Urea compounds as activators of potassium channels KV7.2 / 7.3 useful in the treatment of CNS and PNS disorders

Abstract

The present invention relates to compounds of formula (I) as defined herein which are capable of promoting the opening of Kv7.2 / 7.3 potassium channels, pharmaceutical compositions containing them and their use as medicaments, particularly in the treatment of disorders of the central nervous system (CNS), such as, for example, epilepsy and neurodegenerative disorders, and disorders of the peripheral nervous system (PNS), such as, for example, chronic and neuropathic pain.

Description

[Technical Field]

[0001] The present invention relates to compounds capable of promoting the opening of Kv7.2 / 7.3 potassium channels and their use as drugs, particularly in the treatment of disorders of the central nervous system (CNS), such as epilepsy and neurodegenerative disorders, and disorders of the peripheral nervous system (PNS), such as chronic and neuropathic pain. [Background technology]

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

[0003] Functional Kv channels exist as multimeric structures formed by the association of four alpha and four beta subunits. The alpha subunits contain six transmembrane domains, a pore-forming loop, and a voltage sensor, and are symmetrically arranged around a central pore. The beta or auxiliary subunits can interact with the alpha subunits and modify the properties of the channel complex, including, but not limited to, changes in the electrophysiological or biophysical properties, levels, or expression patterns of the channel.

[0004] Nine families of Kv channel alpha subunits, designated Kv1 through Kv9, have been identified. The Kv7 channel family consists of at least five members, including Kv7.1, Kv7.2, Kv7.3, Kv7.4, and Kv7.5. Alternatively, members of this family are referred to by their 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 regulating neuronal excitability. Kv7 channels, particularly the Kv7.2 / 7.3 heterotetramer, underlie the M-current (Wang et al. Science. 1998 Dec. 4;282(5395):1890-1893).

[0006] The M-current has a characteristic time- and voltage-dependence and leads to stabilization of the membrane potential in response to multiple excitatory stimuli, thus participating in the control of neuronal excitability (Delmas and Brown, Nature, 2005, 6, 850-862).

[0007] The M-current is a non-inactivating potassium current found in many neuronal cell types. In each cell type, it is the only sustained current in the range of action potential initiation and therefore predominates in the control of membrane excitability (Marrion, Annual Review Physiology, 1997, 59, 483-504).

[0008] The five members of this family of ion channels have distinct expression patterns. While Kv7.1 expression is restricted to the heart, peripheral epithelia, and smooth muscle, Kv7.2, Kv7.3, Kv7.4, and Kv7.5 appear to predominate in the nervous system, including the hippocampus, cortex, ventral tegmental area, and dorsal root ganglion neurons. Kv7.4 is a subtype selectively expressed in the auditory pathway, including hair cells of the inner ear. 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 convulsions (Rogawski, Trends in Neuroscience 2000, 23, 393-398). The proteins encoded by the KCNQ2 and KCNQ3 genes have been localized to pyramidal neurons of the human cortex and hippocampus, regions of the brain involved in the generation and propagation of seizures (Cooper et al., Proceedings National Academy of Science USA 2000, 97(9), 4914-4919).

[0010] Furthermore, Kv7.2, Kv7.3, and Kv7.5 mRNAs are expressed in astrocytes and glial cells. Thus, Kv7.2, Kv7.3, and Kv7.5 channels may help modulate synaptic activity in the CNS and contribute to the neuroprotective effects of KCNQ channel activators (Noda et al., Society for Neuroscience Abstracts 2003, 53.9), which may be relevant for the treatment of neurodegenerative disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0011] Kv7.2 and Kv7.3 mRNAs are found in brain regions associated with anxiety and emotional behaviors, including 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 also been reported to be upregulated in neuropathic pain models (Wickenden et al., Society for Neuroscience Abstracts, 2002, 454.7), and potassium channel modulators have been hypothesized to be active in both neuropathic pain and epilepsy (Schroder et al., Neuropharmacology 2001, 40(7), 888-898). Kv7.2-5 mRNA expression in the trigeminal and dorsal root ganglia and the trigeminal nucleus caudalis suggests that activators of these channels may affect the sensory processing of migraine pain in addition to their role in neuropathic pain (Goldstein et al., Society for Neuroscience Abstracts, 2003, 53.8).

[0013] Retigabine and flupirtine are known Kv7.2 / 7.3 potassium channel activating compounds used to treat epilepsy, migraine, neuropathic pain, acute pain, and tinnitus. Retigabine was withdrawn from the market due to its adverse side effects, particularly urinary retention and changes in retinal and skin pigmentation. Due to its hepatotoxicity, flupirtine should be used by individuals who do not respond to other analgesic treatments and within 2 weeks. Summary of the Invention [Problem to be solved by the invention]

[0014] The applicant has addressed the problem of providing novel therapies for treating disorders of the central nervous system (CNS), such as epilepsy and neurodegenerative disorders, and disorders of the peripheral nervous system (PNS), such as chronic and neuropathic pain. [Means for solving the problem]

[0015] The applicant has focused his attention on potassium channel activating compounds Kv7.2 / 7.3 and initiated research activities that may provide alternative compounds to retigabine and flupirtine.

[0016] After extensive experimentation, the applicant has identified several novel compounds that can act as drugs, particularly for treating disorders modulated by Kv7.2 / 7.3 potassium channels.

[0017] In particular, as demonstrated in the Examples in the Experimental Section below, Applicants have identified several compounds that can act as activators of Kv7.2 / 7.3 potassium channels.

[0018] Based on information known to those skilled in the art, Applicants believe that these compounds may be effective in treating a variety of disorders of the central nervous system (CNS), such as epilepsy and neurodegenerative disorders, and disorders of the peripheral nervous system (PNS), such as chronic and neuropathic pain.

