention relates to a compound of formula (I) as defined above for use in a method for treating cardiac diseases, disorders, or conditions in mammals such as humans. In one embodiment, the cardiac disease, disorder, or condition is selected from cardiac diseases, disorders, or conditions in which the cardiac disease, disorder, or condition is associated with an abnormal rhythm or dysmorphism of the heart and exercise-induced angina. In another embodiment, the cardiac disease, disorder, or condition is selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal rhythms that occur after cardiac surgery or cardiac ablation procedures.

[0042] A further embodiment of this specification provides a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient.

[0043] Further embodiments of this specification provide pharmaceutical compositions comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of cardiac diseases, disorders, or conditions in mammals such as humans. In one embodiment, the cardiac disease, disorder, or condition is selected from cardiac diseases, disorders, or conditions in which the disease, disorder, or condition relates to an abnormal rhythm or dysmorphism of the heart and exercise-induced angina. In another embodiment, the cardiac disease, disorder, or condition is selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal rhythms that occur after cardiac surgery or cardiac ablation procedures.

[0044] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use as pharmaceuticals.

[0045] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for therapeutic use.

[0046] Further aspects of this specification provide compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, for use in methods of treating the body of a human or animal by therapeutic means.

[0047] Further embodiments of this specification provide compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in the prevention or treatment of mammals such as humans.

[0048] Further embodiments of this specification provide the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a mammal, such as a human.

[0049] Further embodiments of this specification provide methods for the prevention or treatment of cardiac diseases, disorders, or conditions in mammals such as humans. In one embodiment, the cardiac disease, disorder, or condition is selected from cardiac diseases, disorders, or conditions related to abnormal cardiac rhythms or dysmorphisms and exercise-induced angina. In another embodiment, the cardiac disease, disorder, or condition is selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal rhythms occurring after cardiac surgery or cardiac ablation procedures, and the method comprises administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof to a mammal such as a human that requires such treatment.

[0050] In a further embodiment, the present invention relates to a method for treating a heart disease, disorder, or condition in a mammal such as a human, wherein a therapeutically effective amount of at least one compound of formula (I) as defined above is administered to the mammal in need of the treatment. In an embodiment, the heart disease, disorder, or condition in the mammal is selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal rhythms occurring after cardiac surgery or cardiac ablation procedures.

[0051] In a further embodiment, the present invention relates to a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as well as intermediates, comprising steps described in relation to reaction schemes 1 to 9. [Modes for carrying out the invention]

[0052] In a broader embodiment, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof. [ka] Here, A and R1-R13 are as defined above.

[0053] In a particular embodiment, C 1‐6 Alkyl or C 1‐6 Whenever the alkoxy is substituted with at least one halogen, such C 1‐6 Alkyl or C 1‐6 It is preferable that the alkoxy is substituted with 1 to 3 halogens, for example, 1 to 3 fluorine atoms, with CF3 and OCF3 being preferred.

[0054] In further embodiments, A is selected from one of pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, flazanil, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinil, pyridinyl, diazinyl, pyridazinyl, triazinyl, and tetradinyl.

[0055] In a further embodiment, A is C 1‐6 Substituted with a group selected from alkyl groups, one of the following: pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, flazanyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyridinyl, diazinyl, pyridadinyl, triazinyl, and tetradinyl.

[0056] In embodiments, A is a five-membered aromatic heterocycle containing one to two nitrogen atoms and optionally one oxygen atom, such as imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, or oxadiazolyl.

[0057] In further embodiments, A is a five-membered aromatic heterocycle containing one to two nitrogen atoms and optionally one oxygen atom, and C such as imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, and methyl. 1‐6 Selected from oxadiazolyls substituted with one or two alkyl groups.

[0058] In another embodiment, A is a six-membered aromatic heterocycle containing one or two nitrogen atoms, such as a pyrimidine.

[0059] In a further embodiment, A is C 1‐6 The group is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, and pyrimidinyl, substituted with at least one group selected from alkyl groups.

[0060] In one embodiment, R1 is H. In another embodiment, R1 is methyl.

[0061] In a further embodiment, A and R1, together with the nitrogen atom to which they are linked, form a five-membered aromatic heterocycle containing one or two nitrogen atoms and one oxygen atom, and optionally a halogen, C 1‐6 C substituted with alkyl or halogen 1‐6 Alkyl, C 1‐6 C substituted with alkoxy and halogens 1‐6 Alkoxy, C 1‐6 It is substituted with a group selected from alkylthio, =NH, -OH, =O, and cyano.

[0062] In a further embodiment, A and R1, together with the nitrogen atom they link, form a five-membered aromatic heterocycle containing two nitrogen atoms substituted with a group selected from =O, such as 2,3-dihydro-1H-imidazole-2-one.

[0063] In a further embodiment, A and R1, together with the nitrogen atom to which they are linked, form a five-membered aromatic heterocycle containing one nitrogen atom and one oxygen atom substituted with a group selected from =NH, such as 2-imino-2,3-dihydro-1,3-oxazole-3-yl.

[0064] In a further embodiment, A and R1, together with the nitrogen atom to which they are attached, form a 5-membered aromatic heterocycle containing one nitrogen atom and one sulfur atom substituted with a group selected from =NH, such as 2-imino-2,3-dihydro-1,3-thiazol-3-yl.

[0065] In a further embodiment, A and R1, together with the nitrogen atom to which they are attached, form a 5-membered non-aromatic heterocycle containing one nitrogen atom and one oxygen atom optionally substituted with a group selected from halogen, C 1‐6 alkyl, C 1‐6 alkyl substituted with halogen, C 1‐6 alkoxy, C 1‐6 alkoxy substituted with halogen, C 1‐6 alkylthio, =NH, -OH; =O and cyano. Typically, the 5-membered non-aromatic heterocycle is substituted with one or more, for example 1 to 3, selected from methyl and =NH, and examples include 2,3-dihydro-1,3-oxazol-2-imine optionally substituted with one or two methyl groups.

[0066] In a further embodiment, A and R1, together with the nitrogen atom to which they are attached, form a 5-membered non-aromatic heterocycle containing 1 to 2 nitrogen atoms and one oxygen atom, and optionally substituted with a group selected from halogen, C 1‐6 alkyl, C 1‐6 alkyl substituted with halogen, C 1‐6 alkoxy, C 1‐6 alkoxy substituted with halogen, C<tmp>0000094alkylthio, =NH, -OH, =O and cyano. Typically, the 5-membered non-aromatic heterocycle is substituted with one or more, for example 1 to 3, of methyl and =NH.

[0067] In a further embodiment, A and R1 together with the nitrogen atom to which they are attached form a 5-membered non-aromatic heterocyclic ring containing two nitrogen atoms, substituted with =O and optionally substituted with one methyl, such as imidazolidin-2-one or methylimidazolidin-2-one.

[0068] In a further embodiment, A and R1 together with the nitrogen atom to which they are attached form a 5-membered non-aromatic heterocyclic ring containing one nitrogen atom and one sulfur atom, substituted with =O, such as 1,3-thiazolidin-2-one.

[0069] In a further embodiment, A and R1 together with the nitrogen atom to which they are attached form a 5-membered non-aromatic heterocyclic ring containing one nitrogen atom, substituted with =O, such as pyrrolidin-2-one.

[0070] In a further embodiment, A and R1 together with the nitrogen atom to which they are attached form a 6-membered aromatic heterocyclic ring containing 1 to 2 nitrogen atoms, optionally substituted with a group selected from halogen, C 1‐6 alkyl, C 1‐6 alkyl substituted with halogen, C 1‐6 alkoxy, C 1‐6 alkoxy substituted with halogen, C 1‐6 alkylthio, =NH, -OH, =O and cyano.

[0071] In a further embodiment, A and R1 together with the nitrogen atom to which they are attached form a 6-membered non-aromatic heterocyclic ring containing 1 to 2 nitrogen atoms, optionally substituted with a group selected from halogen, C 1‐6 alkyl, C 1‐6 alkyl substituted with halogen, C 1‐6 alkoxy, C 1‐6 alkoxy substituted with halogen, C 1‐6 alkylthio, =NH, -OH, =O and cyano.

[0072] In a further embodiment, R2 is H and C 1‐3 Alkyl atoms are selected, for example, from H. In a further embodiment, R3 is H and C 1‐3 Selected from alkyl groups, typically R3 is H. In one embodiment, R3 is methyl.

[0073] In a further embodiment, R2 and R3, together with the carbon atoms to which they are linked, form cyclopropyl. In another embodiment, R2 and R3, together with the carbon atoms to which they are linked, form cyclobutyl.

[0074] In further embodiments, R4 is selected from H, F, Cl, methyl, for example, H. In further embodiments, R5 is selected from H, F, Cl, methyl, for example, H.

[0075] In further embodiments, R6 is selected from H, F, Cl, methyl, for example, H. In further embodiments, R7 is H. In another embodiment, R7 is C such as methyl or ethyl. 1‐3 It is alkyl.

[0076] In a further embodiment, R8 is a C such as methyl 1‐4 It is alkyl. In a further embodiment, R8 is a C substituted with one OH group such as CH2OH or CH2CH2OH. 1‐4 It is alkyl.

[0077] In a further embodiment, R8 is one OC 1‐3 C substituted with alkyl 1‐4 It is an alkyl group, for example, a C group substituted with at least one methoxy or ethoxy group. 1‐3 It is alkyl, typically CH2OCH3 or CH2CH2OCH3.

[0078] In a further embodiment, R7 and R8, together with the carbon atoms to which they are linked, form cyclopropyl. In another embodiment, R7 and R8, together with the carbon atoms to which they are linked, form cyclobutyl.

[0079] In a further embodiment, R9 is H. In another embodiment, R9 is a halogen such as F or Cl. In a further embodiment, R9 is C substituted with at least one halogen, such as CF3. 1‐6 It is alkyl. In another embodiment, R9 is a C substituted with at least one halogen, such as OCF3. 1‐6 It is an alkoxy.

[0080] In a further embodiment, R10 is a halogen such as F or Cl. In a further embodiment, R10 is H. In a further embodiment, R10 is C substituted with at least one halogen, such as CF3. 1‐6 It is alkyl. In another embodiment, R10 is a C substituted with at least one halogen, such as OCF3. 1‐6 It is an alkoxy.

[0081] In a further embodiment, R11 is H. In another embodiment, R11 is a halogen such as F or Cl. In a further embodiment, R11 is C substituted with at least one halogen, such as CF3. 1‐6 It is alkyl. In another embodiment, R11 is a C substituted with at least one halogen, such as OCF3. 1‐6 It is an alkoxy.

[0082] In a further embodiment, R12 is H. In another embodiment, R12 is a halogen such as F or Cl. In a further embodiment, R12 is C substituted with at least one halogen, such as CF3. 1‐6 It is alkyl. In another embodiment, R12 is a C substituted with at least one halogen, such as OCF3. 1‐6It is an alkoxy.

[0083] In a further embodiment, R13 is H. In another embodiment, R13 is a halogen such as F or Cl. In a further embodiment, R13 is C substituted with at least one halogen, such as CF3. 1‐6 It is alkyl. In another embodiment, R13 is a C substituted with at least one halogen, such as OCF3. 1‐6 It is an alkoxy.

[0084] In a further embodiment, R9, R12, and R13 are all H, and R10 is a halogen, C substituted with at least one halogen. 1‐6 C substituted with alkyl and at least one halogen 1‐6 The group is selected from alkoxys, and R11 is H, a halogen, or C substituted with at least one halogen. 1‐6 C substituted with alkyl and at least one halogen 1‐6 It is a group selected from alkoxy groups.

[0085] In further embodiments, R9, R12, and R13 are all H, R10 is a group selected from F, Cl, CF3, and OCF3, and R11 is a group selected from H, F, Cl, CF3, and OCF3.

[0086] In further embodiments, each of R9, R10, R11, and R12 is a group selected from H and a halogen, and R13 is H. Preferably, each of R9, R10, R11, and R12 is a group selected from H, Cl, and F, and R13 is H. However, at least two of R9 to R12 are halogens, for example, halogens selected from F and Cl.

[0087] Each of the compounds described in the experimental section constitutes an embodiment of the present invention in any form, such as a salt or a free base, and such compounds or salts thereof may be the subject of the claims.

[0088] In further embodiments, the compound of formula (I) is selected from any one of the trifluoroacetates of the compounds of Examples 1 to 30b.

[0089] In further embodiments, the compound of formula (I) is selected from any one trifluoroacetate of the compounds of Examples 1 to 49b.

[0090] In further embodiments, the compound of formula (I) is selected from any one of the trifluoroacetates of the compounds of Examples 31 to 49b.

[0091] heart disease In the context of the present invention, "cardiac disease, disorder, or condition" means any cardiac disease, disorder, or condition, including but not limited to abnormal heart rhythms or dysmorphisms and exercise-induced angina.

[0092] In a more specific embodiment, the cardiac disease, disorder, or condition is any disease, disorder, or condition associated with an abnormal or malformed rhythm of the heart and exercise-induced angina.

[0093] In a more specific embodiment, the cardiac disease, disorder, or condition is any disease, disorder, or condition related to an abnormal rhythm of the heart.

[0094] In a more specific embodiment, the cardiac disease, disorder, or condition associated with an abnormal rhythm of the heart is selected from cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, and bradyarrhythmias.

[0095] In another embodiment, the cardiac disease, disorder, or condition of the present invention is an abnormal rhythm caused by myocardial ischemia, myocardial infarction, cardiac hypertrophy, or cardiomyopathy.

[0096] In another embodiment, the cardiac disease, disorder, or condition of the present invention is an abnormal rhythm that occurs after cardiac surgery or cardiac ablation procedure.

[0097] In a further specific embodiment, the cardiac disease, disorder, or condition associated with an abnormal rhythm of the heart is a cardiac arrhythmia caused by a genetic disorder.

[0098] In a more preferred embodiment, the cardiac disease, disorder, or condition related to an abnormal rhythm of the heart is cardiac arrhythmia.

[0099] In a preferred embodiment, the cardiac disease, disorder, or condition associated with an abnormal rhythm of the heart is atrial fibrillation.

[0100] In certain embodiments, the compound of formula (I) of the present invention is useful for treating atrial fibrillation by acute defibrillation to normal sinus rhythm.

[0101] In another specific embodiment, the compounds of formula (I) of the present invention are useful in treating atrial fibrillation by maintaining normal sinus rhythm and preventing or reducing the occurrence of new episodes of atrial fibrillation.

[0102] Pharmacological treatment of atrial fibrillation In the context of this invention, and as will be understood by those skilled in the art, the treatment of atrial fibrillation is acute defibrillation, maintenance of sinus rhythm, or both. Acute conversion is defined as the application of a compound having the ability to convert atrial fibrillation to normal cardiac sinus rhythm. Normal sinus rhythm is defined as a regular and stable heartbeat at rest in adults, with normal and regular p waves on a standard 12-lead electrocardiogram, and a frequency of 40 to 100 beats per minute. Maintenance of sinus rhythm is defined as the ability of a compound to maintain normal and stable sinus rhythm over a long period without recurrence of atrial fibrillation, or the ability of a compound to significantly reduce the incidence of recurrence from atrial fibrillation to normal sinus rhythm compared to a control group that does not receive the compound.

[0103] General process description Schemes 1-9 summarize some synthetic approaches that can be used to prepare compounds of general formula (I).

change

[0104] Scheme 1: Numerous ketones and aldehydes (1) are commercially available or can be readily prepared by many routes described in the literature. Ketones and aldehydes (1) can be converted to hydantoin derivatives (2) by a wide range of methods, such as reacting (1) with potassium cyanide under the influence of an ammonium salt (e.g., ammonium carbonate) by heating (50°C to 100°C) in a solvent such as water or alcohol (e.g., ethanol). Hydantoin derivatives (2) can be converted to amino acid derivatives (3) by hydrolysis under the influence of heat with a strong base (e.g., sodium hydroxide) in water (100°C). There are many well-established methods for preparing amino acids in addition to those described in the literature. Also, many amino acid derivatives are commercially available and readily available. Amino acids (3) can be protected as N-(tert-butoxy)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) at 0°C to ambient temperature. Intermediate (4) can be reduced to the alcohol derivative (5) by various methods involving a hydride reducing agent (such as sodium borohydride or lithium aluminum hydride). This can be achieved by direct reduction of the acid group at ambient temperature (e.g., using lithium aluminum hydride in a solvent such as tetrahydrofuran), or by initial activation of the acid group of (4) by conversion to a mixed anhydride (e.g., using isobutyl chloroformate and triethylamine in tetrahydrofuran) at 0°C, followed by reduction with sodium borohydride (e.g., in water) from 0°C to ambient temperature. The alcohol derivative (5) may require protection, such as conversion to an ester (e.g., 2,2-dimethylpropanoate ester) by reacting 2,2-dimethylpropanoyl chloride and a base (e.g., triethylamine) in a solvent (e.g., dichloromethane) at 0°C to ambient temperature. The intermediate (6) can be deprotected to the amine derivative (7) by treatment with an acid (such as hydrochloric acid or trifluoroacetic acid) in a suitable solvent (such as dioxane or dichloromethane) at 0°C to ambient temperature.The intermediate (7) can be converted to an isothiocyanate derivative (8) by reacting it with thiophosgene in a suitable solvent (e.g., dichloromethane) under the influence of a base (e.g., sodium bicarbonate) at 0°C to ambient temperature.

[0105] [ka]

[0106] Scheme 2: Ketones and aldehydes (1) can be converted to sulfinamide derivatives (9) by reacting (1) with 2-methylpropane-2-sulfinamide under the influence of a Lewis acid (e.g., titanium(IV) ethoxide) and heating at 70°C in a suitable solvent (e.g., tetrahydrofuran). Sulfinamide derivatives (9) can be converted to β-amino acid esters (10) by reacting methyl 2-bromoacetate at 0-5°C in a solvent (e.g., tetrahydrofuran) under the influence of zinc and copper(I) iodide. There are many other well-established methods for preparing β-amino acids described in the literature. Several β-amino acid derivatives are commercially available and readily available. β-amino acid esters (10) can be reduced to alcohol derivatives (11) by various methods including a hydride reducing agent (e.g., lithium aluminum hydride) at 0°C in a suitable solvent (e.g., tetrahydrofuran). The alcohol derivative (12) may require protection, such as being converted to an ester (e.g., 2,2-dimethylpropanoate ester) by reacting it with 2,2-dimethylpropanoyl chloride and a base (e.g., triethylamine) in a solvent (e.g., dichloromethane) at 0°C. The intermediate (12) can be deprotected to the free derivative (13) by treating it with an acid (e.g., hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g., dioxane or dichloromethane) at 0°C. The intermediate (13) can be converted to the isothiocyanate derivative (14) by reacting it with thiophosgene in a suitable solvent (e.g., dichloromethane) under the influence of a base (e.g., sodium bicarbonate) at ambient temperature.

[0107] [ka]

[0108] Scheme 3: The alcohol derivative (5) can be converted to intermediate (15) by alkylating it on the alcohol oxygen atom by reacting it with methyl iodide in a solvent (e.g., acetonitrile) at ambient temperature under the influence of a metal oxide (e.g., silver oxide). Intermediate (15) can be deprotected to amine derivative (16) by treating it with an acid (e.g., hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g., dioxane or dichloromethane) at 0°C to ambient temperature. Intermediate (16) can be converted to isothiocyanate derivative (17) by reacting it with thiophosgene in a suitable solvent (e.g., dichloromethane) at 0°C to ambient temperature under the influence of a base (e.g., sodium bicarbonate).

[0109] [ka]

[0110] Scheme 4: A wide range of intermediates (18) are available, which are commercially available and readily accessible, or can be prepared by methods described in the literature. Intermediate (18) can be converted to isothiocyanate derivatives (19) by reacting with thiophosgene in a suitable solvent (e.g., dichloromethane) under the influence of a base (e.g., sodium bicarbonate) at ambient temperature.

[0111] [ka]

[0112] Scheme 5: There are extensive benzene-1,2-diamine intermediates (20), which are commercially available and easily accessible, or can be prepared by methods described in the literature. Intermediate (20) can be converted into 2,1,3-benzothiadiazole derivative (21) by reacting with thionyl chloride in pyridine (temperature is 0 °C to 45 °C). Intermediate (21) can be converted into benzyl bromide derivative (22) by heating at reflux temperature and reacting with N-bromosuccinimide in a solvent (such as chloroform) under the influence of a radical initiator (such as benzoyl peroxide). Intermediate (22) can react with a wide range of aminoheterocycles when heated at 60 °C in a solvent (such as acetonitrile) to obtain intermediate (23). Intermediate (23) can be converted into benzene-1,2-diamine derivative (24) by desulfurization with hydrogen gas at ambient temperature in a suitable solvent (such as methanol) under the influence of a metal catalyst (such as Raney nickel).

[0113]

Chemical formula

[0114] Scheme 6: Intermediate (22) can be converted into alcohol derivative (25) by reacting with a metal carbonate (such as potassium carbonate) at reflux temperature in a suitable solvent (such as dioxane / water). Alcohol derivative (25) can be oxidized into an aldehyde or ketone derivative (26) at ambient temperature in a solvent (such as dichloromethane) using an oxidizing agent (such as Dess-Martin Periodinane). Intermediate (26) can be protected as a 1,3-dioxolan-2-yl derivative (27) by reacting with 1,2-ethanediol at ambient temperature in a solvent (such as dichloromethane) under the influence of tetra-butylammonium tribromide. Intermediate (27) can be converted into benzene-1,2-diamine derivative (28) by desulfurization with hydrogen gas at ambient temperature in a suitable solvent (such as methanol) under the influence of a metal catalyst (such as Raney nickel).

[0115] [ka]

[0116] Scheme 7, Route 1 to Example of Formula (I): The benzene-1,2-diamine derivative (24) can be reacted with an isothiocyanate (8) or (14) in a suitable solvent (e.g., dichloromethane) at ambient temperature to obtain a mixture of thiourea products (29) and (30). A wide range 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., nitration and subsequent reduction of commercially available substituted benzene starting materials). The thiourea derivatives (29) and (30) can be converted to the 2-aminobenzimidazole derivative (31) by a ring-forming reaction occurring in a suitable solvent (e.g., methanol or acetonitrile) at ambient temperature under the influence of iodoacetic acid. The cyclization of (29) and (30) to obtain (31) can also be carried out in a suitable solvent (e.g., acetonitrile) under the influence of a mercury salt (e.g., mercury oxide) while heating. The 2-aminobenzimidazole ester derivative (31) can be converted to the compound of formula (I) by deprotecting the ester at ambient temperature under the influence of a base (e.g., sodium hydroxide) in a suitable solvent (e.g., methanol). The 2-aminobenzimidazole derivative formula (I) may be a racemic mixture and can be separated into two enantiomers A and B by various methods, including chromatography using a chiral stationary phase. This can be normal-phase or reverse-phase chromatography, using a suitable solvent mixture as the eluent (e.g., chloroform, dichloromethane, ethanol, ethyl acetate, methanol, ethanol), and possibly with additives (e.g., ammonia, triethylamine, trifluoroacetic acid, acetic acid).

[0117] [ka]

[0118] Scheme 8, Route 2 to Examples of Formula (I): The benzene-1,2-diamine derivative (28) can be reacted with an isothiocyanate (8) or (14) in a suitable solvent (e.g., dichloromethane) at ambient temperature to obtain a mixture of thiourea products (32) and (33). A wide range 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., nitration and subsequent reduction of commercially available substituted benzene starting materials). The thiourea derivatives (32) and (33) can be converted to the 2-aminobenzimidazole derivative (34) by a ring-forming reaction occurring in a suitable solvent (e.g., methanol or acetonitrile) at ambient temperature under the influence of iodoacetic acid. The intermediate (34) can be deprotected to the ketone and aldehyde derivative (35) by reacting with an acid (e.g., p-toluenesulfonic acid) in a suitable solvent (e.g., acetone) at ambient temperature. Derivative (35) can be reacted with a wide range of amino heterocycles under reflux in tetrahydrofuran under the influence of a dehydrating agent (e.g., titanium(IV) isopropoxide), and then reacted with a reducing agent (e.g., sodium cyanoborohydride) in tetrahydrofuran at ambient temperature to obtain intermediate (36). The 2-aminobenzimidazole ester derivative (36) can be converted to the compound of formula (I) by deprotecting the ester in a suitable solvent (e.g., methanol) at ambient temperature under the influence of a base (e.g., sodium hydroxide). The 2-aminobenzimidazole derivative formula (I) may be a racemic mixture and can be separated into two enantiomers A and B by various methods, including chromatography using a chiral stationary phase. This may be normal-phase or reverse-phase chromatography, using a suitable solvent mixture as the eluent (e.g., chloroform, dichloromethane, ethanol, ethyl acetate, methanol, ethanol), and possibly with additives (e.g., ammonia, triethylamine, trifluoroacetic acid, acetic acid).

[0119] [ka]

[0120] Scheme 9, Route 3 to Examples of Formula (I): The benzene-1,2-diamine derivative (24) can be reacted with an isothiocyanate (17) or (19) in a suitable solvent (e.g., dichloromethane) at ambient temperature to obtain a mixture of thiourea products (37) and (38). The thiourea derivatives (37) and (38) can be converted to the 2-aminobenzimidazole derivative formula (I) by a ring-forming reaction occurring in a suitable solvent (e.g., methanol or acetonitrile) at ambient temperature under the influence of iodoacetic acid. The cyclization of (37) and (38) to obtain the derivative formula (I) can also occur in a suitable solvent (e.g., acetonitrile) under the influence of a mercury salt (e.g., mercury oxide) with heating. The 2-aminobenzimidazole derivative formula (I) may be a racemic mixture and can be separated into two enantiomers A and B by various methods, including chromatography using a chiral stationary phase. This is either normal-phase or reverse-phase chromatography, using a suitable solvent mixture as the eluent (e.g., chloroform, dichloromethane, ethanol, ethyl acetate, methanol, ethanol), and possibly additives (e.g., ammonia, triethylamine, trifluoroacetic acid, acetic acid). Those skilled in the art will understand that it may be necessary to adjust or change the order of the steps in the above process, and that such changes in order are included in the above-mentioned aspects of the process in the accompanying description of the reaction scheme and process steps. Furthermore, those skilled in the art will understand that in the processes described above and below, the functional groups of the intermediate compound may need to be protected by protecting groups.

[0121] Functional groups that are desirable to protect include hydroxyl, amino, and carboxylic acids. Suitable protecting groups for hydroxyl include optionally substituted and / or unsaturated alkyl groups (e.g., methyl, allyl, benzyl, or tert-butyl), trialkylsilyl groups or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), AcO (acetoxy), TBS (t-butyldimethylsilyl), TMS (trimethylsilyl), PMB (p-methoxybenzyl), and tetrahydropyranyl. Suitable protecting groups for carboxylic acids include (C1-C6)-alkyl or benzyl esters. Suitable protecting groups for aminos include t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxymethyl, or 2-trimethylsilylethoxycarbonyl (Teoc). Suitable protecting groups for S include S-C(=N)NH2 and TIPS.

[0122] Protection and deprotection of functional groups may be performed before or after the reaction in the above process.

[0123] Furthermore, those skilled in the art will understand that, in order to obtain the compounds of the present invention by alternative, and possibly more convenient methods, the individual process steps described herein may be carried out in a different order, and / or the individual reactions may be carried out at different stages of the overall pathway (i.e., substituents may be added to intermediates different from those described herein, and / or chemical transformations may be carried out in relation to a particular reaction). This may eliminate or necessitate the need for protecting groups.

[0124] Compounds of formula (I) have at least one chiral center, and may have further chiral centers, and any optical isomers (i.e., enantiomers or diastereomers) in the form of separated, pure, or partially purified optical isomers, and any mixtures thereof, including racemic mixtures, i.e., mixtures of stereoisomers, are intended to be within the scope of the present invention. In particular, the carbon atom of formula (I) is a chiral center with a tetravalent bond linked to R7, R8, NH, phenyl, giving rise to two optical isomers, the R and S isomers. In one embodiment, the compound of the present invention has the S isomer. In another embodiment, the compound of the present invention has the R isomer. In a further embodiment, the compound of the present invention is a racemic mixture.

[0125] In this context, when identifying an enantiomer form, the compound is understood to be enantiomer-rich, for example, essentially a pure monoenantiomer form. Accordingly, one embodiment of the present invention relates to a compound of the present invention having an enantiomer excess of at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%.

[0126] The racemic mixture can be separated into optically active compounds by known methods, for example, by separating its diastereomer salt with an optically active acid and treating it with a base to liberate the optically active amine compound. Another method for separating the racemic mixture into optically active compounds is based on chromatography of the optically active matrix. The compounds of the present invention can also be degraded by the formation of diastereomer derivatives.

[0127] Additional methods for separating optical isomers, known to those skilled in the art, may be used. Such 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 can also be prepared from optically active starting materials.

[0128] Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule, geometric isomers may be formed. Isolated, pure or partially purified geometric isomers, or geometric isomers as mixtures thereof, are intended to be included within the scope of the present invention. Similarly, molecules having bonds with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.

[0129] Furthermore, the compounds of general formula I of the present invention have a benzimidazole structure that exists as tautomers, and when used herein, only one is shown, but all tautomers are constituted by the compounds of formula I.

[0130] The tautomers of formula (I) are as follows:

Chemical formula

[0131] The benzimidazole tautomers of formula I above mean that hydrogen switches back and forth from one nitrogen to the other, and as a result, the double bond switches back and forth between the bonding points of the nitrogen and the NH group of carbon. Furthermore, when benzimidazole is shown as part of the general structure or as an individual specific compound, benzimidazole includes all tautomers, and thus, even if only one tautomer is shown, it should be understood to include all of them.

[0132] As used herein, the term "compound of formula (I)" means any form of the compound of formula (I) including its salts such as the free form or its pharmaceutically acceptable salts, unless otherwise indicated herein or clearly inconsistent with the context.

[0133] Whenever substituents are disclosed as R1 to R13, it is always implied that each substituent may be consecutive, for example, R2 to R4 means R2, R3, and R4, and for example, R9 to R13 means R9, R10, R11, R12, and R13. In further embodiments, compound I is in a free form. In one embodiment, the free form is an anhydride. In another embodiment, the free form is a solvate, such as a hydrate.

[0134] In further embodiments, the compound is in crystalline form. Those skilled in the art can perform tests to find polymorphs, and such polymorphs are intended to be included in the term "crystalline form" as used herein.

[0135] When the compounds and pharmaceutical compositions disclosed herein are used for the above-mentioned treatment, a therapeutically effective amount of at least one compound is administered to a mammal in need of the treatment.

[0136] As used herein, the term "free form" means, as may be, a free base or a free acid, and not a compound of formula (I) in any form of salt.

[0137] The term "C" as used in this specification 1‐x "Alkyl" refers to an alkyl group containing 1 to x carbon atoms, for example, C 1‐3 , C 1‐4 , C 1‐5 or C 1‐6 Examples include methyl, ethyl, propyl, butyl, pentyl, or hexyl, and further, branched C 3‐6 Alkyl groups, such as isopropyl, isobutyl, tert-butyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl, are also included. 1‐x Alkyl, for example, C 1‐6When an alkyl group is substituted with a halogen group, such as fluorine (F), it means that such F groups, for example, three F groups, are bonded to one carbon atom (CF3), two carbon atoms (CF2-CF), or even three carbon atoms (CF-CF-CF).

[0138] The term "C" as used in this specification 1‐x "Alkylene" refers to an alkylene group containing 1 to x carbon atoms, for example, C 1‐3 , C 1‐4 , C 1‐5 or C 1‐6 Examples include methylene, ethylene, propylene, butylene, pentylene, or hexylene, and branched C 3‐6 Alkylenes, such as isopropylene, isobutylene, tert-butylene, isopentylene, 3-methylbutylene, 2,2-dimethylpropylene, n-hexylene, 2-methylpentylene, 2,2-dimethylbutylene, and 2,3-dimethylbutylene, are also included.

[0139] The term "C" as used in this specification 1‐x "Alkoxy" or "O-C 1‐x Alkyl (used interchangeably) is an alkyl group containing 1 to x carbon atoms, for example C 1‐5 or C 1‐6 This refers to a single oxygen atom covalently bonded to, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, n-pentyloxy, or n-hexyloxy.

[0140] The term "C" as used in this specification 1‐x "Alkylthio" or "S-C" 1‐x Alkyl (used interchangeably) refers to an alkyl group containing 1 to x carbon atoms, such as methylthio, ethylthio, n-propylthio, etc. 1‐5 or C 1‐6 It refers to a single sulfur atom covalently bonded to it.

[0141] The term "C" as used in this specification 3‐4"Cycloalkyl" refers to a cyclic alkyl group containing 3 to 4 carbon atoms, such as cyclopropyl or cyclobutyl.

[0142] As used herein, the term "CN" means cyano or nitrile (C and N linked by a triple bond).

[0143] The term used herein refers to "C substituted with at least one halogen." 1‐6 "Alkyl" means C as defined herein, such as CHFCF3 or CF3. 1‐6 This means one or more halogen atoms, as defined herein, bonded to one or more carbon atoms of an alkyl group.

[0144] The term used herein refers to "C substituted with at least one halogen." 1‐6 "Alkoxy" refers to C as defined herein, such as OCH2CHF2 or OCF3. 1‐6 This means one or more halogen atoms, as defined herein, linked to one or more carbon atoms of an alkoxy.

[0145] The term used herein refers to "a single OH-substituted C 1‐4 "Alkyl" means C as defined herein. 1‐4 This refers to a single OH group linked to one carbon atom of an alkyl group via an oxygen atom, such as CH2OH, CH2CH2OH, or CHOHCH3.

[0146] The term "1 OC" as used herein 1‐3 C substituted with alkyl 1‐4 "Alkyl" is defined as C in this specification. 1‐4 One OC is linked to one carbon atom of the alkyl group via oxygen. 1‐3 This refers to alkyl groups, such as CH2OCH3 or CH2CH2OCH3.

[0147] As used herein, the term "halogen" means an atom selected from chloro(Cl), fluoro(F), iod(I), and bromo(Br). Where a halogen is disclosed in any one of the embodiments herein, it is preferably F or Cl.

