Urea compounds as potassium channel Kv7.2 / 7.3 activators useful in treatment of CNS and PNS disorders

Abstract

The present invention relates to compounds of formula (I), as defined in the specification, capable of promoting the opening of the Kv7.2 / 7.3 potassium channel, pharmaceutical compositions comprising them, and their use as medicaments, in particular in the treatment of central nervous system (CNS) disorders such as, for example, epilepsy and neurodegenerative diseases and peripheral nervous system (PNS) disorders such as, for example, epilepsy and neurodegenerative diseases. Chronic and neuropathic pain).

Description

Field of the Invention

[0001] The present invention relates to compounds that can promote the opening of Kv7.2 / 7.3 potassium channels and their use as drugs, in particular, their use as drugs in the treatment of central nervous system (CNS) disorders (e.g., epilepsy and neurodegenerative diseases) and peripheral nervous system (PNS) disorders (e.g., chronic and neuropathic pain). Background Art

[0002] Voltage-gated potassium (Kv) channels conduct potassium (K+) ions across the cell membrane in response to changes in membrane potential and can therefore regulate cellular excitability by modulating (increasing or decreasing) the electrical activity of the cell.

[0003] Functional Kv channels exist as multimeric structures composed of four α subunits and four β subunits. The α subunits contain six transmembrane domains, a pore-forming ring, and a voltage sensor, arranged symmetrically around a central pore. β subunits or accessory subunits interact with α subunits and can alter the properties of the channel complex, including, but not limited to, changes in the channel's electrophysiological or biophysical properties, levels, or expression patterns.

[0004] Nine families of Kv channel alpha subunits have been identified, referred to as Kv1-Kv9. The Kv7 channel family consists of at least five members, including Kv7.1, Kv7.2, Kv7.3, Kv7.4, and Kv7.5. Alternatively, the members of this family are referred to by the gene names KCNQ1, KCNQ2, KCNQ3, KCNQ4, and KCNQ5, respectively (Dalby-Brown, et al., Current Topics in Medicinal Chemistry, 2006, 6 (10), 999-1023).

[0005] As mentioned above, neuronal Kv7 potassium channels play a role in controlling neuronal excitation. Kv7 channels, particularly Kv7.2 / 7.3 heterotetramers, are the basis of M currents (Wang et al. Science. 1998, Dec 4; 282(5395): 1890-1893).

[0006] The M current has a characteristic time and voltage dependence that causes the membrane potential to remain stable in response to a variety of excitatory stimuli. Therefore, the M current is involved in the control of neuronal excitability (Delmas and Brown, Nature, 2005, 6, 850-862).

[0007] The M current is a non-inactivating potassium current present in a variety of neuronal cell types. In each cell type, it plays a dominant role in the control of membrane excitability and is the only persistent current within the action potential initiation range (Marrion, Annual Review Physiology, 1997, 59, 483-504).

[0008] The five members of this ion channel family are different in their expression patterns. The expression of Kv7.1 is limited to the heart, peripheral epithelium and smooth muscle, while the expression of Kv7.2, Kv7.3, Kv7.4 and Kv7.5 seems to dominate the nervous system including hippocampus, cortex, ventral tegmental area and dorsal root ganglion neurons. Kv7.4 is a subtype selectively expressed in the auditory pathway including inner ear hair cells. In addition to neurons, Kv7.4 and Kv7.5 are also expressed in various smooth muscle cells (Greene and Hoshi, Cellular and Molecular Life Sciences, 2017, 74 (3), 495-508).

[0009] The KCNQ2 and KCNQ3 genes appear to be mutated in an inherited form of epilepsy known as benign familial neonatal epilepsy (Rogawski, Trends in Neuroscience 2000, 23, 393-398). The proteins encoded by the KCNQ2 and KCNQ3 genes are localized in pyramidal neurons of the human cortex and hippocampus, areas of the brain involved in the generation and propagation of epileptic seizures (Cooper et al., Proceedings National Academy of Science USA, 2000, 97(9), 4914-4919).

[0010] In addition, the mRNA of Kv7.2, Kv7.3 and Kv7.5 is expressed in astrocytes and neuroglia. Therefore, Kv7.2, Kv7.3 and Kv7.5 channels may contribute to the synaptic activity in the central nervous system, and promote the neuroprotective effect of KCNQ channel activators (Noda, et al., Society for Neuroscience Abstracts 2003, 53.9), which is relevant to the treatment of neurodegenerative diseases (such as, but not limited to Alzheimer's disease, Parkinson's disease and Huntington's disease).

[0011] Kv7.2 and Kv7.3 mRNAs are present in brain regions associated with anxiety and emotional behaviors such as depression and bipolar disorder, such as the hippocampus, ventral tegmental area, and amygdala (Saganich et al., Journal of Neuroscience, 2001, 21(13), 4609-4624; Friedman et al., Nat. Commun., 2016, 7, 11671).

[0012] Kv7.2 / 7.3 channels have been reported to be upregulated in neuropathic pain models (Wickenden et al., Society for Neuroscience Abstracts, 2002, 454.7), and it has been speculated that potassium channel modulators are active in both neuropathic pain and epilepsy (Schroder et al., Neuropharmacology 2001, 40(7), 888-898). In addition to their role in neuropathic pain, the expression of Kv7.2-5 mRNA in the trigeminal and dorsal root ganglia and the caudate nucleus of the trigeminal nerve suggests that activators of these channels may also affect sensory processing in migraine (Goldstein et al., Society for Neuroscience Abstracts 2003, 53.8).

[0013] Retigabine and flupirtine are known Kv7.2 / 7.3 potassium channel activating compounds that have been used to treat epilepsy, migraine, neuropathic pain, acute pain, and tinnitus. Retigabine has been withdrawn from the market due to its adverse side effects, particularly urinary retention and changes in retinal and skin pigmentation. Flupirtine should be used by people who have not responded to other analgesic treatments and should not be used for more than two weeks due to its hepatotoxicity. SUMMARY OF THE INVENTION

[0015] Applicants have addressed the problem of providing new therapies for treating central nervous system (CNS) disorders (eg, epilepsy and neurodegenerative diseases) and peripheral nervous system (PNS) disorders (eg, chronic and neuropathic pain).

[0016] The applicant has focused its attention on potassium channel activating compounds Kv7.2 / 7.3 and has conducted research work that may provide alternative compounds to retigabine and flupirtine.

[0017] After extensive experimentation, Applicants have identified a number of novel compounds that are capable of acting as drugs, particularly for the treatment of disorders modulated by Kv7.2 / 7.3 potassium channels.

[0018] In particular, as shown in the Examples in the Experimental Section below, Applicants have identified a number of compounds that are capable of acting as activators of Kv7.2 / 7.3 potassium channels.

[0019] Based on information known to those skilled in the art, Applicants believe that these compounds may be effective in treating a variety of central nervous system (CNS) disorders (e.g., epilepsy and neurodegenerative diseases), as well as peripheral nervous system (PNS) disorders (e.g., chronic and neuropathic pain).

[0020] Thus, in a first aspect, the present invention relates to a Kv7.2 / 7.3 potassium channel activator compound or a pharmaceutically acceptable salt thereof for use in the treatment of disorders modulated by KV7.2 / KV7.3 potassium channels, preferably selected from central nervous system (CNS) and peripheral nervous system (PNS) disorders, said compound having the following general formula (I):

[0021]

[0022] R1 is represented by ---L1---A1, where

[0023] L1 is a bond or a linear or branched C1-C6 alkyl chain, optionally substituted with one or more halogen atoms or hydroxyl groups, and optionally containing an oxy (—O—) group within the alkyl chain or at any terminus, and

[0024] A1 is a hydrogen atom, or

[0025] (i) an aromatic or aliphatic ring having 3 to 6 members, optionally containing one or more heteroatoms selected from N, O and S, unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3, a C1-C3 alkyl chain optionally substituted by one or more halogen atoms and AR, wherein AR is an aromatic or aliphatic ring, optionally containing one or more heteroatoms selected from N, O and S, unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3 and a C1-C3 alkyl chain optionally substituted by one or more halogen atoms, or

[0026] (ii) a fused or bridged bicyclic ring having 5 to 12 members, optionally containing one or more heteroatoms selected from N, O and S, unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3, O-Gr and C1-C3 alkyl optionally substituted by one or more halogen atoms, wherein Gr is an aliphatic ring having 3 to 6 members, optionally containing one or more heteroatoms selected from N, O and S, unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3, C1-C3 alkyl chain optionally substituted by one or more halogen atoms;

[0027] R2 is hydrogen or a C1-C3 alkyl chain;

[0028] R3 is hydrogen or a C1-C3 alkyl chain or aliphatic ring optionally substituted by a hydroxyl group, optionally containing one or more heteroatoms selected from N, O and S, unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN and CF3;

[0029] R4 is represented by ---L2---A2, where

[0030] L2 is a bond or a C1-C3 alkyl chain, and

[0031] A2 is an aromatic ring having 6 members and containing 1 or 2 nitrogen atoms, optionally fused to an aliphatic ring having 5 or 6 carbon atoms, said aromatic ring being substituted by one or more substituents selected from

[0032] (i) halogen atoms,

[0033] (ii) a C1-C3 alkyl chain, optionally substituted by one or more halogen atoms,

[0034] (iii) an aliphatic ring having 4 to 6 members containing one or more heteroatoms selected from O and N, optionally substituted by one or more halogen atoms or a C1-C3 alkyl chain, said C1-C3 alkyl chain optionally substituted by one or more halogen or hydroxyl groups, and

[0035] (iv) a group represented by the following formula: S6---L3---A3, wherein S6 is an oxygen or nitrogen atom, L3 is a bond or a C1-C4 alkyl chain, and A3 is

[0036] (a) an aliphatic or aromatic ring having 3 to 6 members, optionally containing one or more heteroatoms selected from O and N, and optionally substituted by a halogen atom or a C1-C3 alkyl chain, said C1-C3 alkyl chain optionally substituted by one or more halogen, hydroxyl or CN, or

[0037] (b) a C1-C3 alkyl chain, optionally substituted by one or more halogen atoms

[0038] R5 is hydrogen or a C1-C3 alkyl chain;

[0039] or R4 together with R2 or R3, and / or R5 together with R1, and / or R3 together with R2, form a 5-6 membered aliphatic ring, which is optionally substituted by an alkyl chain having 1 to 3 carbon atoms, a halogen atom or a hydroxyl group, said aliphatic ring optionally containing an oxygen atom and optionally fused to or substituted by a benzene or pyridine ring, said benzene or pyridine ring being optionally substituted by a halogen or an alkyl or alkoxy chain having 1 to 3 carbon atoms, said chain being optionally substituted by one or more halogen atoms;

[0040] The prerequisite is that when R2, R3 and R5 are hydrogen atoms and R4 is

[0041] hour,

[0042] Then R1 is different from

[0043]

[0044] wherein R6 is H or OH, and

[0045] Provided that, when L1 is a bond, A1 is not a substituted or unsubstituted cyclobutane ring.

[0046] In a second aspect, the present invention relates to a Kv7.2 / 7.3 potassium channel activator compound selected from Table A and Table B below, or a pharmaceutically acceptable salt thereof.

[0047] In a third aspect, the present invention relates to a pharmaceutical composition comprising (i) a Kv7.2 / 7.3 potassium channel activating compound according to the second aspect of the invention or a pharmaceutically acceptable salt thereof and (ii) at least one pharmaceutically acceptable excipient.

[0048] Advantageously, the pharmaceutical composition according to the third aspect of the invention may be used to treat disorders modulated by Kv7.2 / 7.3 potassium channels, preferably central nervous system (CNS) and peripheral nervous system (PNS) disorders.

[0049] In a fourth aspect, the present invention relates to a method for treating a disorder regulated by Kv7.2 / 7.3 potassium channels in a subject in need thereof, the method comprising administering a therapeutically effective amount of a Kv7.2 / 7.3 potassium channel activating compound according to the first or second aspect of the invention or a pharmaceutically acceptable salt thereof.

[0050] For the purpose of this specification and the claims that follow, the phrase "pharmaceutically acceptable" is intended to define, without any specific limitations, any material that is suitable for preparing a pharmaceutical composition to be administered to an organism.

[0051] For the purposes of this specification and the claims that follow, the phrase "therapeutically effective amount" means that amount of a compound sufficient to alleviate, arrest, partially arrest, eliminate or delay the clinical manifestations of a disease and its complications in a therapeutic treatment comprising the administration of the compound.

[0052] For the purpose of this specification and the claims that follow, the term "treatment" refers to the management and care of a patient in order to alleviate, arrest, partially arrest, eliminate or delay the progression of the clinical manifestations of a disease. The patient to be treated is preferably a mammal, especially a human.

[0053] For the purpose of this specification and the appended claims, unless otherwise indicated, the expressions "such as" and the terms "preferably", "advantageously", "particularly" etc. are used to better illustrate the present invention without adding any limitation to the scope of the present invention.

[0054] For the purposes of this specification and the claims that follow, the phrase "Kv7.2 / Kv7.3 potassium channel activator" refers to a compound that causes the voltage dependence of channel opening to shift toward more negative potentials, meaning that in the presence of said compound, Kv7.2 / Kv7.3 potassium channels open to more negative potentials, facilitating the transport of ions through them. Detailed Description of the Invention

[0056] The first aspect of the present invention relates to a Kv7.2 / 7.3 potassium channel activator compound or a pharmaceutically acceptable salt thereof for use in treating disorders mediated by KV7.2 / KV7.3 potassium channels, preferably selected from central nervous system (CNS) and peripheral nervous system (PNS) disorders, wherein the compound has the above-mentioned general formula (I).

[0057] In one embodiment of the present invention, L1 is a bond or a C1-C2 alkyl chain.

[0058] In another embodiment, L1 is a linear or branched C3-C6 alkyl chain, optionally substituted with one or more halogen atoms or hydroxyl groups, and optionally comprising an oxy (-O-) group within the alkyl chain or at any terminus, such as, for example, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CHOH-C(CH3)2-CH2-, -CH2-CHOH-C(CH3)2-CH2-, -CH2-CH2-CCF3OH-CH2-, -CH2-CH2-CCF3OH-CH2-, -CH2-CH2-O-CCF3 CH3-CH2-, -CH2-CCH3OH-CH2-.

[0059] In one embodiment of the present invention, A1 is hydrogen or

[0060] (i) an aromatic or aliphatic ring selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3, a C1-C3 alkyl chain, optionally substituted by one or more halogen atoms, or

[0061] (ii) a bicyclic ring selected from bicyclo[1,1,1]pentane, indane (2,3-dihydro-1H-indene), 2,3-dihydro-1H-indole, 6,7-dihydro-5H-cyclopenta[c]pyridine, chroman (3,4-dihydro-2H-1-benzopyran), dihydrocoumarin (2,3-dihydro-1-benzofuran), tetrahydronaphthalene (1,2,3,4-tetrahydronaphthalene), thiochroman (3,4-dihydro-2H-1-benzothiopyran), 5,6-dihydro-4H-cyclopentane diene [b] thiophene, 6,7-dihydro-5H-cyclopenta [b] pyridine, 5,6,7,8-tetrahydroisoquinoline, 5,6,7,8-tetrahydroquinoxaline, 2,3,4,5-tetrahydro-1-benzoxepin and 6,7,8,9-tetrahydro-5H-benzo [7] annulene, optionally substituted with one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3, a C1-C3 alkyl chain optionally substituted with one or more halogen atoms.

[0062] In a preferred embodiment of the present invention, L2 is a bond or a C1-C2 alkyl chain, more preferably a bond.

[0063] In a preferred embodiment of the present invention, A2 is pyridine, pyridazine, pyrimidine or pyrazine, more preferably pyridine or pyrimidine, optionally fused to an aliphatic ring having 5 or 6 carbon atoms.

[0064] In an embodiment of the present invention, A2 is substituted by a halogen atom, preferably selected from chlorine and fluorine.

[0065] In an embodiment of the present invention, A2 is substituted by a C1-C3 alkyl chain, preferably selected from methyl, ethyl, propyl and isopropyl, optionally substituted by one or more halogen atoms, preferably selected from chlorine and fluorine.

[0066] In an embodiment of the present invention, A is substituted by an aliphatic ring having 4 to 6 members, the members comprising one nitrogen atom, one oxygen atom or both, optionally substituted by one or more halogen atoms or a C1-C3 alkyl chain, the C1-C3 alkyl chain being optionally substituted by one or more halogen or hydroxyl groups, wherein the halogen atoms are preferably selected from chlorine and fluorine. In a preferred embodiment, the aliphatic ring having 4 to 6 members is azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, oxazetidine, oxazolidine or morpholine, more preferably azetidine, pyrrolidine, piperidine or morpholine.

[0067] In an embodiment of the present invention, A2 is substituted with a group represented by the formula ---S6---L3---A3.

[0068] S6 is preferably an oxygen atom.

[0069] L3 is preferably a bond or a C1-C3 alkyl chain, more preferably selected from methyl, ethyl, propyl and isopropyl, optionally substituted by one or more halogen atoms, preferably selected from chlorine and fluorine.

[0070] A3 is preferably an aliphatic ring with 3 to 6 members or an aromatic ring with 5 or 6 members, optionally containing one or more heteroatoms selected from O and N, and optionally substituted with a halogen atom or a C1-C3 alkyl chain, optionally substituted with one or more halogen, hydroxyl, CN. In a more preferred embodiment, the aliphatic ring is cyclopropane, cyclobutane, azetidine, oxetane, tetrahydropyran. In a more preferred embodiment, the aromatic ring is phenyl, pyrrole, furan, oxazole, pyrimidine or pyridine.

[0071] Alternatively, A3 is preferably a C1-C2 alkyl chain, optionally substituted by one or more halogen atoms, preferably selected from chlorine and fluorine. More preferably, A3 is a CF3 or C2F5 group.

[0072] In an embodiment of the present invention, R4 together with R2 or R3 and / or R3 together with R2 form a 5-6 membered aliphatic ring which is fused to or substituted by a benzene or pyridine ring which is substituted by halogen or an alkyl or alkoxy chain having 1 to 3 carbon atoms which is optionally substituted by one or more halogen atoms.

[0073] In a further embodiment of the invention, R4 together with R2 or R3 and / or R3 together with R2 forms a 5-membered aliphatic ring which is fused to or substituted by a pyridine ring which is substituted by an alkoxy chain having 1 to 3 carbon atoms, which chain is optionally substituted by one or more halogen atoms, preferably one or more fluorine atoms.

[0074] In one embodiment of the present invention, R4 or R3 together with R2 form the following ring A or B, wherein the asterisked nitrogen atom is derived from the urea structure of formula (I):

[0075]

[0076] In one embodiment of the present invention, R4 and R3 together form the following ring C, wherein the asterisked bond is attached to the nitrogen atom of the ureido structure of formula (I):

[0077]

[0078] In an embodiment of the present invention, R5 and R1 together form a 5-6 membered aliphatic ring optionally substituted by an alkyl chain having 1 to 3 carbon atoms, said aliphatic ring optionally containing oxygen atoms and optionally fused to a benzene ring, said benzene ring optionally substituted by halogen or an alkyl or alkoxy chain having 1 to 3 carbon atoms, said chain optionally substituted by one or more halogen atoms.

[0079] In a further embodiment of the present invention, R5 together with R1 forms a 5-6 membered aliphatic ring optionally substituted by a methyl group, said aliphatic ring optionally comprising an oxygen atom and optionally fused to a benzene ring, said benzene ring optionally substituted by halogen.

[0080] In a specific embodiment of the present invention, R5 and R1 together form the following rings D and E, wherein the asterisked nitrogen atom is derived from the urea structure of formula (I):

[0081]

[0082] Advantageously, the second aspect of the present invention relates to a KV7.2 / KV7.3 potassium channel activator compound selected from the compounds of Table A and Table B below, or a pharmaceutically acceptable salt thereof: Table A

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098] Table B

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108] Certain compounds of the present invention may exist in tautomeric forms and, unless otherwise stated, the present invention includes all tautomeric forms of such compounds.

[0109] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Individual stereochemical isomers of the compounds according to the invention, as well as enantiomeric and diastereomeric mixtures, are within the scope of the invention. The invention includes any diastereomer or enantiomer that is substantially free of other isomers (>90% and preferably >95% free of other stereoisomers on a molar basis), as well as mixtures of such isomers.

[0110] Specific optical isomers can be obtained by resolving the racemic mixture according to conventional methods, for example by forming diastereomeric salts, separating the diastereomeric mixture by treatment with an optically active acid or base and subsequent crystallization of the corresponding salts, and finally liberating the optically active base from such salts. Examples of suitable acids include tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid.

[0111] Another method for separating optical isomers involves the use of a chiral chromatographic column that is optimally selected to maximize the separation of the enantiomers. Yet another method involves synthesizing covalent diastereomers by reacting the compounds of the present invention with an activated form of an optically pure acid or optically pure isocyanate. The synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to provide enantiomerically pure compounds. The optically active compounds of the present invention can be obtained using active starting materials. These isomers can be in the form of free acids, free bases, esters, or salts.

[0112] The compounds of the present invention may exist in radiolabeled form, that is, the compounds may contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioactive isotopes of hydrogen, carbon, phosphorus, fluorine and chlorine include 3 H. 14 C. 32 P. 35 S. 18 F and 36 Compounds of the invention containing these radioisotopes and / or other radioisotopes of other atoms are within the scope of the invention. Tritiated radioisotopes (i.e., 3 H) and carbon-14 (i.e., 14 C) is particularly preferred due to its ease of preparation and detectability.