[0019] Thus, in a first aspect, the present invention provides a Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder modulated by the Kv7.2 / Kv7.3 potassium channel, said disorder preferably being selected from the group consisting of central nervous system (CNS) and peripheral nervous system (PNS) disorders, said compound being represented by the following general formula (I):

[0020] [ka] (In the formula, R1 is represented by -L1-A1, L1 is a bond or a linear or branched C1-C6 alkyl chain, which may be substituted with one or more halogen atoms or hydroxyl groups and which may contain an oxy (—O—) group within the alkyl chain or at any terminus thereof; A1 is a hydrogen atom, or (i) a 3- to 6-membered aromatic or aliphatic ring, which may contain one or more heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, methoxy, CN, CF3, a C1-C3 alkyl chain optionally substituted with one or more halogen atoms, and AR, wherein AR is an aromatic or aliphatic ring which may contain one or more heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, methoxy, CN, CF3, and a C1-C3 alkyl chain optionally substituted with one or more halogen atoms, or (ii) 5- to 12-membered fused or bridged bicyclic rings, which may contain one or more heteroatoms selected from the group consisting of N, O, and S, and are unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, methoxy, CN, CF3, O-Gr, and C1-C3 alkyl optionally substituted with one or more halogen atoms, and Gr is a 3- to 6-membered aliphatic ring, which may contain one or more heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, methoxy, CN, CF3, and C1-C3 alkyl chains optionally substituted with one or more halogen atoms. and; R2 is hydrogen or a C1-C3 alkyl chain; R3 is hydrogen or an aliphatic ring, which may contain a C1-C3 alkyl chain optionally substituted with a hydroxyl group, or one or more heteroatoms selected from the group consisting of N, O and S, and which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, methoxy, CN, and CF3; R4 is represented by -L2-A2, L2 is a bond or a C1-C3 alkyl chain; A2 is a 6-membered aromatic ring containing 1 or 2 nitrogen atoms, said aromatic ring optionally fused with an aliphatic ring having 5 or 6 carbon atoms, said aromatic ring being (i) a halogen atom, (ii) a C1-C3 alkyl chain optionally substituted with one or more halogen atoms; (iii) a 4- to 6-membered aliphatic ring containing one or more heteroatoms selected from O and N, optionally substituted with one or more halogen atoms or a C1-C3 alkyl chain optionally substituted with one or more halogens or hydroxyls; 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) a 3- to 6-membered aliphatic or aromatic ring, which may contain one or more heteroatoms selected from O and N, and which may be substituted with a halogen atom or a C1-C3 alkyl chain which may be substituted with one or more halogens, hydroxyl, or CN; or (b) a C1-C3 alkyl chain optionally substituted with one or more halogen atoms is) and is substituted with one or more substituents selected from: R5 is hydrogen or a C1-C3 alkyl chain; or R4 taken together with R2 or R3, and / or R5 taken together with R1, and / or R3 taken together with R2 form a 5- to 6-membered aliphatic ring optionally substituted with an alkyl chain having 1 to 3 carbon atoms, a halogen atom, or a hydroxyl group, which may contain an oxygen atom and which may be fused to or substituted with a benzene or pyridine ring, said benzene or pyridine ring optionally substituted with a halogen, or an alkyl or alkoxy chain having 1 to 3 carbon atoms, said chain optionally substituted with one or more halogen atoms; However, R2, R3 and R5 are hydrogen atoms, and R4 is

[0021] [ka] If so, then R1 is

[0022] [ka] (wherein R6 is H or OH) Unlike, provided that when L1 is a bond, A1 is not a substituted or unsubstituted cyclobutane ring. or a pharmaceutically acceptable salt thereof.

[0023] In a second aspect, the present invention relates to a Kv7.2 / 7.3 potassium channel activator compound selected from Tables A and B below, or a pharmaceutically acceptable salt thereof.

[0024] 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 present invention, or a pharmaceutically acceptable salt thereof, and (ii) at least one pharmaceutically acceptable excipient.

[0025] Advantageously, the pharmaceutical composition according to the third aspect of the present invention can be used in the treatment of disorders modulated by Kv7.2 / 7.3 potassium channels, preferably in the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders.

[0026] In a fourth aspect, the present invention relates to a method of treating a disorder modulated by the Kv7.2 / 7.3 potassium channel in a subject in need thereof, 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.

[0027] For purposes of this specification and the claims that follow, the phrase "pharmaceutically acceptable" is intended to define, without limitation, any material that is suitable for the preparation of a pharmaceutical composition to be administered to an organism.

[0028] For purposes of this specification and the claims that follow, the phrase "therapeutically effective amount" means an amount of a compound sufficient to alleviate, arrest, partially arrest, eliminate or delay the clinical manifestations of a particular disease and its complications in a therapeutic treatment that includes the administration of said compound.

[0029] For purposes of this specification and the claims that follow, the term "treatment" or "treating" means the management and care of a patient for the purpose of alleviating, halting, partially halting, eliminating or slowing the progression of clinical signs of disease. The patient being treated is preferably a mammal, in particular a human.

[0030] For the purposes of this specification and the claims that follow, the expressions "for example" and terms such as "preferably," "advantageously," and "particularly," unless otherwise indicated, are used to better describe the present invention without imposing limitations on the scope of the invention.

[0031] For purposes of this specification and the claims that follow, the phrase "KV7.2 / KV7.3 potassium channel activator" refers to a compound that causes a voltage-dependent shift in channel opening to more negative potentials, meaning that KV7.2 / KV7.3 potassium channels open to more negative potentials in the presence of the compound, facilitating the transmission of ions through them. DETAILED DESCRIPTION OF THE INVENTION

[0032] A 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 the treatment of a disorder modulated by the Kv7.2 / Kv7.3 potassium channel, said disorder preferably being selected from the group consisting of central nervous system (CNS) and peripheral nervous system (PNS) disorders, said compound having the above general formula (I), or a pharmaceutically acceptable salt thereof.

[0033] In one embodiment of the invention, L1 is a bond or a C1-C2 alkyl chain.