[0148] As used herein, the term "five- or six-membered aromatic heterocycle containing at least one nitrogen atom, optionally one oxygen atom, and optionally one sulfur atom" means a chemically stable monocyclic aromatic ring system containing at least one nitrogen atom, preferably 1 to 3 N atoms, and possibly five or fewer carbon atoms, one oxygen atom, and / or one sulfur atom, including, but not limited to, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, flazanyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyridinyl, diazinyl, pyridazinyl, triazinyl, and tetradinyl.

[0149] As used herein, the terms “treatment” and “to treat” mean the management and care of a patient aimed at combating a condition such as a disease or disorder. This term is intended to encompass the entire range of treatment for a given condition in which a patient is suffering, including the administration of active compounds to alleviate symptoms or complications, the administration of active compounds to slow the progression of a disease, disorder or condition, the administration of active compounds to alleviate or reduce symptoms and complications, and / or the administration of active compounds to cure or eliminate a disease, disorder or condition, and the administration of active compounds to prevent a condition. Here, prevention is understood as the management and care of a patient aimed at combating a disease, condition or disorder, and includes the administration of active compounds to prevent the onset of symptoms or complications. Treatment may be acute or chronic. Patients being treated are preferably mammals, particularly humans, but may also include animals such as dogs, cats, cattle, sheep, and pigs.

[0150] As used herein, the term “pharmaceutically acceptable salt” is used to specify that the salt is suitable for use in the body of a human or animal. An exemplary list of pharmaceutically acceptable salts is provided in Handbook of Pharmaceutical Salts: Properties, Selection and Use, PHStahl and CGWermuth, editors, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmacologically acceptable salts of the compound of formula (I) include salts that may be formed in the body of a human or animal after administration of the compound to the human or animal body.

[0151] As used herein, the term “therapeutically effective amount” of the compound of formula (I) of the present invention means an amount sufficient to cure, alleviate, or partially prevent the clinical symptoms of a given disease and its complications. An amount appropriate to achieve this is defined as a “therapeutically effective amount.” The effective amount for each purpose will vary depending not only on the subject’s weight and overall condition, but also on the severity of the disease or injury. Determining an appropriate dosage can be achieved by constructing a matrix of values ​​and testing different points within the matrix using routine experiments, all of which are within the normal skill of a skilled physician or veterinarian.

[0152] In further embodiments, 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. Typically, 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.

[0153] As used herein, “pharmaceutically acceptable additives” are intended to include, but are not limited to, carriers, excipients, diluents, adjuvants, colorants, fragrances, preservatives, and the like, which a person skilled in the art might consider using when formulating the compounds of the present invention for the manufacture of a pharmaceutical composition.

[0154] Adjuvants, diluents, excipients, and / or carriers that may be used in the compositions of the present invention must be pharmaceutically acceptable in the sense that they are compatible with the compound of formula (1) and the other components of the pharmaceutical composition and are not harmful to their receptors. Preferably, the compositions do not contain substances that may cause adverse reactions such as allergic reactions. Adjuvants, diluents, excipients, and carriers that may be used in the pharmaceutical compositions of the present invention are well known to those skilled in the art.

[0155] As described above, the compositions disclosed herein, in particular pharmaceutical compositions, may further include, in addition to the compounds disclosed herein, 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 the active ingredient and the pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier shall not exceed 100% by weight of the composition, in particular pharmaceutical composition.

[0156] In some embodiments, only one compound, such as those disclosed herein, is used for the purposes described above.

[0157] In some embodiments, two or more compounds, such as those disclosed herein, are used in combination for the purposes described above.

[0158] The compositions, in particular pharmaceutical compositions containing the compounds described herein, can be adapted for oral administration, intravenous administration, topical administration, intraperitoneal administration, intranasal administration, oral administration, sublingual administration, or subcutaneous administration, or for respiratory administration, for example, in the form of an aerosol or air-suspended fine powder. Accordingly, the pharmaceutical compositions may be in the form of, for example, tablets, capsules, powders, nanoparticles, crystals, amorphous materials, solutions, transdermal patches or suppositories.

[0159] Further embodiments of the process are described in the experimental section of this specification, and each individual process, as well as each starting material, constitutes an embodiment that may form part of the embodiment.

[0160] Unless otherwise explicitly stated that the embodiments relate to a particular aspect(s) of the Invention, the embodiments described herein should be considered to refer to any one of the embodiments described herein, not just any one of the aspects described herein (such as “methods for treatment,” “pharmaceutical compositions,” “compounds for use as pharmaceuticals,” or “compounds for use in methods”).

[0161] All references cited herein, including publications, patent applications, and patents, are incorporated herein by reference to the same extent as they would be incorporated in whole herein, provided that each reference is individually and specifically indicated as being incorporated by reference.

[0162] All headings and subheadings in this specification are for convenience only and should not be construed as limiting the invention in any way.

[0163] Unless otherwise stated herein or unless the context clearly contradicts it, any combination of any possible modification of the above elements is incorporated into the present invention.

[0164] The terms "a," "an," "the," and similar reference terms used in the context describing this invention shall be construed to cover both singular and plural forms unless otherwise specifically indicated herein or unless the context clearly contradicts this interpretation.

[0165] Unless otherwise stated herein, the ranges of values ​​described herein are intended to function merely as abbreviations for individually referring to each individual value that falls within the range, and each individual value is incorporated herein as if it were individually described herein. Unless otherwise stated herein, all exact values ​​provided herein represent the corresponding approximations (for example, all exact exemplary values ​​provided with respect to a particular factor or measurement can be considered to also provide the corresponding approximate measurements, modified with “about” where appropriate).

[0166] All methods described herein may be carried out in any suitable order, unless otherwise specifically indicated herein or unless it is clearly inconsistent with the context.

[0167] Any examples or illustrative expressions provided herein (e.g., “like” or “for example”) are intended solely to better illustrate the invention and, unless otherwise stated, do not limit the scope of the invention. Nothing in this specification should be construed as indicating that any element is essential for carrying out the invention unless expressly stated otherwise.

[0168] The references and inclusions of patent documents in this specification are for convenience only and do not reflect any opinion regarding the validity, patentability, and / or applicability of such patent documents.

[0169] In this specification, any description of an aspect or embodiment of the Invention using terms such as “comprising,” “having,” “including,” or “containing” in reference to an element (singular or plural) is intended to provide support for a similar aspect or embodiment of the Invention that “consists of,” “essentially consists of,” or “substantially contains” that particular element (singular or plural) unless otherwise stated or clearly contradicted by the context (for example, a composition described in this specification as containing a particular element should be understood to also describe a composition consisting of that element, unless otherwise stated or clearly contradicted by the context).

[0170] The present invention includes all modifications and equivalents of the subject matter described herein or in the claims, to the maximum extent permitted by applicable law.

[0171] The present invention is further illustrated by the following embodiments, which are not intended to limit the scope of protection. The features disclosed in the foregoing description and the following embodiments, individually and in any combination thereof, can serve as materials for realizing the present invention in its various forms. [Examples]

[0172] Experimental Procedure Automatic patch clamping Automated whole-cell patch-clamp recordings the human SK3 channel (hK Ca 2.3) was stably expressed in HEK-293 cells using the QPatch 16 HT system and single-hole Qplates (Sophion, Denmark). Cells were cultured using standard cell culture procedures and prepared for the experiment. A total of 4-5 million cells were used per experiment. Qpatch automatically generated gigaseals, whole cell formation, compound coating, and current recordings. Ca 2.3 Current is symmetric K +Recordings were made in solution. The intracellular / pipetted solution contained 154 mM KCl, 10 mM HEPES, and 10 mM EGTA. CaCl2 was calculated to contain 0.4 μM of free Ca. 2+ It is added to achieve the desired concentration, and MgCl2 is added to achieve a free concentration of 1 mM. 156 mM total [K + To maintain the concentration (equivalent to that in extracellular Ringer's solution), a constant amount of KOH (15 mM) was added, and then the pH was adjusted to pH=7.2 with HCl. Expected osmolality: 275 mOsm. Sucrose was added to achieve a final osmolality of 295 mOsm. The extracellular solution (in mM) consisted of CaCl2 0.1, MgCl2 3, KCl 150, HEPES 10, and glucose 10, and was adjusted to pH=7.4 with KOH. The osmolality was 285-295 mOsm. The cells were maintained at 0 mV, and hK Ca 2.3 Current was induced by applying a linear voltage gradient from -80mV to +80mV (with a duration of 200ms) every 5 seconds.

[0173] The compound application protocol consisted of 12 recording times of 200 seconds each: 1) baseline recording in extracellular solution; 2) application of N-methylbicuculline (100 μM) as a positive control, which is characterized by sufficient efficiency with fast on and off speeds; 3-4) washing; 5-10) increasing the concentration of the test compound to set the IC50 value; 11-12) washing; 13) positive control with compound NS8593 (N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-1H-benzimidazole-2-amine) (1 μM) or N-methylbicuculline (100 μM).

[0174] Data were sampled at 10 kHz, using a 4th-order Bessel filter, with a cutoff frequency of 3 kHz. Current was corrected for rundown. Titer was quantified as the concentration required to inhibit half of the SK channel activity and reported as the IC50 value.

[0175] All effects of the compounds of the present invention tested were normalized to the observed inhibitory effect of N-methylbicucurin. Current was measured at -80mV.

[0176] result The described examples are potent inhibitors of the SK3 channel, and in the automated patch-clamp assay described above, the following IC was obtained. 50 This was shown: Examples 1, 3b, 6, 8b, 10, 11, 12b, 14, 15, 16, 17, 18b, 19b, 21, 22, 24a, 25, 26, 27b, 28, 31, 33, 34, 35, 36, 37, 38, 39b, 40a, 40b, 41b, 42a, 42b, 43a, 43b, 44a, 44b, 45b, 46a, 46b, 47b, 48a, 48b, 49a, and 49b are all ICs with a minimum particle size of 30 μm. 50 It has.

[0177] Examples 2, 3, 3a, 4, 5, 7, 8, 8a, 9, 12, 12a, 13, 13a, 13b, 18, 18a, 19, 19a, 20, 23, 23a, 23b, 24, 24b, 27, 27a, 29, 30, 30a, 30b, 32, 32a, 32b, 39a, 41a, 45a, and 47a are all ICs. 50 The concentration is less than 1 μM.

[0178] Materials and methods Unless otherwise specified, commercially available reagents were used without further purification. Analytical TLC was performed using silica gel 60-F 254 Fluorescence detection was performed using a Merck detector and by immersion in a KMnO4 solution [KMnO4 solution recipe: 1.5 g KMnO4, 10 g K2CO3, and 1.25 mL of 10% NaOH dissolved in 200 mL of water], followed by carbonization. The compound was purified by column chromatography using silica gel (60-120 mesh, Swambe Chemicals, India). Deuterated DMSO-d6, CDCl3, CD3CO2D (AcOH-d4), or CD3OD were used as the solvent for NMR. 1 H, 13 NMR spectra such as C and 2D COSY were measured using a Bruker AV 400MHz spectrometer. 1 H is 400MHz, 13C was recorded at ambient temperature using a 100 MHz thermometer. The unit of chemical shift is δ ppm. ESI-MS was recorded using an Agilent LC1200 series MS single quadrupole 6130 mass spectrometer.

[0179] Abbreviations used in the experiment section: BOP = (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate PyBOP = (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate EDC.HCl = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride HBTU = N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate DCM = Dichloromethane; DMF = N,N-dimethylformamide; TEA = Triethylamine TFA = trifluoroacetic acid; Boc-anhydride = di-tert-butyldicarbonate; THF = tetrahydrofuran; t-BuOH = 2-methylpropan-2-ol; DEA = diethylamine; DIEA = ethylbis(propan-2-yl)amine; IPA = propan-2-ol; Pd / C = palladium on carbon; RT = ambient temperature; MeOH = methanol.

[0180] Grace Flash Chromatography System: Sample purification was performed using flash chromatography with a pre-packed silica flash cartridge, employing the Grace REVELERIS® preparative purification system. Columns used: Hi-Purit Flash Column Silica (Normal Phase); 12g, 60A, maximum pressure 350psi (24bar), 24g, 60A, maximum pressure 350psi (24bar), 40g, 60A, maximum pressure 350psi (24bar), 80g, 60A, maximum pressure 350psi (24bar). Solvents: Hexane, ammonium, CHCl3, and MeOH.

[0181] Example 1: N-[1-(3-chlorophenyl)cyclopropyl]-4-[(2-imino-2,3-dihydro-1,3-oxazol-3-yl)methyl]-1H-1,3-benzodiazole-2-amine [ka]

[0182] Example 1, Step 1: Preparation of 1-chloro-3-(1-isothiocyanatocyclopropyl)benzene [ka] To an ice-cold solution of 1-(3-chlorophenyl)cyclopropanamine (commercial product) (1.00 g, 5.97 mmol) in dichloromethane (50 mL), add 10% sodium bicarbonate solution (50 mL), then thiophosgene (1.14 mL, d=1.50 g / cm³). 3 (14.90 mmol) was added, and the entire mixture was stirred at ambient temperature for 30 minutes. The organic layer was separated, washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated to obtain 1-chloro-3-(1-isothiocyanatocyclopropyl)benzene (1.00 g) as a pale yellow liquid, which was used in the next step without further purification.

[0183] 1 H NMR (400 MHz, DMSO-d6) δ 7.44 (s, 1H), 7.39 (d, J = 8.00 Hz, 1H), 7.34 (t, J = 7.20 Hz, 1H), 7.31 (d, J = 7.60 Hz, 1H), 1.67 (t, J = 4.80 Hz, 2H), 1.51 (t, J = 6.00 Hz, 2H).

[0184] Example 1, Step 2: Preparation of 4-methyl-2,1,3-benzothiadiazole [ka] A solution of 3-methylbenzene-1,2-diamine (commercial product) (330.0 g, 2700.0 mmol) in dried pyridine (1800 mL) is prepared by adding thionyl chloride (500.0 mL, d=1.64 g / cm³). 3 6750.00 mmol of methyl benzothiadiazole was added dropwise over 60 minutes at 0°C, maintaining the internal temperature below 45°C during this addition, and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was quenched by adding concentrated hydrochloric acid (1300 mL) dropwise until the reaction pH was adjusted to between pH 2 and pH 3, maintaining the internal temperature below 65°C during this stage. The reaction mixture was diluted with water (1500 mL) and ethyl acetate (2000 mL), stirred for 2 hours, filtered through a Celite bed to separate the organic layer, and the aqueous layer was further extracted with ethyl acetate (3 x 1500 mL). The combined organic layers were washed with brine solution (300 mL), dried over sodium sulfate, filtered, and concentrated to obtain 4-methyl-2,1,3-benzothiadiazole (380.0 g) as a brown liquid, which was used in the next step without further purification.

[0185] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 8.80 Hz, 1H), 7.61 (t, J = 8.80 Hz, 1H), 7.51 (d, J = 6.80 Hz, 1H), 2.69 (s, 3H); MS: m / z 151.2 (M+1).

[0186] Example 1, Step 3: Preparation of 4-(bromomethyl)-2,1,3-benzothiadiazole [ka] In 1200 mL of dry chloroform under a nitrogen atmosphere, 100.0 g, 666.0 mmol of 4-methyl-2,1,3-benzothiadiazole (Step 2 of Example 1) was stirred, to which 3.23 g, 13.30 mmol of benzoyl peroxide was added, followed by 118.0 g, 666.0 mmol of N-bromosuccinimide. The reaction mixture was refluxed for 28 hours. The reaction mixture was cooled to allow succinimide to solidify, and it was removed by filtration. The filtrate was concentrated to obtain a brown semi-solid crude solid (170.0 g), which was placed in 1000 mL of methanol and stirred for 30 minutes. The solid was filtered and dried under high vacuum to obtain 110.0 g of 4-(bromomethyl)-2,1,3-benzothiadiazole as a yellow solid, which was used in the next step without further purification.

[0187] 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 8.60 Hz, 1H), 7.87 (d, J = 8.80 Hz, 1H), 7.71 (t, J = 8.40 Hz, 1H), 5.13 (s, 2H).

[0188] Example 1, Step 4: Preparation of 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-2,3-dihydro-1,3-oxazole-2-imine hydrobromide [ka] To a solution of 4-(bromomethyl)-2,1,3-benzothiadiazole (Example 1, Step 3) (30.00 g, 131.00 mmol) in acetonitrile (300 mL), oxazole-2-amine (22.00 g, 262.00 mmol) was added, and the mixture was stirred at 60°C for 16 hours. The solid formed in the reaction mixture was filtered and dried to obtain a crude mass (33.00 g) as an off-white solid. This was dissolved in a mixed solvent of acetonitrile:water (1:1; 60 mL), and the solvent volume was reduced to approximately 40 mL at 40°C, and the mixture was kept at ambient temperature overnight. The resulting crystals were filtered and dried under high vacuum at 40°C to obtain 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-2,3-dihydro-1,3-oxazole-2-imine hydrobromide (21.00 g) as an off-white solid.

[0189] 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (bs, 2H), 8.13 (d, J = 8.40 Hz, 1H), 7.93 (d, J = 2.00 Hz, 1H), 7.77 (t, J = 9.20 Hz, 1H), 7.69 (d, J = 9.20 Hz, 1H), 7.60 (d, J = 2.40 Hz, 1H), 5.62 (s, 2H); MS: m / z 233.2 [(M+1)-HBr].

[0190] Example 1, Step 5: Preparation of 3-[(2-imino-2,3-dihydro-1,3-oxazol-3-yl)methyl]benzene-1,2-diamine [ka] To a degassed solution of 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-2,3-dihydro-1,3-oxazole-2-imine hydrobromide (from Example 1, Step 4) (12.00 g, 38.34 mmol) in dry methanol (1200 mL), Raney nickel (36.00 g, 300% w / w, pre-washed 5 times with dry methanol) was added. The resulting reaction mixture was then subjected to a hydrogen atmosphere and a bladder pressure of approximately 1.5 kg / cm². 2 The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was filtered through a Celite bed, and the bed was washed with methanol (1000 mL). The combined filtrate was concentrated to obtain 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (10.00 g) as a gray gum, which was used in the next step without further purification. MS: m / z 205.2 (M+1).

[0191] Example 1, Step 6: Preparation of 1-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-3-[1-(3-chlorophenyl)cyclopropyl]thiourea and 1-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-3-[1-(3-chlorophenyl)cyclopropyl]thiourea (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from Example 1, Step 5) (0.192 g, 0.954 mmol) in a mixed solvent of dichloromethane:methanol (4:1; 10 mL), 1-chloro-3-(1-isothiocyanatocyclopropyl)benzene (from Example 1, Step 1) (0.200 g, 0.954 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated in a water bath at 30°C to obtain 1-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-3-[1-(3-chlorophenyl)cyclopropyl]thiourea and 1-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-3-[1-(3-chlorophenyl)cyclopropyl]thiourea (as a mixture of inseparable positional isomers) (0.395 g) as a yellow gum, which was used in the next step without further purification. MS: m / z 414.1 (M+1).

[0192] Example 1: N-[1-(3-chlorophenyl)cyclopropyl]-4-[(2-imino-2,3-dihydro-1,3-oxazol-3-yl)methyl]-1H-1,3-benzodiazole-2-amine [ka] To a solution of 1-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-3-[1-(3-chlorophenyl)cyclopropyl]thiourea and 1-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-3-[1-(3-chlorophenyl)cyclopropyl]thiourea (as a mixture of inseparable positional isomers) (from Example 1, Step 6) (0.390 g, 0.660 mmol) in methanol (30 mL), iodoacetic acid (0.274 g, 1.45 mmol) was added, and the mixture was stirred at 65°C for 1 hour. The reaction mixture was concentrated, and the solvent methanol was removed at 30°C to obtain a crude mass (0.320 g) as a brown gum. This was purified by preparative HPLC using the TFA method to obtain N-[1-(3-chlorophenyl)cyclopropyl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine isolated as trifluoroacetate (0.275 g) as a yellow solid.

[0193] 1 H NMR (400 MHz, AcOH-d4) δ 7.58 (s, 1H), 7.53 (d, J = 7.60 Hz, 1H), 7.36 (d, J = 8.00 Hz, 2H), 7.31 (d, J = 7.20 Hz, 3H), 7.25 (t, J = 6.00 Hz, 2H), 5.44 (s, 2H), 1.67 (t, J = 4.80 Hz, 2H), 1.51 (t, J = 6.00 Hz, 2H); MS: m / z 380.2 (M+1).

[0194] Example 2: Preparation of N-[2-(3-chlorophenyl)propan-2-yl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine [ka]

[0195] Example 2, Step 1: Preparation of 1-chloro-3-(2-isothiocyanatopropan-2-yl)benzene [ka] To an ice-cold solution of 2-(3-chlorophenyl)propan-2-amine (commercial product) (1.00 g, 5.89 mmol) in dichloromethane (40 mL), add 10% sodium bicarbonate solution (40 mL), followed by thiophosgene (0.452 mL, d=1.50 g / cm³). 3 (5.89 mmol) was added, and the mixture was stirred at ambient temperature for 30 minutes. The organic layer was separated, washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated to obtain 1-chloro-3-(2-isothiocyanatopropan-2-yl)benzene (0.800 g) as a pale yellow liquid, which was used in the next step without further purification.

[0196] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 8.40 Hz, 1H), 7.45 (t, J = 8.00 Hz, 1H), 7.43 (s, 1H), 7.41 (dd, J = 2.00, 5.20 Hz, 1H), 1.77 (s, 6H).

[0197] Example 2, Step 2: Preparation of 3-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)propan-2-yl]thiourea and 3-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)propan-2-yl]thiourea (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from Example 1, Step 5) (0.289 g, 1.42 mmol) in dichloromethane (6 mL), 1-chloro-3-(2-isothiocyanatopropan-2-yl)benzene (from Example 2, Step 1) (0.300 g, 1.42 mmol) was added, and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was concentrated in a water bath at 30°C to obtain 3-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)propan-2-yl]thiourea and 3-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)propan-2-yl]thiourea (as a mixture of inseparable positional isomers) (0.500 g) as a yellow gum, which was used in the next step without further purification. MS: m / z 416.1 (M+1).

[0198] Example 2: Preparation of N-[2-(3-chlorophenyl)propan-2-yl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine [ka] To a solution of 3-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)propan-2-yl]thiourea and 3-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)propan-2-yl]thiourea (as a mixture of inseparable positional isomers) (from Example 2, Step 2) (0.200 g, 0.481 mmol) in methanol (20 mL), iodoacetic acid (0.089 g, 0.481 mmol) was added, and the mixture was stirred at 65°C for 1 hour. The reaction mixture was concentrated, and the solvent methanol was removed at 30°C to obtain a crude mass (0.240 g) as brown gum. This was purified by preparative HPLC using the TFA method to obtain N-[2-(3-chlorophenyl)propan-2-yl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine (0.040 g), isolated as trifluoroacetate, as brown gum.

[0199] 1 H NMR (400 MHz, AcOH-d4) δ 7.58 (d, J = 7.12 Hz, 2H), 7.50 (d, J = 7.44 Hz, 1H), 7.40 (d, J = 7.92 Hz, 1H), 7.37 (d, J = 7.68 Hz, 1H), 7.33 (d, J = 7.96 Hz, 1H), 7.30 (t, J = 7.56 Hz, 1H), 7.26 (d, J = 7.04 Hz, 2H), 5.40 (s, 2H), 1.87 (s, 6H); MS: m / z 381.2 (M+1).

[0200] Example 3: Preparation of 2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka]

[0201] Example 3, Step 1: Preparation of 5-(3-chlorophenyl)-5-methylimidazolidined-2,4-dione [ka] To a stirred solution of 1-(3-chlorophenyl)ethane-1-one (commercial product) (120.00 g, 776.00 mmol) in an ethanol / water (1:1; 2400 mL) mixed solvent, ammonium carbonate (448.00 g, 4660.00 mmol) was added, followed by potassium cyanide (45.60 g, 931.00 mmol), and the mixture was stirred at 60°C for 16 hours. The reaction mixture was poured into ice-cold water (1500 mL) and stirred for 30 minutes. The resulting solid was filtered and dried to obtain 5-(3-chlorophenyl)-5-methylimidazolidined-2,4-dione (160.00 g) as an off-white solid, which was used in the next step without further purification.

[0202] 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (bs, 1H), 8.63 (s, 1H), 7.50 (d, J = 1.60 Hz, 1H), 7.47 (d, J = 4.80 Hz, 1H), 7.45 (t, J = 2.40 Hz, 1H), 7.42 (dd, J = 2.40 Hz, 1H), 1.65 (s, 3H); MS: m / z 225.2 (M+1).

[0203] Example 3, Step 2: Preparation of 2-amino-2-(3-chlorophenyl)propanoic acid [ka] 5-(3-chlorophenyl)-5-methylimidazolidined-2,4-dione (from Step 1 of Example 3) (160.00 g, 712.00 mmol) was added to 1200 mL of 10% aqueous sodium hydroxide solution, and the mixture was stirred at 110°C for 72 hours. The reaction mixture was neutralized with 6.0 N HCl (500 mL) (adjusted to pH=7), and the resulting solid was filtered and dried to obtain 2-amino-2-(3-chlorophenyl)propanoic acid (205.00 g) as a white solid, which was used in the next step without further purification.

[0204] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.56 (s, 1H), 7.46 (d, J = 7.60 Hz, 1H), 7.37 (t, J = 7.60 Hz, 1H), 7.35 (d, J = 7.60 Hz, 1H), 1.65 (s, 3H); MS: m / z 200.1 (M+1).

[0205] Example 3, Step 3: Preparation of 2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)propanoic acid [ka] A suspension of 2-amino-2-(3-chlorophenyl)propanoic acid (from Step 2 of Example 3) (286.00 g, 1430.00 mmol) in a mixed solvent of tetrahydrofuran:water (1:1; 5000 mL), to which sodium bicarbonate (842.00 g, 10000.0 mmol) was added, followed by di-tert-butyl dicarbonate (658.00 mL, d: 0.950 g / cm³). 32870.00 mmol) was added, and the mixture was stirred at ambient temperature for 15 days. The reaction mixture was diluted with water (2000 mL) and extracted with ethyl acetate (4 x 5000 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain 2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)propanoic acid (410.00 g) as a colorless gum, which was used in the next step without further purification.

[0206] 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (dd, J = 6.40 Hz, 2H), 7.16 (t, J = 6.40 Hz, 2H), 1.70 (s, 3H), 1.34 (s, 9H); MS: m / z 200.1 [(M+1)-Boc].

[0207] Example 3, Step 4: Preparation of tert-butyl N-[2-(3-chlorophenyl)-1-hydroxypropan-2-yl]carbamate [ka] A solution of 2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)propanoic acid (from step 3 of Example 3) (250.00 g, 834.00 mmol) in dry tetrahydrofuran (2000 mL) is mixed with triethylamine (349.0 mL, d=0.726 g / cm³). 3 (2500.0 mmol), followed by isobutyl chloroformate (130.0 mL, d=1.053 g / cm³). 31080.0 mmol of sodium borohydride was added at 0°C and the mixture was stirred at the same temperature for 4 hours. The resulting solid was filtered off at 0°C, and the residue was washed with tetrahydrofuran (400 mL). The combined filtrate was added to a cooled mixture of sodium borohydride (221.00 g, 5840.00 mmol) in water (500 mL). The reaction mixture was slowly warmed to ambient temperature and stirred for 48 hours. The reaction mixture was quenched with ice-cold water (1000 mL), extracted with ethyl acetate (4 x 5000 mL), the combined organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated to obtain a yellowish liquid (250.00 g). This was purified by gravity column chromatography using 60-120 silica gel, and the product was eluted with 30-35% ethyl acetate in petroleum ether to obtain tert-butyl N-[2-(3-chlorophenyl)-1-hydroxypropan-2-yl]carbamate (95.00 g) as a colorless liquid.

[0208] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.34 (s, 1H), 7.32 (d, J = 7.60 Hz, 1H), 7.28 (t, J = 7.40 Hz, 1H), 7.25 (d, J = 7.20 Hz, 1H), 3.57 (d, J = 6.40 Hz, 2H), 1.52 (s, 3H), 1.34 (s, 9H); MS: m / z 186.1 [(M+1)-Boc].

[0209] Example 3, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate [ka] Under a nitrogen atmosphere, a solution of tert-butyl(2-(3-chlorophenyl)-1-hydroxypropan-2-yl) carbamate (from step 4 of Example 3) (170.00 g, 595.00 mmol) in dry dichloromethane (1500 mL) was mixed with triethylamine (250.00 mL, d=0.726 g / cm³). 3 (1780.00 mmol), followed by pivaloyl chloride (145.50 mL, d=0.985 g / cm³). 3 1190.00 mmol of propyl

[0210] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.35 (d, J = 8.00 Hz, 1H), 7.32 (s, 1H), 7.30 (d, J = 7.20 Hz, 1H), 7.28 (t, J = 6.80 Hz, 1H), 4.30 (d, J = 10.40 Hz, 1H), 4.21 (d, J = 10.80 Hz, 1H), 1.50 (s, 3H), 1.31 (s, 9H), 1.10 (s, 9H); MS: m / z 270.2 [(M+1)-Boc].

[0211] Example 3, Step 6: Preparation of 2-amino-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate hydrochloride [ka] Under a nitrogen atmosphere, a solution of 2-{[(tert-butoxy)carbonyl]amino}-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (from Example 3, Step 5) (218.00 g, 589.00 mmol) in dry dichloromethane (1200 mL) was added dropwise to a 4 M HCl solution in dioxane (442.00 mL, 1770.00 mmol) at 0°C, and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under high vacuum to obtain 2-amino-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate hydrochloride (180.00 g) as a yellowish gum, which was used in the next step without further purification.

[0212] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.64 (s, 1H), 7.51-7.47 (m, 3H), 4.44 (d, J = 11.60 Hz, 1H), 4.26 (d, J = 11.60 Hz, 1H), 1.69 (s, 3H), 1.04 (s, 9H); MS: m / z 270.1 [(M+1)-HCl].

[0213] Example 3, Step 7: Preparation of 2-(3-chlorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate [ka] To a solution of 2-amino-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate hydrochloride (from Example 3, Step 6) (90.00 g, 294.00 mmol) in dry dichloromethane (900 mL), 10% sodium bicarbonate aqueous solution (900 mL) was added at 0°C. After 30 minutes, thiophosgene (33.80 mL, d=1.5 g / cm³) was added. 3441.00 mmol) was added and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was extracted with dichloromethane (3 x 2000 mL), the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow liquid (95.00 g). This was used as the eluent and purified by gravity column chromatography on 60-120 mesh silica gel using 3-5% ethyl acetate in hexane to obtain 2-(3-chlorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate (75.00 g) as a yellow liquid.

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.55-7.45 (m, 3H), 4.45 (dd, J = 11.20 Hz, 2H), 1.79 (s, 3H), 1.11 (s, 9H).

[0215] Example 3, Step 8: Preparation of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from Example 1, Step 5) (4 g, 13.70 mmol) in a mixed solvent of dichloromethane:methanol (1:1; 70 mL), [2-(3-chlorophenyl)-2-isothiocyanatopropyl]2,2-dimethylpropanoate (from Example 3, Step 7) (3.56 g, 11.40 mmol) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in a water bath at 30°C to obtain 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (7.00 g) as a yellow gum, which was used in the next step without purification. MS: m / z 516.2 / 517.4 (M+1).

[0216] Example 3, Step 9: Preparation of 2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}aminopropyl 2,2-dimethylpropanoate [ka] To a solution of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (Example 3, Step 8) (7.00 g, 13.60 mmol) in methanol (40 mL), iodoacetic acid (3.78 g, 20.30 mmol) was added, and the mixture was refluxed for 1 hour. The reaction mixture was concentrated, and the solvent methanol was removed at 30°C to obtain a red gum (6.50 g). This was purified by preparative HPLC (TFA / acetonitrile) to obtain 2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate (0.800 g), which was isolated as a trifluoroacetate, and obtained as a yellow gum.

[0217] 1 H NMR (400 MHz, AcOH-d4) δ 7.59 (s, 2H), 7.52-7.50 (m, 1H), 7.4 4-7.38 (m, 2H), 7.34 (d, J = 8.00 Hz, 1H), 7.26 (t, J = 8.00 Hz, 1H), 7.22 (d, J = 1.60 Hz, 1H), 7.17 (d, J = 7.60 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J = 11.60 Hz, 1H), 4.46 (d, J = 11.60 Hz, 1H), 1.96 (s, 3H), 1.18 (s, 9H); MS: m / z 482.4 / 484.1 (M+1).

[0218] The above product was separated into two enantiomers by chiral SFC using the following method: Column: YMC cellulose-SB; Mobile phase: 0.5% isopropylamine in isopropyl alcohol; Cosolvent: 30% CO2; Flow rate: 3 mL / min, Pressure: 100 bar, Temperature: 35°C.

[0219] Example 3-9a: 2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate (enantiomer A) The first enantiomer to elute from the column was enantiomer A: [ka]

[0220] 1 H NMR (400 MHz, AcOH-d4) δ 7.59 (s, 2H), 7.52-7.50 (m, 1H), 7.44-7.38 (m, 2H), 7.34 (d, J = 8.00 Hz, 1H), 7.26 (t, J = 8.00 Hz, 1H), 7.22 (d, J = 1.60 Hz, 1H), 7.17 (d, J = 7.60 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J = 11.60 Hz, 1H), 4.46 (d, J = 11.60 Hz, 1H), 1.96 (s, 3H), 1.18 (s, 9H); MS: m / z 482.4 / 484.1 (M+1).

[0221] Example 3-9b: 2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate (enantiomer B) The second enantiomer eluted from the column was enantiomer B. [ka]

[0222] 1 H NMR (400 MHz, AcOH-d4) δ 7.59 (s, 2H), 7.52-7.50 (m, 1H), 7.44-7.38 (m, 2H), 7.34 (d, J = 8.00 Hz, 1H), 7.26 (t, J = 8.00 Hz, 1H), 7.22 (d, J = 1.60 Hz, 1H), 7.17 (d, J = 7.60 Hz, 1H), 5.40 (s, 2H), 4.55 (d, J = 11.60 Hz, 1H), 4.46 (d, J = 11.60 Hz, 1H), 1.96 (s, 3H), 1.18 (s, 9H); MS: m / z 482.4 / 484.1 (M+1).