[0113] Radiolabeled compounds of the invention can generally be prepared by methods well known to those skilled in the art. Such radiolabeled compounds can be conveniently prepared by substituting a non-radiolabeled reagent for a readily available non-radiolabeled reagent to carry out the methods described herein.

[0114] The compounds according to the invention are preferably used in the form of salts with pharmaceutically acceptable organic and inorganic acids or bases.

[0115] Preferably, the pharmaceutically acceptable organic acid is selected from oxalic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, succinic acid, citric acid, malic acid, tartaric acid and lactic acid.

[0116] Preferably, the pharmaceutically acceptable organic base is selected from tromethamine, lysine, arginine, glycine, alanine and ethanolamine.

[0117] Preferably, the pharmaceutically acceptable inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid.

[0118] Preferably, the pharmaceutically acceptable inorganic base is selected from hydroxides or carbonates of alkali metals or alkaline earth metals such as sodium, potassium and calcium.

[0119] The compounds of the present invention or their pharmaceutically acceptable salts can be prepared by a variety of methods known to those skilled in the art, some of which are described in the preparations described in the Examples of the Experimental Section. Intermediates and final compounds can be recovered by conventional methods well known in the art, such as, for example, extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization. Reagents and starting materials are known to those skilled in the art and are readily available.

[0120] Advantageously, the compounds of the present invention are useful as medicaments, in particular for the treatment of disorders modulated by Kv7.2 / 7.3 potassium channels, preferably central nervous system (CNS) and peripheral nervous system (PNS) disorders.

[0121] Preferred central nervous system (CNS) disorders that are treated with the compounds of the present invention are, for example, epilepsy, epileptic syndromes, epileptic symptoms, epilepsy that is resistant or refractory to treatment, epileptic seizures, bipolar disorder, bipolar depression, schizophrenia, psychosis, mania, stress-related disorders, acute stress reactions, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulsive behavior disorders, personality disorders, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, tinnitus, and the like.

[0122] Advantageously, the central nervous system (CNS) disorders preferably treated with the compounds of the present invention are epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy, seizures, bipolar disorder, bipolar depression, schizophrenia and amyotrophic lateral sclerosis.

[0123] Peripheral nervous system (PNS) disorders preferably treated with the compounds of the present invention are, for example, migraine, chronic pain, acute pain, neuropathic pain, visceral pain, inflammatory pain, muscle pain, and the like.

[0124] Advantageously, peripheral nervous system (PNS) disorders preferably treated with the compounds of the present invention are neuropathic pain, chronic pain, visceral pain and inflammatory pain.

[0125] Typically, the compounds of the present invention are administered in the form of a pharmaceutical composition containing a pharmaceutically acceptable excipient.

[0126] Thus, one aspect of the present invention relates to a pharmaceutical composition comprising (i) a Kv7.2 / 7.3 potassium channel activating compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt thereof, and (ii) at least one pharmaceutically acceptable excipient.

[0127] Preferably, the pharmaceutical composition according to the present invention is for systemic use.

[0128] The pharmaceutical compositions according to the present invention may be administered orally, parenterally, by inhalation (spray, powder or aerosol), rectally, nasally, buccally, vaginally or via an implanted device.

[0129] The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0130] More preferably, the pharmaceutical composition according to the present invention is formulated for oral or parenteral administration.

[0131] Preferably, the pharmaceutical composition according to the present invention is prepared into a suitable dosage form, which comprises an effective amount of at least one compound according to the first or second aspect of the present invention, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, and at least one pharmaceutically acceptable excipient.

[0132] Examples of suitable dosage forms include tablets, capsules, coated tablets, granules and solutions and syrups for oral administration; suppositories for rectal or vaginal administration; and solutions, suspensions, dispersions or emulsions for administration by injection or infusion.

[0133] Preferred dosage forms include tablets, coated tablets, capsules and solutions for oral administration, and aqueous to non-aqueous sterile solutions for administration by injection or infusion.

[0134] The amount of the compound according to the first or second aspect of the invention or a pharmacologically acceptable salt thereof present in the pharmaceutical composition of the invention may vary over a wide range, depending on known factors such as the type of disease, the severity of the disease, the patient's weight, the dosage form, the route of administration selected, the number of administrations per day, and the efficacy of the compound itself. However, the optimal amount can be readily and routinely determined by those skilled in the art.

[0135] Typically, the amount of the compound according to the first or second aspect of the invention or a pharmacologically acceptable salt thereof in the pharmaceutical composition of the invention will be such as to provide an administration level of 0.0001 to 100 mg / kg / day. Preferably, the administration level is 0.001 to 50 mg / kg / day, and even more preferably 0.01 to 10 mg / kg / day.

[0136] As will be appreciated by those skilled in the art, lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, the patient's predisposition to the disease, and the judgment of the treating physician.

[0137] The dosage form of the pharmaceutical composition of the present invention can be prepared according to techniques well known to those skilled in the pharmaceutical field, including mixing, granulation, tableting, dissolution, sterilization, etc.

[0138] Advantageously, such dosage forms are formulated to provide controlled release of the active ingredient over time. Specifically, depending on the type of treatment, the desired release time may be very short, normal or very long.

[0139] Preferably, the pharmaceutical composition of the present invention is contained in a single dosage form and is administered once a day, or several times a day (two, three or four times).

[0140] The pharmaceutically acceptable excipients can be selected from thickeners, glidants, binders, disintegrants, fillers, diluents, preservatives, stabilizers, surfactants, buffers, fluidizers, lubricants, humectants, absorbents, salts for regulating osmotic pressure, emulsifiers, flavorings, colorants, sweeteners, etc.

[0141] Particularly preferred excipients include water, ethanol, propylene glycol, glycerol, polyethylene glycol, poloxamer, mono-, di- and tri-glycerides, coconut oil, palm oil, sodium carbonate, magnesium carbonate, magnesium stearate, stearic acid, talc, sugar, lactose, mannitol, sorbitol, polysorbate, povidone, pectin, dextrin, starch (especially corn starch), sodium starch glycolate, cross-linked sodium carboxymethylcellulose, sucrose, cyclodextrin, gelatin, microcrystalline cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, povidone, glyceryl monostearate, hypromellose, cocoa butter, titanium dioxide (E171), red iron oxide and yellow iron oxide (E172), and the like.

[0142] Experimental part

[0143] The following examples are intended to further illustrate the present invention but are not intended to limit the present invention.

[0144] Example 1

[0145] Analytical methods

[0146] Analytical data are included in the following method steps, in the description of the general method steps, or in the example tables. Unless otherwise stated, all data were collected on a Bruker Avance 400 MHz equipped with a 5 mm QNP probe or a Bruker Avance III 400 MHz, 5 mm BBFO probe or a Fourier 300 MHz, 5 mm dual probe instrument. 1 H NMR data are presented with chemical shifts expressed in parts per million (ppm). LC / MS was performed on an Acquity UPLC H-Class coupled to a QDa mass spectrometer (quaternary pump / PDA detector), an Acquity UPLC coupled to a ZQ mass spectrometer (binary pump / PDA detector), or an Acquity UPLC coupled to a SQD2 mass spectrometer with a Waters DAD. LC / MS data are referenced to the LC / MS conditions using the method numbers provided in Table 1.

[0147] Table 1. LC / MS analysis method

[0148]

[0149]

[0150] Purification method

[0151] For the general procedures, intermediates and final compounds can be purified by any technique or combination of techniques known to those skilled in the art. Some non-limiting examples include Flash chromatography performed on a Companion purification system or Biotage SP1 purification system, using SPE Si II cartridges ("Isolute SPESi cartridges" refer to pre-packed polypropylene columns containing unbonded activated silica with irregular particles having an average size of 50 μm and a nominal porosity), and a solvent or solvent combination (heptane, EtOAc, DCM, MeOH, MeCN, water, etc.) to elute the desired compound; RP-HPLC purification was performed on a Waters mass-guided FractionLynx system (2767 autosampler, System Fluidics Organiser, 2998 photodiode array, 2545 pumps, 3x515 pumps, QDa mass spectrometer), a Gilson system (GX281 autosampler, 322 pumps, 155 UV / Vis detector), an Interchim PuriFlash 4125 coupled to a UV DAD (see Table 2 for some non-limiting conditions); RP-HPLC purification was performed on a Waters Thar Prep100 system (P200 CO2 pump, 2545 regulator pump, 2998 UV / Vis detector, 2767 liquid handler with stacked injection module) or a Waters SFC purification was performed on a TharInvestigator semi-preparative system (Waters fluid delivery module, 2998 UV / Vis detector, Waters fraction collection module) (see Table 2 for some non-limiting conditions); recrystallization from an appropriate solvent (MeOH, EtOH, i-PrOH, EtOAc, toluene, etc.) or solvent combination (EtOAc / heptane, EtOAc / MeOH, etc.); precipitation from a solvent combination (DMF / water, DMSO / DCM, EtOAc / heptane, etc.); trituration with an appropriate solvent (EtOAc, DCM, MeCN, MeOH, EtOH, i-PrOH, n-PrOH, etc.); by dissolving the compound in a liquid and rinsing with an appropriate immiscible liquid (DCM / water, EtOAc / water, DCM / saturated NaHCO3, EtOAc / saturated NaHCO3, DCM / 10% aqueous HCl, EtOAc / 10% HCl aqueous solution, etc.); and / or distillation (simple distillation, fractional distillation, Kugelrohr, etc.).Descriptions of these techniques can be found in the following references: Gordon, AJ and Ford, RA "The Chemist's Companion", 1972; Palleros, DR "Experimental Organic Chemistry", 2000; Still, WC, Kahn and M. Mitra, AJ Org. Chem. 1978, 43(14), 2923-2925; Yan, B. "Analysis and Purification Methods in Combinatorial Chemistry" 2003; Harwood, LM, Moody, CJ and Percy, JM "Experimental Organic Chemistry: Standard and Microscale, 2nd Edition", 1999.

[0152] Table 2. RP-HPLC and SFC purification methods

[0153]

[0154]

[0155] Preparation and Examples

[0156] All starting materials are commercially available from Sigma-Aldrich (including Fluka and Discovery CPR) or Acros, unless otherwise indicated after the chemical name. The reagent / reactant names given are the same as those on commercial bottles or are generated by IUPAC conventions or ChemDraw 16.0. The specific conditions and reagents indicated herein should not be construed as limiting the scope of the invention and are provided for illustrative purposes only.

[0157] abbreviation

[0158] ℃ degrees Celsius

[0159] CAS Chemical Abstracts Service CDCl₃ deuterated chloroform CDI 1,1′-Carbonyldiimidazole CF₃ COOH trifluoroacetic acid DAD diode array detector DCM dichloromethane DEA diethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d₆ deuterated dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol h hour HBTU N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HCl hydrochloride HCOOH formic acid i-PrOH isopropanol IMS industrial methanolic alcohol LC / MS liquid chromatography / mass spectrometry m / z mass-to-charge ratio MeCN acetonitrile MeOD deuterated methanol MeOH methanol MgSO₄ magnesium sulfate MHz megahertz min minute MS mass spectrometer Na₂SO₄ sodium sulfate NaHCO₃ sodium bicarbonate NH₄CO₃ ammonium bicarbonate

[0160] NH4OH ammonium hydroxide

[0161] NMR Nuclear Magnetic Resonance

[0162] PDA Photodiode Array

[0163] RP-HPLC reverse phase-high performance liquid chromatography

[0164] R t Retention time

[0165] RT Room temperature

[0166] SFC Supercritical Fluid Chromatography

[0167] tBuBrettPhos Pd G3 methanesulfonic acid [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II)

[0168] THF Tetrahydrofuran

[0169] UPLC ultra-performance liquid chromatography

[0170] UV / VIS ultraviolet / visible light

[0171] The synthesis of compounds 1-88 can be accomplished as follows. The synthesis of compounds 89-250 can be accomplished in a similar manner by modifying the starting reagents.

[0172] Compound 1

[0173] 1-((2-(Benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea

[0174] The reaction vessel was charged with (2-(benzyloxy)pyridin-4-yl)methanamine (CAS:869293-84-5, 75 mg, 0.35 mmol), CDI (60 mg, 0.37 mmol) and solvated in DCM (2.5 mL). N,N-diisopropylethylamine (0.12 mL, 0.70 mmol) was added and the reactants were stirred at room temperature under a nitrogen atmosphere for 30 min. 3-Fluoroaniline (CAS:372-19-0, 0.040 mL, 0.42 mmol) was added and the reactants were stirred at room temperature under a nitrogen atmosphere for 21.5 h. The reactants were then heated to 45 ° C and stirred at 45 ° C for 24 h. The reaction mixture was then partitioned between DCM and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The title compound was purified by reverse phase HPLC (Table 2, Method 1) to provide an off-white solid (57 mg, 46%).

[0175] 1 H NMR (400MHz, DMSO-d6) δ8.96 (s, 1H), 8.11 (dd, J = 0.48Hz, 5.24Hz, 1H), 7.47-7.25 (m, 7H), 7.08- 7.09(m,1H),6.94-6.93(m,1H),6.82(m,1H),6.76(m,2H),5.36(s,2H),4.31(d,J=6.16Hz,2H).

[0176] LC / MS (Table 1, Method A) Rt=5.07 min; MS m / z: 352 [M+H] + .

[0177] Compound 2

[0178] 1-((2-(Benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorobenzyl)urea

[0179] Starting from the appropriate commercially available starting materials (2-(benzyloxy)pyridin-4-yl)methanamine (CAS: 869293-84-5) and 3-fluorobenzylamine (CAS: 100-82-3), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 2) followed by reverse phase HPLC (Table 2, Method 1) to provide an off-white solid (60 mg, 47%).

[0180] 1H NMR(400MHz,DMSO-d6)δ8.08(dd,J=0.52Hz,5.20Hz,1H),7.47-7.30(m,6H),7.13-7.01(m,3H)6 .88(dd,J=1.32Hz,5.20Hz,1H)6.71(s,1H),6.69-6.61(m,2H),5.35(s,2H),4.28-4.21(m,4H).

[0181] LC / MS (Table 1, Method A) R t =4.79 min; MS m / z: 366 [M+H] + .

[0182] Compound 3

[0183] 1-((2-(Benzyloxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0184] Starting from the appropriate commercially available starting materials (2-(benzyloxy)pyridin-4-yl)methanamine (CAS: 869293-84-5) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 3) to afford an off-white solid (62 mg, 45%).

[0185] 1 H NMR(400MHz, DMSO-d6)δ8.08(d,J=5.6Hz,1H),7.46-7.32(m,5H),6.87(dd,J=1.4,5.3Hz,1H),6.69(s,1H),6.52(t,J=6.1Hz,1H),6.08(t ,J=5.8Hz,1H),5.35-5.34(m,2H),4.19(d,J=6.1Hz,2H),3.12(dd,J=6.1,15.2Hz,2H),1.71-1.66(m,2H),0.92-0.88(m,2H),0.76(s,2H).

[0186] LC / MS (Table 1, Method A) R t =5.21min; MS m / z:394[M+H] + .

[0187] Compound 4

[0188] (S)-1-((2-(Benzyloxy)pyridin-4-yl)methyl)-3-(2-hydroxy-3,3-dimethylbutyl)urea

[0189] Starting from the appropriate commercially available starting materials (2-(benzyloxy)pyridin-4-yl)methanamine (CAS: 869293-84-5) and (S)-1-amino-3,3-dimethylbutan-2-ol hydrochloride (CAS: 2460615-95-4), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 3) to afford an off-white solid (53 mg, 42%).

[0190] 1 H NMR (400MHz, DMSO-d6) δ8.08(d,J=5.3Hz,1H),7.46-7.32(m,6H),6.88(dd,J=1.3,5.3Hz,1H),6.72-6.62(m,2H),5.98(dd,J=3.6 ,7.3Hz,1H),5.35(s,2H),4.74(d,J=5.6Hz,1H),4.21(d,J=6.1Hz,2H),3.10-3.04(m,1H),2.75-2.67(m,1H),0.86-0.85(m,9H).

[0191] LC / MS (Table 1, Method A) R t =4.59 min; MS m / z: 358 [M+H] + .

[0192] Compound 5

[0193] (±)-1-((2-(Benzyloxy)pyridin-4-yl)methyl)-3-(2-hydroxy-2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0194] Starting from the appropriate commercially available starting materials (2-(benzyloxy)pyridin-4-yl)methanamine (CAS: 869293-84-5) and (±)-2-amino-1-(1-(trifluoromethyl)cyclopropyl)ethane-1-ol hydrochloride (prepared according to WO2020163268 Preparation 3), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 3) to afford an off-white oil (58 mg, 41%).

[0195] 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 5.3 Hz, 1H), 7.46-7.32 (m, 5H), 6.88 (dd, J = 1.1, 5.3 Hz, 1H), 6.71-6.58 (m, 2H), 6.14 (dd, J = 4.4, 7.2 Hz, 1H), 5.38-5.34 (m, 3H), 4.21 (dd, J = 2.9, 5.8 Hz, 2H), 3.60-3.30 (m, 2H, two protons were partially obscured by the solvent peak), 2.95-2.87 (m, 1H), 0.87-0.84 (m, 4H).

[0196] LC / MS (Table 1, Method A) R t =4.74min; MS m / z:410[M+H] + .

[0197] Compound 6

[0198] 1-Methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0199] (i) tert-Butyl (2-(1-(trifluoromethyl)cyclopropyl)ethyl)carbamate

[0200] 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS:1454690-80-2,50mg,0.264mmol) was added to the reaction vessel and solvated in THF (0.80mL) and distilled water (0.80mL). Potassium carbonate (182mg,1.32mmol) and di-tert-butyl dicarbonate (0.12mL,0.527mmol) were added and the reactants were stirred at room temperature for 2h. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (63mg, 94%).

[0201] 1 H NMR (300MHz, CDCl3) δ4.66 (s, 1H), 3.25 (q, J = 7.1Hz, 2H), 1.75 (t, J = 7.6Hz, 2H), 1.44 (s, 9H), 1.00-0.94 (m, 2H), 0.63 (s, 2H).

[0202] (ii) tert-Butyl methyl (2-(1-(trifluoromethyl)cyclopropyl)ethyl)carbamate

[0203] To a solution of tert-butyl (2-(1-(trifluoromethyl)cyclopropyl)ethyl)carbamate ((compound 6, step (i), 63 mg, 0.249 mmol)) in anhydrous THF (1.0 mL) was added sodium hydride (60%, 10 mg, 0.249 mmol) at 0°C under a nitrogen atmosphere. The reactants were stirred at 0°C for 30 min. Iodomethane (0.017 mL, 0.274 mmol) was added and the reactants were stirred at 0°C for 1 h. The reactants were allowed to warm to room temperature and stirred at room temperature for 2 h. The reactants were then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4) and concentrated in vacuo to provide the title compound (50 mg, 75%).

[0204] 1 H NMR (300MHz, CDCl3) δ3.36-3.28(m,2H),2.85(s,3H),1.80-1.69(m,2H),1.45(s,9H),0.97(s,2H),0.69-0.56(m,2H).

[0205] (iii) N-methyl-2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride

[0206] To a solution of tert-butyl methyl(2-(1-(trifluoromethyl)cyclopropyl)ethyl)carbamate ((Compound 6, Step (ii), 282 mg, 1.06 mmol)) in DCM (4.0 mL) was added 4M HCl in 1,4-dioxane (4.0 mL, 15.8 mmol) at 0°C. The reaction was allowed to warm to room temperature and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to provide the title compound (210 mg, 98%).

[0207] 1 H NMR (300MHz, MeOD) δ3.19-3.12(m,2H),2.71(s,3H),1.96-1.90(m,2H),1.09-1.03(m,2H),0.83-0.76(m,2H).

[0208] (iv) 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0209] The title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea starting from appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine dihydrochloride (CAS: 2460508-43-2) and N-methyl-2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride ((compound 6, step (iii)). The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (31 mg, 27%).

[0210] 1 H NMR (400MHz, DMSO-d6) δ8.09(dd,J=0.6,5.3Hz,1H),6.97(dd,J=1.3,5.3Hz,1H),6.93(t,J=5.8Hz,1H),6.76(dd,J=0.6,1.3Hz,1H),4 .97(q,J=9.2Hz,2H),4.22(d,J=5.9Hz,2H),3.31-3.28(m,2H),2.83(s,3H),1.74-1.68(m,2H),0.92-0.87(m,2H),0.79-0.74(m,2H).

[0211] LC / MS (Table 1, Method B) R t =4.71 min; MS m / z:400 [M+H] + .

[0212] Compound 7

[0213] 1-Methyl-1-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0214] (i) tert-Butyl ((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)carbamate

[0215] The title compound was prepared starting from the appropriate commercially available starting material, (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine dihydrochloride (CAS: 2460508-43-2) using a reaction scheme similar to that described for compound 6: 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (i). The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (184 mg, 87%).

[0216] LC / MS (Table 1, Method C) R t =1.72min; MS m / z:307[M+H] + .

[0217] (ii) tert-Butyl methyl((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)carbamate

[0218] The title compound was prepared from the appropriate starting material, tert-butyl ((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)carbamate (compound 7, step (i)), using a reaction scheme similar to that described for compound 6: 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (ii). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound (358 mg, 89%).