[0034] In another embodiment, L1 is a straight or branched C3-C6 alkyl chain which may be substituted with one or more halogen atoms or hydroxyl groups and which may include 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-CCF3CH3-CH2-, -CH2-CCH3OH-CH2-.

[0035] In one embodiment of the invention, A1 is hydrogen, or (i) an aromatic or aliphatic ring selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, methoxy, CN, CF3, and a C1-C3 alkyl chain optionally substituted with one or more halogen atoms; or (ii) Bicyclic[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), coumaran (2,3-dihydro-1-benzofuranoside), optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, methoxy, CN, CF3, and C1-C3 alkyl chains optionally substituted with one or more halogen atoms. a bicyclic ring selected from the group consisting of tetralin (1,2,3,4-tetrahydronaphthalene), thiochroman (3,4-dihydro-2H-1-benzothiopyran), 5,6-dihydro-4H-cyclopenta[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; is.

[0036] In a preferred embodiment of the present invention, L2 is a bond or a C1-C2 alkyl chain, more preferably a bond.

[0037] In a preferred embodiment of the present invention, A2 is pyridine, pyridazine, pyrimidine, or pyrazine, optionally fused with an aliphatic ring having 5 or 6 carbon atoms, more preferably pyridine or pyrimidine.

[0038] In one embodiment of the invention, A2 is substituted with a halogen atom, preferably selected from the group consisting of chlorine and fluorine.

[0039] In one embodiment of the present invention, A2 is substituted with a C1-C3 alkyl chain, preferably selected from the group consisting of methyl, ethyl, propyl, and isopropyl, optionally substituted with one or more halogen atoms, preferably selected from the group consisting of chlorine and fluorine.

[0040] In one embodiment of the present invention, A2 is substituted with a 4- to 6-membered aliphatic ring containing one nitrogen atom, one oxygen atom, or both, optionally substituted with one or more halogen atoms or a C1-C3 alkyl chain optionally substituted with one or more halogen atoms or hydroxyl (the halogen atoms are preferably selected from the group consisting of chlorine and fluorine). In a preferred embodiment, the 4- to 6-membered aliphatic ring is azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, oxazetidine, oxazolidine, or morpholine, more preferably azetidine, pyrrolidine, piperidine, or morpholine.

[0041] In one embodiment of the invention, A2 is substituted with a group represented by the formula -S6-L3-A3.

[0042] S6 is preferably an oxygen atom.

[0043] L3 is preferably a bond or, more preferably, a C1-C3 alkyl chain selected from the group consisting of methyl, ethyl, propyl, and isopropyl, optionally substituted with one or more halogen atoms, preferably selected from the group consisting of chlorine and fluorine.

[0044] A3 is a 3- to 6-membered aliphatic ring or a 5- or 6-membered aromatic ring, which may contain one or more heteroatoms preferably selected from O and N and may be substituted with a halogen atom or a C1-C3 alkyl chain optionally substituted with one or more halogens, hydroxyl, or CN. In a more preferred embodiment, the aliphatic ring is cyclopropane, cyclobutane, azetidine, oxetane, or tetrahydropyran. In a more preferred embodiment, the aromatic ring is phenyl, pyrrole, furan, oxazole, pyrimidine, or pyridine.

[0045] Alternatively, preferably, A3 is a C1-C2 alkyl chain optionally substituted with one or more halogen atoms, preferably selected from the group consisting of chlorine and fluorine. More preferably, A3 is a CF3 or C2F5 group.

[0046] In one embodiment of the invention, R4 together with R2 or R3 and / or R3 together with R2 form a 5- to 6-membered aliphatic ring fused to or substituted with a benzene or pyridine ring, the benzene or pyridine ring being substituted with a halogen or an alkyl or alkoxy chain having 1 to 3 carbon atoms, the chain optionally being substituted with one or more halogen atoms.

[0047] In a further embodiment of the invention, R4 together with R2 or R3 and / or R3 together with R2 form a 5-membered aliphatic ring fused to or substituted with a pyridine ring, said pyridine ring being substituted with an alkoxy chain having 1 to 3 carbon atoms, said chain optionally being substituted with one or more halogen atoms, preferably one or more fluorine atoms.

[0048] In a specific embodiment of the present invention, R4 or R3 together with R2 form the following ring A or B (wherein the nitrogen atom with an asterisk is of the ureido structure of formula (I)):

[0049] [ka] Form.

[0050] In a specific embodiment of the present invention, R4 together with R3 forms the following ring C (wherein the asterisked bond is attached to the nitrogen atom of the ureido structure of formula (I)):

[0051] [ka] Form.

[0052] In one embodiment of the present invention, R5 together with R1 form a 5- to 6-membered aliphatic ring optionally substituted with an alkyl chain having 1 to 3 carbon atoms, the aliphatic ring optionally containing an oxygen atom and optionally fused to a benzene ring, the benzene ring optionally substituted with a halogen or an alkyl or alkoxy chain having 1 to 3 carbon atoms, the chain optionally substituted with one or more halogen atoms.

[0053] In a further embodiment of the present invention, R5 together with R1 form a 5- to 6-membered aliphatic ring optionally substituted with a methyl group, the aliphatic ring optionally containing an oxygen atom and optionally fused with a benzene ring, and the benzene ring optionally substituted with a halogen.

[0054] In a specific embodiment of the present invention, R5 together with R1 form the following rings D and E (wherein the nitrogen atom with an asterisk is of the ureido structure of formula (I)):

[0055] [ka] Form.

[0056] Advantageously, the second aspect of the invention is a compound of Table A and Table B below:

[0057] [Table 1-1]

[0058] [Table 1-2]

[0059] [Table 1-3]

[0060] [Table 1-4]

[0061] [Table 1-5]

[0062] [Table 1-6]

[0063] [Table 1-7]

[0064] [Table 1-8]

[0065] [Table 1-9]

[0066] [Table 1-10]

[0067] Table 1-11

[0068] Table 1-12

[0069] Table 1-13

[0070] Table 1-14

[0071] Table 1-15

[0072] Table 1-16

[0073] Table 2-1

[0074] Table 2-2

[0075] Table 2-3

[0076] Table 2-4

[0077] [Table 2-5]

[0078] [Table 2-6]

[0079] [Table 2-7]

[0080] [Table 2-8] or a pharmaceutically acceptable salt thereof.