[0223] Example 3: Preparation of 2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka] To a solution of 2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate; trifluoroacetic acid (Example 3, Step 9) (0.090 g, 0.151 mmol) in methanol (10 mL), 0.900 mL, 0.453 mmol of 0.5 M sodium hydroxide in methanol was added dropwise, and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with 1 mL of 1.5 N hydrochloride solution and concentrated under reduced pressure at 30°C to obtain (0.070 g) as a brown gum. This was purified by preparative HPLC using 0.1% TFA in acetonitrile:water to isolate 2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol (0.040 g) as a trifluoroacetate, which was obtained as a brown gum.

[0224] 1 H NMR (400 MHz, AcOH-d4) δ 7.57 (d, J = 2.88 Hz, 2H), 7.50-7.48 (m, 1H), 7.41-7.35 (m, 3H), 7.31-7.24 (m, 2H), 7.20 (d, J = 1.48 Hz, 1H), 5.40 (d, J = 5.64 Hz, 2H), 4.36 (d, J = 12.04 Hz, 1H), 4.08 (d, J = 11.96 Hz, 1H), 1.76 (s, 3H); MS: m / z 398.1 (M+1).

[0225] Example 3a: Preparation of (-)-2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka] To a solution of 2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate (Example 3-9a, enantiomer A) (0.180 g, 0.302 mmol) in methanol (20 mL), 0.5 M sodium hydroxide (2.42 mL, 1.21 mmol) in methanol was added dropwise, and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with 1.5 N hydrochloride solution (2 mL) and concentrated under reduced pressure at 30°C to obtain a brown gum (0.15 g). This was purified by preparative HPLC using 0.1% TFA in acetonitrile:water, and (-)-2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol (0.065 g), isolated as trifluoroacetate, was obtained as brown gum.

[0226] 1 H NMR (400 MHz, AcOH-d4) δ 7.57 (d, J = 2.88 Hz, 2H), 7.50-7.48 (m, 1H), 7.41-7.35 (m, 3H), 7.31-7.24 (m, 2H), 7.20 (d, J = 1.48 Hz, 1H), 5.40 (d, J = 5.64 Hz, 2H), 4.36 (d, J = 12.04 Hz, 1H), 4.08 (d, J = 11.96 Hz, 1H), 1.76 (s, 3H); MS: m / z 398.1 (M+1); SOR: [α] D 22.9 (-) 9.12, (MeOH, c = 0.5).

[0227] Example 3b: Preparation of (+)-2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka] To a solution of 2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate (Example 3-9b, enantiomer B) (0.170 g, 0.285 mmol) in methanol (20 mL), 0.5 N sodium hydroxide (2.28 mL, 1.14 mmol) in methanol was added dropwise, and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with 1.5 N hydrochloride solution (2 mL) and concentrated under reduced pressure at 30°C to obtain a brown gum (0.15 g). This was purified by preparative HPLC using 0.1% TFA in acetonitrile:water, and (+)-2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol (0.060 g) was isolated as a trifluoroacetate and obtained as a brown gum.

[0228] 1 H NMR (400 MHz, AcOH-d4) δ 7.58-7.57 (m, 2H), 7.50-7.47 (m, 1H), 7.41-7.36 (m, 3H), 7.32-7.26 (m, 2H), 7.21 (d, J = 1.60 Hz, 1H), 5.40 (d, J = 4.56 Hz, 2H), 4.36 (d, J = 12.08 Hz, 1H), 4.08 (d, J = 12.08 Hz, 1H), 1.77 (s, 3H); MS: m / z 398.1 (M+1); SOR: [α] D 22.9 (+) 9.20, (MeOH, c = 0.5).

[0229] Example 4: Preparation of 4-[(2-imino-2,3-dihydro-1,3-oxazol-3-yl)methyl]-N-{1-[3-(trifluoromethyl)phenyl]ethyl}-1H-1,3-benzodiazole-2-amine [ka]

[0230] Example 4, Step 1: Preparation of 1-(1-isothiocyanatoethyl)-3-(trifluoromethyl)benzene [ka] To an ice-cold solution of 1-[3-(trifluoromethyl)phenyl]ethanamine (commercial product) (10.0 g, 52.86 mmol) in dichloromethane (200 mL), add 10% sodium bicarbonate solution (200 mL), followed by thiophosgene (10.10 mL, d=1.50 g / cm³). 3 (132.15 mmol) was added, and the entire mixture was stirred at ambient temperature for 30 minutes. The organic layer was separated, washed with brine (80 mL), dried over sodium sulfate, filtered, and concentrated to obtain a yellow gum (11.00 g). The product was purified by chromatography on a Grace apparatus using a 60.0 g pre-packed flash cartridge packed with 60 Å, 40-63 μm normal-phase silica gel, and the product was eluted with 8-12% ethyl acetate in hexane to obtain 1-(1-isothiocyanatoethyl)-3-(trifluoromethyl)benzene (12.00 g) as a pale yellow liquid.

[0231] 1 H NMR (400 MHz, DMSO-d6) δ 7.65-7.77 (m, 4H), 5.41 (q, J = 5.40 Hz, 1H), 1.65 (d, J = 8.80 Hz, 3H).

[0232] Example 4, Step 2: Preparation of 3-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-{1-[3-(trifluoromethyl)phenyl]ethyl}thiourea and 3-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-{1-[3-(trifluoromethyl)phenyl]ethyl}thiourea (mixture of positional isomers) [ka] To a solution of 1-(1-isothiocyanatoethyl)-3-(trifluoromethyl)benzene (Example 4, from Step 1) (0.414 g, 1.791 mmol) in a mixed solvent of dichloromethane:methanol (4:2; 6 mL), 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (Example 1, from Step 5) (0.350 g, 1.710 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated to obtain 3-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-{1-[3-(trifluoromethyl)phenyl]ethyl}thiourea and 3-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-{1-[3-(trifluoromethyl)phenyl]ethyl}thiourea (as a mixture of inseparable positional isomers) (0.750 g) as a brown gum, which was used in the next step without purification. MS: m / z 436.1 (M+1)

[0233] Example 4: Preparation of 4-[(2-imino-2,3-dihydro-1,3-oxazol-3-yl)methyl]-N-{1-[3-(trifluoromethyl)phenyl]ethyl}-1H-1,3-benzodiazole-2-amine [ka] 3-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-{1-[3-(trifluoromethyl)phenyl]ethyl}thiourea and 3-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-{1-[3-(trifluoromethyl)phenyl]ethyl}thiourea (as a mixture of inseparable positional isomers) (from Example 4, Step 2) (0.450 g, 1.03 mmol) were dissolved in methanol (8 mL), to which iodoacetic acid (0.288 g, 1.55 mmol) was added, and the mixture was stirred at 65 °C for 1.5 hours. The reaction mixture was concentrated at 25 °C to obtain yellow gum (0.500 g). This was purified by preparative HPLC using the TFA method, and 4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-N-{1-[3-(trifluoromethyl)phenyl]ethyl}-1H-1,3-benzodiazole-2-amine (0.300 g) was isolated as a trifluoroacetate and obtained as an off-white solid.

[0234] 1 H NMR (400 MHz, AcOH-d4) δ 7.78 (t, J = 1.00 Hz, 2H), 7.63-7.53 (m, 4H), 7.32 (t, J = 7.92 Hz, 1H), 7.18 (t, J = 1.44 Hz, 2H), 5.42 (d, J = 4.60 Hz, 2H), 5.21 (d, J = 7.64 Hz, 1H), 1.73 (d, J = 7.72 Hz, 3H); MS: m / z 402.1 (M+1).

[0235] Example 5: Preparation of 2-(3-chlorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka]

[0236] Example 5, Step 1: 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-4-methyl-2,3-dihydro-1,3-oxazole-2-imine hydrobromide [ka] To a solution of 4-(bromomethyl)-2,1,3-benzothiadiazole (Example 1, Step 3) (20.00 g, 87.30 mmol) in N,N-dimethylformamide (100 mL), 4-methyloxazole-2-amine (10.30 g, 105.00 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated to obtain a yellow gum (22.00 g). This was purified by chromatography in a Grace apparatus using a 120.00 g pre-packed flash cartridge packed with 60 Å, 40-63 μm normal-phase silica gel. The product was eluted with 25-30% ethyl acetate in hexane to obtain 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-4-methyl-2,3-dihydro-1,3-oxazole-2-imine hydrobromide (15.20 g) as a yellow solid.

[0237] 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (bs, 2H), 8.13 (dd, J = 3.60, 8.20 Hz, 1H), 7.95 (s, 1H), 7.76 (dd, J = 2.00, 6.60 Hz, 1H), 7.68 (t, J = 6.00 Hz, 1H), 5.63 (s, 2H), 1.86 (s, 3H); MS: m / z 247.1 [(M+1)-HBr].

[0238] Example 5, Step 2: Preparation of 3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine [ka] To a degassed solution of 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-4-methyl-2,3-dihydro-1,3-oxazole-2-imine hydrobromide (Example 5, from Step 1) (1.00 g, 3.08 mmol) in dry methanol (100 mL), Raney nickel (3.00 g, 300% w / w, pre-washed 5 times with dry methanol) was added. The resulting reaction mixture was then subjected to a hydrogen atmosphere and a bladder pressure of approximately 1.5 kg / cm². 2 The mixture was stirred at ambient temperature for 16 hours. The reaction mixture was filtered through a Celite bed, and the bed was washed with methanol (750 mL). The combined filtrate was concentrated to obtain 3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (0.650 g) as a black gum, which was used in the next step without further purification. MS: m / z 219.2 (M+1).

[0239] Example 5, Step 3: Preparation of 2-[({2-amino-3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from Example 5, Step 2) (0.210 g, 0.962 mmol) in a mixed solvent of dichloromethane:methanol (4:1; 6 mL), [2-(3-chlorophenyl)-2-isothiocyanatopropyl]2,2-dimethylpropanoate (from Example 3, Step 7) (0.300 g, 0.962 mmol) was added, and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was concentrated in a water bath at 30°C to obtain 2-[({2-amino-3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (0.510 g) as a brown gum, which was used in the next step without further purification. MS: m / z 531.1 (M+1).

[0240] Example 5, Step 4: Preparation of 2-(3-chlorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}aminopropyl 2,2-dimethylpropanoate [ka] To a solution of 2-[({2-amino-3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chlorophenyl)propyl 2,2-dimethylpropanoate (from Example 5, Step 3) (0.300 g, 0.566 mmol) in methanol (15 mL), iodoacetic acid (0.126 g, 0.679 mmol) was added, and the mixture was stirred at 65°C for 1 hour. The reaction mixture was concentrated under high vacuum, the residue was diluted with 25 mL of 10% sodium bicarbonate aqueous solution, and extracted with a mixed solvent of dichloromethane / methanol (9:1) (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain a brown gum (0.280 g), which was purified by preparative HPLC using the TFA method to obtain 2-(3-chlorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate (0.090 g) isolated as trifluoroacetate, and the brown gum was obtained. MS: m / z 497.2 (M+1).

[0241] Example 5: Preparation of 2-(3-chlorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka] To a solution of 2-(3-chlorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate; trifluoroacetic acid (from Example 5, Step 4) (0.090 g, 0.147 mmol) in methanol (3 mL), a solution of 1.5 M sodium hydroxide in methanol (0.400 mL, 0.590 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with 1.5 N hydrochloric acid (2 mL), and the resulting reaction mixture was concentrated under high vacuum to obtain a brown gum (0.100 g). This was purified by preparative HPLC using the TFA method, and 2-(3-chlorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol (0.020 g), isolated as a trifluoroacetate, was obtained as a brown solid.

[0242] 1 H NMR (400 MHz, AcOH-d4) δ 7.59 (s, 1H), 7.50 (d, J = 6.76 Hz, 1H), 7.44 (s, 1H), 7.40 (t, J = 7.32 Hz, 1H), 7.35 (d, J = 8.00 Hz, 2H), 7.24 (t, J = 7.96 Hz, 1H), 6.86 (d, J = 7.68 Hz, 1H), 5.46 (s, 2H), 4.36 (d, J = 12.08 Hz, 1H), 4.09 (d, J = 12.12 Hz, 1H), 2.09 (s, 3H), 1.77 (s, 3H); MS: m / z 412.2 (M+1).

[0243] Example 6: Preparation of N-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine [ka]

[0244] Example 6, Step 1: Preparation of tert-butyl(2-(3-chlorophenyl)-1-methoxypropan-2-yl)carbamate [ka] In acetonitrile (150 mL) under a nitrogen atmosphere, tert-butyl(2-(3-chlorophenyl)-1-hydroxypropan-2-yl) carbamate (from Example 3, Step 4) (6.00 g, 21.00 mmol) was dissolved, then silver oxide (24.30 g, 105.00 mmol) was added, followed by iodomethane (12.00 mL, d=2.28 g / cm³). 3 0.189 mmol) was added, and the resulting mixture was stirred at ambient temperature for 48 hours. The reaction mixture was filtered through a Celite bed, the bed was washed with ethyl acetate (3 x 500 mL), and the combined filtrate was concentrated under vacuum to obtain a brown gum (6.00 g). This was purified by chromatography in a Grace apparatus using an 80.00 g pre-packed flash cartridge packed with normal-phase silica gel 60 Å, 40-63 μm. The product was eluted with 18% ethyl acetate in petroleum ether to obtain tert-butyl(2-(3-chlorophenyl)-1-methoxypropan-2-yl)carbamate (4.50 g) as a yellow gum.

[0245] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.35 (s, 1H), 7.32 (d, J = 7.96 Hz, 2H), 7.27 (t, J = 6.76 Hz, 1H), 3.47 (s, 2H), 3.22 (s, 3H), 1.53 (s, 3H), 1.19 (s, 9H); MS: m / z 200.1 [(M+1)-Boc].

[0246] Example 6, Step 2: Preparation of 2-(3-chlorophenyl)-1-methoxypropane-2-amine hydrochloride [ka] Under a nitrogen atmosphere, a solution of tert-butyl(2-(3-chlorophenyl)-1-methoxypropan-2-yl) carbamate (from Example 6, Step 1) (4.50 g, 15.00 mmol) in dry dichloromethane (50 mL) was added dropwise with a 4 M HCl solution in dioxane (11.25 mL, 45.00 mmol) at 0°C, and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under high vacuum to obtain 2-(3-chlorophenyl)-1-methoxypropan-2-amine hydrochloride (3.50 g) as a yellowish gum, which was used in the next step without further purification.

[0247] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.50 (s, 1H), 7.46 (t, J = 7.60 Hz, 1H), 7.43-7.39 (m, 2H), 3.67 (d, J = 10.40 Hz, 1H), 3.56 (d, J = 10.40 Hz, 1H), 3.27 (s, 3H), 1.54 (s, 3H); MS: m / z 200.1 [(M+1)-HCl].

[0248] Example 6, Step 3: Preparation of 1-chloro-3-(2-isothiocyanato-1-methoxypropan-2-yl)benzene [ka] To an ice-cold solution of 2-(3-chlorophenyl)-1-methoxypropan-2-amine hydrochloride (Example 6, from Step 2) (3.00 g, 12.70 mmol) in dichloromethane (50 mL), add 10% sodium bicarbonate solution (50 mL), then thiophosgene (1.20 mL, d=1.50 g / cm³). 3 (15.20 mmol) was added, and the entire mixture was stirred at ambient temperature for 30 minutes. The organic layer was separated, washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated to obtain 1-chloro-3-(2-isothiocyanato-1-methoxypropan-2-yl)benzene (2.10 g) as a pale yellow liquid, which was used in the next step without further purification.

[0249] 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 7.45 (t, J = 7.20 Hz, 1H), 7.41 (dd, J = 2.40, 9.80 Hz, 2H), 3.68 (q, J = 10.40 Hz, 2H), 3.33 (s, 3H), 1.58 (s, 3H).

[0250] Example 6, Step 4: Preparation of 3-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea and 3-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea (a mixture of positional isomers). [ka] To a solution of 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine in dichloromethane:methanol (4:2; 6 mL), 1-chloro-3-(2-isothiocyanato-1-methoxypropan-2-yl)benzene (from Example 6, Step 3) (0.470 g, 1.96 mmol) was added, and the mixture was stirred at ambient temperature for 96 hours. The reaction mixture was concentrated under high vacuum at 25°C to obtain 3-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea and 3-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea (as a mixture of inseparable positional isomers) (0.850 g) as a brown gum, which was used in the next step without further purification. MS: m / z 446.2 (M+1).

[0251] Example 6: Preparation of N-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine [ka] To a solution of 3-{2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea and 3-{2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea (as a mixture of inseparable positional isomers) (0.400 g, 0.896 mmol) in methanol (5 mL), iodoacetic acid (0.250 g, 1.34 mmol) was added, and the mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated to obtain a dark brown gum (0.450 g), which was purified by preparative HPLC using the TFA method to isolate N-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine (0.060 g) as a trifluoroacetate, which was then obtained as a brown gum.

[0252] 1 H NMR (400 MHz, AcOH-d4) δ 7.58 (d, J = 1.00 Hz, 1H), 7.54 (s, 1H), 7.46-7.44 (m, 1H), 7.39-7.37 (m, 3H), 7.29 (d, J = 4.60 Hz, 2H), 7.24 (d, J = 7.64 Hz, 1H), 5.42 (d, J = 7.72 Hz, 2H), 4.03 (d, J = 10.40 Hz, 1H), 3.79 (d, J = 10.0 Hz, 1H), 3.49 (s, 3H), 1.81 (s, 3H); MS: m / z 412.2 (M+1).

[0253] Example 7: Preparation of 4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-N-{2-[3-(trifluoromethyl)phenyl]propan-2-yl}-1H-1,3-benzodiazole-2-amine [ka] Starting from commercially available 2-[3-(trifluoromethyl)phenyl]propan-2-amine, the title compound was prepared by the method described in Example 2 and isolated as trifluoroacetate.

[0254] 1 H NMR (400 MHz, AcOH-d4) δ 7.86 (s, 1H), 7.84 (d, J = 8.40 Hz, 1H), 7.67 (dd, J = 7.60 Hz, 2H), 7.60 (dd, J = 1.60, 8.20 Hz, 1H), 7.33 (t, J = 7.60 Hz, 1H), 7.27 (dd, J = 1.60, 8.80 Hz, 3H), 5.40 (s, 2H), 1.92 (s, 6H); MS: m / z 416.1 (M+1).

[0255] Example 8: Preparation of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka]

[0256] Example 8, Step 1: Preparation of 5-(3-chloro-4-fluorophenyl)-5-methylimidazolidined-2,4-dione [ka] To a stirred solution of 1-(3-chloro-4-fluorophenyl)ethane-1-one (commercial product) (45.00 g, 261.00 mmol) in an ethanol / water (1:1; 1200 mL) mixed solvent, ammonium carbonate (125.00 g, 1300.00 mmol) was added, followed by potassium cyanide (20.40 g, 313.00 mmol), and the mixture was stirred at 65°C for 18 hours. The reaction mixture was poured into ice-cold water (1500 mL) and stirred for 30 minutes. The resulting solid was filtered and dried to obtain 5-(3-chloro-4-fluorophenyl)-5-methylimidazolidined-2,4-dione (55.00 g) as an off-white solid, which was used in the next step without further purification.

[0257] 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (bs, 1H), 8.65 (s, 1H), 7.65 (d, J = 6.80 Hz, 1H), 7.52 (s, 1H,), 7.50 (d, J = 6.80 Hz, 1H), 1.65 (s, 3H); MS: m / z 243.0 (M+1).

[0258] Example 8, Step 2: Preparation of 2-amino-2-(3-chloro-4-fluorophenyl)propanoic acid [ka] 5-(3-chloro-4-fluorophenyl)-5-methylimidazolidined-2,4-dione (from Example 8, Step 1) (55.00 g, 227.00 mmol) was dissolved in 600 mL of 10% aqueous sodium hydroxide solution, and the mixture was stirred at 110°C for 120 hours. The reaction mixture was neutralized with 500 mL of 6.0 N HCl (to adjust pH to 7), the resulting solid was filtered, washed with 150 mL of petroleum ether, and dried to obtain 49.00 g of 2-amino-2-(3-chloro-4-fluorophenyl)propanoic acid as a white solid, which was used in the next step without further purification.

[0259] 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (bs, 2H), 7.69 (d, J = 6.80 Hz, 1H), 7.48 (s, 1H), 7.37 (d, J = 7.38 Hz, 1H), 1.61 (s, 3H); MS: m / z 218.1 (M+1).

[0260] Example 8, Step 3: Preparation of 2-((tert-butoxycarbonyl)amino)-2-(3-chloro-4-fluorophenyl)propanoic acid [ka] A suspension of 2-amino-2-(3-chloro-4-fluorophenyl)propanoic acid (from Example 8, Step 2) (75.00 g, 345.00 mmol) in a mixed solvent of tetrahydrofuran:water (1:1; 1500 mL) is added, followed by sodium bicarbonate (29.00 g, 345.00 mmol), and then di-tert-butyl dicarbonate (158.00 mL, d: 0.950 g / cm³). 3 689.00 mmol) was added, and the mixture was stirred at ambient temperature for 72 hours. The reaction mixture was diluted with water (750 mL) and extracted with ethyl acetate (4 x 1500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain 2-((tert-butoxycarbonyl)amino)-2-(3-chloro-4-fluorophenyl)propanoic acid (100.00 g) as a colorless gum, which was used in the next step without further purification.

[0261] 1 H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J = 7.80 Hz, 1H), 7.25 (d, J = 7.60 Hz, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 1.71 (s, 3H), 1.33 (s, 9H); MS: m / z 316.0 (M-1).

[0262] Example 8, Step 4: Preparation of tert-butyl N-[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]carbamate [ka] A solution of 2-((tert-butoxycarbonyl)amino)-2-(3-chloro-4-fluorophenyl)propanoic acid (from step 3 of Example 8) (70.00 g, 220.00 mmol) in dry tetrahydrofuran (500 mL) is mixed with triethylamine (92.10 mL, d=0.726 g / cm³). 3 (661.00 mmol) was added, followed by isobutyl chloroformate (34.25 mL, d = 1.053 g / cm³). 3 263.00 mmol of sodium borohydride was added at 0°C, and the mixture was stirred at the same temperature for 4 hours. The formed solid was filtered off at 0°C, and the residue was washed with tetrahydrofuran (100 mL). The combined filtrate was added to a cooled mixture of sodium borohydride (58.30 g, 1540.00 mmol) in water (75 mL). The reaction mixture was slowly warmed to ambient temperature and stirred for 30 hours. The reaction mixture was quenched with ice-cold water (500 mL), extracted with ethyl acetate (4 x 2000 mL), the combined organic layer was washed with brine (75 mL), dried over sodium sulfate, filtered, and concentrated to obtain a yellowish liquid (70.00 g). This was purified by gravity column chromatography using 60-120 silica gel, and the product was eluted with 25-30% ethyl acetate in petroleum ether to obtain tert-butyl(2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)carbamate (32.50 g) as a colorless liquid.

[0263] 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 6.80 Hz, 1H), 7.34 (d, J = 8.40 Hz, 1H), 7.30 (s, 1H), 6.85 (bs, 1H), 4.56 (t, J = 5.20 Hz, 1H), 3.45 (d, J = 6.00 Hz, 2H), 1.55 (s, 3H), 1.26 (s, 9H); MS: m / z 304.0 (M+1).

[0264] Example 8, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate [ka] To a solution of tert-butyl N-[1-(3-chloro-4-fluorophenyl)-2-hydroxy-1-methyl-ethyl]carbamate (from Example 8, Step 4) (55.0 g, 181.00 mmol) in dry dichloromethane, triethylamine (75.50 mL, 543.00 mmol) was added, followed by the addition of 2,2-dimethylpropanoyl chloride (33.40 mL, 272.00 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with water (500 mL), and the aqueous layer was extracted with dichloromethane (4 x 1000 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated to obtain a crude mass (70.50 g) as a yellow liquid. This was purified by gravity column chromatography on 601-20 silica gel, and the product was eluted with 30% ethyl acetate in petroleum ether to obtain 2-{[(tert-butoxy)carbonyl]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (40.20 g) as a yellow oil.

[0265] 1H NMR (400 MHz, DMSO-d6) δ 7.47 (dd, J = 1.60, 7.00 Hz, 1H), 7.36-7.32 (m, 2H), 4.32-4.23 (m, 2H), 1.55 (s, 3H), 1.18 (s, 9H), 1.17 (s, 9H); MS: m / z 288.2 [(M+1)-Boc].

[0266] Example 8, Step 6: Preparation of 2-amino-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate hydrochloride [ka] To a stirred solution of 2-{[(tert-butoxy)carbonyl]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (from Example 8, Step 5) (40.0 g, 103.00 mmol) in dichloromethane (300 mL), 4M HCl (103.00 mL, 413.00 mmol) in dioxane was added at 0°C, and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated to obtain 2-amino-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate hydrochloride (32.30 g) as a brown gum, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.80 Hz, 1H), 7.63-7.60 (m, 1H), 7.55-7.49 (m, 1H), 4.44 (d, J = 15.60 Hz, 1H), 4.29 (d, J = 15.20 Hz, 1H), 1.70 (s, 3H), 1.11 (s, 9H); MS: m / z 288.2 [(M+1)-HCl].

[0267] Example 8, Step 7: Preparation of [2-(3-chloro-4-fluorophenyl)-2-isothiocyanatopropyl]2,2-dimethylpropanoate [ka] To a stirred solution of 2-amino-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate hydrochloride (from Example 8, Step 6) (30.0 g, 92.50 mmol) in dichloromethane (300 mL), 10% sodium bicarbonate aqueous solution (300 mL) was added, followed by thiophosgene (14.2 mL, 185.00 mmol) at 0°C, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with water (100 mL), extracted with dichloromethane (3 x 1000 mL), and the combined organic layer was dried over sodium sulfate, filtered, and concentrated to obtain a yellow liquid (33.5 g). This was purified by gravity column chromatography on 60-120 silica gel, and the product was eluted with 10% ethyl acetate in petroleum ether to obtain [2-(3-chloro-4-fluorophenyl)-2-isothiocyanatopropyl]2,2-dimethylpropanoate (18.20 g) as a yellow oil.

[0268] 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (dd, J = 2.00, 7.00 Hz, 1H), 7.54-7.50 (m, 2H), 4.44 (dd, J = 11.20, 17.20 Hz, 2H), 1.80 (s, 3H), 1.11 (s, 9H);

[0269] Example 8, Step 8: Preparation of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from Example 1, Step 5) (1.70 g, 8.32 mmol) in a mixed solvent of dichloromethane:methanol (1:1; 40 mL), [2-(3-chloro-4-fluorophenyl)-2-isothiocyanatopropyl]2,2-dimethylpropanoate (from Example 8, Step 7) (1.50 g, 3.18 mmol) was added and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated in a water bath at 30°C to obtain 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)-amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (3.20 g) as a yellowish gum, which was used in the next step without purification. MS: m / z 534.2 / 536.2 (M+1).

[0270] Example 8, Step 9: Preparation of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate [ka] To a solution of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (Example 8, Step 8) (3.20 g, 5.99 mmol) in methanol (25 mL), iodoacetic acid (1.67 g, 8.99 mmol) was added, and the mixture was refluxed for 1 hour. The reaction mixture was concentrated and the solvent methanol was removed to obtain a red gum (3 g). This was purified by preparative HPLC (TFA: acetonitrile) to obtain 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate (0.800 g), which was isolated as a trifluoroacetate, and obtained as a yellow gum.

[0271] 1H NMR (400 MHz, AcOH-d4) δ 7.70 (dd, J = 6.84, 2.36 Hz, 1H), 7.59 (d, J = 1.68 Hz, 1H), 7.56-7.53 (m, 1H), 7.37 (dd, J = 7.22, 1.88 Hz, 1H), 7.33-7.26 (m, 3H), 7.24 (d, J = 1.64 Hz, 1H), 5.40 (s, 2H), 4.54 (d, J = 11.64 Hz, 1H), 4.46 (d, J = 11.60 Hz, 1H), 1.99 (s, 3H), 1.19 (s, 9H); MS: m / z 500.1 / 502.1 [(M+1)-TFA].

[0272] Example 8: Preparation of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka] To a solution of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate; trifluoroacetic acid (Example 8, Step 9) (0.780 g, 1.27 mmol) in methanol (80 mL), 0.5 N sodium hydroxide (10.20 mL, 5.08 mmol) in methanol was added dropwise, and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with 1.5N hydrochloride solution (4 mL) and concentrated under reduced pressure at 30°C to obtain a brown gum (0.7 g). This was purified by preparative HPLC using 0.1% TFA in acetonitrile:water, and 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol (0.180 g), isolated as trifluoroacetate, was obtained as the brown gum.

[0273] 1 H NMR (400 MHz, AcOH-d4) δ 7.67 (dd, J = 6.80, 2.36 Hz, 1H), 7.57 (s, 1H), 7.53-7.49 (m, 1H), 7.40 (d, J = 7.48 Hz, 1H), 7.31-7.22 (m, 3H), 7.21 (d, J = 1.52 Hz, 1H), 5.37 (dd, J = 21.86, 7.16 Hz, 2H), 4.32 (d, J = 12.08 Hz, 1H), 4.07 (d, J = 12.08 Hz, 1H), 1.77 (s, 3H); MS: m / z 416.1 / 418.1 (M+1).

[0274] The above product was separated into two enantiomers by chiral SFC using the following method to obtain two enantiomers: column Chiralcel OZ-H, mobile phase: 0.5% isopropylamine in methanol, cosolvent 30% CO2; flow rate: 3 mL / min, pressure: 100 bar, temperature: 35°C.

[0275] Example 8a: (-)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol The (-) enantiomer was the first compound to elute from the column and was isolated as trifluoroacetate. [ka]

[0276] 1 H NMR (400 MHz, AcOH-d4) δ 7.67 (dd, J = 6.80, 2.36 Hz, 1H), 7.57 (s, 1H), 7.53-7.49 (m, 1H), 7.40 (d, J = 7.48 Hz, 1H), 7.31-7.22 (m, 3H), 7.21 (d, J = 1.52 Hz, 1H), 5.37 (dd, J = 21.86, 7.16 Hz, 2H), 4.32 (d, J = 12.08 Hz, 1H), 4.07 (d, J = 12.08 Hz, 1H), 1.77 (s, 3H); MS: m / z 416.1 / 418.1 (M+1); SOR: [α] D 24.2 (-) 7.80, (MeOH, c = 1.0).

[0277] Example 8b: (+)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol The (+) enantiomer was the second compound eluted from the column and isolated as trifluoroacetate. [ka]

[0278] 1 H NMR (400 MHz, AcOH-d4) δ 7.67 (dd, J = 6.80, 2.36 Hz, 1H), 7.57 (s, 1H), 7.53-7.49 (m, 1H), 7.40 (d, J = 7.48 Hz, 1H), 7.31-7.22 (m, 3H), 7.21 (d, J = 1.52 Hz, 1H), 5.37 (dd, J = 21.86, 7.16 Hz, 2H), 4.32 (d, J = 12.08 Hz, 1H), 4.07 (d, J = 12.08 Hz, 1H), 1.77 (s, 3H); MS: m / z 416.1 / 418.1 (M+1).

[0279] Example 9: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(1,2-oxazol-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka]

[0280] Example 9, Step 1: Preparation of 2,1,3-benzothiadiazole-4-ylmethanol [ka] 4-(bromomethyl)-2,1,3-benzothiadiazole (from step 3 of Example 1) (60.00 g, 183.00 mmol) was stirred in a 1:1 mixed solvent of dioxane / water (300 mL) to which potassium carbonate (177.0 g, 1280.0 mmol) was added and refluxed for 48 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 750 mL). The combined organic layers were washed with brine solution (75 mL), dried over sodium sulfate, filtered, and concentrated to obtain a dark brown liquid (31.0 g). This was purified by chromatography in a Grace apparatus using a 220.0 g pre-packed flash cartridge packed with normal-phase silica gel 60 Å, 40-63 μm. The product was eluted with 30-40% ethyl acetate in hexane to obtain 2,1,3-benzothiadiazole-4-ylmethanol (20.0 g) as a yellow solid.

[0281] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 8.40 Hz, 1H), 7.72 (t, J = 10.00 Hz, 2H), 5.52 (t, J = 4.80 Hz, 1H), 5.02 (d, J = 4.00 Hz, 2H);

[0282] Example 9, Step 2: Preparation of 2,1,3-benzothiadiazole-4-carbaldehyde [ka] To a stirred solution of 2,1,3-benzothiadiazole-4-ylmethanol (Example 9, from Step 1) (10.00 g, 60.20 mmol) in dichloromethane (150 mL), Dess-Martin Periodinane (30.60 g, 72.20 mmol) was added, and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with 10% aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (3 x 500 mL). The combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate, filtered, and concentrated to obtain a yellow gum (10.00 g). This was purified by chromatography using an Isolera instrument with a 120.0 g pre-packed flash cartridge filled with 60 Å, 40-63 μm normal-phase silica gel. The product was eluted with 30-40% ethyl acetate in hexane to obtain 2,1,3-benzothiadiazole-4-carbaldehyde (8.20 g) as a pale yellow solid.

[0283] 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.47 (dd, J = 0.80, 8.80 Hz, 1H), 8.30 (dd, J = 0.80, 6.80 Hz, 1H), 7.95 (t, J = 6.80 Hz, 1H); MS: m / z 165.0 (M+1).

[0284] Example 9, Step 3: Preparation of 4-(1,3-dioxolan-2-yl)-2,1,3-benzothiadiazole [ka] A stirring solution of 2,1,3-benzothiadiazole-4-carbaldehyde (from Example 9, Step 2) (5.00 g, 30.50 mmol) in dichloromethane (100 mL) is mixed with 1,2-ethanediol (6.80 mL, d=1.11 g / cm³). 3(122.0 mmol) was added, followed by tetra-butylammonium tribromide (1.47 g, 30.5 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was cooled to 0°C, diluted with ethyl acetate (500 mL), solid sodium bicarbonate (3.00 g) was added, and the mixture was stirred for 30 minutes. The mixture was filtered and concentrated to obtain a yellow gum (6.50 g), which was purified by gravity column chromatography on 60-120 neutral silica gel, and the product was eluted with 10-12% ethyl acetate in hexane to obtain 4-(1,3-dioxolan-2-yl)-2,1,3-benzothiadiazole (4.80 g) as a colorless gum.