[0219] LC / MS (Table 1, Method C) R t =1.89 min; MS m / z: 321 [M+H] + .

[0220] (iii) N-methyl-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine dihydrochloride

[0221] The title compound was prepared from the appropriate starting material tert-butyl methyl((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)carbamate (compound 7, step (ii)) using a reaction scheme analogous to that described for compound 6: 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iii). This afforded the title compound (305 mg, 93%).

[0222] LC / MS (Table 1, Method D) R t =1.19 min; MS m / z: 221 [M+H] + .

[0223] (iv) 1-methyl-1-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0224] Starting from appropriate commercially available starting materials N-methyl-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine dihydrochloride (compound 7, step (iii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 1, non-linear gradient from 20% to 80% MeOH) to afford an off-white solid (17 mg, 15%).

[0225] 1 H NMR (400MHz, DMSO-d6) δ8.14(d,J=5.2Hz,1H),6.92(dd,J=1.3,5.3Hz,1H),6.70(s,1H),6.55(t,J=5.7Hz,1H),4.99(q ,J=9.2Hz,2H),4.44(s,2H),3.20-3.13(m,2H),2.80(s,3H),1.76-1.70(m,2H),0.93-0.89(m,2H),0.76-0.73(m,2H).

[0226] LC / MS (Table 1, Method E) R t =4.83min; MS m / z:400[M+H] + .

[0227] Compound 8

[0228] 1-((4-(Benzyloxy)pyrimidin-2-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0229] (i) tert-Butyl (tert-butoxycarbonyl)((4-chloropyrimidin-2-yl)methyl)carbamate

[0230] At 0 ° C, sodium hydride (60%, 217 mg, 5.42 mmol) was added to a suspension of di-tert-butyl iminodicarboxylate (1.13 g, 5.18 mmol) and sodium iodide (1.48 g, 9.89 mmol) in THF (10.0 mL) under a nitrogen atmosphere. The reactants were stirred at 0 ° C for 30 min. After this, 4-chloro-2-(chloromethyl)pyrimidine (CAS: 3842-28-2, 768 mg, 4.71 mmol) in THF (10.0 mL) was added dropwise. The reactants were allowed to warm to room temperature and stirred at room temperature for 16 h. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (177 mg, 74%).

[0231] LC / MS (Table 1, Method C) R t =1.85min; MS m / z:366[M+H] + .

[0232] (ii) tert-Butyl ((4-(benzyloxy)pyrimidin-2-yl)methyl)carbamate

[0233] To a suspension of sodium hydride (60%, 25 mg, 0.618 mmol) in THF (1.0 mL) was added benzyl alcohol (CAS: 100-51-6, 0.064 mL, 0.618 mmol) at 0°C under a nitrogen atmosphere, and the reaction was stirred at 0°C for 30 min. This was followed by dropwise addition of tert-butyl (tert-butoxycarbonyl)((4-chloropyrimidin-2-yl)methyl)carbamate (Example 8, step (i), 177 mg, 0.515 mmol) in THF (1.0 mL), and the reaction was stirred at 0°C for 15 min. The reaction was allowed to warm to room temperature and then partitioned between distilled water and EtOAc. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (76 mg, 47%).

[0234] LC / MS (Table 1, Method C) R t =1.70min; MS m / z:316[M+H] + .

[0235] (iii) (4-(Benzyloxy)pyrimidin-2-yl)methanamine hydrochloride

[0236] The title compound was prepared from the appropriate starting material, tert-butyl ((4-(benzyloxy)pyrimidin-2-yl)methyl)carbamate (compound 8, step (ii)), using a reaction scheme analogous to that described for compound 6: 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iii). This afforded the title compound (61 mg, quantitative).

[0237] 1 H NMR (400MHz, MeOD) δ 8.54 (d, J = 6.0 Hz, 1H), 7.48-7.44 (m, 2H), 7.41-7.32 (m, 3H), 6.93 (d, J = 6.0 Hz, 1H), 5.52 (s, 2H), 4.31 (s, 2H).

[0238] (iv) 1-((4-(Benzyloxy)pyrimidin-2-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0239] Starting from the appropriate commercially available starting materials (4-(benzyloxy)pyrimidin-2-yl)methanamine hydrochloride (compound 8, step (iii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (25 mg, 45%).

[0240] 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=5.8Hz,1H),7.50-7.46(m,2H),7.42-7.32(m,3H),6.83(d,J=5.8Hz,1H),6.38(t,J=5.9Hz,1H),6. 30(t,J=5.6Hz,1H),5.43(s,2H),4.31(d,J=5.8Hz,2H),3.16-3.08(m,2H),1.69-1.65(m,2H),0.90-0.86(m,2H),0.76-0.71(m,2H).

[0241] LC / MS (Table 1, Method F) R t =4.30min; MS m / z:395[M+H] + .

[0242] Compound 9

[0243] 1,3-Dimethyl-1-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0244] The title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea starting from appropriate commercially available starting materials, N-methyl-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine dihydrochloride ((compound 7, step (iii)) and N-methyl-2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride ((compound 6, step (iii)). The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (47 mg, 80%).

[0245] 1 H NMR (400MHz, DMSO-d6) δ8.14(dd,J=0.6,5.2Hz,1H),6.99(dd,J=1.4,5.2Hz,1H),6.81(dd,J=0.7,1.3Hz,1H),4.98(q,J=9.1 Hz,2H),4.29(s,2H),3.23-3.18(m,2H),2.76(s,3H),2.70(s,3H),1.81-1.75(m,2H),0.92-0.88(m,2H),0.77-0.71(m,2H).

[0246] LC / MS (Table 1, Method F) R t =5.25min; MS m / z:414[M+H] + .

[0247] Compound 10

[0248] 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0249] (i) 2-((1-methylpiperidin-4-yl)methoxy)isonicotinonitrile

[0250] At 0 ° C, under a nitrogen atmosphere, 4-(hydroxymethyl)-1-methylpiperidine (CAS: 20691-89-8, 0.29 mL, 2.17 mmol) was added to a suspension of sodium hydride (60%, 95 mg, 2.38 mmol) in THF (15.0 mL). This was followed by dropwise addition of 2-chloro-4-pyridinecarbonitrile (CAS: 33252-30-1, 300 mg, 2.17 mmol) in THF (5.0 mL). The reactants were allowed to warm to room temperature and stirred at room temperature for 72 h. The reactants were then heated to 60 ° C and stirred at 60 ° C for 2 h. The reaction mixture was cooled to room temperature, quenched by adding distilled water, and then partitioned with EtOAc. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeOH, gradient elution) to provide the title compound (201 mg, 40%).

[0251] LC / MS (Table 1, Method D) Rt=1.24 min; MS m / z: 232 [M+H] + .

[0252] (ii) (2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methanamine

[0253] At 0 ° C, under a nitrogen atmosphere, 2-((1-methylpiperidin-4-yl)methoxy)isonicotinonitrile (280 mg, 1.21 mmol) was added dropwise to a solution of 2M lithium aluminum hydride (0.61 mL, 1.21 mmol) in THF (8.0 mL). The reaction was stirred at 0 ° C for 2 hours. The reaction mixture was quenched by adding distilled water, 2M sodium hydroxide and additional distilled water. The reaction was stirred for 10 minutes and allowed to warm to room temperature. MgSO4 was added. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (DCM to DCM:MeOH[2M NH3]90:10, gradient elution) to provide the title compound (100 mg, 35%).

[0254] LC / MS (Table 1, Method D) Rt=0.93 min; MS m / z: 236 [M+H] + .

[0255] (iii) 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0256] Starting from appropriate commercially available starting materials (2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methanamine (Compound 10, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for Compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 1, non-linear gradient from 20% to 80% MeOH) to afford an off-white solid (34 mg, 39%).

[0257] 1 H NMR (400MHz, DMSO-d6) δ8.04(d,J=5.3Hz,1H),6.82(dd,J=1.4,5.3Hz,1H),6.61(s ,1H),6.50(t,J=6.1Hz,1H),6.08(t,J=5.8Hz,1H),4.17(d,J=6.1Hz,2H),4.09(d, J=6.1Hz,2H),3.16-3.09(m,2H),2.77(d,J=11.3Hz,2H),2.15(s,3H),1.88-1.80( m,2H),1.73-1.65(m,5H),1.33-1.22(m,2H),0.92-0.88(m,2H),0.77-0.74(m,2H).

[0258] LC / MS (Table 1, Method A) R t =2.70 min; MS m / z:415 [M+H] + .

[0259] Compound 11

[0260] 1-((6-(Benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) 6-(Benzyloxy)pyrimidine-4-carbonitrile

[0261] The title compound was prepared starting from the appropriate commercially available starting materials, 6-chloropyrimidine-4-carbonitrile (CAS: 939986-65-9) and benzyl alcohol (CAS: 100-51-6) using a reaction scheme similar to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (i). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (200 mg, 21%).

[0262] LC / MS (Table 1, Method C) R t =1.66min; MS m / z: 212 [M+H] + .

[0263] (ii) (6-(Benzyloxy)pyrimidin-4-yl)methanamine

[0264] 6-(benzyloxy)pyrimidine-4-carbonitrile (145mg, 0.686mmol) was added to the reaction vessel and solvated in EtOAc (4.3mL). Acetic acid (0.74mL) and 10% palladium on carbon (37mg, 0.0343mmol) were added under a nitrogen atmosphere. Next, the reactant was evacuated and placed under a hydrogen atmosphere. The reactant was stirred at room temperature for 45min under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth under a nitrogen atmosphere and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by SCX-2 column chromatography (DCM to DCM:MeOH[2M NH3]90:10, gradient elution) to provide the title compound (105mg, 71%).

[0265] LC / MS (Table 1, Method C) R t =1.60min; MS m / z: 216 [M+H] + .

[0266] (iii) 1-((6-(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0267] Starting from the appropriate starting materials (6-(benzyloxy)pyrimidin-4-yl)methanamine (compound 11, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 1) followed by reverse phase HPLC (Table 2, Method 3) to provide an off-white solid (150 mg, 82%).

[0268] 1H NMR (400MHz, DMSO-d6) δ8.72(d,J=1.0Hz,1H),7.48-7.35(m,5H),6.74(d,J=1.0Hz,1H),6.56(t,J=6.0Hz,1H),6.20(t,J= 5.8Hz,1H),5.43(s,2H),4.22(d,J=5.9Hz,2H),3.16-3.09(m,2H),1.68(t,J=7.8Hz,2H),0.92-0.87(m,2H),0.76(s,2H).

[0269] LC / MS (Table 1, Method A) R t =4.93min; MS m / z:395[M+H] + .

[0270] Compound 12

[0271] 1-((2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0272] The title compound was prepared starting from appropriate starting materials (2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methanamine was also prepared starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 1, non-linear gradient from 20% to 80% MeOH) to afford an off-white solid (45 mg, 47%).

[0273] 1H NMR(400MHz,DMSO-d6)δ8.05(d,J=5.3Hz,1H),6.83(dd,J=1.3,5.2Hz,1H),6.62(s,1H ),6.51(t,J=6.1Hz,1H),6.08(t,J=5.8Hz,1H),4.14(dd,J=6.3,27.7Hz,4H),3.87(dd , J = 2.6, 11.3 Hz, 2H), 3.36-3.30 (m, 2H, two protons were partially obscured by the solvent peak), 3.16-3.08 (m, 2H), 2.06-1.94 (m, 1H), 1.72-1.61 (m, 4H), 1.37-1.25 (m, 2H), 0.92-0.88 (m, 2H), 0.77-0.73 (m, 2H).

[0274] LC / MS (Table 1, Method A) R t =3.84 min; MS m / z: 402 [M+H] + .

[0275] Compound 13

[0276] 1-((2-(oxazol-2-ylmethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0277] The title compound was prepared using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea starting from appropriate commercially available starting materials: (2-(oxazol-2-ylmethoxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2). (2-(oxazol-2-ylmethoxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials according to a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 3) to afford an off-white solid (16 mg, 21%).

[0278] 1H NMR (400MHz, DMSO-d6) δ8.13-8.06(m,2H),7.24(d,J=0.9Hz,1H),6.91(dd,J=1.4,5.3Hz,1H),6.71(s,1H),6.56-6.51(m,1H),6.10(t,J= 5.8Hz,1H),5.44-5.44(m,2H),4.21-4.18(m,2H),3.12(dd,J=6.1,15.2Hz,2H),1.71-1.66(m,2H),0.92-0.88(m,2H),0.77-0.73(m,2H).

[0279] LC / MS (Table 1, Method A) R t =3.86 min; MS m / z: 385 [M+H] + .

[0280] Compound 14

[0281] 1-((2-((4-fluorobenzyl)oxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0282] The title compound was prepared starting from appropriate starting materials (2-((4-fluorobenzyl)oxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-((4-fluorobenzyl)oxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 3) to afford an off-white solid (40 mg, 49%).

[0283] 1H NMR (400MHz, DMSO-d6) δ8.08(d,J=5.5Hz,1H),7.52-7.47(m,2H),7.23-7.18(m,2H),6.87(dd,J=1.4,5.3Hz,1H),6.68(s,1H),6.51(t,J=6.1H z,1H),6.08(t,J=5.8Hz,1H),5.33-5.32(m,2H),4.18(d,J=6.1Hz,2H) ,3.16-3.08(m,2H),1.71-1.65(m,2H),0.92-0.88(m,2H),0.75(s,2H).

[0284] LC / MS (Table 1, Method A) R t =4.88min; MS m / z:412[M+H] + .

[0285] Compound 15

[0286] 1-((2-((3,3-difluorocyclobutyl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0287] Starting from the appropriate commercially available starting materials 2-((3,3-difluorocyclobutyl)methoxy)pyridin-4-yl)methanamine (CAS: 2098043-37-7) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 1) to afford an off-white solid (67 mg, 63%).

[0288] 1 H NMR (400MHz, DMSO-d6) δ8.06(d,J=5.3Hz,1H),6.85(dd,J=1.4,5.3Hz,1H),6.64(s,1H),6.51(t,J=6.1Hz,1H),6.08(t,J=5.9Hz,1H),4.31(d,J=6.5Hz, 2H),4.18(d,J=6.1Hz,2H),3.12(dd,J=6.0,15.3Hz,2H),2.77-2.65(m,3H), 2.49-2.38(m,2H),1.71-1.66(m,2H),0.92-0.88(m,2H),0.77-0.74(m,2H).

[0289] LC / MS (Table 1, Method A) R t =4.61min; MS m / z:408[M+H] + .

[0290] Compound 16

[0291] 1-((2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0292] (i) 2-((2,2,2-trifluoroethyl)amino)isonicotinonitrile

[0293] The reaction vessel was charged with 2,2,2-trifluoroethylamine (CAS: 753-90-2, 0.39 mL, 4.91 mmol) and 4-cyano-2-fluoropyridine (CAS: 3939-14-8, 600 mg, 4.91 mmol), and the reaction was then heated at 160° C. for 12 h under microwave irradiation. The reaction was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash column chromatography (DCM to DCM:MeOH [2M NH 3 ] 90:10, gradient elution) to provide the title compound (473 mg, 48%).

[0294] LC / MS (Table 1, Method D) R t =1.23min; MS m / z: 202 [M+H] + .

[0295] (ii) 4-(Aminomethyl)-N-(2,2,2-trifluoroethyl)pyridin-2-amine

[0296] The title compound was prepared from the appropriate starting material, 2-((2,2,2-trifluoroethyl)amino)isonicotinonitrile (compound 16, step (i)) using a reaction scheme similar to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (ii). The compound was purified by flash column chromatography (DCM to DCM:MeOH [2M NH 3 ] 90:10, gradient elution) to afford the title compound (107 mg, 22%).

[0297] LC / MS (Table 1, Method D) R t =0.87 min; MS m / z: 206 [M+H] + .

[0298] (iii) 1-((2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0299] Starting from appropriate starting materials 4-(aminomethyl)-N-(2,2,2-trifluoroethyl)pyridin-2-amine (compound 16, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 1) to afford an off-white solid (44 mg, 45%).

[0300] 1 H NMR(400MHz, DMSO-d6)δ7.93(d,J=5.1Hz,1H),7.12(t,J=6.7Hz,1H),6.49-6.41(m,3H),6.03(t,J=5.8Hz,1H) ,4.18-4.06(m,4H),3.13(dd,J=6.1,15.5Hz,2H),1.71-1.66(m,2H),0.93-0.89(m,2H),0.76(t,J=6.0Hz,2H).

[0301] LC / MS (Table 1, Method A) R t =3.03 min; MS m / z: 385 [M+H] + .

[0302] Compound 17

[0303] 1-((2-(2-fluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0304] The title compound was prepared starting from appropriate starting materials (2-(2-fluoroethoxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-(2-Fluoroethoxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme similar to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (97 mg, 76%).

[0305] 1 H NMR (400MHz, DMSO-d6) δ8.05(dd,J=0.6,5.3Hz,1H),6.86(dd,J=1.4,5.3Hz,1H),6.66(dd,J=0.7,1.4Hz,1H),6.52(t,J=5.9Hz,1H),6.09(t,J=5. 6Hz,1H),4.80-4.65(m,2H),4.53-4.43(m,2H),4.17(d,J=6.3Hz,2H),3. 15-3.08(m,2H),1.70-1.65(m,2H),0.91-0.87(m,2H),0.77-0.71(m,2H).

[0306] LC / MS (Table 1, Method F) R t =3.78 min; MS m / z: 350 [M+H] + .

[0307] Compound 18

[0308] 1-((2-(2,2-difluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0309] Starting from the appropriate commercially available starting materials (2-(2,2-difluoroethoxy)pyridin-4-yl)methanamine (CAS: 1432680-35-7) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (112 mg, 87%).

[0310] 1 H NMR(400MHz,DMSO-d6)δ8.07(dd,J=0.5,5.3Hz,1H),6.91(dd,J=1.3,5.2Hz,1 H),6.70(dd,J=0.7,1.3Hz,1H),6.54(t,J=6.0Hz,1H),6.36(tt,J=3.6,54.8Hz ,1H),6.10(t,J=5.9Hz,1H),4.54(dt,J=3.7,15.1Hz,2H),4.18(d,J=6.6Hz,2H ),3.15-3.07(m,2H),1.70-1.64(m,2H),0.92-0.87(m,2H),0.77-0.71(m,2H).

[0311] LC / MS (Table 1, Method F) R t =4.16 min; MS m / z: 368 [M+H] + .

[0312] Compound 19

[0313] 1-((2-((2-fluorobenzyl)oxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0314] The title compound was prepared starting from appropriate starting materials (2-((2-fluorobenzyl)oxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-((2-fluorobenzyl)oxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 1) to afford an off-white solid (71 mg, 67%).

[0315] 1 H NMR(400MHz,DMSO-d6)δ8.10-8.08(m,1H),7.56-7.51(m,1H),7.45-7.38(m, 1H),7.27-7.20(m,2H),6.88(dd,J=1.4,5.3Hz,1H),6.69(s,1H),6.51(t,J= 6.1Hz,1H),6.08(t,J=5.8Hz,1H),5.39(s,2H),4.20-4.17(m,2H),3.12(dd, J=6.1,15.2Hz,2H),1.71-1.65(m,2H),0.92-0.87(m,2H),0.77-0.74(m,2H).

[0316] LC / MS (Table 1, Method A) R t =4.93min; MS m / z:412[M+H] + .

[0317] Compound 20

[0318] 1-((2-(2,2-difluoropropoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0319] The title compound was prepared starting from appropriate starting materials (2-(2,2-difluoropropoxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-(2,2-difluoropropoxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 3) followed by reverse phase HPLC (Table 2, Method 4) to afford an off-white solid (60 mg, 44%).

[0320] 1 H NMR (400MHz, DMSO-d6) δ8.08(dd,J=0.6,5.2Hz,1H),6.92(dd,J=1.3,5.3Hz,1H),6.73(dd,J=0.7,1.3Hz,1H),6.53(t,J=6.0Hz,1H),6.10(t,J=5.4Hz, 1H),4.55(t,J=13.2Hz,2H),4.20(d,J=5.9Hz,2H),3.16-3.09(m,2H),1.73 (t,J=19.2Hz,3H),1.72-1.66(m,2H),0.92-0.89(m,2H),0.78-0.73(m,2H).

[0321] LC / MS (Table 1, Method A) R t =4.57min; MS m / z:382[M+H] + .

[0322] Compound 21

[0323] 1-(3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0324] (i) (E)-3-Chloro-7,8-dihydroisoquinolin-5(6H)-one oxime

[0325] Under a nitrogen atmosphere, to a solution of 3-chloro-5,6,7,8-tetrahydroisoquinoline (CAS: 875249-27-7, 900 mg, 5.37 mmol) in THF (3.0 mL) was added a 1 M solution of potassium tert-butoxide in THF (11.0 mL, 10.7 mmol). The reaction was stirred at room temperature for 18 h. The reaction was cooled to 0 ° C and tert-butyl nitrite (2.1 mL, 17.2 mmol) was added. The reaction was allowed to warm to room temperature and stirred at room temperature for 5.5 h. The reaction mixture was poured onto a saturated brine solution for quenching and then partitioned with EtOAc. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was triturated with DCM to provide the title compound (980 mg, 90%).

[0326] LC / MS (Table 1, Method D) R t =1.09 min; MS m / z:197 [M+H] + .