[0081] Some compounds of the present invention may exist in tautomeric forms, and unless otherwise specified, the present invention includes all tautomeric forms of such compounds.

[0082] Unless otherwise specified, 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 as well as enantiomeric and diastereomeric mixtures of the compounds according to the present invention are within the scope of the present invention. The present invention includes any diastereomer or enantiomer substantially free of other isomers (greater than 90%, preferably greater than 95%, on a molar basis, free of other stereoisomers), as well as mixtures of such isomers.

[0083] Specific optical isomers can be obtained by resolution of the racemic mixtures by conventional processes, for example, by the formation of diastereomeric salts by treatment with an optically active acid or base, and subsequent separation of the diastereomeric mixtures by crystallization of the corresponding salts, followed finally by liberation of the optically active bases from such salts. Examples of suitable acids include tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid.

[0084] A different process for separating optical isomers involves the use of a chiral chromatography column optimally selected to maximize the separation of enantiomers. Yet another method involves the synthesis of covalent diastereomers by reacting the compounds of the present invention with activated optically pure acids or optically pure isocyanates. The synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to obtain 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.

[0085] The compounds of the present invention may exist in radiolabeled form, i.e., the compounds may contain one or more atoms that contain an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Radioactive isotopes of hydrogen, carbon, phosphorus, fluorine, and chlorine include, respectively: 3 H, 14 C. 32 P, 35 S, 18 F and 36 Compounds of the present invention that contain these radioisotopes and / or other radioisotopes of other atoms are within the scope of the present 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.

[0086] Radiolabeled compounds of the present invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by performing the procedures described herein by substituting non-radiolabeled reagents for readily available non-radiolabeled reagents.

[0087] The compounds according to the invention are preferably used as salts with pharmaceutically acceptable organic and inorganic acids or bases.

[0088] Preferably, the pharmaceutically acceptable organic acid is selected from the group consisting of oxalic acid, maleic acid, methanesulfonic acid, paratoluenesulfonic acid, succinic acid, citric acid, malic acid, tartaric acid and lactic acid.

[0089] Preferably, the pharmaceutically acceptable organic base is selected from the group consisting of tromethamine, lysine, arginine, glycine, alanine and ethanolamine.

[0090] Preferably, the pharmaceutically acceptable inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid.

[0091] Preferably, the pharmaceutically acceptable inorganic base is selected from the group consisting of hydroxides or carbonates of alkali or alkaline earth metals, such as sodium, potassium and calcium.

[0092] The compounds of the present invention, or their pharmaceutically acceptable salts, can be prepared by various procedures known to those skilled in the art, some of which are described in the preparations shown in the Examples in the Experimental Section. Intermediates and final compounds can be recovered by conventional methods well known in the art, such as extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are known to those skilled in the art and are readily available.

[0093] Advantageously, the compounds of the invention are used as drugs, in particular in the treatment of disorders modulated by Kv7.2 / 7.3 potassium channels, preferably in the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders.

[0094] Preferably, central nervous system (CNS) disorders treated with the compounds of the invention include, for example, epilepsy, epilepsy syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy, convulsions, bipolar disorder, bipolar depression, schizophrenia, psychosis, mania, stress-related disorders, acute stress reaction, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulse control disorders, personality disorders, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, tinnitus, and the like.

[0095] Advantageously, the central nervous system (CNS) disorders preferably treated with the compounds of the present invention are epilepsy, epileptic syndromes, epileptic conditions, treatment-resistant or refractory epilepsy, convulsions, bipolar disorders, bipolar depression, schizophrenia, and amyotrophic lateral sclerosis.

[0096] Peripheral nervous system (PNS) disorders preferably treated with the compounds of the present invention include, for example, migraine, chronic pain, acute pain, neuropathic pain, visceral pain, inflammatory pain, muscle pain, and the like.

[0097] Advantageously, the peripheral nervous system (PNS) disorders preferably treated with the compounds of the present invention are neuropathic pain, chronic pain, visceral pain, and inflammatory pain.

[0098] Typically, the compounds of the invention are administered in the form of a pharmaceutical composition containing a pharmaceutically acceptable excipient.

[0099] 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.

[0100] Preferably, the pharmaceutical composition according to the invention is for systemic use.

[0101] Pharmaceutical compositions according to the present invention can be administered orally, parenterally, by inhalation (spray, powder or aerosol), rectally, nasally, buccally, vaginally or via an implantable device.

[0102] The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0103] More preferably, the pharmaceutical compositions according to the present invention are formulated for oral or parenteral administration.

[0104] Preferably, pharmaceutical compositions according to the present invention are prepared in a suitable dosage form comprising 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.

[0105] 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.

[0106] 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.

[0107] The amount of the compound described in the compound of the first or second aspect of the present invention or its pharmacologically acceptable salt present in the pharmaceutical composition of the present invention can vary widely depending on known factors, such as the type of disease, the severity of disease, patient's weight, dosage form, selected administration route, daily administration frequency and the effectiveness of the compound itself.However, those skilled in the art can easily and routinely determine the optimal amount.

[0108] Typically, the amount of the compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention is such as to provide a dosage level of 0.0001 to 100 mg / kg / day. Preferably, the dosage level is 0.001 to 50 mg / kg / day, and even more preferably 0.01 to 10 mg / kg / day.

[0109] As known to those skilled in the art, lower or higher doses than those mentioned above may be required. The specific dosage and treatment regimen for a particular patient will depend on various factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, severity and course of the disease, and the patient's predisposition to the disease, as well as the judgment of the treating physician.

[0110] The dosage forms of the pharmaceutical compositions of the present invention can be prepared according to techniques well known to those skilled in the pharmaceutical industry, including mixing, granulating, compressing, dissolving, sterilizing, and the like.