[0285] 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (dd, J = 1.20, 8.80 Hz, 1H), 7.81 (d, J = 6.00 Hz, 1H), 7.75 (t, J = 6.80 Hz, 1H), 6.44 (s, 1H), 4.17 (t, J = 2.00 Hz, 2H), 4.07 (t, J = 2.00 Hz, 2H); MS: m / z 209.1 (M+1).

[0286] Example 9, Step 4: Preparation of 3-(1,3-dioxolan-2-yl)benzene-1,2-diamine [ka] To a degassed solution of 4-(1,3-dioxolan-2-yl)-2,1,3-benzothiadiazole (from Example 9, Step 3) (1.50 g, 7.20 mmol) in dry methanol (75 mL), Raney nickel (4.50 g, 300% w / w, pre-washed 5 times with dry methanol) was added. The resulting reaction mixture was then subjected to a hydrogen atmosphere and a bladder pressure of approximately 1.5 kg / cm². 2The mixture was stirred at ambient temperature for 48 hours. The reaction mixture was filtered through a Celite bed, and the bed was washed with methanol (500 mL). The combined filtrate was concentrated to obtain 3-(1,3-dioxolan-2-yl)benzene-1,2-diamine (1.10 g) as a brown gum, which was used in the next step without further purification.

[0287] 1 H NMR (400 MHz, CD3OD) δ 6.77 (dd, J = 2.80, 8.20 Hz, 2H), 6.61 (t, J = 7.60 Hz, 1H), 5.75 (s, 1H), 4.13 (t, J = 3.20 Hz, 2H), 4.04 (t, J = 1.60Hz, 2H); MS: m / z 181.2 (M+1).

[0288] Example 9, Step 5: Preparation of 2-({[2-amino-3-(1,3-dioxolan-2-yl)phenyl]carbamotioil}amino)-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-6-(1,3-dioxolan-2-yl)phenyl]carbamotioil}amino)-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka]

[0289] To a solution of [2-(3-chloro-4-fluorophenyl)-2-isothiocyanatopropyl]2,2-dimethylpropanoate (from Example 8, Step 7) (1.50 g, 4.55 mmol) in a mixed solvent of acetonitrile / dichloromethane / methanol (3:1:1; 50 mL), 3-(1,3-dioxolan-2-yl)benzene-1,2-diamine (from Example 9, Step 4) (0.820 g, 4.55 mmol) was added, and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was evaporated under vacuum at 20°C to obtain a brown gum (2.40 g). This was purified by chromatography in a Grace apparatus using a 60.0 g pre-packed flash cartridge filled with 60 Å, 40-63 μm normal-phase silica gel. The product was eluted with 3% methanol in chloroform to obtain 2-({[2-amino-3-(1,3-dioxolan-2-yl)phenyl]carbamotioil}amino)-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-6-(1,3-dioxolan-2-yl)phenyl]carbamotioil}amino)-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (1.80 g) as a brown solid. MS: m / z 511.2 (M+1).

[0290] Example 9, Step 6: Preparation of 2-(3-chloro-4-fluorophenyl)-2-{[4-(1,3-dioxolan-2-yl)-1H-1,3-benzodiazole-2-yl]amino}propyl 2,2-dimethylpropanoate [ka] To a solution of 2-({[2-amino-3-(1,3-dioxolan-2-yl)phenyl]carbamotioil}amino)-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-({[2-amino-6-(1,3-dioxolan-2-yl)phenyl]carbamotioil}amino)-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (from Example 9, Step 5) (0.620 g, 1.22 mmol) in methanol (20 mL), iodoacetic acid (0.294 g, 1.58 mmol) was added, and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under vacuum at 25°C, diluted with 10% aqueous sodium bicarbonate (75 mL), and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain 2-(3-chloro-4-fluorophenyl)-2-{[4-(1,3-dioxolan-2-yl)-1H-1,3-benzodiazole-2-yl]amino}propyl 2,2-dimethylpropanoate (0.550 g) as a brown solid, which was used in the next step without further purification. MS: m / z 476.1 (M+1).

[0291] Example 9, Step 7: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-formyl-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-(3-chloro-4-fluorophenyl)-2-{[4-(1,3-dioxolan-2-yl)-1H-1,3-benzodiazole-2-yl]amino}propyl 2,2-dimethylpropanoate (from Example 9, Step 5) (0.550 g, 0.573 mmol) in acetone (30 mL), p-toluenesulfonic acid monohydrate (0.164 g, 0.860 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under vacuum at 25°C and diluted with 10% sodium bicarbonate aqueous solution (30 mL). This was extracted with ethyl acetate (3 x 75 mL), and the resulting organic layer was dried over sodium sulfate, filtered, and concentrated to obtain a brown solid (0.500 g). This was purified by chromatography using a Grace apparatus with a 24.0 g pre-packed flash cartridge filled with 60 Å, 40-63 μm normal-phase silica gel. The product was eluted with 21% ethyl acetate in hexane to obtain 2-(3-chloro-4-fluorophenyl)-2-[(4-formyl-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate (0.120 g) as a yellow solid.

[0292] 1 H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 10.04 (s, 1H), 7.65 (dd, J = 2.00, 7.00 Hz, 1H), 7.49 (dd, J = 3.20, 7.20 Hz, 2H), 7.46 (dd, J = 3.60, 7.40 Hz, 1H), 7.38 (t, J = 9.20 Hz, 1H), 7.11 (t, J = 8.00 Hz, 1H), 6.97 (s, 1H), 4.48 (dd, J = 2.40, 8.40 Hz, 2H), 1.86 (s, 3H), 1.06 (s, 9H); MS: m / z 432.1 (M+1).

[0293] Example 9: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(1,2-oxazol-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka] To a solution of [2-(3-chloro-4-fluorophenyl)-2-[(4-formyl-1H-benzimidazole-2-yl)amino]propyl]2,2-dimethylpropanoate (0.18 g, 0.41 mmol) (from Example 9, Step 7) and isoxazole-3-amine (0.042 g, 0.50 mmol) in dried tetrahydrofuran (20 mL), titanium(IV) isopropoxide (0.35 g, 1.25 mmol) was added at 0°C, and the reaction mixture was refluxed for 16 hours. The reaction mixture was cooled, sodium borocyanohydride (0.26 g, 4.17 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. This was filtered through a Celite bed, washed with tetrahydrofuran (10 mL), and concentrated to obtain yellow gum (0.350 g). This was purified by preparative HPLC, and 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol (0.103 g), isolated as a trifluoroacetate, was obtained as a colorless gum.

[0294] 1 H NMR (400 MHz, AcOH-d4) δ 8.20 (d, J = 1.60 Hz, 1H), 7.68 (dd, J = 2.40, 6.80 Hz, 1H), 7.55-7.51 (m, 1H), 7.32 (t, J = 2.40 Hz, 1H), 7.31-7.24 (m, 3H), 6.03 (d, J = 2.00 Hz, 1H), 4.59 (s, 2H), 4.17 (d, J = 11.60 Hz, 1H), 4.02 (d, J = 12.00 Hz, 1H), 1.87 (s, 3H); MS: m / z 416.0 [(M+1)-TFA].

[0295] Example 10: Preparation of N-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]-4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine [ka]

[0296] Example 10, Step 1: 3-{2-amino-3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea and 3-{2-amino-6-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from Example 5, Step 2) (0.271 g, 1.24 mmol) in a mixed solvent of dichloromethane:methanol (4:1; 8 mL), 1-chloro-3-(2-isothiocyanato-1-methoxypropan-2-yl)benzene (from Example 6, Step 3) (0.300 g, 1.24 mmol) was added, and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was concentrated in a water bath at 30°C to obtain 3-{2-amino-3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea and 3-{2-amino-6-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea (as a mixture of inseparable positional isomers) (0.300 g) as a brown gum, which was used in the next step without further purification. MS: m / z 461.1 (M+1).

[0297] Example 10: N-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]-4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine [ka] To a solution of 3-{2-amino-3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea and 3-{2-amino-6-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}-1-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]thiourea (as a mixture of inseparable positional isomers) (from Example 10, Step 4) (0.300 g, 0.652 mmol) in methanol (15 mL), iodoacetic acid (0.121 g, 0.652 mmol) was added, and the mixture was stirred at 65°C for 1 hour. The reaction mixture was concentrated under high vacuum, the residue was diluted with 20 mL of 10% aqueous sodium bicarbonate solution, and extracted with a mixed solvent of dichloromethane / methanol (9:1) (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain a crude mass (0.360 g) as a brown gum. This was purified by preparative HPLC using the TFA method to obtain N-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]-4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine (0.050 g), isolated as a trifluoroacetate, as a brown solid.

[0298] 1 H NMR (400 MHz, AcOH-d4) δ 7.55 (s, 1H), 7.47 (dd, J = 2.00, 6.60 Hz, 2H), 7.38 (t, J = 8.80 Hz, 1H), 7.33 (d, J = 8.40 Hz, 2H), 7.24 (t, J = 8.00 Hz, 1H), 6.86 (d, J = 7.60 Hz, 1H), 5.46 (s, 2H), 4.05 (d, J = 10.40 Hz, 1H), 3.80 (d, J = 10.00 Hz, 1H), 3.49 (s, 3H), 2.11 (s, 3H), 1.82 (s, 3H); MS: m / z 426.1 [(M+1).

[0299] Example 11: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(pyrimidine-4-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka] Starting from a commercially available pyrimidine-4-amine, the title product was prepared by the method described in Example 16 and isolated as trifluoroacetate.

[0300] 1 H NMR (400 MHz, AcOH-d4) δ 8.94 (d, J = 1.20 Hz, 1H), 8.22-8.19 (m, 1H), 7.68-7.65 (m, 1H), 7.52-7.49 (m, 1H), 7.41-7.36 (m, 2H), 7.32-7.22 (m, 2H), 7.01 (d, J = 7.72 Hz, 1H), 5.65 (t, J = 5.20 Hz, 2H), 4.31 (d, J = 12.0 Hz, 1H), 4.06 (d, J = 11.92 Hz, 1H), 1.76 (s, 3H); MS: m / z 427.1 (M+1).

[0301] Example 12: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(5-methyl-1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka] A solution of 2-(3-chloro-4-fluorophenyl)-2-[(4-formyl-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate (from Example 9, Step 7) (0.800 g, 1.85 mmol) in dried tetrahydrofuran (30 mL) is mixed with 3-methylisoxazole-5-amine (0.218 g, 2.22 mmol), followed by titanium isopropoxide (10.80 mL, d=0.937 kg / cm³). 3 (37.00 mmol) was added, and the mixture was heated at 72°C for 48 hours. Dry methanol (20 mL) was added to this reaction mixture, followed by sodium borohydride cyanohydride (0.582 g, 9.26 mmol) at 0°C, and the mixture was stirred at ambient temperature for 24 hours. The reaction mixture was concentrated, the residue was quenched with ice-cold water (50 mL), diluted with a mixed solvent of dichloromethane / methanol (9:1; 200 mL), and filtered through a Celite bed. The two-phase filtrate was separated, and the aqueous layer was further extracted with dichloromethane (2 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain a brown gum (1.10 g). This was purified by preparative HPLC using the TFA method, and 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(5-methyl-1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol (0.360 g), isolated as a trifluoroacetate, was obtained as an off-white solid.

[0302] 1 H NMR (400 MHz, AcOH-d4) δ 7.68 (dd, J = 2.40, 7.00 Hz, 1H), 7.53-7.50 (m, 1H), 7.30 (t, J = 8.40 Hz, 1H), 7.24 (d, J = 8.00 Hz, 2H), 7.21 (t, J = 7.60 Hz, 1H), 5.60 (s, 1H), 4.52 (s, 2H), 4.25 (d, J = 12.00 Hz, 1H), 4.04 (d, J = 12.00 Hz, 1H), 2.29 (s, 3H), 1.78 (s, 3H); MS: m / z 430.0 (M+1).

[0303] The above product was separated into two enantiomers by chiral SFC using the following method to obtain two enantiomers, 12a and 12b: Column: Chiral Pak OX-H; Flow rate: 3.0 mL / min; Cosolvent: 40%; Cosolvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 15.0 μL; Outlet pressure: 100 bar; Temperature: 35°C.

[0304] Example 12a: (-)-2-(3-chloro-4-fluorophenyl)-2-((4-(((5-methylisoxazole-3-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino)propan-1-ol The (-) enantiomer was the first compound to elute from the column and was isolated as trifluoroacetate. [ka]

[0305] 1 H NMR (400 MHz, AcOH-d4) δ 7.67 (dd, J = 2.40, 6.80 Hz, 1H), 7.52-7.49 (m, 1H), 7.30 (t, J = 7.40 Hz, 1H), 7.23 (t, J = 8.80 Hz, 1H), 7.19 (d, J = 7.80 Hz, 2H), 5.63 (s, 1H), 4.51 (s, 2H), 4.25 (d, J = 12.00 Hz, 1H), 4.04 (d, J = 12.00 Hz, 1H), 2.29 (s, 3H), 1.77 (s, 3H); MS: m / z 430.0 (M+1); [α] D 22.7 (-) 2.64 (MeOH, c = 1.0).

[0306] Example 12b: (+)-2-(3-chloro-4-fluorophenyl)-2-((4-(((5-methylisoxazole-3-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino)propan-1-ol The (+) enantiomer was the second compound eluted from the column and was isolated as trifluoroacetate. [ka]

[0307] 1 H NMR (400 MHz, AcOH-d4) δ 7.67 (dd, J = 2.00, 7.00 Hz, 1H), 7.52 (dd, J = 2.80, 7.40 Hz, 1H), 7.30 (t, J = 4.40 Hz, 1H), 7.23 (t, J = 9.20 Hz, 1H), 7.20 (d, J = 4.80 Hz, 2H), 5.63 (s, 1H), 4.51 (s, 2H), 4.25 (d, J = 12.00 Hz, 1H), 4.04 (d, J = 12.00 Hz, 1H), 2.29 (s, 3H), 1.77 (s, 3H); MS: m / z 430.0 (M+1); [α] D 22.6 (+) 2.92 (MeOH, c = 1.0).

[0308] Example 13: Preparation of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka] Starting from 3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from step 2 of Example 5) and [2-(3-chloro-4-fluorophenyl)-2-isothiocyanatopropyl]2,2-dimethylpropanoate (from step 7 of Example 8), the title compound was prepared using the method described in steps 8, 9, and 10 of Example 8 and isolated as trifluoroacetate.

[0309] 1 H NMR (400 MHz, AcOH-d4) δ 7.68 (dd, J = 6.80, 2.40 Hz, 1H), 7.52-7.52 (m, 1H), 7.45 (d, J = 1.60 Hz, 1H), 7.36 (d, J = 8.00 Hz, 1H), 7.28-7.24 (m, 2H), 6.87 (d, J = 7.60 Hz, 1H), 5.46 (s, 2H), 4.33 (d, J = 12.40 Hz, 1H), 4.08 (d, J = 12.00 Hz, 1H), 2.10 (s, 3H), 1.79 (s, 3H); MS: m / z 430.2 / 431.2 (M+1).

[0310] The above product was separated into two enantiomers by chiral SFC using the following method to obtain two enantiomers, 13a and 13b: Column: Lux C4, Mobile phase: 0.5% isopropylamine in methanol, cosolvent: 40% CO2; Flow rate: 3 ml / min, Pressure: 100 bar, Temperature: 35°C.

[0311] Example 13a: (-)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol The (-) enantiomer was the first compound to elute from the column and was isolated as trifluoroacetate. [ka]

[0312] 1 H NMR (400 MHz, AcOH-d4) δ 7.68 (dd, J = 6.80, 2.40 Hz, 1H), 7.52-7.52 (m, 1H), 7.45 (d, J = 1.60 Hz, 1H), 7.36 (d, J = 8.00 Hz, 1H), 7.28-7.24 (m, 2H), 6.87 (d, J = 7.60 Hz, 1H), 5.46 (s, 2H), 4.33 (d, J = 12.40 Hz, 1H), 4.08 (d, J = 12.00 Hz, 1H), 2.10 (s, 3H), 1.79 (s, 3H); MS: m / z 430.2 / 431.2 (M+1); SOR: [α] D 23.0 (-) 7.60, (MeOH, c = 0.5).

[0313] Example 13b: (+)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol The (+) enantiomer eluted second from the column and was isolated as trifluoroacetate. [ka]

[0314] 1H NMR (400 MHz, AcOH-d4) δ 7.68 (dd, J = 6.80, 2.40 Hz, 1H), 7.52-7.52 (m, 1H), 7.45 (d, J = 1.60 Hz, 1H), 7.36 (d, J = 8.00 Hz, 1H), 7.28-7.24 (m, 2H), 6.87 (d, J = 7.60 Hz, 1H), 5.46 (s, 2H), 4.33 (d, J = 12.40 Hz, 1H), 4.08 (d, J = 12.00 Hz, 1H), 2.10 (s, 3H), 1.79 (s, 3H); MS: m / z 430.2 / 431.2 (M+1); SOR: [α] D 23.5 (+) 8.40, (MeOH, c = 0.5).

[0315] Example 14: Preparation of N-[2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine [ka] The title compound was prepared using tert-butyl(2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)carbamate (Example 8, from step 4) and 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (Example 1, from step 5) by the method described in Example 6, and isolated as trifluoroacetate.

[0316] 1H NMR (400 MHz, AcOH-d4) δ 7.64 (dd, J = 2.36, 6.84 Hz, 1H), 7.59 (s, 1H), 7.51-7.48 (m, 1H), 7.39 (dd, J = 2.48, 6.54 Hz, 1H), 7.31 (t, J = 7.64 Hz, 1H), 7.24 (d, J = 8.52 Hz, 3H), 5.41 (s, 2H), 3.99 (d, J = 10.12 Hz, 1H), 3.78 (d, J = 10.12 Hz, 1H), 3.49 (s, 3H), 1.83 (s, 3H); MS: m / z 430.1 n(M+1).

[0317] Example 15: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(5-methyl-1,2,4-oxadiazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka] To a solution of 2-(3-chloro-4-fluorophenyl)-2-[(4-formyl-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate (from Example 9, Step 7) (0.120 g, 0.278 mmol) in 5 mL of dry tetrahydrofuran, 5-methyl-1,2,4-oxadiazole-3-amine (0.033 g, 0.333 mmol) was added, followed by titanium isopropoxide (1.23 mL, d=0.937 kg / cm³). 34.17 mmol) was added, and the mixture was heated at 72°C for 48 hours. Dry methanol (5 mL) was added to this reaction mixture, followed by sodium borohydride cyanohydride (0.087 g, 1.39 mmol) at 0°C, and the mixture was stirred at ambient temperature for 24 hours. The reaction mixture was concentrated, the residue was quenched with ice-cold water (25 mL), diluted with a mixed solvent of dichloromethane / methanol (9:1; 50 mL), and filtered through a Celite bed. The two-phase filtrate was separated, and the aqueous layer was further extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain a brown gum (0.100 g). This was purified by preparative HPLC using the TFA method, and 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(5-methyl-1,2,4-oxadiazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol (0.070 g), isolated as a trifluoroacetate, was obtained as a light brown gum.

[0318] 1 H NMR (400 MHz, AcOH-d4) δ 7.69 (dd, J = 2.00, 7.00 Hz, 1H), 7.53 (d, J = 7.60 Hz, 1H), 7.30 (d, J = 7.60 Hz, 1H), 7.25 (t, J = 6.40 Hz, 1H), 7.22 (s, 1H), 7.20 (d, J = 7.60 Hz, 1H), 4.55 (s, 2H), 4.27 (d, J = 12.00 Hz, 1H), 4.06 (d, J = 12.00 Hz, 1H), 2.49 (s, 3H), 1.79 (s, 3H); MS: m / z 431.1 (M+1).

[0319] Example 16: Preparation of 2-(3-chloro-4-fluorophenyl)-2-((4-(((5-methyl-1,3,4-oxadiazole-2-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino)propan-1-ol [ka]

[0320] Example 16, Step 1: Preparation of N-[(2,1,3-benzothiadiazole-4-yl)methyl]-5-methyl-1,3,4-oxadiazole-2-amine hydrobromide [ka] In 20 mL of dry acetonitrile under a nitrogen atmosphere, 4-(bromomethyl)-2,1,3-benzothiadiazole (from Example 1, Step 3) (4.00 g, 17.4 mmol) was stirred, to which 5-methyl-1,3,4-oxadiazole-2-amine (1.98 g, 20.00 mmol) was added. The resulting reaction mixture was stirred at 70°C for 16 hours. The solid formed in the reaction mixture was filtered, washed with hexane (2 x 100 mL), and dried under high vacuum to obtain N-[(2,1,3-benzothiadiazole-4-yl)methyl]-5-methyl-1,3,4-oxadiazole-2-amine hydrobromide (1.80 g) as an off-white solid, which was used in the next step without further purification.

[0321] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 8.14 (t, J = 8.40 Hz, 1H), 7.77 (d, J = 6.80 Hz, 2H), 5.65 (s, 2H), 2.39 (s, 3H); MS: m / z 248.2 (M+1).

[0322] Example 16, Step 2: Preparation of 3-(((5-methyl-1,3,4-oxadiazole-2-yl)amino)methyl)benzene-1,2-diamine [ka] To a degassed solution of N-[(2,1,3-benzothiadiazole-4-yl)methyl]-5-methyl-1,3,4-oxadiazole-2-amine hydrobromide (Example 16, from Step 1) (1.50 g, 4.60 mmol) in dry methanol (100 mL), Raney nickel (3.00 g, 200% w / w, pre-washed 5 times with dry methanol) was added. The resulting reaction mixture was then subjected to a hydrogen atmosphere and a bladder pressure of approximately 1.5 kg / cm². 2 The mixture was stirred at ambient temperature for 16 hours. The reaction mixture was filtered through a Celite bed, and the bed was washed with methanol (1000 mL). The combined filtrate was concentrated to obtain 3-(((5-methyl-1,3,4-oxadiazole-2-yl)amino)methyl)benzene-1,2-diamine (1.00 g) as a light brown solid, which was used in the next step without further purification.

[0323] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 6.87 (t, J = 7.60 Hz, 1H), 6.70 (d, J = 8.00 Hz, 1H), 6.45 (d, J = 7.20 Hz, 1H), 4.58 (s, 2H), 1.97 (s, 3H); MS: m / z 220.2 (M+1).

[0324] Example 16, Step 3: Preparation of 2-{[(2-amino-3-{[(5-methyl-1,3,4-oxadiazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)-propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{[(5-methyl-1,3,4-oxadiazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)-propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-(((5-methyl-1,3,4-oxadiazole-2-yl)amino)methyl)benzene-1,2-diamine (from Example 16, Step 2) (0.250 g, 11.40 mmol) in a mixed solvent of dichloromethane:methanol (4:1::12 mL), [2-(3-chloro-4-fluorophenyl)-2-isothiocyanatopropyl]2,2-dimethylpropanoate (from Example 8, Step 7) (0.376 g, 11.40 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated in a water bath at 30°C to obtain 2-{[(2-amino-3-{[(5-methyl-1,3,4-oxadiazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{[(5-methyl-1,3,4-oxadiazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (0.650 g) as a yellow gummy substance, which was used in the next step without further purification. MS: m / z 550.1 (M+1).

[0325] Example 16, Step 4: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(5-methyl-1,3,4-oxadiazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-3-{[(5-methyl-1,3,4-oxadiazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{[(5-methyl-1,3,4-oxadiazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (from Example 16, Step 3) (0.650 g, 1.18 mmol) in methanol (40 mL), iodoacetic acid (0.447 g, 2.36 mL) was added, and the mixture was stirred at 65°C for 1 hour. The reaction mixture was concentrated to remove the solvent methanol, and the residue was purified by chromatography in a Grace apparatus using a 24.00 g pre-packed flash cartridge packed with 60 Å, 40-63 μm normal-phase silica gel. The product was eluted with 40-45% ethyl acetate in hexane to obtain 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(5-methyl-1,3,4-oxadiazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate (0.120 g) as a white gum.

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.38 (s, 1H), 7.64 (d, J = 5.20 Hz, 1H), 7.46 (d, J = 4.80 Hz, 1H), 7.39 (t, J = 8.80 Hz, 1H), 7.19 (s, 1H), 7.03 (d, J = 8.00 Hz, 2H), 6.81 (d, J = 6.00 Hz, 1H), 4.80 (s, 2H), 4.40 (d, J = 10.80 Hz, 1H), 4.50 (d, J = 11.20 Hz, 1H), 2.00 (s, 3H), 1.92 (s, 3H), 1.06 (s, 9H); MS: m / z 515.1 (M+1).

[0327] Example 16: Preparation of 2-(3-chloro-4-fluorophenyl)-2-((4-(((5-methyl-1,3,4-oxadiazole-2-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino)propan-1-ol [ka] To a solution of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(5-methyl-1,3,4-oxadiazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate (from Example 16, Step 4) (0.120 g, 0.228 mmol) in methanol (10 mL), sodium hydroxide pellets (0.038 g, 0.912 mmol) were added, and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with 1.5 N hydrochloric acid (2 mL), and the resulting reaction mixture was concentrated under high vacuum to obtain a brown gum (0.100 g). This was purified by preparative HPLC to obtain 2-(3-chloro-4-fluorophenyl)-2-((4-(((5-methyl-1,3,4-oxadiazole-2-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino)propan-1-ol (0.060 g) as an off-white solid.

[0328] 1 H NMR (400 MHz, AcOH-d4) δ 7.61 (s, 1H), 7.41 (d, J = 10.40 Hz, 2H), 7.41 (d, J = 10.40 Hz, 2H), 7.25 (t, J = 8.80 Hz, 1H), 5.00 (d, J = 8.80 Hz, 2H), 4.94 (d, J = 9.20 Hz, 2H), 2.21 (s, 3H), 1.89 (s, 3H); MS: m / z 431.2 (M+1).

[0329] Example 17: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(3-methyl-1,2,4-oxadiazole-5-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka] The title compound was prepared using commercially available 3-methyl-1,2,4-oxadiazole-5-amine by the method described in Example 8, and isolated as a white solid trifluoroacetate.

[0330] 1 H NMR (400 MHz, AcOH-d4) δ 7.75 (dd, J = 2.40, 6.80 Hz, 1H), 7.59-7.56 (m, 1H), 7.39 (d, J = 8.00 Hz, 1H), 7.28 (t, J = 7.60 Hz, 1H), 7.26 (d, J = 10.40 Hz, 1H), 7.22 (t, J = 7.60 Hz, 1H), 4.69 (q, J = 15.32 Hz, 2H), 4.25 (d, J = 11.60 Hz, 1H), 4.06 (d, J = 12.00 Hz, 1H), 2.74 (s, 3H), 1.85 (s, 3H); MS: m / z 431.1 (M+1).

[0331] Example 18: Preparation of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol [ka]

[0332] Example 18, Step 1: Preparation of 5-methyl-5-(3-(trifluoromethyl)phenyl)imidazolidined-2,4-dione [ka] To a stirred solution of 3-trifluoromethylacetophenone (commercial product) (45.00 g, 239.00 mmol) in a mixed solvent of ethanol / water (1:1; 1000 mL), ammonium carbonate (115.00 g, 1200.00 mmol) was added, followed by potassium cyanide (18.70 g, 287.00 mmol), and the mixture was stirred at 60°C for 16 hours. The reaction mixture was poured into ice-cold water (1500 mL) and stirred for 30 minutes. The resulting solid was filtered and dried to obtain 5-methyl-5-(3-(trifluoromethyl)phenyl)imidazolidined-2,4-dione (61.00 g) as an off-white solid, which was used in the next step without further purification.

[0333] (400 MHz, DMSO-d6: D2O) δ 7.78 (d, J = 7.70 Hz, 1H), 7.72 (d, J = 8.90 Hz, 2H), 7.65 (t, J = 7.70 Hz, 1H), 1.69 (s, 3H); MS: m / z 259.0 (M+1).

[0334] Example 18, Step 2: Preparation of 2-amino-2-(3-(trifluoromethyl)phenyl)propanoic acid [ka] 5-Methyl-5-(3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione (from Example 18, Step 1) (110.0 g, 426.0 mmol) was added to 600 mL of 10% aqueous sodium hydroxide solution, and the mixture was refluxed for 48 hours. The reaction mixture was neutralized with 250 mL of 6.0 N hydrochloric acid (to adjust pH to 7), and the resulting solid was filtered and dried to obtain 2-amino-2-(3-(trifluoromethyl)phenyl)propanoic acid (100.0 g) as a white solid, which was used in the next step without further purification.

[0335] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.85 (s, 1H), 7.79 (d, J = 8.00 Hz, 1H), 7.65 (d, J = 7.60 Hz, 1H), 7.60 (t, J = 7.60 Hz, 1H), 1.68 (s, 3H); MS: m / z 234.1 (M+1).

[0336] Example 18, Step 3: Preparation of 2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)propanoic acid [ka] To a suspension of 2-amino-2-(3,4-dichlorophenyl)propanoic acid (from Example 18, Step 2) (100.00 g, 429.00 mmol) in a mixed solvent of tetrahydrofuran:water (1:1; 1400 mL), sodium bicarbonate (216.00 g, 2570.00 mmol) was added, followed by di-tert-butyl dicarbonate (148.00 mL, d=0.95 g / cm³). 3643.00 mmol) was added, and the mixture was stirred at ambient temperature for 72 hours. The reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (4 x 2000 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain 2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)propanoic acid (140.00 g) as a yellowish gum, which was used in the next step without further purification.

[0337] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.64 (s, 1H), 7.57 (s, 1H), 7.47 (d, J = 4.40 Hz, 2H), 1.47 (s, 3H), 1.35 (s, 9H); MS: m / z 234.1 [(M+1)-Boc].

[0338] Example 18, Step 4: Preparation of tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate [ka] A solution of 2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)propanoic acid (from Example 18, Step 3) (140.0 g, 378.0 mmol) in dry tetrahydrofuran (1000 mL) is mixed with triethylamine (158.00 mL, d=0.726 g / cm³). 3 Add 1130.00 mmol of chloroformate (68.8 mL, d = 1.053 g / cm³), followed by isobutyl chloroformate (68.8 mL, d = 1.053 g / cm³). 3529.00 mmol of sodium borohydride was added at 0°C, and the mixture was stirred at the same temperature for 4 hours. The formed solid was filtered off at 0°C, and the residue was washed with dry tetrahydrofuran (400 mL). The combined filtrate was added to a cooled mixture of sodium borohydride (85.8 g, 2270.00 mmol) in water (200 mL). The reaction mixture was slowly warmed to ambient temperature and stirred for 30 hours. The reaction mixture was quenched with ice-cold water (1000 mL) and extracted with ethyl acetate (4 x 2000 mL). The combined organic layer was washed with brine (250 mL), dried over sodium sulfate, filtered, and concentrated to obtain a yellowish liquid (200 g). This was purified by chromatography using a Grace apparatus with a 330g prepacked flash column containing 60-120 silica gel. The product was eluted with 30-35% ethyl acetate in petroleum ether to obtain tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate (63.0g) as a colorless liquid.

[0339] 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (t, J = 6.80 Hz, 2H), 7.57 (s, 1H), 7.53 (t, J = 7.20 Hz, 1H), 6.92 (bs, 1H), 4.98 (t, J = 5.20 Hz, 1H), 3.50 (d, J = 6.00 Hz, 2H), 1.59 (s, 3H), 1.35 (s, 9H); MS: m / z 221.2 [(M+1)-Boc].

[0340] Example 18, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] Under a nitrogen atmosphere, tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate (Example 18, from Step 4) (63.0 g, 197.0 mmol) was dissolved in dry dichloromethane (800 mL) with triethylamine (96.2 mL, d=0.726 g / cm³). 3 Add 691.0 mmol of , followed by pivaloyl chloride (36.4 mL, d = 0.985 g / cm³). 3 296.0 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at ambient temperature for 36 hours. The reaction mixture was quenched with ice-cold water (500 mL) and extracted with dichloromethane (4 x 1000 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain a crude product as a brown liquid (110.0 g). This was purified by chromatography using a Grace apparatus with 330 g of pre-packed 60-120 silica gel, and the product was eluted with 20% ethyl acetate in hexane to obtain 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (70.00 g) as a yellowish liquid.

[0341] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.61 (d, J = 6.80 Hz, 2H), 7.55 (t, J = 7.60 Hz, 1H), 7.51 (s, 1H), 4.26 (q, J = 10.40 Hz, 2H), 1.52 (s, 3H), 1.35 (s, 9H), 1.05 (s, 9H); MS: m / z 304.1 [(M+1)-Boc].

[0342] Example 18, Step 6: Preparation of 2-amino-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate hydrochloride [ka] Under a nitrogen atmosphere, a solution of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)-phenyl]propyl 2,2-dimethylpropanoate (from Example 18, Step 5) (70.0 g, 174.0 mmol) in dry dichloromethane (700 mL) was added dropwise at 0°C with a 4 M HCl solution in dioxane (127.0 mL, 521.0 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under high vacuum to obtain 2-amino-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate hydrochloride (60.0 g) as a yellowish gum, which was used in the next step without further purification.

[0343] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.88 (s, 1H), 7.84 (d, J = 8.00 Hz, 1H), 7.79 (d, J = 7.60 Hz, 1H), 7.71 (t, J = 7.60 Hz, 1H), 4.49 (d, J = 12.00 Hz, 1H), 4.27 (d, J = 12.00 Hz, 1H), 1.72 (s, 3H), 1.01 (s, 9H); MS: m / z 304.1 [(M+1)-HCl].

[0344] Example 18, Step 7: Preparation of 2-isothiocyanato-2-[3-(trifluoromethyl)-phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-amino-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate hydrochloride (Example 18, from Step 6) (40.0 g, 118.0 mmol) in dry dichloromethane (500 mL), 10% sodium bicarbonate aqueous solution (500 mL) was added at 0°C. After 15 minutes, thiophosgene (14.40 mL, d=1.5 g / cm³) was added. 3(188.0 mmol) was added and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was extracted with dichloromethane (3 x 1000 mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow liquid (75.0 g). This was purified by gravity column chromatography on 60-120 mesh silica gel using 5% ethyl acetate in hexane as the eluent to obtain 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (44.0 g) as a yellow liquid.

[0345] 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.81 (d, J = 7.20 Hz, 1H), 7.76 (d, J = 7.60 Hz, 1H), 7.69 (t, J = 8.40 Hz, 1H), 4.51 (q, J = 15.20 Hz, 2H), 1.83 (s, 3H), 1.35 (s, 9H); MS: m / z 344.0 (M-1).