[0327] (ii) 3-Chloro-5,6,7,8-tetrahydroisoquinolin-5-amine

[0328] (E)-3-chloro-7,8-dihydroisoquinolin-5(6H)-one oxime ((Compound 21, step (i), 200 mg, 1.02 mmol)) was added to the reaction vessel and solvated in acetic acid (8.0 mL). Zinc (333 mg, 5.09 mmol) was added and the reaction was stirred at room temperature for 1 hour. Additional zinc (333 mg, 5.09 mmol) was added and the reaction was stirred at room temperature for 45 minutes (1.45 hours in total). The reaction mixture was filtered through celite and washed with EtOH. The filtrate was concentrated in vacuo and then partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to provide the title compound (124 mg, 64%).

[0329] LC / MS (Table 1, Method D) R t =0.92 min; MS m / z: 183 [M+H] + .

[0330] (iii) 1-(3-chloro-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0331] The title compound was prepared from the appropriate starting materials 3-chloro-5,6,7,8-tetrahydroisoquinolin-5-amine (compound 21, step ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (155 mg, 60%).

[0332] LC / MS (Table 1, Method D) R t =1.35min; MS m / z:362[M+H] + .

[0333] (iv) 1-(3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0334] Under nitrogen atmosphere, 1-(3-chloro-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea ((Compound 21, Step (iii), 53 mg, 0.133 mmol), tBuBrettPhos PdG3 (11 mg, 0.0133 mmol), sodium tert-butoxide (64 mg, 0.667 mmol) and solvated in 2,2,2-trifluoroethanol (0.078 mL, 1.07 mmol) and 1,4-dioxane (0.50 mL). The reaction was set to stir at room temperature and then heated to 60 ° C. The reaction was stirred at 60 ° C for 3 h. The reaction was cooled to room temperature. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) followed by reverse phase HPLC (Table 2, method 3) to provide the title compound (53 mg, 93%) as an off-white solid.

[0335] 1H NMR (400MHz, DMSO-d6) δ7.96(s,1H),6.72(s,1H),6.45-6.41(m,1H),5.91(t,J=5.8Hz,1H),5.03-4.88(m,2H),4.76-4.68(m,1H),3.17(dd ,J=6.3,14.8Hz,2H),2.71-2.65(m,2H),1.98-1.82(m,2H),1.75-1.69(m,3H),1.62-1.52(m,1H),0.94-0.89(m,2H),0.78(t,J=5.6Hz,2H).

[0336] LC / MS (Table 1, Method E) R t =4.96 min; MS m / z:426 [M+H] + .

[0337] Compound 22

[0338] 1-((2-((1-fluorocyclopropyl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0339] The title compound was prepared from the appropriate starting materials (2-((1-fluorocyclopropyl)methoxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-((1-fluorocyclopropyl)methoxy)pyridin-4-yl)methanamine was prepared accordingly from the appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 2) to afford an off-white solid (60 mg, 39%).

[0340] 1H NMR (400MHz, DMSO-d6) δ8.05(d,J=5.3Hz,1H),6.87(dd,J=1.3,5.3Hz,1H),6.70(s,1H),6.52(t,J=6.1Hz,1H),6.09(t,J=5.8Hz,1H),4.59( s,1H),4.53(s,1H),4.21-4.17(m,2H),3.13(dd,J=6.1,15.3Hz,2H),1.72-1.67(m,2H),1.22-1.06(m,2H),0.93-0.84(m,4H),0.76(s,2H).

[0341] LC / MS (Table 1, Method A) R t =4.44min; MS m / z:376[M+H] + .

[0342] Compound 23

[0343] 1-((2-(pyridin-2-ylmethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0344] The title compound was prepared from the appropriate starting materials (2-(pyridin-2-ylmethoxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-(pyridin-2-ylmethoxy)pyridin-4-yl)methanamine was prepared accordingly from the appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 3) to afford an off-white solid (61 mg, 41%).

[0345] 1H NMR(400MHz,DMSO-d6)δ8.57-8.55(m,1H),8.07-8.05(m,1H),7.83-7.78(m,1H), 7.44-7.41(m,1H),7.35-7.31(m,1H),6.88(dd,J=1.3,5.2Hz,1H),6.76(s,1H),6. 56-6.51(m,1H),6.10(t,J=5.8Hz,1H),5.43-5.42(m,2H),4.22-4.19(m,2H),3.13 (dd,J=6.1,15.2Hz,2H),1.72-1.67(m,2H),0.92-0.88(m,2H),0.78-0.75(m,2H).

[0346] LC / MS (Table 1, Method A) R t =3.36 min; MS m / z: 395 [M+H] + .

[0347] Compound 24

[0348] 1-((2-((3-fluorooxetan-3-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0349] The title compound was prepared starting from appropriate starting materials (2-((3-fluorooxetan-3-yl)methoxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-((3-fluorooxetan-3-yl)methoxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 3) followed by reverse phase HPLC (Table 2, Method 2, non-linear gradient from 5% to 60% MeCN) to afford an off-white solid (15 mg, 13%).

[0350] 1H NMR (400MHz, DMSO-d6) δ8.09(d,J=5.3Hz,2H),6.90(dd,J=1.4,5.3Hz,2H),6.69(s,2H),6.52(t,J=6.1Hz,2H),6.09(t,J=5.8Hz, 2H), 4.74-4.66 (m, 12H), 4.19 (d, J = 6.0Hz, 4H), 3.13 (dd, J = 6.1, 15.1Hz, 4H), 1.71-1.66 (m, 4H), 0.92-0.88 (m, 4H), 0.76 (s, 4H).

[0351] LC / MS (Table 1, Method A) R t =3.94 min; MS m / z: 392 [M+H] + .

[0352] Compound 25

[0353] 1-((2-((2,4-difluorobenzyl)oxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0354] The title compound was prepared starting from appropriate starting materials (2-((2,4-difluorobenzyl)oxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-((2,4-difluorobenzyl)oxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 1) followed by SFC purification (Table 2, Method 5) to afford an off-white solid (39 mg, 37%).

[0355] 1H NMR(400MHz,DMSO-d6)δ8.09(d,J=5.3Hz,1H),7.64-7.57(m,1H),7.33-7.2 7(m,1H),7.14-7.08(m,1H),6.88(dd,J=1.4,5.3Hz,1H),6.67(s,1H),6.51( t,J=6.1Hz,1H),6.07(t,J=5.8Hz,1H),5.35(s,2H),4.20-4.17(m,2H),3.12 (dd,J=6.1,15.2Hz,2H),1.71-1.65(m,2H),0.92-0.87(m,2H),0.75(s,2H).

[0356] LC / MS (Table 1, Method A) R t =4.92 min; MS m / z:430 [M+H] + .

[0357] Compound 26

[0358] 1-((2-morpholino-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0359] (i) 2-chloro-6-morpholinoisonicotinonitrile

[0360] 2,6-dichloropyridine-4-carbonitrile (CAS: 32710-65-9, 977 mg, 5.65 mmol) was added to the reaction vessel and solvated in EtOH (50 mL). Triethylamine (0.79 mL, 5.65 mmol) and morpholine (0.49 mL, 5.65 mmol) were added under a nitrogen atmosphere. The reactants were set to stir at room temperature and then heated to 70 ° C. The reactants were stirred at 70 ° C for 5.5 h. The reaction mixture was allowed to cool to room temperature and concentrated in a vacuum. The residue was then distributed between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (MgSO 4 ) and concentrated in a vacuum. The residue was purified by flash column chromatography (cyclohexane to THF, gradient elution) to provide the title compound (805 mg, 64%).

[0361] LC / MS (Table 1, Method A) R t =1.58min; MS m / z: 224 [M+H] + .

[0362] (ii) 2-Morpholino-6-(2,2,2-trifluoroethoxy)isonicotinonitrile

[0363] 2-Chloro-6-morpholinonitrile (340 mg, 1.52 mmol), 2,2,2-trifluoroethanol (CAS: 75-89-8, 0.11 mL, 1.52 mmol), cesium carbonate (1.49 g, 4.56 mmol), and XantphosPdG4 (73 mg, 0.0760 mmol) were added to the reaction vessel and solvated in toluene (15.0 mL). The reaction was purged and placed under a nitrogen atmosphere. The reaction was set to stir at room temperature and then heated to 80°C. The reaction was stirred at 80°C for 72 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The reaction was then partitioned between EtOAc and distilled water. The organic layers were separated. The combined organic layers were washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (410 mg, 87%).

[0364] LC / MS (Table 1, Method A) R t =1.74min; MS m / z:288[M+H] + .

[0365] (iii) (2-morpholino-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine

[0366] The title compound was prepared from the appropriate starting material, 2-morpholino-6-(2,2,2-trifluoroethoxy)isonicotinonitrile (compound 26, step (ii)), using a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (ii). This afforded the title compound (465 mg, quantitative).

[0367] LC / MS (Table 1, Method D) R t =1.35min; MS m / z: 292 [MH] + .

[0368] (iv) 1-((2-morpholino-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0369] Starting from appropriate starting materials (2-morpholino-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (compound 26, step (iii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 3) to afford an off-white solid (116 mg, 47%).

[0370] 1 H NMR (400MHz, DMSO-d6) δ6.45(t,J=6.0Hz,1H),6.31(s,1H),6.08(s,1H),6.05-6.01(m,1H),4.92(q,J=9.2Hz,2H),4.11(d,J= 6.0Hz,2H),3.72-3.69(m,4H),3.44-3.39(m,4H),3.16-3.09(m,2H),1.71-1.66(m,2H),0.92-0.88(m,2H),0.78-0.72(m,2H).

[0371] LC / MS (Table 1, Method E) R t =4.77min; MS m / z:471[M+H] + .

[0372] Compound 27

[0373] 1-((2-((4-fluorobenzyl)oxy)-6-morpholinopyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0374] The title compound was prepared starting from appropriate commercially available starting materials (2-((4-fluorobenzyl)oxy)-6-morpholinopyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-((4-fluorobenzyl)oxy)-6-morpholinopyridin-4-yl)methanamine was correspondingly prepared starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 26: 1-((2-morpholino-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-iii). The title compound was purified by reverse phase HPLC (Table 2, Method 2) to afford an off-white solid (27 mg, 29%).

[0375] 1 H NMR (400MHz, DMSO-d6) δ7.49-7.43(m,2H),7.22-7.16(m,2H),6.41(t,J=6.2Hz,1H),6.20(s,1H),6.02-5.98(m,2H),5.27(s,2H),4.0 9(d,J=5.7Hz,2H),3.71-3.67(m,4H),3.42-3.38(m,4H),3.15-3.09(m,2H),1.70-1.65(m,2H),0.92-0.88(m,2H),0.77-0.72(m,2H).

[0376] LC / MS (Table 1, Method A) R t =5.21min; MS m / z:497[M+H] + .

[0377] Compound 28

[0378] (±)-1-((2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0379] (i)(±)-2-(3-fluoropiperidin-1-yl)isonicotinonitrile

[0380] Under a nitrogen atmosphere, 4-cyano-2-fluoropyridine (CAS: 3939-14-8, 675 mg, 5.53 mmol), (±)-3-fluoropiperidine hydrochloride (CAS: 116574-75-5, 842 mg, 6.03 mmol) were added to the reaction vessel and solvated in EtOH (10.0 mL). Triethylamine (1.9 mL, 13.8 mmol) was added. The reactants were set to stir at room temperature and then heated to 70 ° C. The reactants were stirred at 70 ° C for 18 h. The reaction mixture was allowed to cool to room temperature and then distributed between DCM and distilled water. The organic layer was separated. The combined organic layers were dried (MgSO 4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (730 mg, 64%).

[0381] LC / MS (Table 1, Method C) R t =1.78min; MS m / z: 206 [M+H] + .

[0382] (ii) (±)-(2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methanamine

[0383] The title compound was prepared from the appropriate starting material (±)-2-(3-fluoropiperidin-1-yl)isonicotinonitrile (compound 28, step (i)) using a reaction protocol similar to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl), step (ii). The compound was purified by flash column chromatography (DCM to DCM:MeOH [2M NH 3 ] 90:10, gradient elution) to afford the title compound (520 mg, 70%).

[0384] LC / MS (Table 1, Method D) R t =1.30min; MS m / z:210[M+H] + .

[0385] (iii) (±)-1-((2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0386] Starting from the appropriate commercially available starting materials (±)-(2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methanamine (compound 28, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 3, non-linear gradient from 5% to 60% MeCN) to provide a white solid (63 mg, 34%).

[0387] 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=5.0Hz,1H),6.68(s,1H),6.50(d,J=5.0Hz,1H),6. 44(dd,J=6.1,6.1Hz,1H),6.03(dd,J=5.8,5.8Hz,1H),4.83-4.64(m,1H),4.12(d,J= 6.0Hz,2H),3.75-3.55(m,3H),3.42-3.39(m,1H),3.13(dd,J=6.2,15.1Hz,2H),2.01 -1.73(m,3H),1.71-1.66(m,2H),1.58-1.49(m,1H),0.92-0.88(m,2H),0.76(s,2H).

[0388] LC / MS (Table 1, Method E) R t =4.17 min; MS m / z: 389 [M+H] + .

[0389] Compound 29

[0390] 1-((2-(3-(difluoromethyl)azetidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0391] The title compound was prepared starting from appropriate starting materials (2-(3-(difluoromethyl)azetidin-1-yl)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-(3-(difluoromethyl)azetidin-1-yl)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 28: (±)-1-((2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 2, non-linear gradient from 5% to 60% MeCN) to afford a white solid (22 mg, 35%).

[0392] 1 H NMR(400MHz, DMSO-d6)δ7.99(dd,J=0.6,5.2Hz,1H),6.56-6.02(m,5H),4.12(d,J=6.1Hz,2H),4.02(t,J=8.2Hz,2H) ,3.87-3.82(m,2H),3.30-3.17(m,1H),3.12(q,J=7.1Hz,2H),1.69(t,J=8.1Hz,2H),0.92-0.88(m,2H),0.76(s,2H).

[0393] LC / MS (Table 1, Method A) R t =3.01 min; MS m / z: 393 [M+H] + .

[0394] Compound 30

[0395] 1-((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0396] Starting from the appropriate commercially available starting materials (4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)methanamine, hydrochloride (CAS: 1196154-15-0) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 2) to provide a white solid (56 mg, 40%).

[0397] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=5.8Hz,1H),7.01(d,J=5.6Hz,1H),6.41(dd,J=5.8,5.8Hz,1H),6.28(dd,J=5.9,5.9Hz,1H ),5.16-5.09(m,2H),4.34(d,J=5.8Hz,2H),3.13(dd,J=6.1,15.4Hz,2H),1.71-1.66(m,2H),0.93-0.88(m,2H),0.76(s,2H).

[0398] LCMS (Table 1, Method E) R t =4.18min MS, m / z:387[M+H] + .

[0399] Compound 31

[0400] 1-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0401] Starting from the appropriate commercially available starting materials (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine (CAS: 1250054-65-9) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 3) to afford an off-white solid (77 mg, 47%).

[0402] 1 H NMR (400MHz, DMSO-d6) δ7.79-7.75(m,1H),6.97(d,J=6.9Hz,1H),6.83(d,J=7.9Hz,1H),6.48(t,J=6.0Hz,1H),6.15(t,J=5.8Hz, 1H), 5.01 (q, J = 9.2Hz, 2H), 4.23 (d, J = 6.0Hz, 2H), 3.17-3.10 (m, 2H), 1.69 (t, J = 7.8Hz, 2H), 0.93-0.88 (m, 2H), 0.77-0.74 (m, 2H).

[0403] LCMS (Table 1, Method A) R t=4.87min MS, m / z:386[M+H] + .

[0404] Compound 32

[0405] 1-((2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0406] The title compound was prepared starting from appropriate starting materials (2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by flash column chromatography (cyclohexane to EtOAc:IMS 3:1, gradient elution) followed by flash column chromatography (DCM to EtOAc, gradient elution) to afford a white solid (63 mg, 56%).

[0407] 1 H NMR (400MHz, DMSO-d6) δ7.07(d,J=1.0Hz,1H),6.79(d,J=1.1Hz,1H),6.60(t,J=6.0Hz,1H),6.17(t,J=5.4Hz,1H),4.9 6(q,J=9.1Hz,2H),4.20(d,J=5.8Hz,2H),3.14-3.08(m,2H),1.71-1.65(m,2H),0.91-0.87(m,2H),0.76-0.71(m,2H).

[0408] LCMS (Table 1, Method F) R t =4.92min MS, m / z:420[M+H] + .

[0409] Compound 33

[0410] 1-(4,4,4-Trifluoro-3-hydroxy-3-methylbutyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0411] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine hydrochloride (CAS: 2044704-69-8) and 4-amino-1,1,1-trifluoro-2-methylbutan-2-ol (CAS: 911060-86-1), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 3) to provide a white solid (57 mg, 35%).

[0412] 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=5.3Hz,1H),6.98(d,J=5.3Hz,1H),6.78(s,1H),6.55(dd,J=6.1,6.1Hz,1H),6.11(dd,J=5 .6,5.6Hz,1H),5.90(s,1H),4.99(q,J=9.1Hz,2H),4.22(d,J=6.1Hz,2H),3.26-3.12(m,2H),1.79-1.66(m,2H),1.27(s,3H).

[0413] LCMS (Table 1, Method E) R t =3.95min MS, m / z:390[M+H] + .

[0414] Compound 34

[0415] (±)-1-((2-(3-fluoropyrrolidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0416] The title compound was prepared starting from appropriate starting materials (±)-(2-(3-fluoropyrrolidin-1-yl)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (±)-(2-(3-fluoropyrrolidin-1-yl)pyridin-4-yl)methanamine was correspondingly prepared starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 28: (±)-1-((2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 2, non-linear gradient from 5% to 60% MeCN) to afford a white solid (52 mg, 28%).

[0417] 1 H NMR(400MHz,DMSO-d6)δ7.99(d,J=5.5Hz,1H),6.48-6.42(m,2H),6.34(s,1H) ,6.03(t,J=5.8Hz,1H),5.52-5.36(m,1H),4.13(d,J=6.1Hz,2H),3.73-3.50( m,2H),3.44-3.37(m,1H),3.29(s,1H),3.13(dd,J=6.1,15.1Hz,2H),2.36-2. 10(m,2H),1.72-1.66(m,2H),0.92-0.88(m,2H),0.76(dd,J=6.7,6.7Hz,2H).

[0418] LC / MS (Table 1, Method A) R t =2.90 min; MS m / z:375 [M+H] + .

[0419] Compound 35

[0420] 1-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-((1-(trifluoromethyl)cyclopropyl)methyl)urea

[0421] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (1-(trifluoromethyl)cyclopropyl)methanamine hydrochloride (CAS: 1783418-59-6), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 2) to afford an off-white solid (65 mg, 53%).

[0422] 1 H NMR (400MHz, DMSO-d6) δ8.12(d,J=5.3Hz,1H),6.97(dd,J=1.4,5.3Hz,1H),6.78(s,1H),6.57(t,J=6.1Hz,1H ), 6.33 (t, J = 6.1Hz, 1H), 4.99 (q, J = 9.2Hz, 2H), 4.24 (d, J = 6.1Hz, 2H), 3.40-3.31 (m, 2H), 0.90-0.79 (m, 4H).

[0423] LCMS (Table 1, Method A) R t =4.57min MS, m / z:372[M+H] + .

[0424] Compound 36

[0425] 1-(Cyclohexylmethyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0426] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and cyclohexylmethanamine (CAS: 3218-02-8), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 1) to afford an off-white solid (35 mg, 30%).

[0427] 1H NMR (400MHz, DMSO-d6) δ8.11(d,J=5.3Hz,1H),6.98(dd,J=1.3,5.3Hz,1H),6.77(s,1H),6.38(t,J=5.9Hz,1H),6.10(t,J=5.8Hz,1H),4.99 (q,J=9.2Hz,2H),4.22(d,J=6.1Hz,2H),2.87(t,J=6.3Hz,2H),1.69-1.61(m,5H),1.39-1.31(m,1H),1.25-1.06(m,3H),0.92-0.82(m,2H).

[0428] LCMS (Table 1, Method E) R t =4.72min MS, m / z:346[M+H] + .

[0429] Compound 37

[0430] 1-(2-methylbenzyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0431] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and 2-methylbenzylamine (CAS: 89-93-0), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 2) to afford an off-white solid (47 mg, 42%).

[0432] 1 H NMR (400MHz, DMSO-d6) δ8.12(dd,J=0.5,5.4Hz,1H),7.24-7.20(m,1H),7.18-7.14(m,3H),7.00(dd,J=1.3,5.3Hz,1H),6.81(s,1H), 6.55(t,J=6.1Hz,1H), 6.49(t,J=5.9Hz,1H), 5.00(q,J=9.1Hz,2H), 4.26(d,J=6.2Hz,2H), 4.23(d,J=5.9Hz,2H), 2.28-2.27(m,3H).

[0433] LCMS (Table 1, Method A) R t =4.64min MS, m / z:354[M+H] + .

[0434] Compound 38

[0435] 1-((6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0436] The title compound was prepared starting from appropriate starting materials (6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 11: 1-((6-(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by flash column chromatography (DCM to DCM:MeOH [2M NH 3 ] 90:10, gradient elution) to afford a white solid (37 mg, 40%).