[0111] Advantageously, such dosage forms are formulated to provide controlled release of the active ingredient over time. Depending particularly on the type of treatment, the required release time may be very short, normal, or extended.

[0112] Preferably, the pharmaceutical composition of the present invention is contained in a single dosage form that is administered once a day or several times (2, 3 or 4 times) a day.

[0113] The pharmaceutically acceptable excipient may be selected from the group consisting of thickeners, glidants, binders, disintegrants, fillers, diluents, preservatives, stabilizers, surfactants, buffers, flow agents, lubricants, wetting agents, absorbents, salts for regulating osmotic pressure, emulsifiers, flavoring agents, coloring agents, sweetening agents, and the like.

[0114] Particularly preferred excipients include water, ethanol, propylene glycol, glycerol, polyethylene glycol, poloxamer, mono-, di- and triglycerides, 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, croscarmellose sodium, 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). [Example]

[0115] Experimental Department The following examples are intended to further illustrate, but not limit, the present invention.

[0116] Example 1 Analysis method Analytical data are included in the procedures, general procedural descriptions, or tables of examples. 1H NMR data were collected on a Bruker Avance 400 MHz instrument 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, and chemical shifts are quoted in parts per million (ppm). LC / MS was performed on an Acquity UPLC H-Class (quaternary pump / PDA detector) coupled to a QDa mass spectrometer, an Acquity UPLC (binary pump / PDA detector) coupled to a ZQ mass spectrometer, or an Acquity UPLC equipped with a Waters DAD coupled to an SQD2 mass spectrometer. LC / MS data are referenced to the LC / MS conditions using the method numbers provided in Table 1.

[0117] [Table 3]

[0118] Purification method For the general procedures, intermediates and final compounds may 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 COMBIFLASH® Companion purification system or a Biotage SP1 purification system (products were purified using an Isolute® SPE Si II cartridge ("Isolute SPE Si cartridge" refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles having an average diameter of 50 μm and a nominal 60 Å porosity) and a solvent or combination of solvents (heptane, EtOAc, DCM, MeOH, MeCN, water, etc.) that elutes the desired compound); a Waters Mass Directed FractionLynx system (2767 autosampler, System Fluidics Organizer, 2998 photodiode array, 2545 pump, 3×515 pumps, QDa mass spectrometer), a Gilson system (GX281 autosampler, 322 pump, 155 UV / VIS detector), an Interchim PuriFlash coupled with a UV DAD RP-HPLC purification performed on a 4125 (see Table 2 for some non-limiting conditions); SFC purification performed on a Waters Thar Prep100 system (2767 Liquid Handler with P200 CO2 pump, 2545 Modifier Pump, 2998 UV / VIS Detector, Stack Injection Module) or a Waters Thar Investigator Semi-Prep System (Waters Fluid Delivery Module, 2998 UV / VIS Detector, Waters Fraction Collection Module) (see Table 2 for some non-limiting conditions); recrystallization from a suitable 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 a suitable solvent (EtOAc, DCM, MeCN, MeOH, EtOH, i-PrOH, n-PrOH, etc.);Extraction by dissolving the compound in a liquid or washing with a suitable immiscible liquid (DCM / water, EtOAc / water, DCM / saturated NaHCO3, EtOAc / saturated NaHCO3, DCM / 10% aqueous HCl, EtOAc / 10% aqueous HCl, etc.); and / or distillation (simple, fractional, 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.

[0119] [Table 4]

[0120] Preparation and Examples All starting materials are commercially available from Sigma-Aldrich (including Fluka and Discovery CPR) or Acros unless otherwise noted after the chemical name. Reagent / reactant names given are as named on the commercially available bottle or as generated by IUPAC conventions or ChemDraw 16.0. None of the specific conditions and reagents mentioned herein should be construed as limiting the scope of the invention but are provided for illustrative purposes only.

[0121] Abbreviation ℃ Celsius CAS Chemical Abstracts Services CDCl3 deuterated chloroform CDI 1,1'-carbonyldiimidazole CF3COOH 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 time HBTU N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HCl hydrochloride HCOOH formic acid i-PrOH isopropyl alcohol IMS Industrial Denatured 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 MS mass spectrometer Na2SO4 Sodium Sulfate NaHCO3 Sodium bicarbonate NH4CO3 Ammonium bicarbonate NH4OH Ammonium hydroxide NMR nuclear magnetic resonance PDA Photodiode Array RP-HPLC Reversed-phase high-performance liquid chromatography R t retention time RT room temperature SFC Supercritical Fluid Chromatography tBuBrettPhos Pd G3 [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate THF tetrahydrofuran UPLC Ultra High Performance Liquid Chromatography UV / VIS Ultraviolet / Visible

[0122] The synthesis of compounds 1-88 can be achieved as described below. The synthesis of compounds 89-250 can be achieved in a similar manner by modifying the starting reagents.

[0123] compound 1 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea A 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 reaction was stirred at RT under a nitrogen atmosphere for 30 minutes. 3-Fluoroaniline (CAS: 372-19-0, 0.040 mL, 0.42 mmol) was added, and the reaction was stirred at RT under a nitrogen atmosphere for 21.5 hours. The reaction was then heated to 45°C and stirred at 45°C for 24 hours. 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 give an off-white solid (57 mg, 46%). 1H 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). LC / MS (Table 1, Method A) Rt=5.07 min; MS m / z:352[M+H] + .

[0124] compound 2 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorobenzyl)urea The title compound was prepared from the appropriate commercially available starting materials, (2-(benzyloxy)pyridin-4-yl)methanamine (CAS: 869293-84-5) and 3-fluorobenzylamine (CAS: 100-82-3), using a reaction protocol 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 give an off-white solid (60 mg, 47%). 1 H 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). LC / MS (Table 1, Method A)R t =4.79 min;MS m / z:366[M+H] + .