[0346] Example 18, Step 8: Preparation of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (Example 1, Step 5) (1.80 g, 5.29 mmol) in a mixed solvent of dichloromethane:methanol (1:1; 50 mL), [2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl]2,2-dimethylpropanoate (Example 18, from Step 7) (1.50 g, 4.34 mmol) was added and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated at 30°C to obtain 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)-phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)-phenyl]propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (2.90 g) as a brown gum, which was used in the next step without purification. MS: m / z 550.2 (M+1).

[0347] Example 18, Step 9: Preparation of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (Example 18, Step 8) (2.90 g, 5.28 mmol) in methanol (20 mL), iodoacetic acid (1.47 g, 7.91 mmol) was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated at 30°C to obtain brown gum (3.3 g), which was purified by preparative HPLC (TFA: acetonitrile) to obtain 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (0.390 g), which was isolated as trifluoroacetate, and was obtained as brown gum.

[0348] 1 H NMR (400 MHz, AcOH-d4) δ 7.87 (s, 1H), 7.86 (s, 1H), 7.72 (d, J = 7.76 Hz, 1H), 7.64 (t, J = 7.92 Hz, 1H), 7.60 (d, J = 1.48 Hz, 1H), 7.33-7.16 (m, 4H), 5.41 (s, 2H), 4.55 (q, J = 11.64 Hz, 2H), 2.03 (s, 3H), 1.17 (s, 9H); MS: m / z 516.2 (M+1).

[0349] The above product was separated into two enantiomers by chiral SFC using the following method to obtain two enantiomers, 18-9a and 18-9b: Chiralcel OX-H, mobile phase: 0.5% isopropylamine in isopropyl alcohol; cosolvent: 40% CO2; flow rate: 3 mL / min, pressure: 100 bar, temperature: 35°C.

[0350] Example 18-9a: 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (enantiomer A). The first compound to elute from the column was enantiomer A, which was isolated as trifluoroacetate. [ka]

[0351] 1 H NMR (400 MHz, AcOH-d4) δ 7.87 (s, 1H), 7.86 (s, 1H), 7.72 (d, J = 7.76 Hz, 1H), 7.64 (t, J = 7.92 Hz, 1H), 7.60 (d, J = 1.48 Hz, 1H), 7.33-7.16 (m, 4H), 5.41 (s, 2H), 4.55 (q, J = 11.64 Hz, 2H), 2.03 (s, 3H), 1.17 (s, 9H); MS: m / z 516.2 (M+1).

[0352] Example 18-9b: 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (enantiomer B). The second compound eluted from the column was enantiomer B, isolated as trifluoroacetate. [ka]

[0353] 1 HNMR (400 MHz, AcOH-d4) δ 7.87 (s, 1H), 7.86 (s, 1H), 7.72 (d, J = 7.76 Hz, 1H), 7.64 (t, J = 7.92 Hz, 1H), 7.60 (d, J = 1.48 Hz, 1H), 7.33-7.16 (m, 4H), 5.41 (s, 2H), 4.55 (q, J = 11.64 Hz, 2H), 2.03 (s, 3H), 1.17 (s, 9H); MS: m / z 516.2 (M+1).

[0354] Example 18: Preparation of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid (Example 18, Step 9) (0.100 g, 0.159 mmol) in methanol (20 mL), 0.5 N sodium hydroxide (1.00 mL, 0.500 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with 1.5 N hydrochloride solution (1 mL), concentrated under reduced pressure at 30°C, and a brown gum (0.080 g) was obtained. This was purified by preparative HPLC using acetonitrile:water with 0.1% TFA, and 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)-phenyl]propan-1-ol (0.030 g) was isolated as a trifluoroacetate and obtained as brown gum.

[0355] 1 H NMR (400 MHz, AcOH-d4) δ 7.84 (t, J = 7.84 Hz, 2H), 7.69 (d, J = 7.80 Hz, 1H), 7.62-7.56 (m, 2H), 7.39 (d, J = 7.24 Hz, 1H), 7.31-7.26 (m, 2H), 7.21 (s, 1H), 5.40 (d, J = 4.20 Hz, 2H), 4.42 (d, J = 12.00 Hz, 1H), 4.13 (d, J = 12.16 Hz, 1H), 1.81 (s, 3H); MS: m / z 432.1 (M+1).

[0356] Example 18a: Preparation of (-)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)-phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid (Example 18, enantiomer A) (0.13 g, 0.0206 mmol) in methanol (20 mL), 0.5 N sodium hydroxide (1.65 mL, 0.826 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with 1.5 N hydrochloride solution (2 mL), concentrated under reduced pressure at 30°C, and a brown gum (0.11 g) was obtained. This was purified by preparative HPLC using acetonitrile:water with 0.1% TFA, and (-)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol (0.080 g) was isolated as a trifluoroacetate and obtained as a colorless gum.

[0357] 1 H NMR (400 MHz, AcOH-d4) δ 7.84 (t, J = 8.00 Hz, 2H), 7.68 (d, J = 7.68 Hz, 1H), 7.62-7.56 (m, 2H), 7.39 (dd, J = 7.36, 1.60 Hz, 1H), 7.31-7.26 (m, 2H), 7.20 (d, J = 1.64 Hz, 1H), 5.40 (q, J = 15.80 Hz, 2H), 4.42 (d, J = 12.04 Hz, 1H), 4.13 (d, J = 12.12 Hz, 1H), 1.81 (s, 3H); MS: m / z 432.1 (M+1); SOR: [α] D 24.8 (-) 8.00, (MeOH, c = 0.5)).

[0358] Example 18b: Preparation of (+)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)-phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid (Example 18, enantiomer B) (0.130 g, 0.0206 mmol) in methanol (20 mL), 0.5 N sodium hydroxide in methanol (1.65 mL, 0.826 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with 1.5N hydrochloride solution (2 mL) and concentrated under reduced pressure at 30°C to obtain a brown gum (0.11 g). This was purified by preparative HPLC using 0.1% TFA in acetonitrile:water, and the isolated trifluoroacetate (+)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol (0.075 g) was obtained as a colorless gum.

[0359] 1H NMR (400 MHz, AcOH-d4) δ 7.84 (t, J = 8.00 Hz, 2H), 7.68 (d, J = 7.68 Hz, 1H), 7.62-7.56 (m, 2H), 7.39 (dd, J = 7.36, 1.60 Hz, 1H), 7.31-7.26 (m, 2H), 7.20 (d, J = 1.64 Hz, 1H), 5.40 (q, J = 15.80 Hz, 2H), 4.42 (d, J = 12.04 Hz, 1H), 4.13 (d, J = 12.12 Hz, 1H), 1.81 (s, 3H); MS: m / z 432.1 (M+1); SOR: [α] D 25.0 (+) 6.80, (MeOH, c = 0.5).

[0360] Example 19: Preparation of 2-(3,4-dichlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka]

[0361] Example 19, Step 1: Preparation of 5-(3,4-dichlorophenyl)-5-methylimidazolidined-2,4-dione [ka] To a stirred solution of 1-(3,4-dichlorophenyl)ethane-1-one (commercial product) (45.0 g, 238.0 mmol) in an ethanol / water (1:1; 1000 mL) mixed solvent, ammonium carbonate (114.0 g, 1190.0 mmol) was added, followed by potassium cyanide (18.60 g, 286.0 mmol), and the mixture was stirred at 65°C for 16 hours. The reaction mixture was poured into ice-cold water (1500 mL) and stirred for 30 minutes. The resulting solid was filtered and dried to obtain 5-(3,4-dichlorophenyl)-5-methylimidazolidined-2,4-dione (55.0 g) as an off-white solid, which was used in the next step without further purification.

[0362] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (bs, 1H), 8.68 (s, 1H), 7.70 (s, 1H), 7.68 (d, J = 6.40 Hz, 1H), 7.49 (d, J = 8.40 Hz, 1H), 1.65 (s, 3H); MS: m / z 260.1 (M+1).

[0363] Example 19, Step 2: Preparation of 2-amino-2-(3,4-dichlorophenyl)propanoic acid [ka] A solution of 5-(3,4-dichlorophenyl)-5-methylimidazolidined-2,4-dione (from Example 19, Step 1) (50.0 g, 193.0 mmol) in a 10% aqueous sodium hydroxide solution (400 mL) was refluxed for 48 hours. The reaction mixture was neutralized with 6.0 N hydrochloric acid (150 mL) (adjusted to pH=7), and the resulting solid was filtered and dried to obtain 2-amino-2-(3,4-dichlorophenyl)propanoic acid (43.0 g) as a white solid, which was used in the next step without further purification.

[0364] 1H NMR (400 MHz, DMSO-d6) δ 8.77 (bs, 2H), 7.80 (s, 1H), 7.70 (d, J = 8.40 Hz, 1H), 7.52 (dd, J = 2.00, 8.40 Hz, 1H), 1.76 (s, 3H); MS: m / z 235.1 (M+1).

[0365] Example 19, Step 3: Preparation of 2-((tert-butoxycarbonyl)amino)-2-(3,4-dichlorophenyl)propanoic acid [ka] A suspension of 2-amino-2-(3,4-dichlorophenyl)propanoic acid (Example 19, from Step 2) (100.0 g, 429.0 mmol) in a tetrahydrofuran:water (1:1; 900 mL) mixed solvent is mixed with sodium bicarbonate (15.40 g, 184.0 mmol), followed by di-tert-butyl dicarbonate (84.4 mL, d=0.95 g / cm³). 3 (367.0 mmol) was added, and the mixture was stirred at ambient temperature for 4 days. The reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (4 x 2000 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain 2-((tert-butoxycarbonyl)amino)-2-(3,4-dichlorophenyl)propanoic acid (140.0 g) as a yellowish gum, which was used in the next step without further purification.

[0366] 1 1H NMR (400 MHz, DMSO-d 6: D2O) δ 7.45 (d, J = 8.40 Hz, 1H), 7.39 (s, 1H), 7.25 (dd, J = 2.00, 8.40 Hz, 1H), 1.68 (s, 3H), 1.33 (s, 9H); MS: m / z 235.1 [(M+1)-Boc].

[0367] Example 19, Step 4: Preparation of tert-butyl N-[2-(3,4-dichlorophenyl)-1-hydroxypropan-2-yl]carbamate [ka] A solution of 2-((tert-butoxycarbonyl)amino)-2-(3,4-dichlorophenyl)propanoic acid (from Example 19, Step 3) (45.0 g, 135.0 mmol) in dry tetrahydrofuran (650 mL) is mixed with triethylamine (56.3 mL, d=0.726 g / cm³). 3 (404.0 mmol), followed by isobutyl chloroformate (19.40 mL, d=1.053 g / cm³). 3 Add 162.0 mmol of sodium borohydride at 0°C and stir at the same temperature for 4 hours. The formed solid was filtered off at 0°C, and the residue was washed with dry tetrahydrofuran (200 mL). The combined filtrate was added to a cooled mixture of sodium borohydride (50.9 g, 1350.0 mmol) in water (200 mL). The reaction mixture was slowly warmed to ambient temperature and stirred for 72 hours. The reaction mixture was quenched with ice-cold water (1000 mL), extracted with ethyl acetate (4 x 1500 mL), the combined organic layer was washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated to obtain a yellowish liquid (45.0 g). This was purified by chromatography using a Grace apparatus with a 200g prepacked flash column containing 60-120 silica gel. The product was eluted with 30-35% ethyl acetate in petroleum ether to obtain tert-butyl N-[2-(3,4-dichlorophenyl)-1-hydroxypropan-2-yl]carbamate (28.0g) as an off-white solid.

[0368] 1H NMR (400 MHz, DMSO-d6:D2O) δ 7.51 (d, J = 8.40 Hz, 1H), 7.43 (s, 1H), 7.26 (dd, J = 2.00, 8.40 Hz, 1H), 3.46 (d, J = 10.80 Hz, 2H), 1.50 (s, 3H), 1.31 (s, 9H); MS: m / z 319.2 (M-1).

[0369] Example 19, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-(3,4-dichlorophenyl)propyl 2,2-dimethylpropanoate [ka] Under a nitrogen atmosphere, a solution of tert-butyl N-[2-(3,4-dichlorophenyl)-1-hydroxypropan-2-yl]carbamate (Example 19, from Step 4) (28.0 g, 87.4 mmol) in dry dichloromethane (200 mL) was prepared by adding triethylamine (36.50 mL, d=0.726 g / cm³). 3 (262.00 mmol), followed by pivaloyl chloride (21.50 mL, d=0.985 g / cm³). 3 175.0 mmol of propyl

[0370] 1H NMR (400 MHz, DMSO-d6: D2O) δ 7.58 (d, J = 8.44 Hz, 1H), 7.50 (s, 1H), 7.32 (dd, J = 1.76, 8.42 Hz, 1H), 4.26 (q, J = 10.44 Hz, 2H), 1.55 (s, 3H), 1.22 (s, 9H), 1.11 (s, 9H); MS: m / z 305.2 [(M+1)-Boc].

[0371] Example 19, Step 6: Preparation of 2-amino-2-(3,4-dichlorophenyl)propyl 2,2-dimethylpropanoate hydrochloride [ka] Under a nitrogen atmosphere, a solution of 2-{[(tert-butoxy)carbonyl]amino}-2-(3,4-dichlorophenyl)propyl 2,2-dimethylpropanoate (from Example 19, Step 5) (30.0 g, 74.20 mmol) in dry dichloromethane (300 mL) was added dropwise with a 4 M HCl solution in dioxane (70.0 mL, 223.0 mmol) at 0°C, and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under high vacuum to obtain 2-amino-2-(3,4-dichlorophenyl)propyl 2,2-dimethylpropanoate hydrochloride (23.0 g) as a yellowish gum, which was used in the next step without further purification.

[0372] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.85 (s, 1H), 7.75 (dd, J = 2.88, 8.52 Hz, 1H), 7.53 (dd, J = 2.24, 5.72 Hz, 1H), 4.43 (d, J = 11.76 Hz, 1H), 4.25 (d, J = 11.72 Hz, 1H), 1.68 (s, 3H), 1.11 (s, 9H); MS: m / z 305.1 [(M+1)-HCl].

[0373] Example 19, Step 7: Preparation of 2-(3,4-dichlorophenyl)-2-isocyanatopropyl 2,2-dimethylpropanoate [ka] To a solution of 2-amino-2-(3,4-dichlorophenyl)propyl 2,2-dimethylpropanoate hydrochloride (Example 19, from Step 6) (25.0 g, 73.40 mmol) in dry dichloromethane (200 mL), 10% sodium bicarbonate aqueous solution (200 mL) was added at 0°C. After 15 minutes, thiophosgene (7.40 mL, d=1.5 g / cm³) was added. 3 95.40 mmol) was added and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was extracted with dichloromethane (3 x 750 mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow liquid (26.0 g). This was purified by gravity column chromatography on 60-120 mesh silica gel with 25% ethyl acetate in hexane as the eluent to obtain 2-(3,4-dichlorophenyl)-2-isocyanatopropyl 2,2-dimethylpropanoate (15.0 g) as a yellow liquid.

[0374] 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.73 (d, J = 8.40 Hz, 1H), 7.51 (dd, J = 2.40, 8.40 Hz, 1H), 4.45 (q, J = 11.60 Hz, 2H), 1.79 (s, 3H), 1.12 (s, 9H).

[0375] Example 19, Step 8: Preparation of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3,4-dichlorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3,4-dichlorophenyl)propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from Example 1, Step 5) (1.50 sg, 7.34 mmol) in a mixed solvent of dichloromethane:methanol (1:1; 50 mL), 2-(3,4-dichlorophenyl)-2-isocyanatopropyl 2,2-dimethylpropanoate (from Example 19, Step 7) (1.53 g, 4.41 mmol) was added, and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was concentrated to obtain 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3,4-dichlorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3,4-dichlorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (4.00 g) as a yellow gum, which was used in the next step without further purification. MS: m / z 551.1 (M+1).

[0376] Example 19, Step 9: Preparation of 2-(3,4-dichlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}aminopropyl 2,2-dimethylpropanoate [ka] To a solution of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3,4-dichlorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3,4-dichlorophenyl)propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (from Example 19, Step 8) (4.00 g, 7.27 mmol) in methanol (100 mL), iodoacetic acid (1.35 g, 7.27 mmol) was added, and the mixture was stirred at 65°C for 1 hour. The reaction mixture was concentrated to remove the solvent methanol, and the residue was dissolved in 100 mL of 10% sodium bicarbonate aqueous solution and extracted with ethyl acetate (3 x 200 mL). The combined organic extract was dried over sodium sulfate, filtered, and concentrated to obtain a brown gum (4.00 g). This was purified by preparative HPLC to obtain 2-(3,4-dichlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate (0.900 g) as the brown gum.

[0377] 1H NMR (400 MHz, DMSO-d6: D2O) δ 7.69 (s, 1H), 7.62 (d, J = 8.40 Hz, 2H), 7.44 (dd, J = 2.00, 8.40 Hz, 1H), 7.29 (d, J = 8.00 Hz, 1H), 7.14 (s, 1H), 7.05 (t, J = 7.20 Hz, 1H), 7.03 (d, J = 7.20 Hz, 1H), 5.11 (s, 2H), 4.45 (q, J = 11.20 Hz, 2H), 1.82 (s, 3H), 1.05 (s, 9H); MS: m / z 517.1 (M+1).

[0378] Example 19: Preparation of 2-(3,4-dichlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka] To a solution of 2-(3,4-dichlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate (from Example 19, Step 9) (0.750 g, 1.19 mmol) in methanol (50 mL), 0.5 M sodium hydroxide (5.95 mL, 2.97 mmol) in methanol was added dropwise, and the mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was quenched at 0°C with 10 mL of 1.5 N hydrochloric acid solution and concentrated at 28°C to obtain a brown gum (0.520 g). This was purified by preparative HPLC to obtain 2-(3,4-dichlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol (0.380 g) as the brown gum.

[0379] 1 H NMR (400 MHz, AcOH-d4) δ 7.72 (s, 1H), 7.57 (d, J = 7.20 Hz, 1H), 7.53 (d, J = 8.40 Hz, 1H), 7.48 (dd, J = 2.40, 8.60 Hz, 1H), 7.41 (dd, J = 1.20, 7.40 Hz, 1H), 7.31 (t, J = 7.60 Hz, 1H), 7.27 (dd, J = 1.60, 7.60 Hz, 1H), 7.21 (d, J = 7.20 Hz, 1H), 5.40 (q, J = 15.60 Hz, 2H), 4.33 (d, J = 12.00 Hz, 1H), 4.08 (d, J = 12.40 Hz, 1H), 1.78 (s, 3H); MS: m / z 433.1 (M+1).

[0380] The above product was separated into two enantiomers by chiral SFC using the following method to obtain two enantiomers, 19a and 19b: Column: Chiral Pak OX-H; Flow rate: 5.0 mL / min; Cosolvent: 50%; Cosolvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 7.0 μL; Outlet pressure: 100 bar; Temperature: 35°C.

[0381] Example 19a: (-)-2-(3,4-dichlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol The (-) enantiomer was the first compound to elute from the column. [ka]

[0382] 1H NMR (400 MHz, AcOH-d4) δ 7.72 (s, 1H), 7.57 (d, J = 7.20 Hz, 1H), 7.53 (d, J = 8.40 Hz, 1H), 7.48 (dd, J = 2.40, 8.60 Hz, 1H), 7.41 (dd, J = 1.20, 8.40 Hz, 1H), 7.30 (t, J = 7.60 Hz, 1H), 7.27 (dd, J = 2.40, 8.00 Hz, 1H), 7.22 (d, J = 7.60 Hz, 1H), 5.40 (q, J = 15.60 Hz, 2H), 4.33 (d, J = 12.00 Hz, 1H), 4.08 (d, J = 12.40 Hz, 1H), 1.77 (s, 3H);

[0383] MS: m / z 432.1 (M+1); [α] D 25.4 (-) 8.00 (MeOH, c = 0.5).

[0384] Example 19b: (+)-2-(3,4-dichlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol The (+) enantiomer was the second compound eluted from the column. [ka]

[0385] 1H NMR (400 MHz, AcOH-d4) δ 7.72 (s, 1H), 7.57 (d, J = 8.00 Hz, 1H), 7.53 (d, J = 8.40 Hz, 1H), 7.48 (dd, J = 2.00, 8.40 Hz, 1H), 7.40 (dd, J = 1.20, 7.60 Hz, 1H), 7.30 (t, J = 7.60 Hz, 1H), 7.26 (dd, J = 1.60, 7.80 Hz, 1H), 7.22 (d, J = 7.60 Hz, 1H), 5.40 (q, J = 16.00 Hz, 2H), 4.33 (d, J = 12.00 Hz, 1H), 4.08 (d, J = 12.00 Hz, 1H), 1.77 (s, 3H);

[0386] MS: m / z 432.1 (M+1); [α] D 25.5 (+) 7.20 (MeOH, c = 0.5).

[0387] Example 20: Preparation of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-4,5-dimethyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka] Starting from commercially available 4,5-dimethyloxazole-2-amine, the title compound was prepared by the method described in Example 8 and isolated as trifluoroacetate.

[0388] 1H NMR (400 MHz, AcOH-d4) δ 7.68 (dd, J = 2.40, 6.80 Hz, 1H), 7.54-7.51 (m, 1H), 7.35 (d, J = 8.00 Hz, 1H), 7.25 (dd, J = 8.00, 16.00 Hz, 2H), 6.87 (d, J = 8.00 Hz, 1H), 5.40 (s, 2H), 4.32 (d, J = 12.00 Hz, 1H), 4.08 (d, J = 12.40 Hz, 1H), 2.28 (d, J = 0.80 Hz, 3H), 2.02 (d, J = 1.20 Hz, 3H), 1.78 (s, 3H); MS: m / z 444.1 (M+1).

[0389] Example 21: Preparation of 2-(4-(((1-methyl-1H-pyrazole-5-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino)-2-(3-(trifluoromethyl)phenyl)propan-1-ol [ka] The title compound was prepared using the methods described in Examples 16 and 18, starting with commercially available 2-methylpyrazol-l-3-amine.

[0390] 1H NMR (400 MHz, AcOH-d4) δ 7.85 (s, 1H), 7.81 (d, J = 8.00 Hz, 1H), 7.66 (d, J = 8.00 Hz, 1H), 7.58 (t, J = 7.60 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J = 14.80 Hz, 1H), 7.26 (d, J = 6.80 Hz, 2H), 7.20 (t, J = 7.20 Hz, 1H), 4.54 (q, J = 15.60 Hz, 2H), 4.42 (d, J = 12.00 Hz, 1H), 4.13 (d, J = 12.00 Hz, 1H), 3.70 (s, 3H), 1.82 (s, 3H); MS: m / z 445.2 (M+1).

[0391] Example 22: Preparation of 2-((4-(((1-methyl-1H-imidazole-2-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino)-2-(3-(trifluoromethyl)phenyl)propan-1-ol [ka] The title compound was prepared starting from commercially available 1-methylimidazole-2-amine by the method described in Examples 1 and 18.

[0392] 1H NMR (400 MHz, AcOH-d4) δ 7.84 (s, 1H), 7.81 (d, J = 8.00 Hz, 1H), 7.67 (d, J = 7.60 Hz, 1H), 7.60 (t, J = 7.60 Hz, 1H), 7.34 (d, J = 8.00 Hz, 1H), 7.23 (t, J = 8.00 Hz, 1H), 7.02 (d, J = 7.60 Hz, 1H), 6.85 (d, J = 2.80 Hz, 1H), 6.78 (d, J = 2.40 Hz, 1H), 5.35 (d, J = 7.60 Hz, 2H), 4.41 (d, J = 12.40 Hz, 1H), 4.11 (d, J = 12.00 Hz, 1H), 3.60 (s, 3H), 1.78 (s, 3H); MS: m / z 445.2 (M+1).

[0393] Example 23: Preparation of 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]-propan-1-ol [ka]

[0394] Example 23, Step 1: Preparation of 2-[({2-amino-3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from Example 5, Step 2) (1.8 g, 8.25 mmol) in a mixed solvent of dichloromethane:methanol (1:1; 40 mL), [2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl]2,2-dimethylpropanoate (from Example 18, Step 7) (1.71 g, 4.95 mmol) was added and the mixture was stirred at ambient temperature for 72 hours. The reaction mixture was concentrated at 30°C to obtain 2-[({2-amino-3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (3.30 g) as a brown gum, which was used in the next step without purification. MS: m / z 564.2.2(M+1).

[0395] Example 23, Step 2: Preparation of 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-[({2-amino-3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (Example 23, Step 1) (3.30 g, 5.85 mmol) in methanol (40 mL), iodoacetic acid (1.63 g, 8.78 mmol) was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated at 30°C to obtain a brown gum (3.3 g), which was purified by preparative HPLC (TFA: acetonitrile) to isolate 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (0.550 g) as the trifluoroacetate, which was obtained as the brown gum.

[0396] 1 H NMR (400 MHz, AcOH-d4) δ 7.88 (d, J = 7.52 Hz, 2H), 7.73 (d, J = 8.04 Hz, 1H), 7.65 (t, J = 7.92 Hz, 1H), 7.47 (d, J = 1.56 Hz, 1H), 7.30-7.23 (m, 2H), 6.86 (d, J = 0.92 Hz, 1H), 5.48 (s, 2H), 4.55 (q, J = 11.64 Hz, 2H), 2.13 (s, 3H), 2.05 (s, 3H), 1.19 (s, 9H); MS: m / z 530.2 (M+1).

[0397] The above products were separated by chiral SFC using the following method to obtain two enantiomers, 23-2a and 23-2b: Chiralcel OX-H, mobile phase: 0.5% isopropylamine in isopropyl alcohol; cosolvent: 40% CO2; flow rate: 3 ml / min, pressure: 100 bar, temperature: 35°C.

[0398] Example 23-2a: 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (enantiomer A) Enantiomer A was the first compound to elute from the column. [ka]

[0399] 1 H NMR (400 MHz, AcOH-d4) δ 7.88 (d, J = 7.52 Hz, 2H), 7.73 (d, J = 8.04 Hz, 1H), 7.65 (t, J = 7.92 Hz, 1H), 7.47 (d, J = 1.56 Hz, 1H), 7.30-7.23 (m, 2H), 6.86 (d, J = 0.92 Hz, 1H), 5.48 (s, 2H), 4.55 (q, J = 11.64 Hz, 2H), 2.13 (s, 3H), 2.05 (s, 3H), 1.19 (s, 9H); MS: m / z 530.2 [(M+1).

[0400] Example 23-2b: 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (enantiomer B) Enantiomer B was the second compound eluted from the column. [ka]

[0401] 1 H NMR (400 MHz, AcOH-d4) δ 7.88 (d, J = 7.52 Hz, 2H), 7.73 (d, J = 8.04 Hz, 1H), 7.65 (t, J = 7.92 Hz, 1H), 7.47 (d, J = 1.56 Hz, 1H), 7.30-7.23 (m, 2H), 6.86 (d, J = 0.92 Hz, 1H), 5.48 (s, 2H), 4.55 (q, J = 11.64 Hz, 2H), 2.13 (s, 3H), 2.05 (s, 3H), 1.19 (s, 9H); MS: m / z 530.2 [(M+1).

[0402] Example 23: 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid (Example 23, Step 2) (0.050 g, 0.077 mmol) in methanol (10 mL), 0.600 ml, 0.311 mmol of 0.5 N sodium hydroxide in methanol was added dropwise, and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was quenched with 1.5N hydrochloride solution (1 mL) and concentrated under reduced pressure at 30°C to obtain a brown gum (0.04 g). This was purified by preparative HPLC using 0.1% TFA in acetonitrile:water, and 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol (0.028 g) was isolated as trifluoroacetate and obtained as the brown gum.

[0403] 1 H NMR (400 MHz, AcOH-d4) δ 7.85 (t, J = 8.00 Hz, 2H), 7.69 (d, J = 7.84 Hz, 1H), 7.61 (t, J = 7.64 Hz, 1H), 7.44 (d, J = 1.52 Hz, 1H), 7.35 (d, J = 7.88 Hz, 1H), 7.25 (t, J = 8.00 Hz, 1H), 6.87 (d, J = 7.60 Hz, 1H), 5.46 (s, 2H), 4.42 (d, J = 12.08 Hz, 1H), 4.14 (d, J = 12.12 Hz, 1H), 2.08 (s, 3H), 1.82 (s, 3H); MS: m / z 446.1[(M+1)-TFA].

[0404] Example 23a: Preparation of (-)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (Example 23-2a, enantiomer A) (0.150 g, 0.233 mmol) in methanol (20 mL), 0.5 N sodium hydroxide in methanol (1.86 ml, 0.932 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was quenched with 1.5N hydrochloride solution (1 mL) and concentrated under reduced pressure at 30°C to obtain a brown gum (0.130 g). This was purified by preparative HPLC using 0.1% TFA in acetonitrile:water, and the isolated trifluoroacetate (-)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol (0.060 g) was obtained as a colorless gum.

[0405] 1H NMR (400 MHz, AcOH-d4δ 7.84 (t, J = 8.40 Hz, 2H), 7.68 (d, J = 7.60 Hz, 1H), 7.60 (t, J = 8.00 Hz, 1H), 7.43 (d, J = 1.20 Hz, 1H), 7.34 (d, J = 8.00 Hz, 1H), 7.24 (t, J = 8.00 Hz, 1H), 6.86 (d, J = 8.00 Hz, 1H), 5.45 (s, 2H), 4.42 (d, J = 12.00 Hz, 1H), 4.13 (d, J = 12.00 Hz, 1H), 2.07 (s, 3H), 1.81 (s, 3H);

[0406] MS: m / z 446.1[(M+1)]; SOR: [α] D 20.6 (-) 10.16, (MeOH, c = 0.5).

[0407] Example 23b: Preparation of (+)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (Example 23-2b, enantiomer B) (0.11 g, 0.171 mmol) in methanol (12 mL), 0.5 N sodium hydroxide in methanol (1.37 ml, 0.684 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was quenched with 1.5N hydrochloride solution (1 mL) and concentrated under reduced pressure at 30°C to obtain a brown gum (0.09 g). This was purified by preparative HPLC using 0.1% TFA in acetonitrile:water, and the isolated trifluoroacetate (+)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol (0.030 g) was obtained as a colorless gum.

[0408] 1 H NMR (400 MHz, AcOH-d4δ 7.84 (t, J = 8.40 Hz, 2H), 7.68 (d, J = 7.60 Hz, 1H), 7.60 (t, J = 8.00 Hz, 1H), 7.43 (d, J = 1.20 Hz, 1H), 7.34 (d, J = 8.00 Hz, 1H), 7.24 (t, J = 8.00 Hz, 1H), 6.86 (d, J = 8.00 Hz, 1H), 5.45 (s, 2H), 4.42 (d, J = 12.00 Hz, 1H), 4.13 (d, J = 12.00 Hz, 1H), 2.07 (s, 3H), 1.81 (s, 3H);

[0409] MS: m / z 446.1 (M+1); SOR: [α] D 20.2 (+) 5.60, (MeOH, c = 0.5).

[0410] Example 24: Preparation of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol [ka]

[0411] Example 24, Step 1: Preparation of 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-5-methyl-2,3-dihydro-1,3-oxazole-2-imine hydrobromide [ka] To a solution of 4-(bromomethyl)-2,1,3-benzothiadiazole (Example 1, Step 3) (2.00 g, 8.73 mmol) in acetonitrile (20 mL), 5-methyloxazole-2-amine (1.03 g, 10.50 mmol) was added, and the mixture was stirred at ambient temperature for 60 hours. The reaction mixture was concentrated to obtain an off-white gum (2.10 g), which was purified by preparative HPLC (H2O:acetonitrile). The solution was concentrated at 40°C to obtain 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-5-methyl-2,3-dihydro-1,3-oxazole-2-imine hydrobromide (1.60 g) as an off-white solid.

[0412] 1 H-NMR (400 MHz, DMSO-d6: D2O) δ 8.12 (d, J = 8.72 Hz, 1H), 7.76 (t, J = 8.60 Hz, 1H), 7.67 (d, J = 6.72 Hz, 1H), 7.12 (s, 1H), 5.50 (s, 2H), 2.18 (s, 3H); MS: m / z 247.1 [(M+1)-HBr].

[0413] Example 24, Step 2: Preparation of 3-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine [ka] To a degassed solution of 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-5-methyl-2,3-dihydro-1,3-oxazole-2-imine hydrobromide (Example 24, from Step 1) (1.90 g, 7.71 mmol) in dry methanol (190 mL), Raney nickel (5.70 g, 300% w / w, pre-washed 5 times with dry methanol) was added. The resulting reaction mixture was then subjected to a hydrogen atmosphere and a bladder pressure of approximately 1.5 kg / cm². 2 The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was filtered through a Celite bed, and the bed was washed with methanol (200 mL). The combined filtrate was concentrated at 15-20°C to obtain 3-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (1.50 g) as a gray gum, which was used in the next step without purification. MS: m / z 219.2 (M+1)

[0414] Example 24, Step 3: Preparation of 2-[({2-amino-3-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-(((5-methyloxazol-2-yl)amino)methyl)benzene-1,2-diamine (Example 24, Step 2) (1.50 g, 6.87 mmol) in a mixed solvent of dichloromethane:methanol (1:1; 60 mL), [2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl]2,2-dimethylpropanoate (Example 18, from Step 7) (1.90 g, 5.50 mmol) was added and the mixture was stirred at ambient temperature for 72 hours. The reaction mixture was concentrated at 30°C to obtain 2-[({2-amino-3-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (3.40 g) as a brown gum, which was used in the next step without purification. MS: m / z 564.2.2 (M+1)

[0415] Example 24, Step 4: Preparation of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-[({2-amino-3-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (Example 24, Step 3) (3.40 g, 6.03 mmol) in methanol (30 mL), iodoacetic acid (1.68 g, 9.05 mmol) was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated at 30°C to obtain a brown gum (3.80 g), which was purified by preparative HPLC (TFA: acetonitrile) to obtain 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (1.00 g) as the trifluoroacetate, which was then isolated as the brown gum.