[0437] 1 H NMR (400MHz, DMSO-d6) δ8.76(d,J=1.1Hz,1H),6.84(d,J=1.0Hz,1H),6.58(t,J=5.9Hz,1H),6.23(t,J=5.6Hz,1H),5.09 (q, J = 9.1Hz, 2H), 4.24 (d, J = 6.3Hz, 2H), 3.15-3.09 (m, 2H), 1.67 (t, J = 7.8Hz, 2H), 0.91-0.87 (m, 2H), 0.77-0.71 (m, 2H).

[0438] LCMS (Table 1, Method B) R t =4.16min MS, m / z:387[M+H] + .

[0439] Compound 39

[0440] 1-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0441] (i) 1-((2-chloro-6-methylpyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0442] Starting from the appropriate commercially available starting materials (2-chloro-6-methyl-4-pyridyl)methanamine dihydrochloride (CAS: 1909336-63-5) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to provide the title compound (103 mg, 70%).

[0443] LC / MS (Table 1, Method A) R t =1.46min; MS m / z:336[M+H] + .

[0444] (ii) 1-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0445] The title compound was prepared using a reaction scheme similar to that described for compound 21: 1-(3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iv) starting from the appropriate commercially available starting materials 1-((2-chloro-6-methylpyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (compound 39, step (i)) and 2,2,2-trifluoroethanol (CAS: 75-89-8). The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (84 mg, 67%).

[0446] 1 H NMR (400MHz, DMSO-d6) δ6.80(s,1H),6.56(s,1H),6.52(t,J=6.1Hz,1H),6.10(t,J=5.8Hz,1H),4.95(q,J=9.2Hz,2 H), 4.15 (d, J = 6.1Hz, 2H), 3.14-3.08 (m, 2H), 2.37 (s, 3H), 1.70-1.64 (m, 2H), 0.91-0.86 (m, 2H), 0.75-0.73 (m, 2H).

[0447] LC / MS (Table 1, Method F) R t =4.79 min; MS m / z:400 [M+H] + .

[0448] Compound 40

[0449] 1-(3-fluorobenzyl)-3-((2-((2-fluorobenzyl)oxy)pyridin-4-yl)methyl)urea

[0450] The title compound was prepared starting from appropriate starting materials (2-((2-fluorobenzyl)oxy)pyridin-4-yl)methanamine and 3-fluorobenzylamine (CAS: 100-82-3) using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-((2-fluorobenzyl)oxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme similar to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford a white solid (15 mg, 37%).

[0451] 1 H NMR(400MHz, DMSO-d6)δ8.08(d,J=5.6Hz,1H),7.52(dt,J=1.8,7.5Hz,1H),7.44-7.38(m,1H),7.36-7.30(m,1H),7. 27-7.19(m,2H),7.10-7.00(m,3H),6.88(dd,J=1.3,5.3Hz,1H),6.70-6.63(m,3H),5.37(s,2H),4.25-4.20(m,4H).

[0452] LCMS (Table 1, Method F) R t =4.46min MS, m / z:384[M+H] + .

[0453] Compound 41

[0454] 1-(4,4,4-trifluoro-3,3-dimethylbutyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0455] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 56129-93-6) and 4,4,4-trifluoro-3,3-dimethylbutan-1-amine hydrochloride (CAS: 1454690-74-4), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 2) to afford an off-white solid (89 mg, 69%).

[0456] 1 H NMR (400MHz, DMSO-d6) δ8.12(d,J=5.3Hz,1H),6.98(dd,J=1.4,5.3Hz,1H),6.78(s,1H),6.53(t,J=6.3Hz,1H),6.1 3(t,J=5.8Hz,1H),4.99(q,J=9.1Hz,2H),4.22(d,J=6.1Hz,2H),3.14-3.07(m,2H),1.62-1.57(m,2H),1.11(s,6H).

[0457] LCMS (Table 1, Method A) R t =4.83min MS, m / z:388[M+H] + .

[0458] Compound 42

[0459] 1-(3-Fluorobenzyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0460] The title compound was prepared from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 56129-93-6) and 3-fluorobenzylamine (CAS: 100-82-3) using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was triturated with diethyl ether to afford an off-white solid (42 mg, 37%).

[0461] 1H NMR(400MHz, DMSO-d6)δ8.10(d,J=5.2Hz,1H),7.38-7.32(m,1H),7.11-7.02(m,3H),6.98(dd,J=1.4 ,4.9Hz,1H),6.78(s,1H),6.71(td,J=6.1,15.3Hz,2H),4.98(q,J=9.1Hz,2H),4.24(d,J=6.2Hz,4H).

[0462] LCMS (Table 1, Method B) R t =4.28min MS, m / z:358[M+H] + .

[0463] Compound 43

[0464] 1-Cyclohexyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0465] The title compound was prepared from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 56129-93-6) and cyclohexylamine (CAS: 108-91-8) using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was triturated with diethyl ether to afford an off-white solid (75 mg, 71%).

[0466] 1 H NMR (400MHz, DMSO-d6) δ8.10(d,J=5.2Hz,1H),6.96(dd,J=1.1,5.2Hz,1H),6.76(s,1H),6.32(t,J=6.0Hz,1H),5.99(d,J=8.0Hz,1H) ,4.98(q,J=9.2Hz,2H),4.20(d,J=6.1Hz,2H),1.77-1.73(m,2H),1.67-1.62(m,2H),1.52(dd,J=3.8,8.4Hz,1H),1.31-1.05(m,6H).

[0467] LCMS (Table 1, Method F) R t =4.38min MS, m / z:332[M+H] + .

[0468] Compound 44

[0469] 1-((2-(3-(trifluoromethyl)azetidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0470] The title compound was prepared starting from appropriate starting materials (2-(3-(trifluoromethyl)azetidin-1-yl)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-(3-(trifluoromethyl)azetidin-1-yl)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 28: (±)-1-((2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 6) to afford a white solid (118 mg, 60%).

[0471] 1 H NMR(400MHz, DMSO-d6)δ8.02(d,J=5.1Hz,1H),6.60-6.57(m,1H),6.46(dd,J=6.1,6.1Hz,1H),6.30(s,1H),6.05(dd,J=5.8,5.8Hz,1H),4.18- 4.12(m,4H),3.91(dd,J=5.3,8.7Hz,2H),3.78-3.68(m,1H),3.12(dd,J=6.2,15.0Hz,2H),1.71-1.66(m,2H),0.92-0.88(m,2H),0.76(s,2H).

[0472] LCMS (Table 1, Method A) R t =3.18min MS, m / z:411[M+H] + .

[0473] Compound 45

[0474] 1-((2-(3-fluoroazetidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0475] (i) 2-(3-Fluoroazetidin-1-yl)isonicotinonitrile

[0476] The title compound was prepared starting from the appropriate commercially available starting materials, 4-cyano-2-fluoropyridine (CAS: 3939-14-8) and 3-fluoroazetidine hydrochloride (CAS: 690257-76-2), using a reaction scheme similar to that described for compound 28: (±)-1-((2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (i). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (387 mg, 68%).

[0477] LC / MS (Table 1, Method C) R t =1.16min; MS m / z:178[M+H] + .

[0478] (ii) (2-(3-fluoroazetidin-1-yl)pyridin-4-yl)methanamine

[0479] The title compound was prepared from the appropriate starting material, 2-(3-fluoroazetidin-1-yl)isonicotinonitrile (compound 45, step (i)) using a reaction scheme similar to that described for compound 11: 1-((6-(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (ii). The compound was purified by flash column chromatography (cyclohexane to EtOAc:IMS 3:1, gradient elution) to provide the title compound (94 mg, 46%).

[0480] LC / MS (Table 1, Method G) R t =1.01 min; MS m / z:182 [M+H] + .

[0481] (iii) 1-((2-(3-fluoroazetidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0482] Starting from the appropriate starting materials (2-(3-fluoroazetidin-1-yl)pyridin-4-yl)methanamine (compound 45, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 6) to afford an off-white solid (84 mg, 45%).

[0483] 1H NMR(400MHz,DMSO-d6)δ8.01(d,J=5.5Hz,1H),6.57(d,J=5.3Hz,1H),6.45( t,J=6.1Hz,1H),6.29(s,1H),6.04(t,J=5.8Hz,1H),5.60-5.40(m,1H),4.30 -4.19(m,2H),4.13(d,J=6.1Hz,2H),4.01-3.91(m,2H),3.12(dd,J=6.2,15. 1Hz, 2H), 1.71-1.66 (m, 2H), 0.93-0.88 (m, 2H), 0.75 (dd, J = 6.8, 6.8Hz, 2H).

[0484] LC / MS (Table 1, Method A) R t =2.84min; MS m / z:361[M+H] + .

[0485] Compound 46

[0486] 1-(o-Tolyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0487] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and o-toluidine (CAS: 95-53-4), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (51 mg, 45%).

[0488] 1 H NMR (400MHz, DMSO-d6) δ8.14(d,J=5.2Hz,1H),7.86(s,1H),7.78(d,J=7.6Hz,1H),7.15-7 .03(m,4H),6.92-6.85(m,2H),4.99(q,J=9.1Hz,2H),4.33(d,J=6.0Hz,2H),2.20(s,3H).

[0489] LC / MS (Table 1, Method F) R t =4.39 min; MS m / z: 340 [M+H] + .

[0490] Compound 47

[0491] (S)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-3-((2-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)urea

[0492] The title compound was prepared starting from appropriate starting materials (S)-(2-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (S)-(2-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 3, non-linear gradient from 40% to 100% MeCN) to afford an off-white solid (108 mg, 45%).

[0493] 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=4.9Hz,1H),6.96(d,J=5.3Hz,1H),6.73(s,1H),6.54(dd,J=6.1,6.1Hz,1H),6.11(dd,J=5.8,5.8Hz,1H),5.93-5.85 (m,1H),4.21(d,J=6.1Hz,2H),3.13(dd,J=6.1,15.1Hz,2H),1.72-1.66(m, 2H), 1.44 (d, J = 6.4Hz, 3H), 0.92-0.88 (m, 2H), 0.75 (dd, J = 6.7, 6.7Hz, 2H).

[0494] LC / MS (Table 1, Method E) R t =4.80min; MS m / z:400[M+H] + .

[0495] Compound 48

[0496] 1-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0497] (i) tert-Butyl (2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate

[0498] At 0 ° C, under a nitrogen atmosphere, sodium hydride (60%, 93 mg, 2.33 mmol) was added to a solution of 3-boc-1,2,3-oxathiazolidine 2,2-dioxide (400 mg, 1.79 mmol) and 2-trifluoromethyl-2-propanol (0.27 mL, 2.51 mmol) in DMF (3.0 mL). The reactants were allowed to warm to room temperature and then heated to 60 ° C for 18 h. The reaction mixture was then distributed between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (MgSO4) and concentrated in vacuo to provide the title compound (327 mg, 86%).

[0499] 1 H NMR (400MHz, CDCl3) δ4.87-4.87 (m, 1H), 3.57 (t, J = 5.0Hz, 2H), 3.33-3.25 (m, 2H), 1.45 (s, 9H), 1.35 (s, 6H).

[0500] (ii) 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethan-1-amine hydrochloride

[0501] The title compound was prepared from the appropriate starting material, tert-butyl (2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate ((compound 48, step (i)) using a reaction scheme similar to that described for compound 6: 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iii). The compound was triturated with diethyl ether to afford the title compound (216 mg, 86%).

[0502] 1 H NMR (400MHz, DMSO-d6) δ8.08 (s, 2H), 3.70 (t, J = 5.3Hz, 2H), 2.95 (t, J = 5.4Hz, 2H), 1.36 (s, 6H).

[0503] (iii) 1-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0504] Starting from appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethane-1-amine hydrochloride (compound 48, step (ii)), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (91 mg, 72%).

[0505] 1 H NMR (400MHz, DMSO-d6) δ8.09(d,J=5.2Hz,1H),6.96(dd,J=0.9,5.3Hz,1H),6.76(s,1H),6.63(t,J=6.1Hz,1H),6.11( t,J=5.8Hz,1H),4.97(q,J=9.1Hz,2H),4.22(d,J=6.1Hz,2H),3.47(t,J=5.5Hz,2H),3.18-3.12(m,2H),1.31(s,6H).

[0506] LCMS (Table 1, Method F) R t =4.47min MS, m / z:404[M+H] + .

[0507] Compound 49

[0508] 1-((2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0509] (i) (2-chloropyrimidin-4-yl)methyl 4-methylbenzenesulfonate

[0510] At 0 ° C, triethylamine (0.51 mL, 3.65 mmol) was added to a solution of (2-chloropyrimidin-4-yl)methanol (CAS: 34953-87-2, 397 mg, 2.75 mmol) and p-toluenesulfonyl chloride (628 mg, 3.30 mmol) in THF (15.0 mL). The reaction was stirred at 0 ° C for 3 h. The reaction was allowed to warm to room temperature and stirred at room temperature for 16 h. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (570 mg, 69%). The product was directly entered into step (ii) without characterization.

[0511] (ii) tert-Butyl (tert-butoxycarbonyl)((2-chloropyrimidin-4-yl)methyl)carbamate

[0512] The title compound was prepared from the appropriate starting material (2-chloropyrimidin-4-yl)methyl 4-methylbenzenesulfonate (compound 49, step (i)) using a reaction scheme similar to that described for compound 8: 1-((4-(benzyloxy)pyrimidin-2-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (i). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (638 mg, quantitative).

[0513] LC / MS (Table 1, Method C) R t =1.88min; MS m / z:366[M+H] + .

[0514] (iii) tert-Butyl ((2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)carbamate

[0515] The title compound was prepared from the appropriate starting materials tert-butyl (tert-butoxycarbonyl)((2-chloropyrimidin-4-yl)methyl)carbamate (compound 49, step (ii)) and 2,2,2-trifluoroethanol (CAS: 75-89-8) using a reaction scheme similar to that described for compound 21: 1-(3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iv). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (47 mg, 8%).

[0516] LC / MS (Table 1, Method C) R t =1.61min; MS m / z:308[M+H] + .

[0517] (iv) (2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methanamine hydrochloride

[0518] The title compound was prepared from the appropriate starting material, tert-butyl ((2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)carbamate (compound 49, step (iii)), using a reaction scheme analogous to that described for compound 6: 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iii). This afforded the title compound (38 mg, quantitative).

[0519] LC / MS (Table 1, Method A) R t =0.92 min; MS m / z: 208 [M+H] + .

[0520] (v) 1-((2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0521] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methanamine hydrochloride (compound 49, step (iv)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (33 mg, 54%).

[0522] 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=5.1Hz,1H),7.09(d,J=5.1Hz,1H),6.60(dd,J=6.0,6.0Hz,1H),6.26(dd,J=5.8,5.8Hz,1H), 5.03(q,J=9.0Hz,2H),4.24(d,J=5.9Hz,2H),3.11(dd,J=6.1,15.2Hz,2H),1.70-1.65(m,2H),0.91-0.86(m,2H),0.74(s,2H).

[0523] LCMS (Table 1, Method F) R t =4.12min MS, m / z:387[M+H] + .

[0524] Compound 50

[0525] 1-((6-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0526] The title compound was prepared starting from appropriate starting materials (6-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (6-Methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methanamine was correspondingly prepared starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 49: 1-((2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-iv). The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (75 mg, 68%).

[0527] 1 H NMR (400MHz, DMSO-d6) δ6.96(s,1H),6.55(dd,J=6.0,6.0Hz,1H),6.23(dd,J=5.8,5.8Hz,1H),5.01(q,J=9.0Hz,2H),4.20(d ,J=5.9Hz,2H),3.11(dd,J=6.1,15.1Hz,2H),2.41(s,3H),1.70-1.65(m,2H),0.91-0.86(m,2H),0.74(dd,J=6.7,6.7Hz,2H).

[0528] LCMS (Table 1, Method F) R t =4.31min MS, m / z:401[M+H] + .

[0529] Compound 51

[0530] (R)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-3-((2-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)urea

[0531] The title compound was prepared starting from appropriate starting materials (R)-(2-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (R)-(2-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 2) to afford an off-white solid (67 mg, 55%).

[0532] 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=5.5Hz,1H),6.96(d,J=5.3Hz,1H),6.72(s,1H),6.54(dd,J=6.1,6.1Hz,1H),6.11(dd,J=5.8,5.8Hz,1H),5.93- 5.85(m,1H),4.21(d,J=6.1Hz,2H),3.13(dd,J=6.1,15.1Hz,2H),1.72-1 .66(m,2H),1.44(d,J=6.5Hz,3H),0.92-0.88(m,2H),0.78-0.74(m,2H).

[0533] LC / MS (Table 1, Method A) R t =4.99 min; MS m / z:400 [M+H] + .

[0534] Compound 52

[0535] 1-((5-methyl-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0536] The title compound was prepared starting from appropriate starting materials (5-methyl-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (5-methyl-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (88 mg, 67%).

[0537] 1 H NMR (400MHz, DMSO-d6) δ7.91(s,1H),6.68(s,1H),6.49(dd,J=6.0,6.0Hz,1H),6.12(dd,J=5.8,5.8Hz,1H),4.94(q,J=9.1Hz,2H),4 .16(d,J=5.9Hz,2H),3.13(dd,J=6.2,15.0Hz,2H),2.16(s,3H),1.71-1.66(m,2H),0.92-0.87(m,2H),0.75(dd,J=6.7,6.7Hz,2H).

[0538] LCMS (Table 1, Method F) R t =4.75min MS, m / z:400[M+H] + .

[0539] Compound 53

[0540] 1-((6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0541] The title compound was prepared starting from appropriate starting materials (6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme similar to that described for compound 11: 1-((6-(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (59 mg, 52%).

[0542] 1 H NMR (400MHz, DMSO-d6) δ8.89(d,J=1.7Hz,1H),7.10(d,J=1.0Hz,1H),6.61(dd,J=6.0,6.0Hz,1H),6.21(dd,J=5.7,5.7Hz ,1H),5.18(q,J=9.0Hz,2H),4.25(d,J=5.9Hz,2H),3.15-3.07(m,2H),1.70-1.65(m,2H),0.91-0.86(m,2H),0.74(s,2H).

[0543] LCMS (Table 1, Method F) R t =4.11min MS, m / z:387[M+H] + .

[0544] Compound 54

[0545] 1-((2-((3-fluoropyridin-2-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0546] The title compound was prepared starting from appropriate starting materials (2-((3-fluoropyridin-2-yl)methoxy)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-((3-fluoropyridin-2-yl)methoxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate starting materials following a reaction scheme analogous to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (65 mg, 43%).

[0547] 1 H NMR(400MHz,DMSO-d6)δ8.42-8.39(m,1H),8.04(d,J=5.3Hz,1H),7.78-7.73 (m,1H),7.51-7.46(m,1H),6.86(dd,J=1.3,5.3Hz,1H),6.66(s,1H),6.50(t, J=6.2Hz,1H),6.06(t,J=5.8Hz,1H),5.46-5.45(m,2H),4.17(d,J=6.1Hz,2H) ,3.14-3.07(m,2H),1.69-1.64(m,2H),0.90-0.85(m,2H),0.75-0.71(m,2H).

[0548] LCMS (Table 1, Method F) R t =4.05min MS, m / z:413[M+H] + .

[0549] Compound 55

[0550] 1-((2-(pyrimidin-2-ylmethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0551] (i) 2-(pyrimidin-2-ylmethoxy)isonicotinonitrile

[0552] The title compound was prepared starting from the appropriate commercially available starting materials, 4-cyano-2-fluoropyridine (CAS: 3939-14-8) and pyrimidin-2-ylmethanol (CAS: 42839-09-8), using a reaction scheme similar to that described for compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (i). The compound was triturated with diethyl ether to afford the title compound (889 mg, 79%).

[0553] LCMS (Table 1, Method D) R t =1.03min MS, m / z:213[M+H] + .

[0554] (ii) (2-(pyrimidin-2-ylmethoxy)pyridin-4-yl)methanamine

[0555] At 0°C, sodium borohydride (107 mg, 2.83 mmol) was added portionwise to a solution of 2-(pyrimidin-2-ylmethoxy)isonicotinonitrile (compound 55, step (i), 200 mg, 0.942 mmol) and nickel(II) chloride hexahydrate (269 mg, 1.13 mmol) in EtOH (10.0 mL) under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred at room temperature for 18 h. The reaction mixture was then partitioned between DCM and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to DCM:MeOH [2M NH3] 90:10, gradient elution) to provide the title compound (71 mg, 35%).

[0556] LCMS (Table 1, Method D) R t =0.76min MS, m / z:217[M+H] + .

[0557] (iii) 1-((2-(pyrimidin-2-ylmethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0558] Starting from appropriate starting materials (2-(pyrimidin-2-ylmethoxy)pyridin-4-yl)methanamine (compound 55, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (EtOAc to MeOH, gradient elution) to afford an off-white solid (52 mg, 44%).

[0559] 1 H NMR (400MHz, DMSO-d6) δ8.76(s,1H),8.75(s,1H),7.93(d,J=5.2Hz,1H),7.40(t,J=4.9Hz,1H),6.81(dd,J=1.3,5.3Hz,1H),6.73(s,1H),6.53(t,J =6.1Hz,1H),6.09(t,J=5.8Hz,1H),5.50(s,2H),4.19(d,J=6.1Hz,2H),3. 16-3.08(m,2H),1.71-1.65(m,2H),0.91-0.86(m,2H),0.77-0.72(m,2H).