[0125] compound 3 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (62 mg, 45%). 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). LC / MS (Table 1, Method A)R t =5.21 min;MS m / z:394[M+H] + .

[0126] compound 4 (S)-1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(2-hydroxy-3,3-dimethylbutyl)urea The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (53 mg, 42%). 1H 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). LC / MS (Table 1, Method A)R t =4.59 min;MS m / z:358[M+H] + .

[0127] compound 5 (±)-1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(2-hydroxy-2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate commercially available starting materials, (2-(benzyloxy)pyridin-4-yl)methanamine (CAS: 869293-84-5) and (±)-2-amino-1-(1-(trifluoromethyl)cyclopropyl)ethan-1-ol hydrochloride (prepared according to WO 2020163268 Preparation 3), using a reaction protocol 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 give an off-white oil (58 mg, 41%). 1 H NMR (400 MHz, DMSO-d) 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 partially obscured by solvent peaks), 2.95–2.87 (m, 1H), 0.87–0.84 (m, 4H). LC / MS (Table 1, Method A)Rt =4.74 min;MS m / z:410[M+H] + .

[0128] compound 6 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) tert-butyl (2-(1-(trifluoromethyl)cyclopropyl)ethyl)carbamate A reaction vessel was charged with 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2, 50 mg, 0.264 mmol) and solvated in THF (0.80 mL) and distilled water (0.80 mL). Potassium carbonate (182 mg, 1.32 mmol) and di-tert-butyl dicarbonate (0.12 mL, 0.527 mmol) were added, and the reaction was stirred at RT for 2 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 give the title compound (63 mg, 94%). 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).

[0129] (ii) tert-butyl methyl (2-(1-(trifluoromethyl)cyclopropyl)ethyl)carbamate 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) under a nitrogen atmosphere at 0° C. was added sodium hydride (60%, 10 mg, 0.249 mmol). The reaction was stirred at 0° C. for 30 minutes. Iodomethane (0.017 mL, 0.274 mmol) was added and the reaction was stirred at 0° C. for 1 hour. The reaction was allowed to warm to RT and stirred at RT for 2 hours. 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 (NaSO), and concentrated in vacuo to give the title compound (50 mg, 75%). 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).

[0130] (iii) N-methyl-2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride 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) at 0° C. was added 4 M HCl in 1,4-dioxane (4.0 mL, 15.8 mmol). The reaction was allowed to warm to RT and the reaction was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo to give the title compound (210 mg, 98%). 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).

[0131] (iv) 1-methyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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)) using a reaction protocol 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 (31 mg, 27%). 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). LC / MS (Table 1, Method B)R t =4.71 min;MS m / z:400[M+H] + .

[0132] compound 7 1-methyl-1-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) tert-butyl ((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)carbamate The title compound was prepared from the appropriate commercially available starting material, (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine dihydrochloride (CAS: 2460508-43-2), using a reaction protocol 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 give the title compound (184 mg, 87%). LC / MS (Table 1, Method C)R t =1.72 min;MS m / z:307[M+H] + .

[0133] (ii) tert-butyl methyl ((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)carbamate 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 protocol 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%). LC / MS (Table 1, Method C)R t =1.89 min;MS m / z:321[M+H] + .

[0134] (iii) N-methyl-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine dihydrochloride 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 protocol 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 (305 mg, 93%). LC / MS (Table 1, Method D)R t =1.19 min;MS m / z:221[M+H] + .

[0135] (iv) 1-methyl-1-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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, nonlinear gradient from 20% to 80% MeOH) to afford an off-white solid (17 mg, 15%). 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). LC / MS (Table 1, Method E)Rt =4.83min;MS m / z:400[M+H] + .

[0136] compound 8 1-((4-(benzyloxy)pyrimidin-2-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) tert-butyl (tert-butoxycarbonyl)((4-chloropyrimidin-2-yl)methyl)carbamate 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 at 0 °C, sodium hydride (60%, 217 mg, 5.42 mmol) was added. The reaction was stirred at 0 °C for 30 minutes. Following this, 4-chloro-2-(chloromethyl)pyrimidine (CAS: 3842-28-2, 768 mg, 4.71 mmol) in THF (10.0 mL) was added dropwise. The reaction was allowed to warm to RT and stirred at RT for 16 hours. 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 afford the title compound (177 mg, 74%). LC / MS (Table 1, Method C)R t =1.85 min;MS m / z:366[M+H] + .

[0137] (ii) tert-butyl ((4-(benzyloxy)pyrimidin-2-yl)methyl)carbamate To a suspension of sodium hydride (60%, 25 mg, 0.618 mmol) in THF (1.0 mL) under a nitrogen atmosphere at 0° C., benzyl alcohol (CAS: 100-51-6, 0.064 mL, 0.618 mmol) was added, and the reaction was stirred at 0° C. for 30 minutes. Following this, tert-butyl (tert-butoxycarbonyl) ((4-chloropyrimidin-2-yl)methyl)carbamate (Example 8, step (i), 177 mg, 0.515 mmol) in THF (1.0 mL) was added dropwise, and the reaction was stirred at 0° C. for 15 minutes. The reaction was allowed to warm to RT and then partitioned between distilled water and EtOAc. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound (76 mg, 47%). LC / MS (Table 1, Method C)R t =1.70 min;MS m / z:316[M+H] + .

[0138] (iii) (4-(benzyloxy)pyrimidin-2-yl)methanamine hydrochloride 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 protocol 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 (61 mg, quantitative). 1 H NMR (400MHz, MeOD) δ8.54(d,J=6.0Hz,1H), 7.48~7.44(m,2H), 7.41~7.32(m,3H), 6.93(d,J=6.0Hz,1H), 5.52(s,2H), 4.31(s,2H).

[0139] (iv) 1-((4-(benzyloxy)pyrimidin-2-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate commercially available starting materials, (4-(benzyloxy)pyrimidin-2-yl)methanamine hydrochloride (compound 8, step (iii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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%). 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). LC / MS (Table 1, Method F)R t =4.30 min;MS m / z:395[M+H] + .