[0416] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.80-7.65 (m, 4H), 7.32 (d, J = 10.40 Hz, 1H), 7.20 (d, J = 10.00 Hz, 1H), 7.06 (d, J = 10.40 Hz, 1H), 6.89 (s, 1H), 5.16 (s, 2H), 4.48 (s, 2H), 2.16 (s, 3H), 1.91 (s, 3H), 1.03 (s, 9H); MS: m / z 530.2 [(M+1)-TFA].

[0417] The above product was separated into two enantiomers by chiral SFC using the following method to obtain two enantiomers, 24-4a and 24-4b: Chiralcel OX-H, mobile phase: 0.5% isopropylamine in methanol; cosolvent: 30% CO2; flow rate: 3 ml / min, pressure: 100 bar, temperature: 35°C.

[0418] Example 24-4a: 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (enantiomer A) The first compound to elute from the column was enantiomer A. [ka]

[0419] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.80-7.65 (m, 4H), 7.32 (d, J = 10.40 Hz, 1H), 7.20 (d, J = 10.00 Hz, 1H), 7.06 (d, J = 10.40 Hz, 1H), 6.89 (s, 1H), 5.16 (s, 2H), 4.48 (s, 2H), 2.16 (s, 3H), 1.91 (s, 3H), 1.03 (s, 9H); MS: m / z 530.2 [(M+1).

[0420] Example 24-4b: 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (enantiomer B) Enantiomer B was the second compound eluted from the column. [ka]

[0421] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.80-7.65 (m, 4H), 7.32 (d, J = 10.40 Hz, 1H), 7.20 (d, J = 10.00 Hz, 1H), 7.06 (d, J = 10.40 Hz, 1H), 6.89 (s, 1H), 5.16 (s, 2H), 4.48 (s, 2H), 2.16 (s, 3H), 1.91 (s, 3H), 1.03 (s, 9H); MS: m / z 530.2 [(M+1).

[0422] Example 24: Preparation of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid (Example 24, Step 4) (0.130 g, 0.202 mmol) in methanol (20 mL), 0.5 N sodium hydroxide (1.62 ml, 0.808 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was quenched with 1.5 N hydrochloride solution (1 mL), concentrated under reduced pressure at 30°C, and a brown gum (0.110 g) was obtained. This was purified by preparative HPLC using acetonitrile:water with 0.1% TFA, and 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol (0.055 g) was isolated as a trifluoroacetate and obtained as brown gum.

[0423] 1 H NMR (400 MHz, AcOH-d4) δ 7.83 (t, J = 8.00 Hz, 2H), 7.67 (d, J = 7.20 Hz, 1H), 7.59 (t, J = 7.60 Hz, 1H), 7.37 (d, J = 6.80 Hz, 1H), 7.30-7.26 (m, 2H), 6.81 (s, 1H), 5.32 (d, J = 2.80 Hz, 2H), 4.41 (d, J = 12.00 Hz, 1H), 4.12 (d, J = 12.00 Hz, 1H), 2.24 (s, 3H), 1.80 (s, 3H); MS: m / z 446.1[(M+1)].

[0424] Example 24a: Preparation of (-)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)-phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (Example 24-4a, enantiomer A) (0.350 g, 0.545 mmol) in methanol (4.36 ml, 2.18 mmol), 0.5 N sodium hydroxide in methanol was added dropwise, and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with 1.5 N hydrochloride solution (3 mL), concentrated under reduced pressure at 30°C, and a brown gum (0.300 g) was obtained. This was purified by preparative HPLC using acetonitrile:water with 0.1% TFA, and (-)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol (0.160 g) was isolated as a trifluoroacetate and obtained as a colorless gum.

[0425] 1H NMR (400 MHz, AcOH-d4) δ 7.83 (t, J = 8.00 Hz, 2H), 7.67 (d, J = 7.20 Hz, 1H), 7.59 (t, J = 7.60 Hz, 1H), 7.38 (dd, J = 6.62, 2.36 Hz, 1H), 7.30-7.26 (m, 2H), 6.81 (s, 1H), 5.32 (d, J = 2.80 Hz, 2H), 4.41 (d, J = 12.00 Hz, 1H), 4.12 (d, J = 12.00 Hz, 1H), 2.24 (s, 3H), 1.80 (s, 3H);

[0426] MS: m / z 446.1(M+1); SOR: [α] D 20.5 (-) 6.80, (MeOH, c = 0.5).

[0427] Example 24b: Preparation of (+)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)-phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propyl 2,2-dimethylpropanoate (Example 24-4b, enantiomer B) (0.170 g, 0.265 mmol) in methanol (20 mL), 0.5 N sodium hydroxide (2.12 ml, 0.106 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with 1.5 N hydrochloride solution (2 mL), concentrated under reduced pressure at 30°C, and a brown gum (0.150 g) was obtained. This was purified by preparative HPLC using acetonitrile:water with 0.1% TFA, and (+)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol (0.120 g) was isolated as a trifluoroacetate and obtained as a colorless gum.

[0428] 1 H NMR (400 MHz, AcOH-d4) δ 7.83 (t, J = 8.00 Hz, 2H), 7.67 (d, J = 7.20 Hz, 1H), 7.59 (t, J = 7.60 Hz, 1H), 7.38 (dd, J = 6.62, 2.36 Hz, 1H), 7.30-7.26 (m, 2H), 6.81 (s, 1H), 5.32 (d, J = 2.80 Hz, 2H), 4.41 (d, J = 12.00 Hz, 1H), 4.12 (d, J = 12.00 Hz, 1H), 2.24 (s, 3H), 1.80 (s, 3H);

[0429] MS: m / z 446.1 (M+1); SOR: [α] D 20.9 (+) 7.20, (MeOH, c = 0.5).

[0430] Example 25: Preparation of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]butan-1-ol [ka]

[0431] Example 25, Step 1: Preparation of 5-ethyl-5-(3-(trifluoromethyl)phenyl)imidazolidined-2,4-dione [ka] To a stirred solution of 1-(3-(trifluoromethyl)phenyl)propan-1-one (commercial product) (45.0 g, 223.0 mmol) in a mixed solvent of ethanol / water (1:1; 1000 mL), ammonium carbonate (107.0 g, 1110.0 mmol) was added, followed by potassium cyanide (17.10 g, 263.0 mmol), and the mixture was stirred at 60°C for 16 hours. The reaction mixture was poured into ice-cold water (1500 mL) and stirred for 30 minutes. The resulting solid was filtered and dried to obtain 5-ethyl-5-(3-(trifluoromethyl)phenyl)imidazolidined-2,4-dione (55.0 g) as an off-white solid, which was used in the next step without further purification.

[0432] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.78 (d, 1H, J = 7.68 Hz), 7.75 (s, 1H), 7.68 (d, 1H, J = 7.84 Hz), 7.63 (t, 1H, J = 7.76 Hz), 2.08 (q, 1H, J = 7.20 Hz), 1.90 (q, 1H, J = 7.32 Hz), 0.78 (t, 3H, J = 7.24 Hz); MS: m / z 271.1 (M-1).

[0433] Example 25, Step 2: Preparation of 2-amino-2-(3-(trifluoromethyl)phenyl)butanoic acid [ka] 5-Ethyl-5-(3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione (from Example 25, Step 1) (55.0 g, 202.0 mmol) was dissolved in 350 mL of 10% aqueous sodium hydroxide solution, and the mixture was refluxed for 48 hours. The reaction mixture was neutralized with 200 mL of 6.0 N HCl (to adjust pH to 7), and the resulting solid was filtered and dried to obtain 2-amino-2-(3-(trifluoromethyl)phenyl)butanoic acid (31.0 g) as a white solid, which was used in the next step without further purification.

[0434] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.86 (s, 1H), 7.80 (d, 1H, J = 7.60 Hz), 7.62 (d, 1H, J = 7.60 Hz), 7.57 (t, 1H, J = 7.60 Hz), 2.14 - 2.08 (m, 2H), 0.81 (t, 3H, J = 7.60 Hz); MS: m / z 248.2 (M+1).

[0435] Example 25, Step 3: Preparation of 2-amino-2-(3-(trifluoromethyl)phenyl)butan-1-ol [ka] To a solution of 2-amino-2-(3-(trifluoromethyl)phenyl)butanoic acid (from Example 25, Step 2) (40.00 g, 162.00 mmol) in dry tetrahydrofuran (1200 mL), a 2 M solution of lithium aluminum hydride (202.0 mL, 405.0 mmol) in tetrahydrofuran was added at 0°C, and the reaction mixture was slowly warmed to ambient temperature and stirred for 3 hours. The reaction mixture was cooled to 0°C, and ethyl acetate solution (120 mL) was added dropwise to quench the mixture, which was then stirred for 30 minutes. Next, saturated ammonium chloride solution (150 mL) was added dropwise, and the mixture was stirred at 0°C for 15 minutes. The resulting precipitate was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain a yellow gum (40.00 g). This was diluted with 10% sodium hydroxide aqueous solution (100 mL) and extracted with ethyl acetate (4 x 1000 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 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.

[0436] 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.75 (d, 1H, J = 6.00 Hz), 7.53 (d, 2H, J = 6.40 Hz), 4.76 (t, 1H, J = 5.60 Hz), 3.54 (dd, 2H, J = 10.20, 5.60 Hz), 1.84 (s, 2H), 1.75 (q, 1H, J = 7.60 Hz), 1.62 (q, 1H, J = 6.80 Hz), 0.61 (t, 3H, J = 7.60 Hz); MS: m / z 234.1 (M+1).

[0437] Example 25, Step 4: Preparation of tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]butan-2-yl}carbamate [ka] A suspension of 2-amino-2-(3-(trifluoromethyl)phenyl)butan-1-ol (from Example 25, Step 3) (18.50 g, 51.60 mmol) in a mixed solvent of dichloromethane:1,4-dioxane (4:1; 500 mL) was prepared by adding di-tert-butyl dicarbonate (13.50 mL, d: 0.950 g / cm³). 3 61.90 mmol of ethyl acetate was added dropwise at 0°C, and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (4 x 1000 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to obtain a yellow gum (18.00 g). This was purified by chromatography using a Grace apparatus with a 220 g pre-packed flash cartridge filled with 60 Å, 40-63 μm normal-phase silica gel. The product was eluted with 25-30% ethyl acetate in hexane to obtain tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]butan-2-yl}carbamate (11.50 g) as a colorless gum.

[0438] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.58 (s, 1H), 7.56 (d, 2H, J = 2.16 Hz), 7.53 (t, 1H, J = 6.32 Hz), 3.61 (t, 2H, J = 12.40 Hz), 1.97 (q, 2H, J = 7.64 Hz), 1.46 (s, 9H), 0.61 (t, 3H, J = 7.60 Hz); MS: m / z 234.2 [(M+1)-Boc].

[0439] Example 25, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate [ka] Under a nitrogen atmosphere, a solution of tert-butyl N-{1-hydroxy-2-[3-(trifluoromethyl)phenyl]butan-2-yl}carbamate (from Step 4 of Example 25) (11.50 g, 34.50 mmol) in dry dichloromethane (300 mL) was mixed with triethylamine (31.30 mL, d=0.726 g / cm³). 3 (224.0 mmol), followed by pivaloyl chloride (12.70 mL, d=0.985 g / cm³). 3 103.00 mmol of butyl 2,2-dimethylpropanoate was added dropwise at 0°C, and the reaction mixture was stirred at ambient temperature for 48 hours. The reaction mixture was quenched with ice-cold water (100 mL) and extracted with dichloromethane (4 x 500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain a brown gum (15.00 g). This was purified by chromatography using a Grace apparatus with a 120 g pre-packed flash cartridge filled with 60 Å, 40-63 μm normal-phase silica gel. The product was eluted with 15-20% ethyl acetate in hexane to obtain 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (10.0 g) as a colorless gum.

[0440] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.61 (s, 1H), 7.59 (d, 2H, J = 7.52 Hz), 7.58 (t, 1H, J = 7.00 Hz), 4.38 (q, 2H, J = 14.40 Hz), 1.95 (q, 2H, J = 7.28 Hz), 1.39 (s, 9H), 1.11 (s, 9H), 1.09 (t, 3H, J = 6.08 Hz); MS: m / z 318.2 [(M+1)-Boc].

[0441] Example 25, Step 6: Preparation of 2-amino-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate hydrochloride [ka] Under a nitrogen atmosphere, a solution of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (from Example 25, Step 5) (10.00 g, 24.00 mmol) in dry dichloromethane (300 mL) was added dropwise at 0°C with a 4 M HCl solution in dioxane (15.00 mL, 59.90 mmol). The reaction mixture was stirred at ambient temperature for 16 hours, then concentrated, and the residue was triturated with hexane (3 x 250 mL). The supernatant was decanted, and the solid was dried to obtain 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.

[0442] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.74 (s, 1H), 7.68 (d, 2H, J = 13.60 Hz), 7.56 (t, 1H, J = 8.84 Hz), 4.56 (d, 1H, J = 12.08 Hz), 4.22 (d, 1H, J = 12.12 Hz), 2.17-1.97 (m, 2H), 1.02 (s, 9H), 0.78 (t, 3H, J = 7.36 Hz); MS: m / z 318.2 [(M+1)-HCl].

[0443] Example 25, Step 7: Preparation of 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate [ka] To a solution of 2-amino-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate hydrochloride (from Example 25, Step 6) (8.50 g, 24.00 mmol) in dry dichloromethane (300 mL), 10% sodium bicarbonate aqueous solution (300 mL) was added at 0°C. After 30 minutes, thiophosgene (11.00 mL, d=1.5 g / cm³) was added. 3 (144.0 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was extracted with dichloromethane (3 x 500 mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow liquid (9.00 g). This was purified by chromatography in a Grace apparatus using a 60.0 g pre-packed flash cartridge packed with normal-phase silica gel 60 Å, 40-63 μm, and the product was eluted with 5-10% ethyl acetate in hexane to obtain 2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (6.50 g) as a yellow liquid.

[0444] 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.59 (d, 2H, J = 7.16 Hz), 7.56 (t, 1H, J = 7.76 Hz), 4.39 (d, 2H, J = 4.04 Hz), 2.21 (q, 1H, J = 7.20 Hz), 2.07 (q, 1H, J = 6.96 Hz), 1.16 (s, 9H), 0.91 (t, 3H, J = 7.12 Hz).

[0445] Example 25, Step 8: Preparation of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (Example 1, Step 5)) (0.300 g, 1.47 mmol) in a mixed solvent of dichloromethane:methanol (1:1; 8 mL), [2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]butyl]2,2-dimethylpropanoate (Example 25, from Step 7)) (0.317 g, 0.880 mmol) was added, and the mixture was stirred at ambient temperature for 72 hours. The reaction mixture was concentrated in a water bath at 30°C to obtain 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (0.600 g) as a brown gum, which was used in the next step without purification. MS: m / z 564.4(M+1).

[0446] Example 25, Step 9: Preparation of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate [ka] To a solution of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (Example 25, Step 8) (0.600 g, 1.06 mmol) in methanol (8 mL), iodoacetic acid (0.297 g, 1.60 mmol) was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated at 30°C, and the solvent methanol was removed to obtain a brown gum (0.700 g). This was purified by preparative HPLC (TFA: acetonitrile) to obtain 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (0.090 g), which was isolated as a trifluoroacetate, as the brown gum.

[0447] 1H NMR (400 MHz, AcOH-d4) δ 7.82 (d, J = 6.44 Hz, 2H), 7.74 (d, J = 7.60 Hz, 1H), 7.66 (t, J = 7.84 Hz, 1H), 7.58 (s, 1H), 7.32-7.30 (m, 3H), 7.23 (s, 1H), 5.40 (s, 2H), 4.94 (d, J = 11.84 Hz, 1H), 4.76 (d, J = 11.92 Hz, 1H), 2.35 (q, J = 7.08 Hz, 2H), 1.15 (s, 9H), 0.92 (t, J = 7.40 Hz, 3H); MS: m / z 530.2 / 531.2 (M+1).

[0448] Example 25: Preparation of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]butan-1-ol [ka] To a solution of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate; trifluoroacetic acid (Example 25, Step 9) (0.080 g, 0.124 mmol) in methanol (10 mL), 0.990 mL, 0.497 mmol of 0.5 N sodium hydroxide in methanol was added dropwise, and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was quenched with 1 mL of 1.5 N hydrochloride solution and concentrated under reduced pressure at 30°C to obtain a brown gum (0.070 g). This was purified by preparative HPLC using acetonitrile:water with 0.1% TFA, and 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]butan-1-ol (0.020 g) was isolated as a trifluoroacetate and obtained as brown gum.

[0449] 1 H NMR (400 MHz, AcOH-d4) δ 7.82 (s, 1H), 7.77 (d, J = 8.00 Hz, 1H), 7.69 (d, J = 8.00 Hz, 1H), 7.61 (t, J = 8.00 Hz, 1H), 7.56 (d, J = 1.60 Hz, 1H), 7.38 (dd, J = 6.80, 2.00 Hz, 1H), 7.31-7.26 (m, 2H), 7.20 (d, J = 1.60 Hz, 1H), 5.40 (q, J = 16.00 Hz, 2H), 4.69 (d, J = 12.40 Hz, 1H), 4.29 (d, J = 12.40 Hz, 1H), 2.07 (q, J = 7.32 Hz, 2H), 0.86 (t, J = 7.20 Hz, 3H); MS: m / z 446.1 / 447.1 [(M+1)].

[0450] Example 26: Preparation of 3-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-3-[3-(trifluoromethyl)phenyl]butan-1-ol [ka]

[0451] Example 26, Step 1: Preparation of (E)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide [ka] In 1500 mL of dry tetrahydrofuran under a nitrogen atmosphere, a solution of 1-(3-(trifluoromethyl)phenyl)ethane-1-one (commercial product) (125.0 g, 664.0 mmol) was added to 2-methylpropan-2-sulfinamide (80.52 g, 664.00 mmol), followed by titanium(IV) ethoxide (278.60 mL, d=1.008 g m / mL, 1328.0 mmol). The mixture was heated at 70°C for 17 hours. The reaction mixture was diluted with brine solution (200 mL), filtered, and the filtrate was evaporated to obtain a yellowish gum (200.0 g). This was purified by gravity column chromatography using silica gel with a 60-120 mesh, and the product was eluted with 10% ethyl acetate in hexane to obtain (E)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (150.0 g) as a yellow gum.

[0452] 1 H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 8.23 ​​(d, J = 7.60 Hz, 1H), 7.88 (d, J = 7.60 Hz, 1H), 7.72 (t, J = 8.00 Hz, 1H), 2.84 (s, 3H), 1.35 (s, 9H); MS: m / z 292.3 (M+1).

[0453] Example 26, Step 2: Preparation of methyl 3-((tert-butylsulfinyl)amino)-3-(3-(trifluoromethyl)phenyl)butanoate [ka] To a suspension of zinc dust (269.3 g, 4.120 g m atom) in dry tetrahydrofuran (750 mL), copper(I) chloride (51.0 g, 515.0 mmol) was added, and the mixture was stirred at 60°C. After 30 minutes, a solution of methyl 2-bromoacetate (122.0 mL, d=1.616 g m / mL, 1287.0 mmol) in dry tetrahydrofuran (500 mL) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. A solution of (E)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (Example 26, from Step 1) (150.0 g, 515.0 mmol) in dry tetrahydrofuran (500 mL) was added dropwise at 0-5°C, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL), the resulting solid was filtered, and the filtrate was extracted with ethyl acetate (3 x 1000 mL). The combined organic extract was dried on anhydrous sodium sulfate, filtered, and evaporated to obtain brown gum (250.0 g). This was purified by gravity column chromatography on 60-120 silica gel, and the product was eluted with 70-75% ethyl acetate in hexane to obtain methyl 3-((tert-butylsulfinyl)amino)-3-(3-(trifluoromethyl)phenyl)butanoate (135.0 g) as a yellowish gum.

[0454] 1H NMR (400 MHz, AcOH-d4) δ 7.81 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.00 Hz, 1H), 7.62 (d, J = 7.60 Hz, 1H), 7.56 (t, J = 8.00 Hz, 1H), 3.62 (s, 3H), 3.20 (q, J = 16.40 Hz, 2H), 1.87 (s, 3H), 1.35 (s, 9H); MS: m / z 366.2 (M+1).

[0455] Example 26, Step 3: Preparation of N-(4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)-2-methylpropane-2-sulfinamide [ka] In 300 mL of dry tetrahydrofuran, under a nitrogen atmosphere, a stirred solution of methyl 3-((tert-butylsulfinyl)amino)-3-(3-(trifluoromethyl)-phenyl)butanoate (from Example 26, Step 2) (20.00 g, 54.70 mmol) was added to a 2 M solution of lithium aluminum hydride in tetrahydrofuran (53.00 mL, 82.10 mmol) at 0°C, and the reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was quenched with ethyl acetate (250 mL), followed by the addition of 200 mL of 10% aqueous ammonium chloride solution at 0°C, and the organic layer was separated and further extracted with ethyl acetate (4 x 750 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain N-(4-hydroxy-2-(3-(trifluoromethyl)-phenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (10.00 g) as a yellow oil, which was used in the next step without further purification.

[0456] 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.75 (d, J = 7.60 Hz, 1H), 7.61 (t, J = 7.60 Hz, 1H), 7.57 (d, J = 7.60 Hz, 1H), 5.80 (s, 1H), 4.81 (t, J = 4.80 Hz, 1H), 3.49 (q, J = 4.80 Hz, 1H), 3.31 (q, J = 4.00 Hz, 1H), 2.11 (q, J = 7.20 Hz, 1H), 1.89 (q, J = 6.00 Hz, 1H), 1.74 (s, 3H), 1.13 (s, 9H); MS: m / z 338.2 (M+1).

[0457] Example 26, Step 4: Preparation of 3-[(2-methylpropane-2-sulfinyl)amino]-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate [ka] In 300 mL of dry tetrahydrofuran, under a nitrogen atmosphere, a suspension of N-(4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (from Example 26, Step 3) (13.00 g, 38.50 mmol) was added to 0°C, and the mixture was stirred at the same temperature for 30 minutes. Pivaloyl chloride (7.10 mL, d=0.985 g / cm³) was added. 357.80 mmol) was added, and the reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was quenched with ethyl acetate (200 mL), followed by the addition of 150 mL of 10% aqueous ammonium chloride solution at 0°C to separate the organic layer, which was then extracted with ethyl acetate (4 x 500 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to obtain a yellow liquid (17.0 g). This was purified by chromatography using a Grace apparatus with a 220.00 g pre-packed flash cartridge filled with 60 Å, 40-63 μm normal-phase silica gel. The product was eluted with 35% ethyl acetate in hexane to obtain 3-[(2-methylpropane-2-sulfinyl)amino]-3-[3-(trifluoromethyl)-phenyl]butyl 2,2-dimethylpropanoate (15.0 g) as a yellow oil.

[0458] 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.76 (d, J = 7.60 Hz, 1H), 7.59 (t, J = 7.32 Hz, 1H), 7.56 (d, J = 7.60 Hz, 1H), 5.51 (s, 1H), 3.91 (t, J = 8.80 Hz, 2H), 2.27 (t, J = 8.40 Hz, 2H), 1.71 (s, 3H), 1.13 (s, 9H), 1.01 (s, 9H); MS: m / z 422.1 (M+1).

[0459] Example 26, Step 5: Preparation of 3-amino-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate hydrochloride [ka] To a stirred solution of 3-[(2-methylpropane-2-sulfinyl)amino]-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (from Example 26, Step 4) (15.00 g, 35.60 mmol) in dichloromethane (200 mL), 4M HCl (4.50 mL, 178.0 mmol) in dioxane was added at 0°C, and the mixture was stirred at ambient temperature for 12 hours. The reaction mixture was concentrated to obtain 3-amino-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate hydrochloride (12.0 g) as a yellow gum, which was used in the next step without further purification.

[0460] 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (bs, 3H), 7.95 (s, 1H), 7.91 (d, J = 7.60 Hz, 1H), 7.78 (d, J = 8.00 Hz, 1H), 7.72 (t, J = 8.00 Hz, 1H), 3.97-3.88 (m, 2H), 2.39 (t, J = 6.80 Hz, 2H), 1.76 (s, 3H), 0.097(s, 9H); MS: m / z 318.2 [(M+1)-HCl].

[0461] Example 26, Step 6: Preparation of 3-isothiocyanato-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate [ka] Add 3-amino-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate hydrochloride (Example 26, from Step 5) (12.00 g, 33.90 mmol) to a stirred solution in a two-phase mixture of dichloromethane (50 mL) and 10% sodium bicarbonate aqueous solution (50 mL) at 0°C, then add thiophosgene (3.90 mL, d=1.50 g / cm³). 3(50.90 mmol) was added and the mixture was stirred for 30 minutes. The organic layer was separated and further extracted with dichloromethane (2 x 250 mL). The combined organic extract was dried over sodium sulfate, filtered, and concentrated to obtain 3-isothiocyanato-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (7.50 g) as a yellow oil, which was used in the next step without further purification.

[0462] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.78 (s, 1H), 7.72 (t, J = 7.20 Hz, 1H), 7.67 (d, J = 8.80 Hz, 1H), 3.95 (t, J = 7.60 Hz, 2H), 2.51 (d, J = 8.80 Hz, 1H), 2.44 (d, J = 8.40 Hz, 1H), 1.87(s, 3H), 1.01 (s, 9H).

[0463] Example 26, Step 7: Preparation of 3-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-3-[3-(trifluoromethyl)-phenyl]butyl 2,2-dimethylpropanoate and 3-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-3-[3-(trifluoromethyl)-phenyl]butyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a stirred solution of [3-isothiocyanato-3-[3-(trifluoromethyl)phenyl]butyl]2,2-dimethylpropanoate (from Example 26, Step 6) (0.400 g, 1.11 mmol) in dichloromethane (10 mL), 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from Example 1, Step 5) (0.273 g, 1.34 mmol) was added, and the reaction mixture was stirred at ambient temperature for 48 hours. The reaction mixture was concentrated to obtain 3-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate and 3-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (0.600 g) as a brown gum, which was used in the next step without further purification. MS: m / z 564.3 (M+1).

[0464] Example 26, Step 8: Preparation of 3-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate [ka] To a solution of 3-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate and 3-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (from Example 26, Step 7) (0.600 g, 1.06 mmol) in methanol (20 mL), iodoacetic acid (0.198 g, 1.06 mmol) was added, and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated to obtain a brown gum (0.400 g), which was purified by preparative HPLC using the TFA method to isolate 3-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate (0.300 g) as a trifluoroacetate, which was obtained as a brown gum.

[0465] 1 H NMR (400 MHz, AcOH-d4) δ 7.91 (s, 1H), 7.85 (d, J = 9.20 Hz, 1H), 7.70 (d, J = 7.60 Hz, 1H), 7.62 (t, J = 7.60 Hz, 1H), 7.59 (d, J = 1.60 Hz, 1H), 7.34 (t, J = 4.80 Hz, 1H), 7.29 (d, J = 4.80 Hz, 2H), 7.25 (d, J = 1.60 Hz, 1H), 5.44 (d, J = 14.00 Hz, 2H), 4.27-4.10 (m, 2H), 2.63-2.53 (m, 2H), 2.02 (s, 3H), 1.11 (s, 9H); MS: m / z 530.6 (M+1).

[0466] Example 26: Preparation of 3-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-3-[3-(trifluoromethyl)phenyl]butan-1-ol [ka] To a solution of 3-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-3-[3-(trifluoromethyl)phenyl]butyl 2,2-dimethylpropanoate; trifluoroacetic acid (from Example 26, Step 8) (0.300 g, 0.466 mmol) in methanol (5 mL), 0.5 M sodium hydroxide (4.66 mL, 2.33 mmol) was added dropwise at 0°C, and the mixture was stirred at 28°C for 4 hours. The reaction mixture was quenched with 1.5 N aqueous HCl (10 mL) and concentrated at 25°C to obtain a brown gum (0.100 g). This was purified by preparative HPLC using the TFA method, and 3-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-3-[3-(trifluoromethyl)phenyl]butan-1-ol (0.040 g) was isolated as a trifluoroacetate and obtained as a white solid.

[0467] 1H NMR (400 MHz, AcOH-d4) δ 7.91 (s, 1H), 7.88 (dd, J = 8.80, 17.80 Hz, 1H), 7.68 (dd, J = 10.00, 17.20 Hz, 1H), 7.62 (t, J = 7.60 Hz, 1H), 7.47-7.39 (m, 1H), 7.27 (d, J = 1.60 Hz, 1H), 7.24 (t, J = 7.20 Hz, 1H), 6.56 (dd, J = 2.80 Hz, 1H), 6.50 (dd, J = 0.80, 3.00 Hz, 1H), 4.88 (d, J = 14.80 Hz, 2H), 3.88-3.80 (m, 2H), 2.51-2.41 (m, 2H), 2.04 (s, 3H); MS: m / z 446.2 (M+1).

[0468] Example 27: Preparation of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol [ka]

[0469] Example 27, Step 1: Preparation of 5-methyl-5-(3-(trifluoromethoxy)phenyl)imidazolidined-2,4-dione [ka] 1-(3-(trifluoromethoxy)phenyl)ethane-1-one (commercial product) (45.0 g, 220.0 mmol) was stirred in a mixed solvent of ethanol / water (1:1; 1000 mL), to which ammonium carbonate (106.0 g, 1100.0 mmol) was added, followed by potassium cyanide (17.20 g, 265.0 mmol). The mixture was stirred at 60°C for 16 hours. The reaction mixture was poured into ice-cold water (1500 mL) and stirred for 30 minutes. The resulting solid was filtered and dried to obtain 5-methyl-5-(3-(trifluoromethoxy)phenyl)imidazolidined-2,4-dione (56.0 g) as an off-white solid, which was used in the next step without further purification.

[0470] 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (bs, 1H), 8.67 (s, 1H), 7.56 (t, 1H, J = 8.00 Hz), 7.53 (d, 1H, J = 7.60 Hz), 7.42 (s, 1H), 7.35 (d, 1H, J = 6.80 Hz), 1.66 (s, 3H); MS: m / z 273.1 (M-1).

[0471] Example 27, Step 2: Preparation of 2-amino-2-(3-(trifluoromethoxy)phenyl)propanoic acid [ka] 5-Methyl-5-(3-(trifluoromethoxy)phenyl)imidazolidine-2,4-dione (Example 27, from Step 1) (60.0 g, 219.0 mmol) was added to 600 mL of 10% aqueous sodium hydroxide solution, and the mixture was stirred at 120°C for 5 days. The reaction mixture was neutralized with 300 mL of 6.0 N HCl (to adjust pH to 7), and the resulting solid was filtered and dried to obtain 2-amino-2-(3-(trifluoromethoxy)-phenyl)propanoic acid (51.0 g) as a white solid, which was used in the next step without further purification.

[0472] 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (bs, 3H), 7.52 (t, 1H, J = 8.00 Hz), 7.51 (s, 1H), 7.47 (d, 1H, J = 7.64 Hz), 7.28 (d, 1H, J = 8.00 Hz), 1.64 (s, 3H); MS: m / z 250.1 (M+1).

[0473] Example 27, Step 3: Preparation of 2-amino-2-(3-(trifluoromethoxy)phenyl)propan-1-ol [ka] To a solution of 2-amino-2-(3-(trifluoromethoxy)phenyl)propanoic acid (from Example 27, Step 2) (40.00 g, 161.00 mmol) in dry tetrahydrofuran (1000 mL), a 2 M solution of lithium aluminum hydride (120.00 mL, 241.0 mmol) in tetrahydrofuran was added, and the reaction mixture was slowly warmed to ambient temperature and stirred for 3 hours. The reaction mixture was cooled to 0°C, quenched by adding ethyl acetate solution (120 mL) dropwise, and stirred for 30 minutes. Then, a saturated solution of ammonium chloride (150 mL) was added dropwise, and the mixture was stirred at 0°C for 15 minutes. The resulting precipitate was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain a yellow gum (38.0 g). This was diluted with 10% sodium hydroxide solution (100 mL) and extracted with ethyl acetate (4 x 1000 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-amino-2-(3-(trifluoromethoxy)phenyl)propan-1-ol (23.0 g) as a yellow oil, which was used in the next step without further purification.

[0474] 1H NMR (400 MHz, DMSO-d6: D2O) δ 7.47 (d, 1H, J = 7.84 Hz), 7.44 (s, 1H), 7.41 (t, 1H, J = 9.00 Hz), 7.15 (d, 1H, J = 7.80 Hz), 3.41 (q, 2H, J = 10.48 Hz), 1.33 (s, 3H); MS: m / z 236.1 (M+1).

[0475] Example 27, Step 4: Preparation of tert-butyl N-{1-hydroxy-2-[3-(trifluoromethoxy)phenyl]propan-2-yl}carbamate [ka] A suspension of 2-amino-2-(3-(trifluoromethoxy)phenyl)propan-1-ol (from Example 27, Step 3) (38.0 g, 162.0 mmol) in a mixture of dichloromethane:1,4-dioxane (4:1; 500 mL) is prepared by adding di-tert-butyl dicarbonate (44.50 mL, d: 0.950 g / cm³). 3 194.00 mmol of ethyl acetate was added dropwise at 0°C, and the mixture was stirred at ambient temperature for 72 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (4 x 1000 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to obtain a yellow gum (55.0 g). This was purified by chromatography in a Grace apparatus using a 220.0 g pre-packed flash cartridge packed with 60 Å, 40-63 μm normal-phase silica gel. The product was eluted with 30-40% ethyl acetate in hexane to obtain tert-butyl N-{1-hydroxy-2-[3-(trifluoromethoxy)phenyl]propan-2-yl}carbamate (36.0 g) as a colorless gum.

[0476] 1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, 1H, J = 7.40 Hz), 7.40 (s, 1H), 7.32 (d, 1H, J = 11.20 Hz), 7.20 (t, 1H, J = 9.60 Hz), 6.85 (bs, 1H), 4.96 (t, 1H, J = 7.20 Hz), 4.03 (q, 2H, J = 9.60 Hz), 1.56 (s, 3H), 1.37 (s, 9H); MS: m / z 336.2 (M+1).