[0560] LCMS (Table 1, Method F) R t =3.42min MS, m / z:396[M+H] + .

[0561] Compound 56

[0562] 1-((2-(3,3-difluoroazetidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0563] The title compound was prepared using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea starting from appropriate starting materials (2-(3,3-difluoroazetidin-1-yl)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2). (2-(3,3-difluoroazetidin-1-yl)pyridin-4-yl)methanamine was prepared accordingly following a reaction scheme analogous to that described for compound 45: 1-((2-(3-fluoroazetidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 6) to afford an off-white solid (55 mg, 53%).

[0564] 1 H NMR (400MHz, DMSO-d6) δ8.06(d,J=5.5Hz,1H),6.67(d,J=5.3Hz,1H),6.48(dd,J=6.1,6.1Hz,1H),6.42(s,1H),6.06(dd,J=5.8,5.8Hz,1H),4.35 (dd,J=12.5,12.5Hz,4H),4.15(d,J=6.1Hz,2H),3.13(dd,J=6.1,15.1Hz,2H),1.71-1.66(m,2H),0.93-0.88(m,2H),0.75(dd,J=6.8,6.8Hz,2H).

[0565] LCMS (Table 1, Method E) R t =3.99min MS, m / z:379[M+H] + .

[0566] Compound 57

[0567] 1-(2-Hydroxy-2-methylpropyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0568] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and 1-amino-2-methyl-2-propanol (CAS: 2854-16-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The reaction mixture was filtered and washed with DCM to afford the title compound as a white solid (68 mg, 67%).

[0569] 1 H NMR (400MHz, DMSO-d6) δ8.10(d,J=5.3Hz,1H),6.97(d,J=5.3Hz,1H),6.78(s,1H),6.60(t,J=6.1Hz,1H),6.06( t,J=5.7Hz,1H),4.97(q,J=9.1Hz,2H),4.48(s,1H),4.23(d,J=6.1Hz,2H),2.97(d,J=5.9Hz,2H),1.05(s,6H).

[0570] LCMS (Table 1, Method F) R t =3.28min MS, m / z:322[M+H] + .

[0571] Compound 58

[0572] 1-((1S,2R)-2-hydroxycyclohexyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0573] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (1R,2S)-cis-2-aminocyclohexanol hydrochloride (CAS: 190792-72-4), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (cyclohexane to EtOAc:IMS 3:1, gradient elution) followed by flash column chromatography (DCM to MeOH, gradient elution) to afford a white solid (60 mg, 54%).

[0574] 1 H NMR (400MHz, DMSO-d6) δ8.10(dd,J=0.5,5.3Hz,1H),6.96(dd,J=1.2,5.3Hz,1H),6.78-6.76(m,1H),6.61(t,J=6.1Hz,1H),5.89(d,J=8.4Hz,1H) ,4.98(q,J=9.1Hz,2H),4.64(d,J=4.0Hz,1H),4.21(d,J=6.1Hz,2H),3.7 1-3.65(m,1H),3.50-3.43(m,1H),1.68-1.39(m,6H),1.30-1.18(m,2H).

[0575] LC / MS (Table 1, Method F) Rt =3.65min; MS m / z:348[M+H] + .

[0576] Compound 59

[0577] (R)-2-Methyl-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)morpholine-4-carboxamide

[0578] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (R)-2-methylmorpholine hydrochloride (CAS: 168038-14-0), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford an off-white solid (75 mg, 69%).

[0579] 1 H NMR (400MHz, DMSO-d6) δ8.10(dd,J=0.5,5.3Hz,1H),7.17(t,J=5.9Hz,1H),6.98(dd,J=1.3,5.3Hz,1H),6.79-6.77(m,1H),4.97(q,J= 9.1Hz,2H),4.24(d,J=5.6Hz,2H),3.85-3.72(m,3H),3.46-3.35(m,2H),2.83-2.74(m,1H),2.47-2.42(m,1H),1.08(d,J=6.1Hz,3H).

[0580] LC / MS (Table 1, Method F) R t =3.71 min; MS m / z: 334 [M+H] + .

[0581] Compound 60

[0582] (S)-2-Methyl-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)morpholine-4-carboxamide

[0583] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (S)-2-methylmorpholine hydrochloride (CAS: 1147108-99-3), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (cyclohexane to EtOAc:IMS 3: 1, gradient elution) to afford an off-white solid (79 mg, 73%).

[0584] 1 H NMR (400MHz, DMSO-d6) δ8.10(dd,J=0.5,5.3Hz,1H),7.17(t,J=5.8Hz,1H),6.99(dd,J=1.3,5.3Hz,1H),6.79-6.77(m,1H),4.98(q,J= 9.1Hz,2H),4.25(d,J=5.6Hz,2H),3.85-3.72(m,3H),3.45-3.35(m,2H),2.83-2.74(m,1H),2.47-2.43(m,1H),1.08(d,J=6.2Hz,3H).

[0585] LC / MS (Table 1, Method F) R t =3.70 min; MS m / z: 334 [M+H] + .

[0586] Compound 61

[0587] 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)acetamide

[0588] (i) tert-Butyl ((5-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)carbamate

[0589] At 0 ° C, under a nitrogen atmosphere, to a solution of 5-(2,2,2-trifluoroethoxy)pyridine-3-carbonitrile (CAS: 1211581-84-8, 355 mg, 1.76 mmol) in anhydrous MeOH (10.0 mL) was added di-tert-butyl dicarbonate (767 mg, 3.51 mmol) and nickel (II) chloride hexahydrate (41.7 mg, 0.176 mmol). The reactants were set to stir at 0 ° C and sodium borohydride (465 mg, 12.3 mmol) was added in batches. The reaction was allowed to warm to room temperature and the reaction was stirred at room temperature for 1 h. The reaction mixture was quenched by adding diethylenetriamine (0.19 mL, 1.76 mmol) and the reactants were stirred at room temperature for 30 min. The reactants were then distributed between DCM and a saturated sodium bicarbonate aqueous solution. The organic layer was separated. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (513 mg, 83%).

[0590] LC / MS (Table 1, Method C) Rt=1.49 min; MS m / z: 307 [M+H] + .

[0591] (ii) (5-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine dihydrochloride

[0592] The title compound was prepared from the appropriate starting material, tert-butyl ((5-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)carbamate (compound 61, step (i)), using a reaction scheme similar to that described for compound 6: 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iii). This afforded the title compound (181 mg, quantitative).

[0593] LC / MS (Table 1, Method C) R t =0.25min; MS m / z: 207 [M+H] + .

[0594] (iii) 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)acetamide

[0595] Starting from the appropriate commercially available starting materials (5-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine dihydrochloride (compound 61, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to DCM:MeOH [2M NH 3 ] 90:10, gradient elution) followed by flash column chromatography (DCM to MeOH, gradient elution) to afford a white solid (128 mg, 50%).

[0596] 1 H NMR (400MHz, DMSO-d6) δ8.27(d,J=2.9Hz,1H),8.17(d,J=1.3Hz,1H),7.35(dd,J=1.9,2.6Hz,1H),6.49(t,J=6.0Hz,1H),6.04(t,J=5.8H z,1H),4.85(q,J=8.8Hz,2H),4.21(d,J=6.1Hz,2H),3.11(q,J=7.1Hz,2H),1.67(t,J=7.8Hz,2H),0.90-0.86(m,2H),0.76-0.70(m,2H).

[0597] LCMS (Table 1, Method F) R t =3.87min MS, m / z:386[M+H] + .

[0598] Compound 62

[0599] 1-((1R,2S)-2-hydroxycyclohexyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0600] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (1S,2R)-2-aminocyclohexan-1-ol hydrochloride (CAS: 200352-28-9), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (cyclohexane to EtOAc:IMS 3: 1, gradient elution) followed by flash column chromatography (DCM to MeOH, gradient elution) to afford a white solid (33 mg, 28%).

[0601] 1 H NMR (400MHz, DMSO-d6) δ8.10(dd,J=0.6,5.3Hz,1H),6.97(dd,J=1.3,5.3Hz,1H),6.78-6.76(m,1H),6.61(t,J=6.1Hz,1H),5.89(d,J=8.4Hz,1H) ,4.97(q,J=9.1Hz,2H),4.65(d,J=4.0Hz,1H),4.21(d,J=6.0Hz,2H),3.7 1-3.66(m,1H),3.51-3.44(m,1H),1.68-1.39(m,6H),1.30-1.19(m,2H).

[0602] LC / MS (Table 1, Method F) R t =3.64 min; MS m / z: 348 [M+H] + .

[0603] Compound 63

[0604] 1-((1S,2S)-2-hydroxycyclohexyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0605] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (1S,2S)-2-aminocyclohexane-1-ol (CAS: 74111-21-0), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The reaction mixture was filtered and washed with DCM to afford the title compound as a white solid (62 mg, 57%).

[0606] 1 H NMR (400MHz, DMSO-d6) δ8.10(dd,J=0.4,5.2Hz,1H),6.98(dd,J=1.2,5.3Hz,1H),6.80-6.78(m,1H),6.47(t,J=6.1Hz,1H),5.99(d,J=6.5Hz,1H) ,4.98(q,J=9.1Hz,2H),4.73(d,J=4.6Hz,1H),4.22(d,J=6.1Hz,2H),3.2 5-3.13(m,2H),1.91-1.78(m,2H),1.63-1.53(m,2H),1.25-1.05(m,4H).

[0607] LC / MS (Table 1, Method F) Rt =3.79 min; MS m / z: 348 [M+H] + .

[0608] Compound 64

[0609] 1-((1R,2R)-2-hydroxycyclohexyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0610] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (1R,2R)-2-aminocyclohexane-1-ol (CAS: 931-16-8), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The reaction mixture was filtered and washed with DCM to afford the title compound as a white solid (64 mg, 59%).

[0611] 1 H NMR (400MHz, DMSO-d6) δ8.10(d,J=5.3Hz,1H),6.98(dd,J=1.3,5.3Hz,1H),6.79(s,1H),6.47(t,J=6.1Hz,1H),5.99(d,J=6.5Hz,1H),4.97 (q,J=9.1Hz,2H),4.73(d,J=4.5Hz,1H),4.22(d,J=6.1Hz,2H),3.24-3.13(m,2H),1.91-1.78(m,2H),1.63-1.53(m,2H),1.25-1.05(m,4H).

[0612] LC / MS (Table 1, Method F) R t =3.79 min; MS m / z: 348 [M+H] + .

[0613] Compound 65

[0614] (R)-1-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0615] (i) N-methoxy-N-methyl-2-(2,2,2-trifluoroethoxy)isonicotinamide

[0616] 2-(2,2,2-trifluoroethoxy)pyridine-4-carboxylic acid (CAS: 262296-01-5, 2.05 g, 9.08 mmol), HBTU (4.13 g, 10.9 mmol), and N,O-dimethylhydroxylamine hydrochloride (1.06 g, 10.9 mmol) were added to the reaction vessel and solvated in DCM (50.0 mL). N,N-diisopropylethylamine (4.0 mL, 22.7 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc:IMS 3:1, gradient elution) to provide the title compound (2.26 g, 94%).

[0617] LC / MS (Table 1, Method C) R t =1.52min; MS m / z: 265 [M+H] + .

[0618] (ii) 1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethan-1-one

[0619] To a solution of N-methoxy-N-methyl-2-(2,2,2-trifluoroethoxy)isonicotinamide ((compound 65, step (i), 1.75 g, 6.62 mmol)) in THF (40.0 mL) was added 3 M methylmagnesium bromide solution (4.4 mL, 13.2 mmol) at 0°C. The reaction was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was poured onto saturated aqueous sodium bicarbonate solution to quench and then partitioned with EtOAc. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (MgSO4), and concentrated in vacuo to provide the title compound (1.29 g, 97%).

[0620] LC / MS (Table 1, Method C) R t =1.65min; MS m / z: 220 [M+H] + .

[0621] (iii) (R,E)-2-methyl-N-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethylidene)propane-2-sulfenamide

[0622] 1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethane-1-one ((Compound 65, Step (ii), 370 mg, 1.64 mmol)), (R)-2-methyl-2-propanesulfenamide (218 mg, 1.80 mmol) were added to the reaction vessel and solvated in THF (10.0 mL). Titanium (IV) tetraethanolate (0.69 mL, 3.28 mmol) was added and the reactants were set to stir at room temperature and then heated to 70 ° C. The reactants were stirred at 70 ° C for 24 h. The reactants were allowed to cool to room temperature. The reaction mixture was then partitioned between EtOAc and saturated brine. The organic layer was separated. The combined organic layers were dried (MgSO 4 ) and concentrated in vacuo to provide the title compound (635 mg, quantitative).

[0623] LC / MS (Table 1, Method C) R t =1.80min; MS m / z:323[M+H] + .

[0624] (iv) (R)-2-methyl-N-((R)-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethyl)propane-2-sulfenamide

[0625] To a solution of (R,E)-2-methyl-N-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethylidene)propane-2-sulfenamide ((compound 65, step (iii), 635 mg, 1.89 mmol)) in THF (10.0 mL) was added 1 M diisobutylaluminum hydride (4.3 mL, 4.26 mmol) dropwise at -78 ° C. The reactants were stirred at -78 ° C for 18 h. MeOH (5 mL) was added and the reactants were allowed to warm to room temperature. The reaction mixture was then partitioned between EtOAc and 2 M aqueous sodium hydroxide solution. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeOH, gradient elution) to provide the title compound (111 mg, 18%).

[0626] LC / MS (Table 1, Method F) R t =4.41min; MS m / z:325[M+H] + .

[0627] (v) (R)-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethan-1-amine hydrochloride

[0628] The title compound was prepared from the appropriate starting material (R)-2-methyl-N-((R)-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethyl)propane-2-sulfinamide (compound 65, step (iv)) using a reaction scheme analogous to that described for compound 6: 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iii). This afforded the title compound (108 mg, quantitative).

[0629] 1 H NMR (400MHz, DMSO) δ8.60-8.60(m,2H),8.26(d,J=5.3Hz,1H),7.25(d,J=5.4Hz,1 H), 7.12 (s, 1H), 5.02 (q, J = 9.1Hz, 2H), 4.47-4.41 (m, 1H), 1.49 (d, J = 6.8Hz, 3H).

[0630] (vi) (R)-1-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0631] Starting from the appropriate commercially available starting materials (R)-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethan-1-amine hydrochloride (compound 65, step (v)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 7) to afford a white solid (50 mg, 64%).

[0632] 1 H NMR (400MHz, DMSO-d6) δ8.10(d,J=5.3Hz,1H),7.01(dd,J=1.2,5.3Hz,1H),6.82(s,1H),6.54(d,J=7.9Hz,1H),5.91(dd,J=5.8,5.8Hz,1H),4.96(q,J =9.1Hz,2H),4.74-4.64(m,1H),3.11-3.04(m,2H),1.64(dd,J=6.4,9.0Hz, 2H), 1.28 (d, J = 7.1Hz, 3H), 0.89-0.85 (m, 2H), 0.71 (dd, J = 6.4, 6.4Hz, 2H).

[0633] LC / MS (Table 1, Method F) R t =4.66min; MS m / z:399[M+H] + .

[0634] Compound 66

[0635] (±)-1-(3-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0636] (i) S-((6-chloropyridin-3-yl)methyl)O-ethyl dithiocarbonate

[0637] 2-Chloro-5-(chloromethyl)pyridine (CAS: 70258-18-3, 5.00 g, 30.9 mmol) was added to the reaction vessel and solvated in acetone (25.0 mL). Potassium ethoxymethanedithioate (5.44 g, 33.9 mmol) was added portionwise and the reaction was stirred at room temperature for 18 h. The reaction mixture was then partitioned between diethyl ether and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to provide the title compound (7.27 g, 95%).

[0638] LC / MS (Table 1, Method D) R t =1.49 min; MS m / z: 248 [M+H] + .

[0639] (ii) (±)-S-(3-(6-chloropyridin-3-yl)-1-(1,3-dioxoisoindolin-2-yl)propyl)O-ethyl dithiocarbonate

[0640] The reaction vessel was charged with S-((6-chloropyridin-3-yl)methyl)O-ethyl dithiocarbonate ((Compound 66, Step (i), 7.27 g, 29.3 mmol)), N-vinylphthalimide (1.27 g, 7.33 mmol) and solvated in EtOAc (30.0 mL). Lauroyl peroxide (73 mg, 0.183 mmol) was added and the reaction was set to stir at room temperature. The reaction was then heated to reflux. Additional lauroyl peroxide (73 mg, 0.183 mmol) was added every hour while the reaction was stirred at reflux for 13 h. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was directly purified by flash column chromatography (pentane to diethyl ether, gradient elution) to provide the title compound (924 mg, 30%).

[0641] LC / MS (Table 1, Method D) R t =1.62min; MS m / z:421[M+H] + .

[0642] (iii) (±)-2-(3-chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)isoindoline-1,3-dione

[0643] The reaction vessel was charged with (±)-S-(3-(6-chloropyridin-3-yl)-1-(1,3-dioxoisoindolin-2-yl)propyl)O-ethyl dithiocarbonate ((Compound 66, Step (ii), 906 mg, 2.15 mmol)), trifluoroacetic acid (0.19 mL, 2.44 mmol) and solvated in 1,2-dichloroethane (20.0 mL). Lauroyl peroxide (172 mg, 0.430 mmol) was added and the reaction was set to stir at room temperature. The reaction was then heated to reflux. Additional lauroyl peroxide (172 mg, 0.430 mmol) was added every hour while the reaction was stirred at reflux for 5 h. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was directly purified by flash column chromatography (pentane to diethyl ether, gradient elution) to provide the title compound (119 mg, 19%).

[0644] LC / MS (Table 1, Method D) R t =1.40min; MS m / z:299[M+H] + .

[0645] (iv) (±)-2-(3-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)isoindoline-1,3-dione

[0646] The title compound was prepared from appropriate starting materials: (±)-2-(3-chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)isoindoline-1,3-dione (compound 66, step (iii)) and 2,2,2-trifluoroethanol (CAS: 75-89-8) using a reaction protocol similar to that described for compound 21: 1-(3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iv). The compound was purified by flash column chromatography (pentane to diethyl ether, gradient elution) to provide the title compound (74 mg, 41%).

[0647] LC / MS (Table 1, Method D) R t =1.64min; MS m / z:362[M+H]+ .

[0648] (v) (±)-3-(2,2,2-Trifluoroethoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-amine

[0649] The reaction vessel was charged with (±)-2-(3-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)isoindoline-1,3-dione ((Compound 66, Step (iv), 74 mg, 0.204 mmol)) and solvated in MeOH (2.0 mL). A 1 M solution of hydrazine in THF (0.41 mL, 0.409 mmol) was added and the reaction was heated to 60 ° C for 18 h. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was directly purified by flash column chromatography (DCM to DCM:MeOH [2M NH 3 ] 90:10, gradient elution) to provide the title compound (32 mg, 67%).

[0650] 1 H NMR(400MHz, CDCl3)δ7.94(s,1H),6.81(s,1H),4.78-4.71(m,2H),4.32-4.27(m,1H),2.94 -2.87(m,1H),2.79-2.70(m,1H),2.57-2.49(m,1H),1.78-1.67(m,1H),1.51-1.58(s,2H).

[0651] (vi) (±)-1-(3-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0652] Starting from the appropriate starting materials (±)-3-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-amine (compound 66, step (v)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (25 mg, 42%).

[0653] 1H NMR (400MHz, DMSO-d6) δ8.02(s,1H),6.68(s,1H),6.43(d,J=8.1Hz,1H),5.89(t,J=5.8Hz,1H),5.07-4.89(m,3H),3.18-3.1 1(m,2H),2.89-2.81(m,1H),2.77-2.66(m,1H),2.44-2.31(m,1H),1.77-1.67(m,3H),0.92-0.88(m,2H),0.78-0.75(m,2H).

[0654] LC / MS (Table 1, Method B) R t =4.76 min; MS m / z:412 [M+H] + .

[0655] Compound 67

[0656] (S)-1-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0657] The title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea starting from the appropriate commercially available starting materials, (S)-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethan-1-amine hydrochloride and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2). Starting from the appropriate commercially available auxiliary (S)-2-methyl-2-propanesulfenamide (CAS: 343338-28-3), (S)-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iv) was followed by a reaction scheme analogous to that described for compound 65: (R)-1-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 7) to afford a white solid (45 mg, 58%).

[0658] 1H NMR (400MHz, DMSO-d6) δ8.10(d,J=5.3Hz,1H),7.01(dd,J=1.0,5.3Hz,1H),6.82(s,1H),6.54(d,J=7.9Hz,1H),5.90(dd,J=5.8,5.8Hz,1H),4. 96(q,J=9.1Hz,2H),4.73-4.65(m,1H),3.11-3.04(m,2H),1.64(dd,J=6.4,9.0Hz,2H),1.28(d,J=7.1Hz,3H),0.89-0.85(m,2H),0.72(s,2H).

[0659] LC / MS (Table 1, Method F) R t =4.66min; MS m / z:400[M+H] + .