[0140] compound 9 1,3-Dimethyl-1-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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)) using a reaction protocol 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 (47 mg, 80%). 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). LC / MS (Table 1, Method F)R t =5.25 min;MS m / z:414[M+H] + .

[0141] compound 10 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) 2-((1-methylpiperidin-4-yl)methoxy)isonicotinonitrile To a suspension of sodium hydride (60%, 95 mg, 2.38 mmol) in THF (15.0 mL) under a nitrogen atmosphere at 0° C. was added 4-(hydroxymethyl)-1-methylpiperidine (CAS: 20691-89-8, 0.29 mL, 2.17 mmol). This was followed by the dropwise addition of 2-chloro-4-pyridinecarbonitrile (CAS: 33252-30-1, 300 mg, 2.17 mmol) in THF (5.0 mL). The reaction was allowed to warm to RT and stirred at RT for 72 h. The reaction was then heated to 60° C. and stirred at 60° C. for 2 h. The reaction mixture was allowed to cool to RT and quenched by the addition of distilled water, then partitioned with EtOAc. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeOH, gradient elution) to afford the title compound (201 mg, 40%). LC / MS (Table 1, Method D) Rt=1.24 min; MS m / z:232[M+H] + .

[0142] (ii) (2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methanamine To a solution of 2 M lithium aluminum hydride (0.61 mL, 1.21 mmol) in THF (8.0 mL) under a nitrogen atmosphere at 0 °C, 2-((1-methylpiperidin-4-yl)methoxy)isonicotinonitrile (280 mg, 1.21 mmol) in THF (4.0 mL) was added dropwise. The reaction was stirred at 0 °C for 2 h. The reaction mixture was quenched by the addition of distilled water, 2 M sodium hydroxide, and additional distilled water. The reaction was stirred for 10 min and allowed to warm to RT. MgSO 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 [2 M NH] 90:10, gradient elution) to give the title compound (100 mg, 35%). LC / MS (Table 1, Method D) Rt=0.93 min; MS m / z:236[M+H] + .

[0143] (iii) 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate commercially available starting materials, (2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methanamine (Compound 10, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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, nonlinear gradient from 20% to 80% MeOH) to afford an off-white solid (34 mg, 39%). 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). LC / MS (Table 1, Method A)R t =2.70 min;MS m / z:415[M+H] + .

[0144] compound 11 1-((6-(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) 6-(benzyloxy)pyrimidine-4-carbonitrile The title compound, compound 10: 1-((2-((1-methylpiperidin-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, was prepared from the appropriate commercially available starting material, 6-chloropyrimidine-4-carbonitrile (CAS: 939986-65-9) and benzyl alcohol (CAS: 100-51-6) using a reaction protocol similar to that described for step (i). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound (200 mg, 21%). LC / MS (Table 1, Method C)R t =1.66 min;MS m / z:212[M+H] + .

[0145] (ii) (6-(benzyloxy)pyrimidin-4-yl)methanamine A reaction vessel was charged with 6-(benzyloxy)pyrimidine-4-carbonitrile (145 mg, 0.686 mmol) and solvated in EtOAc (4.3 mL). Acetic acid (0.74 mL) and 10% palladium on carbon (37 mg, 0.0343 mmol) were added under a nitrogen atmosphere. The reaction was then evacuated and placed under a hydrogen atmosphere. The reaction was stirred under a hydrogen atmosphere at RT for 45 minutes. The reaction mixture was filtered through Celite 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 NH] 90:10, gradient elution) to afford the title compound (105 mg, 71%). LC / MS (Table 1, Method C)R t =1.60 min;MS m / z:216[M+H] + .

[0146] (iii) 1-((6-(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate starting materials, (6-(benzyloxy)pyrimidin-4-yl)methanamine (compound 11, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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 give an off-white solid (150 mg, 82%). 1 H 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). LC / MS (Table 1, Method A)R t =4.93 min;MS m / z:395[M+H] + .

[0147] compound 12 1-((2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following 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)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 give an off-white solid (45 mg, 47%). 1 H 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 partially obscured by solvent peaks), 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). LC / MS (Table 1, Method A)R t =3.84 min;MS m / z:402[M+H] + .

[0148] compound 13 1-((2-(oxazol-2-ylmethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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), using a reaction protocol similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-(oxazol-2-ylmethoxy)pyridin-4-yl)methanamine was similarly prepared from the appropriate commercially available starting materials following 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)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 3) to give an off-white solid (16 mg, 21%). 1 H 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). LC / MS (Table 1, Method A)R t =3.86 min;MS m / z:385[M+H] + .

[0149] compound 14 1-((2-((4-fluorobenzyl)oxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following 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)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 3) to give an off-white solid (40 mg, 49%). 1 H 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). LC / MS (Table 1, Method A)R t =4.88 min;MS m / z:412[M+H] + .

[0150] compound 15 1-((2-((3,3-difluorocyclobutyl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (67 mg, 63%). 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). LC / MS (Table 1, Method A)R t =4.61 min;MS m / z:408[M+H] + .

[0151] compound 16 1-((2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) 2-((2,2,2-trifluoroethyl)amino)isonicotinonitrile A reaction vessel was charged with 2,2,2-trifluoroethylamine (CAS: 753-90-2, 0.39 mL, 4.91 mmol), 4-cyano-2-fluoropyridine (CAS: 3939-14-8, 600 mg, 4.91 mmol), and the reaction was then heated under microwave irradiation at 160 °C for 12 h. The reaction was allowed to cool to RT and then concentrated in vacuo. The residue was purified by flash column chromatography (DCM to DCM:MeOH [2M NH] 90:10, gradient elution) to afford the title compound (473 mg, 48%). LC / MS (Table 1, Method D)R t =1.23 min;MS m / z:202[M+H] + .