[0477] Example 27, Step 5: Preparation of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate [ka] Under a nitrogen atmosphere, a solution of tert-butyl N-{1-hydroxy-2-[3-(trifluoromethoxy)phenyl]propan-2-yl}carbamate (from Step 4 of Example 27) (25.00 g, 74.60 mmol) in dry dichloromethane (500 mL) was mixed with triethylamine (41.54 mL, d=0.726 g / cm³). 3 (298.0 mmol), followed by pivaloyl chloride (18.24 mL, d=0.985 g / cm³). 3149.00 mmol of propyl alcohol was added dropwise at 0°C, and the reaction mixture was stirred at ambient temperature for 48 hours. The reaction mixture was quenched with ice-cold water (150 mL) and extracted with dichloromethane (4 x 750 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain a brown gum (32.0 g). This was purified by chromatography in a Grace apparatus using a 120.0 g pre-packed flash cartridge packed with 60 Å, 40-63 μm normal-phase silica gel. The product was eluted with 15-20% ethyl acetate in hexane to obtain 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethoxy)-phenyl]propyl 2,2-dimethylpropanoate (20.0 g) as a yellowish liquid.

[0478] 1 1H NMR (400 MHz, DMSO-d 6: D2O) δ 7.47 (t, 1H, J = 10.80 Hz), 7.37 (d, 1H, J = 10.80 Hz), 7.27 (s, 1H), 7.23 (d, 1H, J = 10.40 Hz), 4.26 (q, 2H, J = 14.00 Hz), 1.55 (s, 3H), 1.40 (s, 9H), 1.11 (s, 9H); MS: m / z 320.2 [(M+1)-Boc].

[0479] Example 27, Step 6: Preparation of 2-amino-2-[3-(trifluoromethoxy)-phenyl]propyl 2,2-dimethylpropanoate hydrochloride [ka] Under a nitrogen atmosphere, a solution of 2-{[(tert-butoxy)carbonyl]amino}-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (from Example 27, Step 5) (32.00 g, 76.30 mmol) in dry dichloromethane (400 mL) was added dropwise at 0°C with a 4 M HCl solution in dioxane (95.40 mL, 381.00 mmol). The reaction mixture was stirred at ambient temperature for 16 hours, then concentrated, and the residue was triturated with hexane (3 x 250 mL). The supernatant was decanted, and the solid was dried to obtain 2-amino-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate hydrochloride (20.0 g) as a yellowish gum, which was used in the next step without further purification.

[0480] 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 3H), 7.61 (t, 1H, J = 7.48Hz), 7.57 (d, 2H, J = 7.50 Hz), 7.43 (s, 1H), 4.46 (d, 1H, J = 11.60 Hz), 4.28 (d, 1H, J = 12.12 Hz), 1.70 (s, 3H), 1.04 (s, 9H); MS: m / z 320.1 [(M+1)-HCl].

[0481] Example 27, Step 7: Preparation of 2-isothiocyanato-2-[3-(trifluoromethoxy)-phenyl]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-amino-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate hydrochloride (from Example 27, Step 6) (3.80 g, 12.00 mmol) in dry dichloromethane (50 mL), 10% sodium bicarbonate aqueous solution (50 mL) was added at 0°C. After 30 minutes, thiophosgene (1.82 mL, d=1.5 g / cm³) was added. 3 24.00 mmol) was added and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was extracted with dichloromethane (3 x 200 mL), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow liquid (4.30 g). This was purified by chromatography using a Grace apparatus with a 60.0 g pre-packed flash cartridge packed with normal-phase silica gel 60 Å, 40-63 μm. The product was eluted with 8-10% ethyl acetate in hexane to obtain 2-isothiocyanato-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (2.00 g) as a colorless liquid.

[0482] 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (d, 1H, J = 7.90 Hz), 7.56 (t, 1H, J = 4.60 Hz), 7.47 (s, 1H), 7.38 (d, 1H, J = 7.70 Hz), 4.47 (q, 2H, J = 11.32 Hz), 1.79 (s, 3H), 1.05 (s, 9H).

[0483] Example 27, Step 8: Preparation of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from Step 5 of Example 1) (2.20 g, 1.08 mmol) in a mixed solvent of dichloromethane:methanol (4:1; 10 mL), [2-isothiocyanato-2-[3-(trifluoromethoxy)phenyl]propyl]2,2-dimethylpropanoate (from Step 7 of Example 27) (3.89 g, 1.08 mmol) was added, and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was concentrated in a water bath at 30°C to obtain 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (6.00 g) as a brown gum, which was used in the next step without further purification. MS: m / z 566.0 (M+1).

[0484] Example 27, Step 9: Preparation of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]-propyl 2,2-dimethylpropanoate [ka] To a solution of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (from Example 27, Step 8) (6.00 g, 1.06 mmol) in methanol (50 mL), iodoacetic acid (2.96 g, 15.90 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated, and the solvent methanol was removed at 30°C to obtain 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate as brown gum (5.50 g), which was used in the next step without further purification. MS: m / z 532.2 [(M+1)].

[0485] Example 27: Preparation of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (from Example 27, Step 9) (4.0 g, 7.53 mmol) in methanol (50 mL), 0.5 M sodium hydroxide (45.2 mL, 22.6 mmol) in methanol was added dropwise, and the mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was quenched with 1.5 N aqueous HCl (10 mL) at 0°C, and the reaction mixture was concentrated at 28°C to obtain a brown gum (0.520 g). This was purified by preparative HPLC, and 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol (2.2g) was isolated as a trifluoroacetate and obtained as a yellow gum.

[0486] 1 H NMR (400 MHz, AcOH-d4) δ 7.57-7.50 (m, 3H), 7.45 (s, 1H), 7.41 (dd, J = 2.40, 6.80 Hz, 1H), 7.30 (d, J = 6.40 Hz, 3H), 7.21 (d, J = 1.60 Hz, 1H), 5.41 (d, J = 4.80 Hz, 2H), 4.39 (d, J = 12.00 Hz, 1H), 4.11 (d, J = 12.00 Hz, 1H), 1.79 (s, 3H); MS: m / z 448.1 [(M+1)].

[0487] The above product was separated into two enantiomers by chiral SFC using the following method to obtain two enantiomers, 27a and 27b: Column (R,R)-Whelk-01; Flow rate: 3.0 mL / min; Cosolvent: 30%; Cosolvent name: 0.5% isopropylamine in isopropyl alcohol; Injection volume: 3.0 μL; Outlet pressure: 100 bar; Temperature: 35°C.

[0488] Example 27a: (+)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol The (+) enantiomer was the first compound to elute from the column. [ka]

[0489] 1 H NMR (400 MHz, AcOH-d4) δ 7.56-7.52 (m, 3H), 7.45 (s, 1H), 7.41 (d, J = 8.00 Hz, 1H), 7.30-7.27 (m, 3H), 7.20 (d, J = 1.60 Hz, 1H), 5.41 (d, J = 6.40 Hz, 2H), 4.39 (d, J = 12.40 Hz, 1H), 4.11 (d, J = 12.00 Hz, 1H), 1.78 (s, 3H);

[0490] MS: m / z 448.2 (M+1); [α] D 25.4 (+) 9.20 (MeOH, c = 1.0).

[0491] Example 27b: (-)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol The (-) enantiomer was the second compound eluted from the column. [ka]

[0492] 1 H NMR (400 MHz, AcOH-d4) δ 7.57-7.49 (m, 3H), 7.45 (s, 1H), 7.41 (d, J = 8.40 Hz, 1H), 7.30-7.24 (m, 3H), 7.20 (d, J = 1.20 Hz, 1H), 5.41 (d, J = 6.40 Hz, 2H), 4.39 (d, J = 12.00 Hz, 1H), 4.11 (d, J = 12.00 Hz, 1H), 1.78 (s, 3H);

[0493] MS: m / z 448.0 (M+1); [α] D 25.5 (-) 8.6 (MeOH, c = 1.0).

[0494] Example 28: Preparation of 2-({4-[(2-imino-4,5-dimethyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]-propan-1-ol [ka] Starting from a commercially available 4,5-dimethyloxazole-2-amine, the title compound was prepared using [2-isothiocyanato-2-[3-(trifluoromethyl)phenyl]propyl]2,2-dimethylpropanoate (Example 18, from step 7) according to the method described in Example 18, and isolated as a trifluoroacetate.

[0495] 1H NMR (400 MHz, AcOH-d4) δ 7.87 (s, 1H), 7.84 (d, J = 8.00 Hz, 1H), 7.69 (d, J = 8.00 Hz, 1H), 7.61 (t, J = 8.00 Hz, 1H), 7.34 (d, J = 8.00 Hz, 1H), 7.24 (t, J = 8.00 Hz, 1H), 6.87 (d, J = 7.60 Hz, 1H), 5.41 (s, 2H), 4.42 (d, J = 12.00 Hz, 1H), 4.14 (d, J = 12.00 Hz, 1H), 2.28 (d, J = 0.80 Hz, 3H), 2.01 (d, J = 0.80 Hz, 3H), 1.82 (s, 3H); MS: m / z 460 (M+1).

[0496] Example 29: Preparation of 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol [ka] Starting from 3-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (Example 5, from step 2) and [2-isothiocyanato-2-[3-(trifluoromethoxy)phenyl]propyl]2,2-dimethylpropanoate (Example 27, from step 7), the title compound was prepared by the method described for Example 27 and isolated as trifluoroacetate.

[0497] 1H NMR (400 MHz, AcOH-d4) δ 7.59-7.50 (m, 2H), 7.44 (d, J = 1.56 Hz, 2H), 7.37 (d, J = 8.00 Hz, 1H), 7.31-7.24 (m, 2H), 6.88 (d, J = 7.84 Hz, 1H), 5.47 (s, 2H), 4.39 (d, J = 12.04 Hz, 1H), 4.12 (d, J = 12.12 Hz, 1H), 2.02 (s, 3H), 1.80 (s, 3H); MS: m / z 462.2 (M+1).

[0498] Example 30: Preparation of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]-propan-1-ol [ka]

[0499] Example 30, Step 1: Preparation of 2-[({2-amino-3-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)-amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (Example 24, Step 2) (0.280 g, 1.28 mmol) in a mixed solvent of dichloromethane:methanol (2:1; 9 mL), [2-isothiocyanato-2-[3-(trifluoromethoxy)phenyl]propyl]2,2-dimethylpropanoate (Example 27, from Step 7) (0.300 g, 0.830 mmol) was added and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was concentrated in a water bath at 30°C to obtain 2-[({2-amino-3-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (0.580 g) as a brown gum, which was used in the next step without purification. MS: m / z 580.4(M+1).

[0500] Example 30, Step 2: Preparation of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)-phenyl]propyl 2,2-dimethylpropanoate [ka] 2-[({2-amino-3-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (as a mixture of inseparable positional isomers) (Example 30, Step 1) (0.550 g, 0.949 mmol) were dissolved in methanol (8 mL), to which iodoacetic acid (0.265 g, 1.42 mmol) was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated at 30°C to remove the solvent methanol and obtain a brown gum (0.600 g). This was purified by preparative HPLC (TFA: acetonitrile) to obtain 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (0.200 g), which was isolated as a trifluoroacetate, and obtained as the brown gum.

[0501] 1 H-NMR (400 MHz, AcOH-d4): δ 7.58-7.53 (m, 2H), 7.48 (s, 1H), 7.37-7.29 (m, 4H), 6.86 (d, J = 1.20 Hz, 1H), 5.34 (s, 2H), 4.61 (d, J = 11.60 Hz, 1H), 4.50 (d, J = 11.60 Hz, 1H), 2.26 (s, 3H), 2.01 (s, 3H), 1.17 (s, 9H); MS: m / z 546.1 (M+1).

[0502] The above product was separated into two enantiomers by chiral SFC using the following method to obtain two enantiomers, 30-2a and 30-2b: Chiralcel OX-H, mobile phase: 0.5% isopropylamine in isopropyl alcohol; cosolvent: 40% CO2; flow rate: 4 ml / min, pressure: 100 bar, temperature: 35°C.

[0503] Example 30-2a: Preparation of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)-phenyl]propyl 2,2-dimethylpropanoate (enantiomer A). Enantiomer A was the first compound to elute from the column and was isolated as trifluoroacetate. [ka]

[0504] 1 H-NMR (400 MHz, AcOH-d4): δ 7.58-7.53 (m, 2H), 7.48 (s, 1H), 7.37-7.29 (m, 4H), 6.86 (d, J = 1.20 Hz, 1H), 5.34 (s, 2H), 4.61 (d, J = 11.60 Hz, 1H), 4.50 (d, J = 11.60 Hz, 1H), 2.26 (s, 3H), 2.01 (s, 3H), 1.17 (s, 9H); MS: m / z 546.1 (M+1).

[0505] Example 30-2b: Preparation of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]-propyl 2,2-dimethylpropanoate (enantiomer B). Enantiomer B was the second compound eluted from the column and was isolated as trifluoroacetate. [ka]

[0506] 1 H-NMR (400 MHz, AcOH-d4): δ 7.58-7.53 (m, 2H), 7.48 (s, 1H), 7.37-7.29 (m, 4H), 6.86 (d, J = 1.20 Hz, 1H), 5.34 (s, 2H), 4.61 (d, J = 11.60 Hz, 1H), 4.50 (d, J = 11.60 Hz, 1H), 2.26 (s, 3H), 2.01 (s, 3H), 1.17 (s, 9H); MS: m / z 546.1 (M+1).

[0507] Example 30: Preparation of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]-propan-1-ol [ka] To a solution of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate; trifluoroacetic acid (from Example 30, Step 2) (0.200 g, 0.303 mmol) in methanol (20 mL), 0.5 N sodium hydroxide (6.0 ml, 3.03 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 5 hours. The reaction mixture was quenched with 1.5 N hydrochloride solution (3 mL), concentrated under reduced pressure at 30 °C to obtain a brown gum (0.170 g). This was purified by preparative HPLC using acetonitrile:water with 0.1% TFA, and 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol (0.080 g) was isolated as a trifluoroacetate and obtained as brown gum.

[0508] 1 H NMR (400 MHz, AcOH-d4) δ 7.58-7.50 (m, 2H), 7.45 (s, 1H), 7.41 (dd, J = 2.52, 6.56 Hz, 1H), 7.32-7.27 (m, 3H), 6.82 (d, J = 1.40 Hz, 1H), 5.33 (d, J = 3.76 Hz, 2H), 4.39 (d, J = 12.08 Hz, 1H), 4.11 (d, J = 12.12 Hz, 1H), 2.25 (s, 3H), 1.79 (s, 3H); MS: m / z 462.3 (M+1).

[0509] Example 30a: Preparation of (-)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)-phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (Example 30-2a, enantiomer A) (0.480 g, 0.728 mmol) in methanol (48 mL), 0.5 N sodium hydroxide (7.28 ml, 3.64 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 5 hours. The reaction mixture was quenched with 1.5 N hydrochloride solution (4 mL), concentrated under reduced pressure at 30°C, and a brown gum (0.410 g) was obtained. This was purified by preparative HPLC using acetonitrile:water with 0.1% TFA, and (-)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol (0.165 g) was isolated as a trifluoroacetate and obtained as brown gum.

[0510] 1 H NMR (400 MHz, AcOH-d4) δ 7.58-7.50 (m, 2H), 7.45 (s, 1H), 7.41 (dd, J = 2.52, 6.56 Hz, 1H), 7.32-7.27 (m, 3H), 6.82 (d, J = 1.40 Hz, 1H), 5.33 (d, J = 3.76 Hz, 2H), 4.39 (d, J = 12.08 Hz, 1H), 4.11 (d, J = 12.12 Hz, 1H), 2.25 (s, 3H), 1.79 (s, 3H);

[0511] MS: m / z 462.4 (M+1); SOR: [α] D 24.9(-) 9.20, (MeOH, c = 0.5).

[0512] Example 30b: Preparation of (+)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)-phenyl]propan-1-ol [ka] To a solution of 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propyl 2,2-dimethylpropanoate (Example 30-2b, enantiomer B) (0.550 g, 0.834 mmol) in methanol (55 mL), 0.5 N sodium hydroxide (8.34 ml, 4.17 mmol) in methanol was added dropwise, and the mixture was stirred at ambient temperature for 5 hours. The reaction mixture was quenched with 1.5 N hydrochloride solution (4 mL), concentrated under reduced pressure at 30°C, and a brown gum (0.48 g) was obtained. This was purified by preparative HPLC using acetonitrile:water with 0.1% TFA, and (+)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol (0.150 g) was isolated as a trifluoroacetate and obtained as brown gum.

[0513] 1H NMR (400 MHz, AcOH-d4) δ 7.58-7.50 (m, 2H), 7.45 (s, 1H), 7.41 (dd, J = 2.52, 6.56 Hz, 1H), 7.32-7.27 (m, 3H), 6.82 (d, J = 1.40 Hz, 1H), 5.33 (d, J = 3.76 Hz, 2H), 4.39 (d, J = 12.08 Hz, 1H), 4.11 (d, J = 12.12 Hz, 1H), 2.25 (s, 3H), 1.79 (s, 3H); MS: m / z 462.3 (M+1); SOR: [α] D 24.9 (+) 7.20, (MeOH, c = 0.5).

[0514] Example 31: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{1-[(1,3-oxazole-2-yl)amino]ethyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka]

[0515] Example 31, Step 1: Preparation of N-methoxy-N-methyl-2,1,3-benzothiadiazole-4-carboxamide [ka] To a solution of 2,1,3-benzothiadiazole-4-carboxylic acid (6 g, 33.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (8.12 g, 83.2 mmol) in tetrahydrofuran (75 mL), triethylamine (18.6 mL, 133 mmol) and propylphosphonic anhydride (50% in toluene) (63.6 g, 200 mmol) were added, and the reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was washed with water (250 mL), extracted with ethyl acetate (3 x 100 mL), and the combined organic layer was washed with brine solution (100 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product (13 g) as a brown solid. This was purified by column chromatography and eluted with 40% ethyl acetate in petroleum ether to obtain N-methoxy-N-methyl-2,1,3-benzothiadiazole-4-carboxamide (7 g) as an off-white solid.

[0516] 1 H NMR (400 MHz, DMSO-d6) δ 8.21-8.17 (m, 1H), 7.79-7.77 (m, 2H), 3.50 (s, 3H), 3.33 (s, 3H); MS: m / z 224.1 (M+1).

[0517] Example 31, Step 2: Preparation of 1-(2,1,3-benzothiadiazole-4-yl)ethane-1-one [ka] A solution of N-methoxy-N-methyl-2,1,3-benzothiadiazole-4-carboxamide (from Example 31, Step 1) (4 g, 17.9 mmol) in tetrahydrofuran:diethyl ether (1:1, 80 mL) was cooled to 0°C, and methylmagnesium bromide (2 M in THF) (53.7 mL, 107 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with aqueous ammonium chloride (100 mL), extracted with ethyl acetate (3 x 50 mL), washed with brine solution (100 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product (5.2 g) as a brown gum. This was purified by silica gel column chromatography and eluted with 10% ethyl acetate in petroleum ether to obtain 1-(2,1,3-benzothiadiazole-4-yl)ethane-1-one (1.2 g) as a pale yellow solid.

[0518] 1 H NMR (400 MHz, DMSO-d6) δ 8.31-8.25 (m, 2H), 7.76-7.72 (m, 1H), 3.07 (s, 3H); MS: m / z 179.0 (M+1).

[0519] Example 31, Step 3: Preparation of N-[1-(2,1,3-benzothiadiazole-4-yl)ethyl]-1,3-oxazole-2-amine [ka] To a solution of 1-(2,1,3-benzothiadiazole-4-yl)ethane-1-one (from Example 31, Step 2) (1.2 g, 6.73 mmol) and 1,3-oxazole-2-amine (2.26 g, 26.9 mmol) in ethanol (40 mL) cooled to 0°C, titanium(IV) isopropoxide (34.1 mL, 114 mmol) was added, and the reaction mixture was stirred at ambient temperature for 20 hours. Next, the reaction mixture was cooled to 0°C, sodium borohydride (0.764 g, 20.2 mmol) was partially added, and the reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was quenched with ice water (75 mL), filtered through a Celite bed, and washed with ethyl acetate. The filtrate was concentrated, diluted with water (100 mL), extracted with ethyl acetate (3 x 50 mL), the combined organic layer was washed with brine solution (50 mL), dried on sodium sulfate, filtered, and concentrated to obtain the crude product (1.3 g) as a brown gum. This was purified by silica gel column chromatography eluted with 30% ethyl acetate in petroleum ether to obtain N-[1-(2,1,3-benzothiadiazole-4-yl)ethyl]-1,3-oxazole-2-amine (0.320 g) as a pale yellow solid.

[0520] 1 H NMR (400 MHz, DMSO-d6) δ 7.98-7.95 (m, 2H), 7.70 (t, J = 6.80 Hz, 1H), 7.61 (d, J = 7.20 Hz, 1H), 7.40 (d, J = 0.80 Hz, 1H), 6.65 (d, J = 0.80 Hz, 1H), 5.56-5.49 (m, 1H), 1.58 (d, J = 6.80 Hz, 3H); MS: m / z 247.1 (M+1).

[0521] Example 31, Step 4: Preparation of 3-{1-[(1,3-oxazol-2-yl)amino]ethyl}benzene-1,2-diamine [ka] To a solution of N-[1-(2,1,3-benzothiadiazole-4-yl)ethyl]-1,3-oxazole-2-amine (from Example 31, Step 3) (0.400 g, 1.62 mmol) in methanol (30 mL), Raney nickel (1.82 g, 300% wt / wt) was added, and the reaction mixture was allowed to stand at ambient temperature for 16 hours at 1.5 kg / cm². 2 Hydrogenation was performed. The reaction mixture was filtered through a Celite bed, and the filtrate was concentrated to obtain the product (0.295 g) as a brown liquid, which was used in the next step without further purification. MS: m / z 219.2 (M+1).

[0522] Example 31, Step 5: Preparation of 2-{[(2-amino-3-{1-[(1,3-oxazol-2-yl)amino]ethyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{1-[(1,3-oxazol-2-yl)amino]ethyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate [ka] To a solution of 3-(1-(1,3-oxazole-2-ylamino)ethyl)benzene-1,2-diamine (from Example 31, Step 4) (0.295 g, 1.35 mmol) in a mixed solvent of dichloromethane:methanol (1:1, 8 mL), [2-(3-chloro-4-fluorophenyl)-2-isothiocyanatopropyl]2,2-dimethylpropanoate (from Example 8, Step 7) (0.446 g, 1.35 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated to obtain a crude product (0.700 g) as a brown gum, which was used in the next step without further purification. MS: m / z 548.1 (M+1).

[0523] Example 31, Step 6: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{1-[(1,3-oxazol-2-yl)amino]ethyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2-2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-3-{1-[(1,3-oxazole-2-yl)amino]ethyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{1-[(1,3-oxazole-2-yl)amino]ethyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)-propyl 2,2-dimethylpropanoate (a mixture of positional isomers) (from Example 31, Step 5) (0.700 g, 1.28 mmol) in methanol (10 mL), iodoacetic acid (0.237 g, 1.28 mmol) was added, and the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was concentrated and diluted with ice-cold water (50 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (50 mL), then with brine solution (50 mL), dried over sodium sulfate, filtered, and concentrated to obtain a crude product (0.530 g) as brown gum. This was purified by preparative HPLC (acetonitrile: 0.1% TFA in water) to obtain 2-(3-chloro-4-fluorophenyl)-2-[(4-{1-[(1,3-oxazole-2-yl)amino]ethyl}-1H-1,3-benzodiazole-2-yl)amino]-propyl 2,2-dimethylpropanoate (0.340 g) as brown gum.

[0524] 1H NMR (400 MHz, DMSO-d6) δ 12.18 (bs, 1H), 10.18 (bs, 1H), 8.48 (bs, 1H), 7.80-7.78 (m, 1H), 7.50-7.42 (m, 3H), 7.19-7.16 (m, 3H), 6.86 (d, J = 6.00 Hz, 1H), 5.11 (t, J = 4.00 Hz, 1H), 4.52-4.37 (m, 2H), 1.87 (d, J = 6.80 Hz, 3H), 1.48 (d, J = 9.20 Hz, 3H), 1.06 (s, 9H); MS: m / z 514.1 (M+1).

[0525] Example 31, Step 7: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{1-[(1,3-oxazole-2-yl)amino]ethyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka] To a solution of 2-(3-chloro-4-fluorophenyl)-2-[(4-{1-[(1,3-oxazole-2-yl)amino]ethyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate (from Example 31, Step 6) (0.240 g, 0.46 mmol) in methanol (5 mL), 0.5 N sodium hydroxide in methanol (3.7 mL, 1.87 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated, and the residue was diluted with water (10 mL). The aqueous layer was extracted with dichloromethane (3 x 15 mL), and the combined organic layers were washed with water (10 mL), then with brine solution (10 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product (0.180 g). This was purified by preparative HPLC (method: acetonitrile: 0.1% TFA in water) to obtain 2-(3-chloro-4-fluorophenyl)-2-[(4-{1-[(1,3-oxazole-2-yl)amino]ethyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol (0.060 g) as an off-white solid.

[0526] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.58-7.41 (m, 1H), 7.41-7.30 (m, 3H), 7.28-6.94 (m, 1H), 6.87-6.79 (m, 2H), 6.77-6.65 (m, 1H), 4.94-4.89 (m, 1H), 3.83-3.48 (m, 2H), 1.69 (d, J = 4.40 Hz, 3H), 1.49 (d, J = 6.80 Hz, 1H), 1.28 (dd, J = 6.80, 21.20 Hz, 2H); MS: m / z 430.2 (M+1).

[0527] Example 32: Preparation of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka]

[0528] Example 32, Step 1: Preparation of 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-2,3-dihydro-1,3-thiazole-2-imine hydrobromide [ka] To a solution of 4-(bromomethyl)-2,1,3-benzothiadiazole (from step 3 of Example 1) (12.0 g, 52.4 mmol) in acetonitrile (120 mL), 1,3-thiazole-2-amine (commercial product) (10.50 g, 105.0 mmol) was added, and the mixture was stirred at 60°C for 16 hours. The solid formed in the reaction mixture was filtered and dried to obtain the crude product (13 g) as a brown solid. This was stirred with water (6 x 50 mL), the solid was filtered, and dried under high vacuum at 40°C to obtain 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-2,3-dihydro-1,3-thiazole-2-imine hydrobromide (9.0 g) as an off-white solid.

[0529] 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 2H), 8.12 (t, J = 0.40 Hz, 1H), 7.76 (q, J = 6.80 Hz, 1H), 7.49-7.43 (m, 2H), 7.10 (d, J = 4.80 Hz, 1H), 5.81 (s, 2H); MS: m / z 249.1 [(M+1)-HBr].

[0530] Example 32, Step 2: Preparation of 3-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]benzene-1,2-diamine [ka] To a degassed solution of 3-[(2,1,3-benzothiadiazole-4-yl)methyl]-2,3-dihydro-1,3-thiazole-2-imine hydrobromide (Example 32, from Step 1) (2.5 g, 10.1 mmol) in dry methanol (450 mL), Raney nickel (7.5 g, 300% w / w, pre-washed 5 times with dry methanol) was added, and the resulting reaction mixture was heated under a hydrogen atmosphere and under pressure (approximately 1.5 kg / cm²). 2 The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was filtered through a Celite bed, and the bed was washed with methanol (250 mL). The combined filtrate was concentrated at 20°C to obtain 3-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]benzene-1,2-diamine (2.0 g) as a gray gum, which was used in the next step without further purification.

[0531] 1 H NMR (400 MHz, DMSO-d6) δ 6.84 (s, 1H), 6.56-6.41 (m, 4H), 4.79 (s, 2H); MS: m / z 221.1 (M+1).

[0532] Example 32, Step 3: Preparation of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-thiazole-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]benzene-1,2-diamine (from Example 32, Step 2) (4 g, 18.157 mmol) in a mixed solvent of dichloromethane:methanol (1:1, 80 mL), [2-(3-chloro-4-fluorophenyl)-2-isothiocyanatopropyl]2,2-dimethylpropanoate (from Example 8, Step 7) (3.0 g, 9.15 mmol) was added, and the mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated in a water bath at 30°C to obtain 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (a mixture of positional isomers) (7.00 g) as a yellow gum, which was used in the next step without further purification. MS: m / z 550.1 (M+1).

[0533] Example 32, Step 4: Preparation of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}aminopropyl 2,2-dimethylpropanoate) [ka] To a solution of 2-[({2-amino-3-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (a mixture of positional isomers) (from Example 32, Step 3) (7.00 g, 12.70 mmol) in methanol (110 mL), iodoacetic acid (3.55 g, 19.10 mmol) was added, and the mixture was refluxed for 1 hour. The reaction mixture was concentrated, and the solvent methanol was removed at 30°C to obtain the crude product (8.0 g) as red gum. This was purified by preparative HPLC (acetonitrile: 0.1% TFA in water) to isolate 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate as trifluoroacetate (2.5 g) and obtained as brown gum.

[0534] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.67 (q, J = 2.00 Hz, 1H), 7.39-7.49 (m, 2H), 7.32 (d, J = 8.00 Hz, 1H), 7.19 (q, J = 8.40 Hz, 2H), 6.98 (d, J = 4.80 Hz, 1H), 6.87 (d, J = 7.60 Hz, 1H), 5.36 (s, 2H), 4.41 (q, J = 11.20 Hz, 2H), 1.84 (s, 3H), 1.05 (s, 9H); MS: m / z 516.1 [(M+1)].

[0535] Example 32, Step 5: Preparation of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka] To a solution of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate; trifluoroacetic acid (from Example 32, Step 4) (1.6 g, 2.54 mmol) in 1,4-dioxane:water (2:1.90 mL), 4.0 M HCl (3.81 mL, 15.20 mmol) in the dioxane was added dropwise, and the mixture was heated at 80°C for 48 hours. The reaction mixture was concentrated under reduced pressure at 30°C to obtain the crude product (1.2 g) as a brown gum. This was purified by preparative HPLC (method: acetonitrile: 0.1% TFA in water), and 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol (0.9 g), isolated as trifluoroacetate, was obtained as brown gum.

[0536] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.59 (t, J = 2.00 Hz, 1H), 7.39-7.33 (m, 3H), 7.23-7.18 (m, 2H), 7.00 (d, J = 4.40 Hz, 1H), 6.84 (d, J = 7.60 Hz, 1H), 5.37 (s, 2H), 3.72 (q, J = 11.20 Hz, 2H), 1.74 (s, 3H); MS: m / z 432.0 [(M+1)].

[0537] The above product was separated into two enantiomers by chiral SFC using the following method to obtain two enantiomers, 32a and 32b: Column: Chiralpak OX-H; Mobile phase: 0.5% isopropylamine in isopropyl alcohol; Cosolvent: 50% CO2; Flow rate: 5 mL / min, Pressure: 100 bar, Temperature: 35°C.

[0538] Example 32a: (-)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol The (-) enantiomer was the first compound to elute from the column and was isolated as its hydrochloride salt.

[0539] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.54 (d, J = 6.80 Hz, 1H), 7.30-7.21 (m, 2H), 7.22 (t, J = 4.40 Hz, 2H), 7.02-6.95 (m, 2H), 6.83 (d, J = 4.00 Hz, 1H), 5.15 (q, J = 14.80 Hz, 2H), 3.66 (q, J = 10.80 Hz, 2H), 1.72 (s, 3H);

[0540] MS: m / z 432.1 [(M+1)-HCl]; SOR: [α] D 23.3 (-) 22.40, (MeOH, c = 0.5).

[0541] Example 32b: (+)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol The (+) enantiomer was the second compound eluted from the column and was isolated as the hydrochloride salt.

[0542] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.61 (d, J = 5.60 Hz, 1H), 7.42-7.36 (m, 2H), 7.30 (d, J = 7.60 Hz, 1H), 7.24 (d, J = 4.40 Hz, 1H), 7.10 (bs, 1H), 6.94-6.92 (m, 2H), 5.29 (bs, 2H) 3.71 (q, J = 11.20 Hz, 2H), 1.72 (s, 3H);

[0543] MS: m / z 432.1 [(M+1)-HCl]; SOR: [α] D 23.4 (+) 22.80, (MeOH, c = 0.5).

[0544] Example 33: Preparation of 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]-2,3-dihydro-1H-imidazole-2-one [ka]

[0545] Example 33, Step 1: Preparation of 1-[(2,1,3-benzothiadiazole-4-yl)methyl]-2,3-dihydro-1H-imidazole-2-one [ka] To a solution of 2,3-dihydro-1H-imidazole-2-one (commercial product) (2.0 g, 23.80 mmol) in DMSO (200 mL), 60% sodium hydride (0.911 g, 23.8 mmol) was added at 0°C and the mixture was stirred for 30 minutes. 4-(bromomethyl)-2,1,3-benzothiadiazole (from Example 1, Step 3) (4.36 g, 19.0 mmol) was added at 0°C and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain a brown gum. The formed solid was filtered and dried to obtain the crude product (1.2 g) as a brown solid. This was purified by silica gel column chromatography using 10% methanol in DCM as the eluent to obtain 1-[(2,1,3-benzothiadiazole-4-yl)methyl]-2,3-dihydro-1H-imidazole-2-one (0.4 g) as an off-white solid.

[0546] 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.03 (d, J = 8.00 Hz, 1H), 7.70 (q, J = 6.80 Hz, 1H), 7.27 (q, J = 1.20 Hz, 1H), 6.54 (q, J = 2.00 Hz, 1H), 6.42 (t, J = 2.80 Hz, 1H), 5.19 (s, 2H); MS: m / z 232.9 (M+1).

[0547] Example 33, Step 2: Preparation of 1-[(2,3-diaminophenyl)methyl]-2,3-dihydro-1H-imidazole-2-one [ka] To a degassed solution of 1-[(2,1,3-benzothiadiazole-4-yl)methyl]-2,3-dihydro-1H-imidazole-2-one (Example 33, from Step 1) (0.6 g, 2.58 mmol) in dry methanol (43 mL), ranney nickel (1.8 g, 300% w / w, pre-washed 5 times with dry methanol) was added, and the resulting reaction mixture was heated under a hydrogen atmosphere and under pressure (approximately 1.5 kg / cm²). 2 The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was filtered through a Celite bed, and the bed was washed with methanol (150 mL). The combined filtrate was concentrated at 20°C to obtain 1-[(2,3-diaminophenyl)methyl]-2,3-dihydro-1H-imidazole-2-one (0.22 g) as a brown gum, which was used in the next step without further purification. MS: m / z 205.1 (M+1).