[0660] Compound 68

[0661] 1-((2-(methyl(2,2,2-trifluoroethyl)amino)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0662] (i) 2-(Methyl(2,2,2-trifluoroethyl)amino)isonicotinonitrile

[0663] The title compound was prepared starting from the appropriate commercially available starting materials 4-cyano-2-fluoropyridine (CAS: 3939-14-8) and 2,2,2-trifluoro-N-methyl-ethylamine hydrochloride (CAS: 2730-52-1) using a reaction scheme similar to that described for compound 28: (±)-1-((2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (i). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (187 mg, 38%).

[0664] LC / MS (Table 1, Method H) R t =1.72 min; MS m / z: 216 [M+H] + .

[0665] (ii) 4-(Aminomethyl)-N-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine

[0666] The title compound was prepared from the appropriate starting material, 2-(methyl(2,2,2-trifluoroethyl)amino)isonicotinonitrile (compound 68, step (i)) using a reaction scheme similar to that described for compound 11: 1-((6-(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (ii). The compound was purified by flash column chromatography (DCM to DCM:MeOH [2M NH 3 ] 90:10, gradient elution) to afford the title compound (100 mg, 52%).

[0667] LC / MS (Table 1, Method D) R t =1.13min; MS m / z: 220 [M+H] + .

[0668] (iii) 1-((2-(methyl(2,2,2-trifluoroethyl)amino)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0669] Starting from appropriate starting materials 4-(aminomethyl)-N-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine (compound 68, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS:1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) followed by flash column chromatography (DCM to EtOAc, gradient elution) to afford a white solid (43 mg, 45%).

[0670] 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=5.1Hz,1H),6.60-6.56(m,2H),6.46(t,J=6.1Hz,1H),6.03(t,J=5.8Hz,1H),4.47(q,J=9 .6Hz,2H),4.14(d,J=6.1Hz,2H),3.15-3.07(m,2H),3.05(s,3H),1.70-1.64(m,2H),0.91-0.86(m,2H),0.76-0.72(m,2H).

[0671] LC / MS (Table 1, Method F) R t =3.22 min; MS m / z: 399 [M+H] + .

[0672] Compound 69

[0673] 1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-3-((2-(trifluoromethyl)pyridin-4-yl)methyl)urea

[0674] Starting from the appropriate commercially available starting materials (2-(trifluoromethyl)pyridin-4-yl)methanamine (CAS: 916304-20-6) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 3) to provide a white solid (79 mg, 72%).

[0675] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=5.0Hz,1H),7.71(s,1H),7.54(d,J=5.0Hz,1H),6.65(dd,J=6.1,6.1Hz,1H),6.19(dd,J=5.8,5 .8Hz,1H),4.32(d,J=6.1Hz,2H),3.11(dd,J=6.2,15.1Hz,2H),1.70-1.65(m,2H),0.91-0.86(m,2H),0.73(dd,J=6.8,6.8Hz,2H).

[0676] LC / MS (Table 1, Method F) R t =4.19 min; MS m / z: 356 [M+H] + .

[0677] Compound 70

[0678] 1-((4,4-difluorocyclohexyl)methyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0679] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (4,4-difluorocyclohexyl)methanamine (CAS: 810659-05-3), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 7) to provide a white solid (38 mg, 36%).

[0680] 1H NMR (400MHz, DMSO-d6) δ8.10(d,J=5.3Hz,1H),6.96(d,J=5.3Hz,1H),6.76(s,1H),6.42(dd,J=6.1,6.1Hz,1H),6.19(dd,J=6.0,6.0Hz,1H),4.97(q,J= 9.1Hz,2H),4.21(d,J=6.2Hz,2H),2.93(dd,J=6.3,6.3Hz,2H),2.02-1.95( m,2H),1.83-1.68(m,4H),1.49(dd,J=3.5,10.4Hz,1H),1.19-1.11(m,2H).

[0681] LC / MS (Table 1, Method F) R t =4.32 min; MS m / z: 382 [M+H] + .

[0682] Compound 71

[0683] 1-(4,4-difluorocyclohexyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0684] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and 4,4-difluorocyclohexane-1-amine hydrochloride (CAS: 675112-70-6), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 7) to provide a white solid (53 mg, 52%).

[0685] 1 H NMR (400MHz, DMSO-d6) δ8.10(d,J=5.3Hz,1H),6.97(d,J=5.3Hz,1H),6.77(s,1H),6.33(dd,J=6.1,6.1Hz,1H),6.19(d ,J=7.7Hz,1H),4.98(q,J=9.1Hz,2H),4.23-4.20(m,2H),3.59(d,J=8.4Hz,1H),2.01-1.77(m,6H),1.49-1.37(m,2H).

[0686] LC / MS (Table 1, Method F) R t =4.22 min; MS m / z: 368 [M+H] + .

[0687] Compound 72

[0688] 6-Fluoro-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)indoline-1-carboxamide

[0689] (i) 6-Fluoroindoline-1-carbonyl chloride

[0690] At 0 ℃, to 6-fluoroindoline hydrochloride (250mg, 1.44mmol) and pyridine (0.23mL, 2.88mmol) in DCM (5.0mL) solution by dropwise addition triphosgene (214mg, 0.720mmol).Reactant is warmed to room temperature and stirred at room temperature for 18h.Reactant mixture is quenched by adding 1M HCl aqueous solution, and is then distributed with DCM.The organic layer is separated.The organic layer merged is washed with saturated brine, dried (Na2SO4) and concentrated in a vacuum to provide title compound (358mg, quantitative).

[0691] LC / MS (Table 1, Method D) R t =1.55min; MS m / z: 200 [M+H] + .

[0692] (ii) 6-Fluoro-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)indoline-1-carboxamide

[0693] At 0 ° C, under nitrogen, to a solution of 6-fluoroindoline-1-carbonyl chloride (106 mg, 0.534 mmol) and N, N-diisopropylethylamine (0.21 mL, 1.21 mmol) in DCM (2.0 mL) was added a solution of (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methylamine (CAS: 561297-93-6, 100 mg, 0.485 mmol) in DCM (2.0 mL). The reactants were allowed to warm to room temperature and stirred at room temperature for 18 h. The reaction mixture was then partitioned between DCM and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) to provide the title compound (105 mg, 57%) as an off-white solid.

[0694] 1H NMR (400MHz, DMSO-d6) δ8.12(d,J=5.3Hz,1H),7.57(dd,J=2.6,11.3Hz,1H),7.42(t,J=5.9Hz,1H),7.14(dd,J=6.0,8.1Hz,1H),7.06(dd,J=1.3, 5.3Hz, 1H), 6.87 (s, 1H), 6.63 (dq, J = 8.2, 3.9Hz, 1H), 4.98 (q, J = 9.1Hz, 2H), 4.34 (d, J = 5.8Hz, 2H), 4.04 (t, J = 8.7Hz, 2H), 3.12 (t, J = 8.7Hz, 2H).

[0695] LC / MS (Table 1, Method F) R t =4.82 min; MS m / z: 370 [M+H] + .

[0696] Compound 73

[0697] (R)-1-(2-Hydroxy-3,3-dimethylbutyl)-3-((2-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)methyl)urea

[0698] (i) 2-(2,2,3,3,3-pentafluoropropoxy)isonicotinonitrile

[0699] The title compound was prepared from the appropriate commercially available starting materials, 2-chloro-4-pyridinecarbonitrile (CAS: 33252-30-1) and 2,2,3,3,3-pentafluoro-1-propanol (CAS: 422-05-9), using a reaction scheme similar to that described for compound 26: 1-((2-morpholino-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (ii). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (420 mg, 46%).

[0700] LC / MS (Table 1, Method D) R t =1.58min; MS m / z: 253 [M+H] + .

[0701] (ii) (2-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)methanamine

[0702] The title compound was prepared from the appropriate starting material, 2-(2,2,3,3,3-pentafluoropropoxy)isonicotinonitrile (compound 73, step (i)), using a reaction scheme analogous to that described for compound 11: 1-((6-(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (ii). This afforded the title compound (350 mg, 65%). The product was carried forward into step (iii) without further characterization.

[0703] (iii) (R)-1-(2-hydroxy-3,3-dimethylbutyl)-3-((2-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)methyl)urea

[0704] Starting from appropriate starting materials (2-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)methanamine (compound 73, step (ii)) and (R)-1-amino-3,3-dimethylbutan-2-ol hydrochloride (CAS: 2089245-23-6), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to MeOH, gradient elution) to afford a white solid (97 mg, 69%).

[0705] 1 H NMR(400MHz,DMSO-d6)δ8.11(d,J=5.3Hz,1H),6.98(dd,J=1.3,5.3Hz,1H),6.77( s,1H),6.66(t,J=6.1Hz,1H),5.98(dd,J=3.5,7.3Hz,1H),5.07(ddd,J=13.8,13. 8,1.0Hz,2H),4.72(d,J=5.6Hz,1H),4.22(dd,J=2.5,6.0Hz,2H),3.40-3.34(m,1 H), 3.06 (dq, J=2.6, 5.0Hz, 1H), 2.70 (ddd, J=3.7, 9.4, 13.2Hz, 1H), 0.84 (s, 9H).

[0706] LC / MS (Table 1, Method F) R t =4.40min; MS m / z:400[M+H] + .

[0707] Compound 74

[0708] 1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-3-((2-(3,3,3-trifluoropropoxy)pyridin-4-yl)methyl)urea

[0709] The title compound was prepared starting from appropriate starting materials (2-(3,3,3-trifluoropropoxy)pyridin-4-yl)methanamine dihydrochloride and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-(3,3,3-trifluoropropoxy)pyridin-4-yl)methanamine dihydrochloride was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 61: 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)acetamide, steps (i-iii). The title compound was purified by reverse phase HPLC (Table 2, Method 2, non-linear gradient from 5% to 60% MeCN) to afford an off-white solid (90 mg, 65%).

[0710] 1 H NMR (400MHz, DMSO-d6) δ8.08(d,J=5.3Hz,1H),6.88(dd,J=1.4,5.4Hz,1H),6.64(s,1H),6.52(t,J=6.1Hz,1H),6.09(t,J=5.8Hz,1H),4.4 7(t,J=6.0Hz,2H),4.18(d,J=6.1Hz,2H),3.12(q,J=7.1Hz,2H),2.84-2.72(m,2H),1.68(t,J=7.8Hz,2H),0.92-0.88(m,2H),0.76(s,2H).

[0711] LC / MS (Table 1, Method A) R t =4.64min; MS m / z:400[M+H] + .

[0712] Compound 75

[0713] 1-(2-chlorobenzyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0714] Starting from appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and 2-chlorobenzylamine (CAS: 89-97-4), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 6, non-linear gradient from 40% to 100% MeOH) followed by reverse phase HPLC (Table 2, Method 3) to afford an off-white solid (38 mg, 41%).

[0715] 1 H NMR (400MHz, DMSO-d6) δ8.12(dd,J=0.5,5.3Hz,1H),7.44(dd,J=1.3,7.5Hz,1H),7.38-7.27(m,3H),7.00(dd,J=1.3,5.3Hz,1H) ,6.81(s,1H),6.72(t,J=6.3Hz,1H),6.67(t,J=6.0Hz,1H),5.00(q,J=9.2Hz,2H),4.32(d,J=5.9Hz,2H),4.26(d,J=6.0Hz,2H).

[0716] LC / MS (Table 1, Method E) R t =4.58 min; MS m / z: 374 [M+H] + .

[0717] Compound 76

[0718] 1-(3-fluorobenzyl)-3-((6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)urea

[0719] The title compound was prepared using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea starting from appropriate commercially available starting materials (6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methanamine dihydrochloride and 3-fluorobenzylamine (CAS: 100-82-3). (6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methanamine dihydrochloride was correspondingly prepared following a reaction scheme analogous to that described for compound 61: 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)acetamide, steps (i-iii). The title compound was purified by reverse phase HPLC (Table 2, Method 2, non-linear gradient from 5% to 60% MeCN) followed by reverse phase HPLC (Table 2, Method 3) to afford an off-white solid (22 mg, 17%).

[0720] 1 H NMR(400MHz, DMSO-d6)δ8.79(d,J=1.0Hz,1H),7.39-7.33(m,1H),7.13-7.02(m,3H),6.87(s,1H),6.81(t ,J=6.1Hz,1H),6.70(t,J=6.1Hz,1H),5.10(q,J=9.0Hz,2H),4.30(d,J=6.0Hz,2H),4.26(d,J=6.0Hz,2H).

[0721] LC / MS (Table 1, Method A) R t =4.10min; MS m / z:359[M+H] + .

[0722] Compound 77

[0723] 1-(3-chloro-5-fluorophenyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0724] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and 3-chloro-5-fluoroaniline (CAS: 4863-91-6), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 7) to provide a white solid (17 mg, 16%).

[0725] 1H NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 8.13 (d, J = 5.3Hz, 1H), 7.35 (dd, J = 2.0, 2.0Hz, 1H), 7.31-7.26 ( m,1H),7.04-7.00(m,2H),6.93-6.89(m,1H),6.83(s,1H),5.02-4.94(m,2H),4.31(d,J=5.9Hz,2H).

[0726] LC / MS (Table 1, Method B) R t =4.98min; MS m / z:378[M+H] + .

[0727] Compound 78

[0728] (R)-1-(2-Hydroxy-3,3-dimethylbutyl)-3-((2-(3,3,3-trifluoropropoxy)pyridin-4-yl)methyl)urea

[0729] The title compound was prepared starting from appropriate commercially available starting materials (2-(3,3,3-trifluoropropoxy)pyridin-4-yl)methanamine dihydrochloride and (R)-1-amino-3,3-dimethylbutan-2-ol hydrochloride (CAS: 2089245-23-6) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-(3,3,3-trifluoropropoxy)pyridin-4-yl)methanamine was prepared accordingly starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 61: 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)acetamide, steps (i-iii). The title compound was purified by reverse phase HPLC (Table 2, Method 3) to afford an off-white solid (45 mg, 70%).

[0730] 1 H NMR (400MHz, DMSO-d6) δ8.09(d,J=5.3Hz,1H),6.89(dd,J=1.2,5.3Hz,1H),6.65(s,2H),5.98(q,J=3.6Hz,1H),4.74(d,J=5.6Hz ,1H),4.48(t,J=6.0Hz,2H),4.20(dd,J=2.0,5.9Hz,2H),3.42-3.37(m,1H),3.10-3.04(m,1H),2.85-2.67(m,3H),0.85(s,9H).

[0731] LC / MS (Table 1, Method F) R t =4.03min; MS m / z:364[M+H] + .

[0732] Compound 79

[0733] 1-((3,3-difluorocyclohexyl)methyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0734] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (3,3-difluorocyclohexyl)methanamine (CAS: 1379151-12-8), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 7) to afford a white solid (61 mg, 63%).

[0735] 1 H NMR (400MHz, DMSO-d6) δ8.09(d,J=5.3Hz,1H),6.96(d,J=5.3Hz,1H),6.76(s,1H),6.42(dd,J=6.1,6.1Hz,1H),6.21(dd,J=6.0,6.0Hz,1H), 4.97(q,J=9.1Hz,2H),4.21(d,J=6.1Hz,2H),3.01-2.90(m,2H),2.01- 1.93(m,2H),1.79-1.58(m,4H),1.50-1.32(m,2H),1.01-0.88(m,1H).

[0736] LC / MS (Table 1, Method F) R t =4.36min; MS m / z:382[M+H] + .

[0737] Compound 80

[0738] 1-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0739] Starting from the appropriate commercially available starting materials (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine (CAS: 771584-26-0) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 8) to provide a white solid (18 mg, 18%).

[0740] 1 H NMR (400MHz, DMSO-d6) δ8.07(d,J=2.0Hz,1H),7.69(dd,J=2.4,8.5Hz,1H),6.95(d,J=8.5Hz,1H),6.44(dd,J=6.0,6.0Hz,1H),5.99(dd,J=5.8,5.8H z,1H),4.98(q,J=9.2Hz,2H),4.15(d,J=6.0Hz,2H),3.11(dd,J=6.1,15.2 Hz, 2H), 1.70-1.64 (m, 2H), 0.92-0.87 (m, 2H), 0.74 (dd, J = 6.7, 6.7Hz, 2H).

[0741] LC / MS (Table 1, Method A) R t =4.61min; MS m / z:386[M+H] + .

[0742] Compound 81

[0743] (±)-1-(6-Fluoro-2,3-dihydro-1H-inden-1-yl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0744] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (±)-6-fluoro-2,3-dihydro-1H-inden-1-amine hydrochloride (CAS: 1191908-44-7), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford a white solid (51 mg, 54%).

[0745] 1H NMR (400MHz, DMSO-d6) δ8.12 (dd, J = 0.5, 5.3Hz, 1H), 7.27-7.22 (m, 1H), 7.04-6. 98(m,2H),6.94(dd,J=2.2,9.0Hz,1H),6.82(s,1H),6.57(d,J=8.3Hz,1H),6.46( t,J=6.1Hz,1H),5.11(q,J=7.9Hz,1H),4.98(q,J=9.2Hz,2H),4.28(d,J=6.2Hz, 2H),2.91-2.82(m,1H),2.78-2.69(m,1H),2.47-2.39(m,1H),1.82-1.72(m,1H).

[0746] LC / MS (Table 1, Method F) R t =4.57 min; MS m / z: 384 [M+H] + .

[0747] Compound 82

[0748] 1-((2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0749] The title compound was prepared starting from appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyridin-4-yl)methanamine was correspondingly prepared starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 11: 1-((6-(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by flash column chromatography (DCM to MeOH, gradient elution) to afford an off-white solid (51 mg, 31%).

[0750] 1H NMR (400MHz, DMSO-d6) δ7.48(s,1H),7.09(s,1H),6.63(t,J=6.1Hz,1H),6.19(t,J=5.8Hz,1H),5.02(q,J=9.0Hz, 2H), 4.29 (d, J = 6.1Hz, 2H), 3.11 (dd, J = 6.2, 15.0Hz, 2H), 1.70-1.65 (m, 2H), 0.90-0.86 (m, 2H), 0.75-0.71 (m, 2H).

[0751] LC / MS (Table 1, Method F) R t =5.11min; MS m / z:454[M+H] + .

[0752] Compound 83

[0753] (R)-1-(2-Hydroxy-3,3-dimethylbutyl)-3-((2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyridin-4-yl)methyl)urea

[0754] The title compound was prepared starting from appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyridin-4-yl)methanamine and (R)-1-amino-3,3-dimethylbutan-2-ol hydrochloride (CAS: 2089245-23-6) using a reaction scheme analogous to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyridin-4-yl)methanamine was correspondingly prepared starting from appropriate commercially available starting materials following a reaction scheme analogous to that described for compound 11: 1-((6-(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 3, non-linear gradient from 40% to 100% MeCN) to afford an off-white solid (41 mg, 51%).

[0755] 1 H NMR (400MHz, DMSO-d6) δ7.50(s,1H),7.12(s,1H),6.76(t,J=6.1Hz,1H),6.10-6.05(m,1H),5.04(q,J=9 .0Hz,2H),4.73(d,J=5.5Hz,1H),4.35-4.31(m,2H),3.10-3.05(m,1H),2.77-2.68(m,2H),0.85(s,9H).

[0756] LC / MS (Table 1, Method A) R t =4.80 min; MS m / z:418 [M+H] + .

[0757] Compound 84

[0758] (R)-N-(2-Hydroxy-3,3-dimethylbutyl)-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide

[0759] (i) tert-Butyl 6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate

[0760] The title compound was prepared from the appropriate commercially available starting materials tert-butyl 6-chloro-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxylate (CAS: 1700330-18-2) and 2,2,2-trifluoroethanol (CAS: 75-89-8) using a reaction scheme similar to that described for compound 21: 1-(3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iv). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (187 mg, 80%).

[0761] 1 H NMR (400MHz, CDCl3) δ8.03 (d, J = 16.4Hz, 1H), 6.76 (d, J = 21.8Hz, 1H), 4.76 (dd, J = 7.5, 17.5Hz, 2H), 4.65 (s, 2H), 4.62 (s, 2H), 1.52 (s, 9H).

[0762] (ii) 6-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine

[0763] To a solution of tert-butyl 6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate ((Compound 84, Step (i), 187 mg, 0.588 mmol)) in DCM (1.0 mL) was added trifluoroacetic acid (0.45 mL, 5.88 mmol) at 0°C. The reaction was allowed to warm to room temperature and stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by SCX-2 column chromatography (DCM to DCM:MeOH[2M NH3] 90:10, gradient elution) to provide the title compound (106 mg, 83%).

[0764] LC / MS (Table 1, Method D) R t =1.00min; MS m / z: 219 [M+H] + .

[0765] (iii) 6-(2,2,2-Trifluoroethoxy)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carbonyl chloride

[0766] The title compound was prepared from the appropriate starting material, 6-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (compound 84, step (ii)) using a reaction scheme analogous to that described for compound 72: 6-fluoro-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)indoline-1-carboxamide, step (i). This afforded the title compound (71 mg, 84%).

[0767] LC / MS (Table 1, Method D) R t =1.68min; MS m / z:281[M+H] + .

[0768] (iv) (R)-N-(2-hydroxy-3,3-dimethylbutyl)-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide

[0769] Starting from the appropriate commercially available starting materials 6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carbonyl chloride (compound 84, step (iii)) and (R)-1-amino-3,3-dimethylbutan-2-ol hydrochloride (CAS: 2089245-23-6), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to MeOH, gradient elution) to afford an off-white solid (31 mg, 33%).