[0548] Example 33, Step 3: Preparation of 2-[({2-amino-3-[(2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 1-[(2,3-diaminophenyl)methyl]-2,3-dihydro-1H-imidazole-2-one (from Example 33, Step 2) (0.22 g, 1.08 mmol) in acetonitrile (5 mL), [2-(3-chloro-4-fluorophenyl)-2-isothiocyanatopropyl]2,2-dimethylpropanoate (from Example 8, Step 7) (0.42 g, 1.29 mmol) was added and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated at 30°C to obtain 2-[({2-amino-3-[(2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (a mixture of positional isomers) (0.35 g) as a colorless gum, which was used in the next step without further purification. MS: m / z 534.2 (M+1).

[0549] Example 33, Step 4: Preparation of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethyl-propanoate [ka] To a solution of 2-[({2-amino-3-[(2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-[({2-amino-6-[(2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl]phenyl}carbamotioil)amino]-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (a mixture of positional isomers) (from Example 33, Step 3) (0.35 g) in methanol (10 mL), iodoacetic acid (0.183 g, 0.983 mmol) was added, and the mixture was refluxed for 2 hours. The reaction mixture was concentrated, and the solvent methanol was removed at 30°C to obtain the crude product. This was purified by preparative HPLC (acetonitrile: 0.1% TFA in water) to obtain 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate (0.07 g) as a yellow solid. MS: m / z 500.1 (M+1).

[0550] Example 33, Step 5: Preparation of 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]-2,3-dihydro-1H-imidazole-2-one [ka] To a solution of 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-oxo-2,3-dihydro-1H-imidazole-1-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propyl 2,2-dimethylpropanoate; trifluoroacetic acid, (from Example 33, Step 4) (0.07 g, 0.140 mmol) in methanol (5 mL), 0.5 N sodium hydroxide (2.8 mL, 1.40 mmol) in methanol was added dropwise, and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated to obtain a brown gum, which was purified by preparative HPLC (acetonitrile: 0.1% FA in water) to obtain 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]-2,3-dihydro-1H-imidazole-2-one (0.025 g) as a colorless gum.

[0551] 1 H NMR (400 MHz, AcOH-d4) δ 7.67 (dd, J = 2.40, 6.80 Hz, 1H), 7.53-7.49 (m, 1H), 7.42 (d, J = 7.60 Hz, 1H), 7.24-7.20 (m, 3H), 6.50 (s, 2H), 5.00-4.89 (m, 2H), 4.20 (d, J = 12.00 Hz, 1H), 4.01 (d, J = 12.00 Hz, 1H), 1.84 (s, 3H); MS: m / z 416.1 (M+1).

[0552] Example 34: Preparation of 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]imidazolidined-2-one [ka] Instead of 2,3-dihydro-1H-imidazole-2-one, imidazolidine-2-one (commercial product) (1.0 g, 11.615 mmol) was used, and 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)-methyl]imidazolidine-2-one (0.100 g), isolated as a white solid, was prepared using the method described in Example 33.

[0553] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.50 (d, J = 6.80 Hz, 1H), 7.36 (s, 1H), 7.27 (t, J = 8.80 Hz, 1H), 7.08 (d, J = 7.20 Hz, 1H), 7.01(d, J = 7.60 Hz, 1H), 6.87 (d, J = 7.60 Hz, 1H), 4.31 (s, 1H), 4.20 (s, 1H), 3.65 (d, J = 10.80 Hz, 2H), 2.99 (t, J = 7.20 Hz, 4H), 1.64 (s, 3H); MS: m / z 418.0 (M+1).

[0554] Example 35: Preparation of 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]-3-methylimidazolidined-2-one [ka] Starting with 1-methylimidazolidine-2-one (commercial product) (1.0 g, 9.988 mmol) instead of 2,3-dihydro-1H-imidazole-2-one, 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]-3-methylimidazolidine-2-one (0.150 g), isolated as an off-solid, was prepared using the method described in Example 33.

[0555] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.63 (t, J = 2.00 Hz, 1H), 7.40-7.38 (m, 3H), 7.22-7.14 (m, 2H), 4.35 (d, J = 10.40 Hz, 2H), 3.72 (t, J = 6.40 Hz, 2H), 3.24-3.16 (m, 4H), 2.66 (d, J = 12.40 Hz, 3H), 1.75 (s, 3H); MS: m / z 432.0 (M+1).

[0556] Example 36: Preparation of 3-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]-1,3-thiazolidined-2-one [ka] Starting with 1,3-thiazolidinedione-2-one (commercial product) (0.5 g, 4.85 mmol) instead of 2,3-dihydro-1H-imidazole-2-one, 3-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)-methyl]-1,3-thiazolidinedione-2-one (0.2 g), isolated as a colorless gum, was prepared using the method described in Example 33.

[0557] 1 H NMR (400 MHz, AcOH-d4) δ 7.67 (dd, J = 2.40, 6.80 Hz, 1H), 7.66-7.47 (m, 2H), 7.29-0.22 (m, 2H), 7.18 (d, J = 6.80 Hz, 1H), 4.67 (d, J = 15.20 Hz, 1H), 4.50 (d, J = 15.20 Hz, 1H), 4.27 (d, J = 12.00 Hz, 1H), 4.03 (d, J = 12.00 Hz, 1H), 3.64-3.55 (m, 2H), 3.31-3.18 (m, 2H), 1.81 (s, 3H); MS: m / z 435.0 [(M+1)-TFA].

[0558] Example 37: Preparation of 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]pyrrolidine-2-one [ka] Starting with pyrrolidine-2-one (commercial product) (1.0 g, 11.750 mmol) instead of 2,3-dihydro-1H-imidazole-2-one, 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)-methyl]pyrrolidine-2-one (0.130 g), isolated as a trifluoroacetate, was prepared as an off-white solid using the method described in Example 33.

[0559] 1H NMR (400 MHz, DMSO-d6: D2O) δ 7.63-7.61 (m, 1H), 7.41-7.37 (m, 2H), 7.35-7.30 (m, 1H), 7.23-7.14 (m, 2H), 4.45 (q, J = 14.80 Hz, 2H), 3.71 (t, J = 11.60 Hz, 2H), 3.27 (t, J = 7.20 Hz, 2H), 2.26-2.21 (m, 2H), 1.92 (s, 2H), 1.80 (s, 3H); MS: m / z 417.1 (M+1).

[0560] Example 38: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(1,3-oxazol-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka]

[0561] Example 38, Step 1: Preparation of N-[(2,1,3-benzothiadiazole-4-yl)methyl]-1,3-oxazole-2-amine [ka] To a solution of 2,1,3-benzothiadiazole-4-carbaldehyde (from Example 9, Step 2) (0.8 g, 4.87 mmol) and 1,3-oxazole-2-amine (commercial product) (0.819 g, 9.75 mmol) in ethanol (50 mL) cooled to 0°C, titanium(IV) isopropoxide (17.4 ml, 58.5 mmol) was added, and the reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was cooled to 0°C, sodium borohydride (0.368 g, 9.75 mmol) was partially added, and the reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was quenched with ice-cold water (50 mL), filtered through a Celite bed, and washed with ethyl acetate (50 mL). The filtrate was concentrated, the crude mixture was diluted with water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product (1.1 g) as a brown gum. This was purified by silica gel column chromatography and eluted with 38% ethyl acetate in petroleum ether to obtain N-[(2,1,3-benzothiadiazole-4-yl)methyl]-1,3-oxazole-2-amine (0.450 g) as an off-white solid.

[0562] 1 H NMR (400 MHz, DMSO-d6) 7.99 (d, J = 8.80 Hz, 1H), 7.86 (m, 1H), 7.70 (t, J = 6.80 Hz, 1H), 7.60-7.58 (m, 1H), 7.45 (d, J = 0.80 Hz, 1H), 6.75 (d, J = 0.40 Hz, 1H), 4.88 (d, J = 2.00 Hz, 2H); MS: m / z 233.1 (M+1).

[0563] Example 38, Step 2: Preparation of 3-{[(1,3-oxazol-2-yl)amino]methyl}benzene-1,2-diamine [ka] To a degassed solution of N-[(2,1,3-benzothiadiazole-4-yl)methyl]-1,3-oxazole-2-amine (Example 38, from Step 1) (0.400 g, 1.72 mmol) in methanol (40 mL), Raney nickel (1.5 g, 300% w / w, pre-washed 5 times with dry methanol) was added, and the resulting reaction mixture was stirred under hydrogen pressure (approximately 1.5 kg / cm²) at ambient temperature for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under high vacuum to obtain 3-{[(1,3-oxazole-2-yl)amino]methyl}benzene-1,2-diamine (0.285 g) as a brown liquid, which was used in the next step without further purification. MS: m / z 205.2 (M+1).

[0564] Example 38, Step 3: Preparation of 2-{[(2-amino-3-{[(1,3-oxazol-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{[(1,3-oxazol-2-yl)amino]methyl}phenyl)-carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-{[(1,3-oxazole-2-yl)amino]methyl}benzene-1,2-diamine (from Example 38, Step 2) (0.275 g, 1.25 mmol) in a mixed solvent of dichloromethane:methanol (1:1, 8 mL), 2-(3-chloro-4-fluorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate (from Example 8, Step 7) (0.453 g, 1.37 mmol) was added, and the mixture was stirred at ambient temperature for 40 hours. The reaction mixture was concentrated to obtain a crude product (0.620 g) as a brown gum, which was used in the next step without further purification. MS: m / z 534.1 (M+1).

[0565] Example 38, Step 4: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(1,3-oxazol-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-3-{[(1,3-oxazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{[(1,3-oxazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(3-chloro-4-fluorophenyl)propyl 2,2-dimethylpropanoate (a mixture of positional isomers) (from Example 38, Step 3)) (0.620 g, 1.16 mmol) in methanol (15 mL), iodoacetic acid (0.259 g, 1.39 mmol) was added, and the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was concentrated and diluted with ice-cold water (50 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (50 mL), then with brine solution (50 mL), dried over sodium sulfate, filtered, and concentrated to obtain a crude product (0.260 g) as a brown gum. This was purified by preparative HPLC (acetonitrile: 0.1% TFA in water) to obtain 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate (0.125 g) as a brown solid.

[0566] 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.51 (s, 2H), 7.71-7.62 (m, 2H), 7.47-7.23 (m, 3H), 7.01-6.96 (m, 1H), 6.80-6.72 (m, 2H), 4.54-4.45 (m, 4H), 1.82 (s, 3H), 1.06 (s, 9H); MS: m / z 500.2 (M+1).

[0567] Example 38: Preparation of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka] To a solution of 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate (from Example 38, Step 4) (0.085 g, 0.17 mmol) in methanol (5 mL), 0.68 mL, 0.34 mmol of 0.5 N sodium hydroxide in methanol was added, and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated, and the residue was diluted with water (10 mL). The aqueous layer was extracted with dichloromethane (3 x 15 mL). The combined organic layers were washed with water (10 mL), then with brine solution (10 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product (120 mg) as brown gum. This was purified by preparative HPLC (method: water: 10 mmol ammonium acetate in acetonitrile) to obtain 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol (0.028 g) as an off-white solid.

[0568] 1H NMR (400 MHz, CD3OD) δ 7.61-7.58 (m, 1H), 7.46-7.42 (m, 1H), 7.29 (m, 1H), 7.19 (t, J = 8.80 Hz, 1H), 7.13-7.11 (m, 1H), 6.97-6.95 (m, 2H), 6.78 (s, 1H), 4.60 (s, 2H), 3.95 (d, J = 11.60 Hz, 1H), 3.81 (d, J = 11.60 Hz, 1H), 1.31 (s, 3H); MS: m / z 416.1 (M+1).

[0569] Example 39: Preparation of 2-(4-chloro-3-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka] Commercially available 1-(4-chloro-3-fluorophenyl)ethane-1-one and 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from step 5 of Example 1) were used according to the method described for Example 18 to obtain the desired products isolated as two enantiomers.

[0570] Example 39a: 2-(4-chloro-3-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol (enantiomer a) 1H NMR (400 MHz, DMSO-d6: D2O): δ 7.77 (d, J = 10.40 Hz, 1H), 7.57 (t, J = 8.00 Hz, 1H), 7.46 (d, J = 10.80 Hz, 1H), 7.37-7.21 (m, 3H), 7.18 (d, J = 7.60 Hz, 1H), 7.10 (t, J = 5.60 Hz, 1H), 5.27 (d, J = 10.80 Hz, 2H), 3.59 (m, 2H), 1.76 (s, 3H); MS: m / z 416.0 [(M+1)-HCl].

[0571] Example 39b: 2-(4-chloro-3-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol (enantiomer b)

[0572] 1 H NMR (400 MHz, DMSO-d6: D2O) δ 7.76 (s, 1H), 7.56 (t, J = 8.00 Hz, 1H), 7.45 (dd, J = 2.00, 11.20 Hz, 1H), 7.35 (d, J = 8.00 Hz, 1H), 7.23 (m, 3H), 7.09 (d, J = 7.60 Hz, 1H), 5.26 (s, 2H), 3.69 (m, 2H), 1.75 (s, 3H); MS: m / z 416.1 [(M+1)-HCl].

[0573] Example 40 Preparation of 2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka]

[0574] Example 40, Step 1: Preparation of 2-{[(2-amino-3-{[(1,3-oxazol-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(4-chloro-3-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{[(1,3-oxazol-2-yl)amino]methyl}phenyl)-carbamotioil]amino}-2-(4-chloro-3-fluorophenyl)propyl 2,2-dimethylpropanoate (mixture of positional isomers) [ka] To a solution of 3-{[(1,3-oxazole-2-yl)amino]methyl}benzene-1,2-diamine (from Example 38, Step 2) (1.2 g, 4.94 mmol) in a mixed solvent of dichloromethane:methanol (1:1, 24 mL), 2-(4-chloro-3-fluorophenyl)-2-isothiocyanatopropyl 2,2-dimethylpropanoate (1.63 g, 4.94 mmol), (prepared from commercially available 1-(4-chloro-3-fluorophenyl)ethane-1-one by the method described in Example 3, Steps 1 to 7), was added. The reaction mixture was stirred at room temperature for 24 hours, then concentrated in a water bath at 30°C to obtain 2-{[(2-amino-3-{[(1,3-oxazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(4-chloro-3-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{[(1,3-oxazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(4-chloro-3-fluorophenyl)propyl 2,2-dimethylpropanoate (a mixture of positional isomers) (2.80 g) as a yellow gum, which was used in the next step without further purification. MS: m / z 534.0 (M+1).

[0575] Example 40, Step 2: Preparation of 2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazol-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate [ka] To a solution of 2-{[(2-amino-3-{[(1,3-oxazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(4-chloro-3-fluorophenyl)propyl 2,2-dimethylpropanoate and 2-{[(2-amino-6-{[(1,3-oxazole-2-yl)amino]methyl}phenyl)carbamotioil]amino}-2-(4-chloro-3-fluorophenyl)propyl 2,2-dimethylpropanoate (a mixture of positional isomers) (Example 40, from Step 1) (2.80 g, 5.24 mmol) in methanol (30 mL), iodoacetic acid (0.975 g, 5.24 mmol) was added, and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated, and the solvent methanol was removed at 30°C to obtain the crude product, which was dissolved in DCM and washed with a 10% NaHCO3 solution, and then with brine solution. The organic layer was dried over sodium sulfate and concentrated to obtain the product (2.1 g) as a brown gum. This was purified by preparative HPLC (method: water: 10 mmol ammonium acetate in acetonitrile) to obtain 2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]-methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate (1.3 g) as a white solid.

[0576] 1H NMR (400 MHz, DMSO-d6: D2O) δ 7.54-7.35 (m, 4H), 7.01 (t, J = 5.60 Hz, 1H), 6.82-6.71 (m, 3H), 4.54-4.44 (m, 4H), 1.81 (s, 3H), 1.05 (s, 9H); MS: m / z 500.1 (M+1).

[0577] The product from Step 2 was separated into two enantiomers by chiral SFC using the following method to obtain two enantiomers, 40a and 40b: Column: Chiralpak OX-H; Mobile phase: 0.5% isopropylamine in isopropyl alcohol; Cosolvent: 40% CO2; Flow rate: 5 mL / min, Pressure: 100 bar, Temperature: 35°C.

[0578] Example 40, Step 3a: (+)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazol-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate The (+) enantiomer was the first compound to elute from the column. [ka]

[0579] 1 H NMR (AcOH-d4) δ 7.55-7.47 (m, 2H), 7.42-7.40 (m, 2H), 7.29 (dd, J = 1.60, 6.80 Hz, 1H), 7.25-7.19 (m, 2H), 7.16 (d, J = 1.60 Hz, 1H), 4.80 (s, 2H), 4.58 (d, J = 11.60 Hz, 1H), 4.49 (d, J = 11.60 Hz, 1H), 1.95 (s, 3H), 1.18 (s, 9H);

[0580] MS: m / z 500.2 (M+1); SOR: [α] D 23.5 (+) 12.80, (MeOH, c = 0.5).

[0581] Example 40, Step 3b: (-)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazol-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate The (-) enantiomer was the second compound eluted from the column. [ka]

[0582] 1 H NMR (400 MHz, AcOH-d4) δ7.53-7.47 (m, 2H), 7.43-7.40 (m, 2H), 7.30 (dd, J = 1.60, 6.80 Hz, 1H), 7.25-0.21 (m, 2H), 7.17 (d, J = 1.60 Hz, 1H), 4.81 (s, 2H), 4.53 (m, 2H), 1.96 (s, 3H), 1.21 (s, 9H);

[0583] MS: m / z 500.1 (M+1); SOR: [α] D 23.2 (-) 11.60, (MeOH, c = 0.5).

[0584] Example 40a: Preparation of (-)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka] (+)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate (from Example 40, Step 3a) (0.5 g, 1.00 mmol) was stirred in methanol (50.0 mL), to which a solution of 0.5 N sodium hydroxide in methanol (8 mL, 4.00 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated, and the residue was diluted with water (5 mL). The aqueous layer was extracted with DCM (3 x 75 mL), the combined organic layers were washed with brine solution (10 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product (0.36 g) as an off-white solid. This was purified by preparative HPLC (method: water: 10 mmol ammonium acetate in acetonitrile) to obtain (-)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol (0.22 g) as a white solid.

[0585] 1 H NMR (400 MHz, AcOH-d4) δ7.50-7.40 (m, 3H), 5.60 (dd, J = 28.02, 14.08 Hz, 1H), 7.30-7.21 (m, 3H), 7.15 (d, J = 1.20 Hz, 1H), 4.78 (s, 2H), 4.30 (d, J = 12.00 Hz, 1H), 4.08 (d, J = 12.00 Hz, 1H), 1.76 (s, 3H);

[0586] MS: m / z 416.1 (M+1); SOR: [α] D 23.4 (-) 5.60, (MeOH, c = 0.5).

[0587] Example 40b: Preparation of (+)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka] To a stirred solution of (-)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propyl 2,2-dimethylpropanoate (from Example 40, Step 3b) (0.45 g, 0.900 mmol) in methanol (45 mL), a solution of 0.5 N sodium hydroxide in methanol (7.20 mL, 3.600 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated, and the residue was diluted with water (5 mL). The aqueous layer was extracted with DCM (3 x 75 mL), and the combined organic layers were washed with brine solution (10 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product (0.33 g) as an off-white solid. This was purified by preparative HPLC (method: water: 10 mmol ammonium acetate in acetonitrile) to obtain (+)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol (0.14 g) as a white solid.

[0588] 1 H NMR (400 MHz, AcOH-d4) δ 7.49-7.40 (m, 3H), 7.36 (d, J = 8.40 Hz, 1H), 7.30-7.21 (m, 3H), 7.15 (s, 1H), 4.79 (s, 2H), 4.30 (d, J = 12.00 Hz, 1H), 4.08 (d, J = 12.00 Hz, 1H), 1.76 (s, 3H);

[0589] MS: m / z 416.1 (M+1); SOR: [α] D 23.2 (+) 4.80, (MeOH, c = 0.5).

[0590] Example 41: Preparation of 2-(3-chloro-2-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol [ka] Commercially available 1-(3-chloro-2-fluorophenyl)ethane-1-one and 3-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]benzene-1,2-diamine (from step 5 of Example 1) were used according to the method described for Example 18 to obtain the desired products isolated as two enantiomers.

[0591] Example 41a: (-)-2-(3-chloro-2-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol It was isolated as an off-white solid in the form of its hydrochloride salt.

[0592] 1 H NMR (400 MHz, AcOH-d4) δ 7.54-7.41 (m, 4H), 7.33-7.18 (m, 4H), 5.68-5.57 (m, 2H), 4.51 (d, J = 12.40 Hz, 1H), 4.17 (d, J = 12.00 Hz, 1H), 1.89 (s, 3H);

[0593] MS: m / z 416.0 (M+1); [α] D 23.0 (-) 1.60 (MeOH, c = 0.5).

[0594] Example 41b: (+)-2-(3-chloro-2-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol It was isolated as an off-white solid in the form of hydrochloride.

[0595] 1 H NMR (400 MHz, AcOH-d4) δ 7.57 (d, J = 1.60 Hz, 1H), 7.48-7.44 (m, 3H), 7.32-7.27 (m, 2H), 7.22-7.17 (m, 2H), 5.41 (d, J = 5.20 Hz, 2H), 4.52 (d, J = 12.40 Hz, 1H), 4.15 (d, J = 12.00 Hz, 1H), 1.83 (s, 3H);

[0596] MS: m / z 416.0 (M+1); [α] D 22.5 (+) 6.0 (MeOH, c = 0.5).

[0597] Example 42: Preparation of 2-(3-chloro-2-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka] 3-{[(1,3-oxazole-2-yl)amino]methyl}benzene-1,2-diamine (from Step 2 of Example 38) and 2-(3-chloro-2-fluorophenyl)-2-isothiocyanatopropyl-2,2-dimethylpropanoate (prepared from commercially available 1-(3-chloro-2-fluorophenyl)ethane-1-one by the method described in Steps 1 to 7 of Example 3) were used according to the method described in Example 40 to obtain the desired product, which was then separated into two enantiomers.

[0598] Example 42a: (+)-2-(3-chloro-2-fluorophenyl)-2-[(4-{[(1,3-oxazol-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol It was isolated as an off-white solid.

[0599] 1 H NMR (400 MHz, AcOH-d4) δ 7.48-7.46 (m, 2H), 7.37-7.34 (m, 2H), 7.28-7.21 (m, 2H), 7.17-7.13 (m, 2H), 4.78 (t, J = 16.00 Hz, 2H), 4.52 (d, J = 13.20 Hz, 1H), 4.17 (d, J = 12.40 Hz, 1H), 1.81 (s, 3H);

[0600] MS: m / z 416.0 (M+1); [α] D 23.7 (+) 39.6 (MeOH, c = 0.5).

[0601] Example 42b: (+)-2-(3-chloro-2-fluorophenyl)-2-[(4-{[(1,3-oxazol-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol It was isolated as an off-white solid.

[0602] 1 H NMR (400 MHz, AcOH-d4) δ 7.48-7.44 (m, 2H), 7.36-7.34 (m, 2H), 7.28-7.21 (m, 2H), 7.17-7.13 (m, 2H), 4.78 (t, J = 16.00 Hz, 2H), 4.52 (d, J = 13.20 Hz, 1H), 4.17 (d, J = 12.80 Hz, 1H), 1.81 (s, 3H);

[0603] MS: m / z 416.1 (M+1); [α] D 23.6 (-) 37.6 (MeOH, c = 0.5).

[0604] Example 43: Preparation of 2-(3-chloro-2-fluorophenyl)-2-[(4-{[(1,2-oxazol-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol [ka]

[0605] Example 43, Step 1: Preparation of (2,1,3-benzothiadiazole-4-yl)methanol [ka] To a solution of 4-(bromomethyl)-2,1,3-benzothiadiazole (Example 1, Step 3) (50 g, 218 mmol) in 1,4-dioxane:water (1:1,1000 mL), potassium carbonate (151 g, 1091 mmol) was added, and the reaction mixture was stirred at 100 °C for 20 hours. The reaction mass was cooled to ambient temperature, washed with water (500 mL), and extracted with ethyl acetate (3 x 300 mL). The combined organic layer was washed with brine solution (300 mL), dried over sodium sulfate, filtered, and concentrated to obtain the crude product (36 g) as a brown gum. This was purified by silica gel column chromatography and eluted with 25% ethyl acetate in petroleum ether to obtain (2,1,3-benzothiadiazole-4-yl)methanol (27 g) as an off-white solid.

[0606] 1 H NMR (400 MHz, DMSO-d6) δ 7.98-7.96 (m, 1H), 7.75-7.68 (m, 2H),5.51 (t, J = 4.00 Hz, 1H), 5.03 (d, J = 5.60 Hz, 2H);

[0607] Example 43, Step 2: Preparation of 2,1,3-benzot...

Claims

1. Compound of formula (I) or a pharmaceutically acceptable salt thereof 【Chemistry 1】 Here A is halogen, C １‐６ Alkyl, C substituted with at least one halogen １‐６ Alkyl, C １‐６ alkoxy, C substituted with at least one halogen １‐６ Alkoxy, C １‐６ A five- or six-membered aromatic heterocycle containing at least one nitrogen atom, optionally one sulfur atom, and optionally one oxygen atom, optionally substituted with at least one group selected from alkylthio and cyano; R1 is hydrogen and C １‐６ Selected from alkyl groups; Or A and R1 together with the nitrogen atom to which they are attached contain 1 to 2 nitrogen atoms, and optionally 1 oxygen atom, and optionally 1 sulfur atom, and are optionally substituted with a group selected from halogen, C １‐６ alkyl, C １‐６ alkyl substituted with halogen, C １‐６ alkoxy, C １‐６ alkoxy substituted with halogen, C １‐６ alkylthio, =NH, =O, -OH, and cyano, to form a 5- to 6-membered aromatic or non-aromatic heterocyclic ring optionally substituted with a group selected from R2-R3 independently contain hydrogen and C １‐６ It is a group selected from alkyl groups; Alternatively, R2 and R3, together with the carbon atoms they are linked to, C ３‐４ Forms a cycloalkyl group; R4 to R6 are independently hydrogen, halogen, and C １‐４ It is a group selected from alkyl groups; R7-R8 are independently hydrogen, C １‐４ Alkyl, C substituted with one OH group １‐４ Alkyl, 1 OC １‐３ C substituted with alkyl １‐４ Alkyl, C substituted with at least one halogen １‐４ A group selected from alkyl groups, Alternatively, R7 and R8, together with the carbon atoms they are linked to, C ３‐４ Forms a cycloalkyl group; R9 to R13 are independently hydrogen, halogen, and C substituted with at least one halogen. １‐６ Alkyl, C １‐６ alkoxy, C substituted with at least one halogen １‐６ Alkoxy, C １‐６ The group is selected from alkylthio and cyano.

2. A is a five-membered aromatic heterocycle containing 1 to 3 nitrogen atoms and optionally 1 oxygen atom, and is a halogen, C １‐６ Alkyl, C substituted with at least one halogen １‐６ Alkyl, C １‐６ alkoxy, C substituted with at least one halogen １‐６ Alkoxy, C １‐６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with a group selected from alkylthio and cyano.

3. A is a six-membered aromatic heterocycle containing 1 to 3 nitrogen atoms, and is a halogen, C １‐６ Alkyl, C substituted with at least one halogen １‐６ Alkyl, C １‐６ alkoxy, C substituted with at least one halogen １‐６ Alkoxy, C １‐６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with at least one group selected from alkylthio and cyano.

4. A is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl and pyrimidinyl, and halogen, C １‐６ Alkyl, C substituted with at least one halogen １‐６ Alkyl, C １‐６ alkoxy, C substituted with at least one halogen １‐６ Alkoxy, C １‐６ The compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, optionally substituted with at least one group selected from alkylthio and cyano.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen (H) and methyl.

6. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1 is H.

7. A and R1, together with the nitrogen atom to which they are linked, form a five-membered non-aromatic heterocycle containing one or two nitrogen atoms and one oxygen atom, and are substituted with one, two or three groups selected from methyl and =NH, the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

8. R2 to R3 independently control H and C １‐３ A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the group is selected from alkyl groups.

9. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R2 to R3 are both H.

10. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R2 and R3, together with the carbon atoms to which they are linked, form a cyclopropyl group.

11. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R4 to R6 are independently selected from H, F, Cl, and methyl.

12. R7 is H and C １‐３ A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein the group is selected from alkyl groups.

13. R8 is C １‐４ Alkyl, C substituted with one OH group １‐４ Alkyl and one OC １‐３ C substituted with alkyl １‐４ A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the group is selected from alkyl groups.

14. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R7 and R8, together with the carbon atoms to which they are linked, form a cyclopropyl group.

15. R9 to R13 are independently replaced by H, halogen, or at least one halogen C １‐６ C substituted with alkyl and at least one halogen １‐６ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the group is selected from alkoxys.

16. R9, R12, and R13 are all H, and R10 to R11 are independently replaced by H, halogen, or at least one halogen C １‐６ C substituted with alkyl and at least one halogen １‐６ A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the group is selected from alkoxys; provided that R10 and R11 are not both H.

17. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein each of R9, R10, R11, and R12 is a group selected from H and a halogen, and R13 is H.

18. The following compounds: N-[1-(3-chlorophenyl)cyclopropyl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine, N-[2-(3-chlorophenyl)propan-2-yl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine, 2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (-)-2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (+)-2-(3-chlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, 4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-N-{1-[3-(trifluoromethyl)phenyl]ethyl}-1H-1,3-benzodiazole-2-amine, 2-(3-chlorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, N-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine, 4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-N-{2-[3-(trifluoromethyl)phenyl]propan-2-yl}-1H-1,3-benzodiazole-2-amine, 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (-)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (+)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, N-[2-(3-chlorophenyl)-1-methoxypropan-2-yl]-4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine, 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(pyrimidine-4-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(5-methyl-1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (-)-2-(3-chloro-4-fluorophenyl)-2-((4-(((5-methylisoxazole-3-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino)propan-1-ol, (+)-2-(3-chloro-4-fluorophenyl)-2-((4-(((5-methylisoxazole-3-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino)propan-1-ol, 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (-)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (+)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, N-[2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl]-4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-amine, 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(5-methyl-1,2,4-oxadiazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, 2-(3-chloro-4-fluorophenyl)-2-((4-(((5-methyl-1,3,4-oxadiazole-2-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino)propan-1-ol, 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(3-methyl-1,2,4-oxadiazole-5-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol, (-)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol, (+)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol, 2-(3,4-dichlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (-)-2-(3,4-dichlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (+)-2-(3,4-dichlorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-4,5-dimethyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, 2-((4-(((1-methyl-1H-pyrazole-5-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino-2-(3-(trifluoromethyl)phenyl)propan-1-ol, 2-((4-(((1-methyl-1H-imidazole-2-yl)amino)methyl)-1H-benzo[d]imidazole-2-yl)amino)-2-(3-(trifluoromethyl)phenyl)propan-1-ol, 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]-propan-1-ol, (-)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol, (+)-2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol, 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]propan-1-ol, (-)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)-phenyl]propan-1-ol, (+)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)-phenyl]propan-1-ol, 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]butan-1-ol, 3-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-3-[3-(trifluoromethyl)phenyl]butan-1-ol, 2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol, (+)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol, (-)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol, 2-({4-[(2-imino-4,5-dimethyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethyl)phenyl]-propan-1-ol, 2-({4-[(2-imino-4-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol, 2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)phenyl]propan-1-ol, (-)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)-phenyl]propan-1-ol, (+)-2-({4-[(2-imino-5-methyl-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)-2-[3-(trifluoromethoxy)-phenyl]propan-1-ol, 2-(3-chloro-4-fluorophenyl)-2-[(4-{1-[(1,3-oxazole-2-yl)amino]ethyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, 2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (-)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (+)-2-(3-chloro-4-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-thiazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]-2,3-dihydro-1H-imidazole-2-one, 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]imidazolidined-2-one, 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]-3-methylimidazolidined-2-one, 3-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]-1,3-thiazolidined-2-one, 1-[(2-{[2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl]amino}-1H-1,3-benzodiazole-4-yl)methyl]pyrrolidine-2-one, 2-(3-chloro-4-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, 2-(4-chloro-3-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (+)-2-(4-chloro-3-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (-)-2-(4-chloro-3-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, 2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]-methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (-)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (+)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, 2-(3-chloro-2-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (-)-2-(3-chloro-2-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (+)-2-(3-chloro-2-fluorophenyl)-2-{4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, 2-(3-chloro-2-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (+)-2-(3-chloro-2-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (+)-2-(3-chloro-2-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, 2-(3-chloro-2-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (-)-2-(3-chloro-2-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (+)-2-(3-chloro-2-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, 2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (-)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (+)-2-(4-chloro-3-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, 2-(3-chloro-5-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (-)-2-(3-chloro-5-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (+)-2-(3-chloro-5-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, 2-(3-chloro-5-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (-)-2-(3-chloro-5-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (+)-2-(3-chloro-5-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, 2-(5-chloro-2-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (-)-2-(5-chloro-2-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, (+)-2-(5-chloro-2-fluorophenyl)-2-({4-[(2-imino-2,3-dihydro-1,3-oxazole-3-yl)methyl]-1H-1,3-benzodiazole-2-yl}amino)propan-1-ol, 2-(5-chloro-2-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (+)-2-(5-chloro-2-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (-)-2-(5-chloro-2-fluorophenyl)-2-[(4-{[(1,3-oxazole-2-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, 2-(5-chloro-2-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, (+)-2-(5-chloro-2-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol, and (-)-2-(5-chloro-2-fluorophenyl)-2-[(4-{[(1,2-oxazole-3-yl)amino]methyl}-1H-1,3-benzodiazole-2-yl)amino]propan-1-ol A compound according to claim 1, selected from any one of the following, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 and optionally a pharmaceutically acceptable additive.

20. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmacopoeia for the treatment of a heart disease, disorder or condition of a mammal.

21. The use according to claim 20, wherein the disease, disorder, or condition is accompanied by an abnormal rhythm or malformation of the heart and exercise-induced angina.

22. The use according to claim 20, wherein the cardiac disease or disorder or condition is selected from the group consisting of cardiac arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias, atrial tachyarrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and abnormal rhythms occurring after cardiac surgery or cardiac ablation.

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