[0770] 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),6.98(s,1H),6.27(t,J=5.5Hz,1H),4.99(q,J=9.1Hz,2H),4.78(d, J=4.4Hz,1H),4.60-4.56(m,4H),3.42-3.35(m,1H),3.20-3.15(m,1H),2.86-2.78(m,1H),0.87(s,9H).

[0771] LC / MS (Table 1, Method F) R t =4.07min; MS m / z:362[M+H] + .

[0772] Compound 85

[0773] 1-(2-chloro-5-fluorobenzyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0774] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and 2-chloro-5-fluorobenzylamine (CAS: 202522-23-4), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) followed by reverse phase HPLC (Table 2, Method 8) to afford an off-white solid (5.9 mg, 6%).

[0775] 1H NMR(400MHz, DMSO-d6)δ8.12(d,J=5.3Hz,1H),7.49(dd,J=5.1,8.8Hz,1H),7.19-7.09(m,2H),7.00(dd,J=1.3 ,5.3Hz,1H),6.81(t,J=6.2Hz,2H),6.76(t,J=6.0Hz,1H),4.99(q,J=9.1Hz,2H),4.28(dd,J=6.1,9.5Hz,4H).

[0776] LC / MS (Table 1, Method B) R t =4.64min; MS m / z:392[M+H] + .

[0777] Compound 86

[0778] (R)-1-(6-Fluoro-2,3-dihydro-1H-inden-1-yl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0779] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (R)-6-fluoro-2,3-dihydro-1H-inden-1-amine (CAS: 731859-02-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to MeOH, gradient elution) followed by reverse phase HPLC (Table 2, Method 7, non-linear gradient 30% to 95% MeCN) to afford a white solid (49 mg, 52%).

[0780] 1 H NMR(400MHz,DMSO-d6)δ8.12(d,J=5.3Hz,1H),7.24(dd,J=5.3,8.2Hz,1H),7.04-6.9 8(m,2H),6.94(dd,J=2.2,9.0Hz,1H),6.82(s,1H),6.58(d,J=8.3Hz,1H),6.47(t,J=6 .0Hz,1H),5.11(q,J=8.2Hz,1H),4.98(q,J=9.1Hz,2H),4.28(d,J=6.1Hz,2H),2.86(d dd,J=3.0,8.7,15.5Hz,1H),2.78-2.68(m,1H),2.47-2.38(m,1H),1.82-1.72(m,1H).

[0781] LC / MS (Table 1, Method F) R t =4.61min; MS m / z:384[M+H] + .

[0782] Compound 87

[0783] 1-((5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0784] (i) tert-Butyl ((2-chloro-5-fluoropyridin-4-yl)methyl)carbamate

[0785] The title compound was prepared starting from the appropriate commercially available starting material, 2-chloro-5-fluoro-pyridine-4-carbonitrile (CAS: 1057319-20-6) using a reaction scheme similar to that described for compound 61: 2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)acetamide, step (i). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (266 mg, 23%).

[0786] LC / MS (Table 1, Method D) R t =1.57min; MS m / z:261[M+H] + .

[0787] (ii) tert-Butyl ((5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)carbamate

[0788] The title compound was prepared from appropriate starting materials, tert-butyl ((2-chloro-5-fluoropyridin-4-yl)methyl)carbamate (compound 87, step (i)) and 2,2,2-trifluoroethanol (CAS: 75-89-8) using a reaction scheme similar to that described for compound 21: 1-(3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iv). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to provide the title compound (76 mg, 76%).

[0789] LC / MS (Table 1, Method D) R t =1.78min; MS m / z:325[M+H] + .

[0790] (iii) (5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine hydrochloride

[0791] The title compound was prepared from the appropriate starting material, tert-butyl ((5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)carbamate (compound 87, step (ii)), using a reaction scheme analogous to that described for compound 6: 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (iii). The compound was triturated with diethyl ether to afford the title compound (52 mg, 85%).

[0792] LC / MS (Table 1, Method D) R t =1.12 min; MS m / z: 225 [M+H] + .

[0793] (iv) 1-((5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea

[0794] Starting from appropriate starting materials (5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine hydrochloride (compound 87, step (iii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethane-1-amine hydrochloride (CAS: 1454690-80-2), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by flash column chromatography (DCM to MeOH, gradient elution) to afford a white solid (27 mg, 37%).

[0795] 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=1.4Hz,1H),6.78(d,J=5.0Hz,1H),6.56(t,J=6.0Hz,1H),6.19(t,J=5.7Hz,1H),4.9 4(q,J=9.1Hz,2H),4.25(d,J=6.1Hz,2H),3.15-3.07(m,2H),1.70-1.65(m,2H),0.91-0.86(m,2H),0.76-0.71(m,2H).

[0796] LC / MS (Table 1, Method B) R t =4.71min; MS m / z:404[M+H] + .

[0797] Compound 88

[0798] 1-((3,3-difluorocyclopentyl)methyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea

[0799] Starting from the appropriate commercially available starting materials (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (3,3-difluorocyclopentyl)methanamine hydrochloride (CAS: 1439900-13-6), the title compound was prepared using a reaction scheme similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. The title compound was purified by reverse phase HPLC (Table 2, Method 7) to provide a white solid (54 mg, 52%).

[0800] 1 H NMR (400MHz, DMSO-d6) δ8.10(d,J=5.4Hz,1H),6.96(d,J=5.2Hz,1H),6.76(s,1H),6.44(dd,J=6.1,6.1Hz,1H),6.24(dd,J=5.9,5.9Hz, 1H), 4.97 (q, J = 9.1Hz, 2H), 4.21 (d, J = 6.1Hz, 2H), 3.03 (dd, J = 6.3, 6.3Hz, 2H), 2.27-1.96 (m, 4H), 1.87-1.69 (m, 2H), 1.49-1.38 (m, 1H).

[0801] LC / MS (Table 1, Method F) R t =4.20min; MS m / z:368[M+H] + .

[0802] Example 2

[0803] Targeting K V 7.2 / K V 7.3 In vitro efficacy evaluation of channels

[0804] An automated patch-clamp assay was developed for potency testing on the Sophion Qube 384 to identify heteromeric K V 7.2 / K V Small molecule activators of the 7.3 channel (KCNQ2, Uniprot ID 043526; KCNQ3, Uniprot ID 043525).

[0805] The cell line used was a stably transfected CHO-K1 cell line, which has a constitutive K V7.2 / K V 7.3 Expression.

[0806] Maintain CHO-K1 / Kv7.2 / Kv7.3 cells in the following culture medium:

[0807] Contains GlutaMAX TM DMEM / F-12 (Gibco 31331-028),

[0808] 10% fetal clone 2 serum (Perbio Science SH30066.03),

[0809] 1mg / ml Geneticin TM Selective antibiotics (G418, Invitrogen 1013027), and

[0810] ·5μg / ml BlasticidinS HCl (Invivogen Ant-bl-5).

[0811] On the day of the experiment, cells were resuspended in serum-free medium, counted, and diluted to 3.5 x 10 cells per ml of medium. 6 The final concentration of cells.

[0812] The cells were then plated on a Sophion Qube 384 and allowed to rest for at least 1 hour.

[0813] The following solutions were used for recording:

[0814] Extracellular solution (in mM): 145 NaCl, 4 KCl, 1 MgCl2, 2 CaCl2, 10 HEPES, 10 glucose, pH 7.4, 315-320 mOsm.

[0815] Intracellular solution (in mM): 120 KCl, 5.74 CaCl2, 1.75 MgCl2, 10 EGTA, 10 HEPES, 5 Na2ATP, pH 7.2, adjusted to 315 mOsm with sucrose.

[0816] After establishing the full-cell configuration, cells were kept at -80 mV during the entire experiment. A current-voltage (IV) protocol was used, with 1 second steps from -100 mV to +20 mV to measure Kv7.2 / Kv7.3 currents, each followed by a 200 ms pulse to 0 mV to measure tail currents. Boltzmann fitting was applied to generate activation curves from the IV protocol. Data were sampled at 25 kHz and filtered at 5 kHz (Bessel). Multi-porous QChips were used to generate data. The IV protocol was applied multiple times to determine the response under control conditions (usually 0.3% DMSO) and in the presence of the test compound.

[0817] Data were reviewed in Sophion Analyser version 6.5.2 (Sophion Bioscience) to ensure recording quality, and any failed wells were removed using filters. Leakage subtraction was applied to all recordings. Data filters for multi-well QChips were typically: seal resistance >4 MΩ, capacitance >20 pF, baseline V 半 Between 0 and -40 mV, the baseline holding current was between -2 and 2 nA, and the baseline steady-state current at 20 mV was >4 nA (unless otherwise stated).

[0818] Targeting K V 7.4 In vitro potency evaluation of channels

[0819] We also developed a K-type homopolymer on Qube. V 7.4 channel (KCNQ4, Uniprot ID P56696) counter screening assay. The cell line used was stably transfected CHO-K1, which has a constitutive K V 7.4 Expression, provided by Charles River Laboratories.

[0820] Stably express K V CHO-K1 cells at passage 7.4 were maintained in the following culture medium:

[0821] Contains GlutaMAX TM Hams F-12(Life Technologies 31765027),

[0822] 10% fetal clone 2 serum (Perbio Science SH30066.03), and

[0823] 250 μg / ml Geneticin TM Selective antibiotic (G418, Invitrogen 1013-027).

[0824] Cell maintenance, preparation, recording conditions, and voltage protocols were identical to those described above.

[0825] Targeting K V 7.3 / K V 7.5-channel in vitro potency assessment

[0826] Also targets heteromeric K V 7.3 / K V The cells used were stably transfected HEK293 cells, which have a constitutive K V 7.3 Expression and Tetracycline-Inducible K V 7.5 expression, provided by Charles River Laboratories.

[0827] Maintain cells in the following culture medium:

[0828] Contains GlutaMAX TM DMEM / F-12 (Life Technologies 31331-028),

[0829] ·10% Tet Systems FCS (Clonetech 631106),

[0830] 500 μg / ml Geneticin TM Selective antibiotic (G418, Invitrogen 1013-027),

[0831] ·5μg / ml Blasticidin S HCl (InvivoGen ant-bl-5), and

[0832] ·100μg / ml Zeocin (InvivoGen:ant-zn-5).

[0833] Cell maintenance, preparation, recording conditions, and voltage protocols were identical to those described above.

[0834] Analyze data to evaluate performance

[0835] Ten concentrations of test compounds were added to each well in quadruplicate and the potency was assessed in a 1 / 3 dilution series starting from a maximum concentration of 30 μM. The half activation voltage (V 半 ) were used to generate concentration-response curves and fitted with a 4-parameter logistic model to estimate the EC at the inflection point of the curve. 50And V at the vertex of the curve 半 The maximum offset.

[0836] The results are summarized in Table 3 below. 50 The lower the value, the more potent the compound analyzed. 半 Selective compounds showed a Kv7.4 and / or Kv7.3 / 7.5 ΔV shift equal to or less than 15 mV. 1 / 2 (Letter A in Table 3). Non-selective compounds showed Kv7.4 and / or Kv7.3 / 7.5 ΔV greater than 15 mV 1 / 2 (Letter B in Table 3) In Table 3, ND means the selectivity was not determined.

[0837] Table 3

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848] The obtained EC50 values ​​indicate that all tested compounds have the ability to activate Kv7.2 / 7.3 potassium channels. Most of them are also selective for Kv7.4 and / or Kv7.3 / 7.5 potassium channels.

Claims

1. A Kv7.2 / 7.3 potassium channel activator compound or a pharmaceutically acceptable salt thereof for use in treating disorders mediated by Kv7.2 / Kv7.3 potassium channels, wherein the compound has the following general formula (I): R1 is represented by ---L1---A1, where L1 is a bond or a linear or branched C1-C6 alkyl chain, optionally substituted with one or more halogen atoms or hydroxyl groups, and optionally containing an oxy (—O—) group within the alkyl chain or at any terminus, and A1 is a hydrogen atom, or (i) an aromatic or aliphatic ring having 3 to 6 members, optionally containing one or more heteroatoms selected from N, O and S, unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3, a C1-C3 alkyl chain optionally substituted by one or more halogen atoms and AR, wherein AR is an aromatic or aliphatic ring, optionally containing one or more heteroatoms selected from N, O and S, unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3 and a C1-C3 alkyl chain optionally substituted by one or more halogen atoms, or (ii) a fused or bridged bicyclic ring having 5 to 12 members, optionally containing one or more heteroatoms selected from N, O and S, unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3, O-Gr and C1-C3 alkyl optionally substituted by one or more halogen atoms, wherein Gr is an aliphatic ring having 3 to 6 members, optionally containing one or more heteroatoms selected from N, O and S, unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3, C1-C3 alkyl chain optionally substituted by one or more halogen atoms; R2 is hydrogen or a C1-C3 alkyl chain; R3 is hydrogen or a C1-C3 alkyl chain optionally substituted by a hydroxyl group, or an aliphatic ring, optionally containing one or more heteroatoms selected from N, O and S, unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN and CF3; R4 is represented by ---L2---A2, where L2 is a bond or a C1-C3 alkyl chain, and A2 is an aromatic ring having 6 members and containing 1 or 2 nitrogen atoms, optionally fused to an aliphatic ring having 5 or 6 carbon atoms, said aromatic ring being substituted by one or more substituents selected from (i) halogen atoms, (ii) a C1-C3 alkyl chain, optionally substituted by one or more halogen atoms, (iii) an aliphatic ring having 4 to 6 members containing one or more heteroatoms selected from O and N, optionally substituted by one or more halogen atoms or a C1-C3 alkyl chain, said C1-C3 alkyl chain optionally substituted by one or more halogen or hydroxyl groups, and (iv) a group represented by the following formula: S6---L3---A3, wherein S6 is an oxygen or nitrogen atom, L3 is a bond or a C1-C4 alkyl chain, and A3 is (a) an aliphatic or aromatic ring having 3 to 6 members, optionally containing one or more heteroatoms selected from O and N, and optionally substituted by a halogen atom or a C1-C3 alkyl chain, optionally substituted by one or more halogen, hydroxyl or CN, or (b) a C1-C3 alkyl chain, optionally substituted by one or more halogen atoms. R5 is hydrogen or a C1-C3 alkyl chain; or R4 together with R2 or R3, and / or R5 together with R1, and / or R3 together with R2, form a 5-6 membered aliphatic ring, which is optionally substituted by an alkyl chain having 1 to 3 carbon atoms, a halogen atom or a hydroxyl group, said aliphatic ring optionally containing an oxygen atom and optionally fused to or substituted by a benzene or pyridine ring, said benzene or pyridine ring being optionally substituted by a halogen or an alkyl or alkoxy chain having 1 to 3 carbon atoms, said chain being optionally substituted by one or more halogen atoms; The prerequisite is that when R2, R3 and R5 are hydrogen atoms and R4 is hour, Then R1 is different from wherein R6 is H or OH, and Provided that, when L1 is a bond, A1 is not a substituted or unsubstituted cyclobutane ring.

2. A Kv7.2 / 7.3 potassium channel activator compound or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein A1 is hydrogen or (i) an aromatic or aliphatic ring selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, optionally substituted by one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3, a C1-C3 alkyl chain optionally substituted by one or more halogen atoms, or (ii) a bicyclic ring selected from bicyclo[1,1,1]pentane, indane (2,3-dihydro-1H-indene), 2,3-dihydro-1H-indole, 6,7-dihydro-5H-cyclopenta[c]pyridine, chroman (3,4-dihydro-2H-1-benzopyran), dihydrocoumarin (2,3-dihydro-1-benzofuran), tetrahydronaphthalene (1,2,3,4-tetrahydronaphthalene), thiochroman (3,4-dihydro-2H-1-benzothiopyran), 5,6-dihydro-4H-cyclopentane diene [b] thiophene, 6,7-dihydro-5H-cyclopenta [b] pyridine, 5,6,7,8-tetrahydroisoquinoline, 5,6,7,8-tetrahydroquinoxaline, 2,3,4,5-tetrahydro-1-benzoxepin and 6,7,8,9-tetrahydro-5H-benzo [7] annulene, optionally substituted with one or more substituents selected from halogen, hydroxy, methoxy, CN, CF3, a C1-C3 alkyl chain optionally substituted with one or more halogen atoms.

3. A Kv7.2 / 7.3 potassium channel activator compound for use according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A2 is pyridine, pyridazine, pyrimidine or pyrazine, more preferably pyridine or pyrimidine, optionally fused to an aliphatic ring having 5 or 6 carbon atoms.

4. A Kv7.2 / 7.3 potassium channel activator compound or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein A2 is substituted with an aliphatic ring selected from azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, oxazetidine, oxazolidine or morpholine, optionally substituted with one or more halogen atoms or a C1-C3 alkyl chain, wherein the C1-C3 alkyl chain is optionally substituted with one or more halogen atoms.

5. A Kv7.2 / 7,3 potassium channel activator compound or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein A3 is an aliphatic ring having 3 to 6 members or an aromatic ring having 5 or 6 members, optionally containing one or more heteroatoms selected from O and N, and optionally substituted with a halogen atom or a C1-C3 alkyl chain, optionally substituted with one or more halogen, hydroxyl, CN.

6. The Kv7.2 / 7,3 potassium channel activator compound or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein A3 is cyclopropane, cyclobutane, azetidine, oxetane, or tetrahydropyran.

7. The Kv7.2 / 7.3 potassium channel activator compound for use according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A3 is phenyl, pyrrole, furan, oxazole, pyrimidine or pyridine.

8. A Kv7.2 / 7.3 potassium channel activator compound for use according to any one of claims 1 to 7, wherein the pharmaceutically acceptable salt is selected from salts formed with organic acids, preferably oxalic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, succinic acid, citric acid, malic acid, tartaric acid and lactic acid, salts formed with organic bases, preferably trimethylamine, lysine, arginine, glycine, alanine and ethanolamine, salts formed with inorganic acids, preferably hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and salts formed with inorganic bases, preferably hydroxides or carbonates of alkali metals or alkaline earth metals such as sodium, potassium and calcium.

9. A Kv7.2 / 7.3 potassium channel activator compound for use according to claim 1, wherein the disorders modulated by Kv7.2 / 7.3 potassium channels are central nervous system (CNS) and peripheral nervous system (PNS) disorders.

10. A Kv7.2 / 7.3 potassium channel activator compound for use according to claim 9, wherein the central nervous system (CNS) disorder is selected from epilepsy, epileptic syndromes, epileptic symptoms, epilepsy that is resistant or refractory to treatment, seizures, bipolar disorder, bipolar depression, schizophrenia, psychosis, mania, stress-related disorders, acute stress reactions, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulsive behavior disorders, personality disorders, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and tinnitus.

11. A Kv7.2 / 7.3 potassium channel activator compound for use according to claim 9, wherein the peripheral nervous system (PNS) disorder is selected from migraine, chronic pain, acute pain, neuropathic pain, visceral pain, inflammatory pain and muscle pain.

12. A Kv7.2 / 7.3 potassium channel activator compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds of Table A and Table B below, Table A Table B 13. The Kv7.2 / 7.3 potassium channel activator compound according to claim 12, wherein the pharmaceutically acceptable salt is selected from salts formed with organic acids, preferably oxalic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, succinic acid, citric acid, malic acid, tartaric acid and lactic acid, salts formed with organic bases, preferably trimethylamine, lysine, arginine, glycine, alanine and ethanolamine, salts formed with inorganic acids, preferably hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and salts formed with inorganic bases, preferably hydroxides or carbonates of alkali metals or alkaline earth metals such as sodium, potassium and calcium.

14. The Kv7.2 / 7.3 potassium channel activator compound according to claim 12 or a pharmaceutically acceptable salt thereof for use as a medicament.

15. A pharmaceutical composition for treating a disorder modulated by KV7.2 / KV7.3 potassium channels, comprising (i) a Kv7.2 / 7.3 potassium channel activating compound according to any one of claims 1 to 7, and (ii) at least one pharmaceutically acceptable excipient.

16. A pharmaceutical composition comprising (i) a Kv7.2 / 7.3 potassium channel activating compound according to any one of claims 12 to 14, or a pharmaceutically acceptable salt thereof, and (ii) at least one pharmaceutically acceptable excipient.

17. The pharmaceutical composition according to claim 16, for use in treating disorders mediated by KV7.2 / KV7.3 potassium channels.

18. The pharmaceutical composition for use according to claim 15 or 17, wherein the disorders modulated by Kv7.2 / 7.3 potassium channels are central nervous system (CNS) and peripheral nervous system (PNS) disorders.

19. A pharmaceutical composition for use according to claim 18, wherein the central nervous system (CNS) disorder is selected from the group consisting of epilepsy, epileptic syndromes, epileptic symptoms, epilepsy that is resistant or refractory to treatment, seizures, bipolar disorder, bipolar depression, schizophrenia, psychosis, mania, stress-related disorders, acute stress reactions, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulsive behavior disorders, personality disorders, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and tinnitus.

20. The pharmaceutical composition for use according to claim 18, wherein the peripheral nervous system (PNS) disorder is selected from migraine, chronic pain, acute pain, neuropathic pain, visceral pain, inflammatory pain and muscle pain.

21. A method of treating a disorder modulated by Kv7.2 / 7.3 potassium channels selected from central nervous system (CNS) and peripheral nervous system (PNS) disorders, the method comprising administering to a human in need thereof an effective amount of a compound according to any one of claims 1 to 7 or 12.

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