[0152] (ii) 4-(aminomethyl)-N-(2,2,2-trifluoroethyl)pyridin-2-amine The title compound was prepared from the appropriate starting material 2-((2,2,2-trifluoroethyl)amino)isonicotinonitrile (compound 16, 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)cyclopropyl)ethyl)urea, step (ii). The compound was purified by flash column chromatography (DCM to DCM:MeOH [2M NH] 90:10, gradient elution) to give the title compound (107 mg, 22%). LC / MS (Table 1, Method D)R t =0.87 min;MS m / z:206[M+H] + .

[0153] (iii) 1-((2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate starting materials, 4-(aminomethyl)-N-(2,2,2-trifluoroethyl)pyridin-2-amine (compound 16, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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 give an off-white solid (44 mg, 45%). 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). LC / MS (Table 1, Method A)R t =3.03min;MS m / z:385[M+H] + .

[0154] compound 17 1-((2-(2-fluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol 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 similarly prepared from the appropriate commercially available starting materials following 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)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%). 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). LC / MS (Table 1, Method F)R t =3.78 min;MS m / z:350[M+H] + .

[0155] compound 18 1-((2-(2,2-difluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (112 mg, 87%). 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). LC / MS (Table 1, Method F)R t =4.16 min;MS m / z:368[M+H] + .

[0156] compound 19 1-((2-((2-fluorobenzyl)oxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol 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 similarly prepared from the appropriate commercially available starting materials following 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)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 1) to give an off-white solid (71 mg, 67%). 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). LC / MS (Table 1, Method A)R t =4.93 min;MS m / z:412[M+H] + .

[0157] compound 20 1-((2-(2,2-difluoropropoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following 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)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 give an off-white solid (60 mg, 44%). 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). LC / MS (Table 1, Method A)R t =4.57 min;MS m / z:382[M+H] + .

[0158] compound 21 1-(3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) (E)-3-chloro-7,8-dihydroisoquinolin-5(6H)-one oxime 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) under a nitrogen atmosphere was added 1 M potassium tert-butoxide in THF (11.0 mL, 10.7 mmol). The reaction was stirred at RT for 18 h. The reaction was cooled to 0 °C and tert-butylnitrite (2.1 mL, 17.2 mmol) was added. The reaction was allowed to warm to RT and the reaction was stirred at RT for 5.5 h. The reaction mixture was quenched when poured into saturated aqueous brine solution 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 give the title compound (980 mg, 90%). LC / MS (Table 1, Method D)R t =1.09 min;MS m / z:197[M+H] + .

[0159] (ii) 3-chloro-5,6,7,8-tetrahydroisoquinolin-5-amine A reaction vessel was charged with (E)-3-chloro-7,8-dihydroisoquinolin-5(6H)-one oxime ((compound 21, step (i), 200 mg, 1.02 mmol)) and solvated in acetic acid (8.0 mL). Zinc (333 mg, 5.09 mmol) was added and the reaction was stirred at RT for 1 h. Additional zinc (333 mg, 5.09 mmol) was added and the reaction was stirred at RT for 45 min (1.45 h 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. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the title compound (124 mg, 64%). LC / MS (Table 1, Method D)R t =0.92 min;MS m / z:183[M+H] + .

[0160] (iii) 1-(3-chloro-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea 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 protocol 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 give the title compound (155 mg, 60%). LC / MS (Table 1, Method D)R t =1.35 min;MS m / z:362[M+H] + .

[0161] (iv) 1-(3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea A reaction vessel was charged with 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 Pd G3 (11 mg, 0.0133 mmol), sodium tert-butoxide (64 mg, 0.667 mmol) were charged and solvated in 2,2,2-trifluoroethanol (0.078 mL, 1.07 mmol) and 1,4-dioxane (0.50 mL) under a nitrogen atmosphere. The reaction was set to stir at RT and then heated to 60°C. The reaction was stirred at 60°C for 3 h. The reaction was allowed to cool to RT. The reaction mixture was filtered through Celite 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 afford the title compound as an off-white solid (53 mg, 93%). 1 H 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). LC / MS (Table 1, Method E)R t =4.96 min;MS m / z:426[M+H] + .

[0162] compound 22 1-((2-((1-fluorocyclopropyl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following 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)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 2) to give an off-white solid (60 mg, 39%). 1 H 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). LC / MS (Table 1, Method A)R t =4.44 min;MS m / z:376[M+H] + .

[0163] compound 23 1-((2-(pyridin-2-ylmethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following 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)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse phase HPLC (Table 2, Method 3) to give an off-white solid (61 mg, 41%). 1 H 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). LC / MS (Table 1, Method A)R t =3.36 min;MS m / z:395[M+H] + .

[0164] compound 24 1-((2-((3-fluorooxetan-3-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following 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)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 give an off-white solid (15 mg, 13%). 1 H 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). LC / MS (Table 1, Method A)R t =3.94 min;MS m / z:392[M+H] + .

[0165] compound 25 1-((2-((2,4-difluorobenzyl)oxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following 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)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 give an off-white solid (39 mg, 37%). 1 H 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). LC / MS (Table 1, Method A)R t =4.92 min;MS m / z:430[M+H] + .

[0166] compound 26 1-((2-morpholino-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) 2-chloro-6-morpholinoisonicotinonitrile A reaction vessel was charged with 2,6-dichloropyridine-4-carbonitrile (CAS: 32710-65-9, 977 mg, 5.65 mmol) 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 reaction was set to stir at room temperature and then heated to 70 °C. The reaction was stirred at 70 °C for 5.5 h. The reaction mixture was allowed to cool to RT and concentrated in vacuo. The residue was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to THF, gradient elution) to afford the title compound (805 mg, 64%). LC / MS (Table 1, Method A)R t =1.58 min;MS m / z:224[M+H] + .

[0167] (ii) 2-morpholino-6-(2,2,2-trifluoroethoxy)isonicotinonitrile A reaction vessel was charged with 2-chloro-6-morpholinoisonicotinonitrile (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), XantphosPdG4 (73 mg, 0.0760 mmol), and solvated in toluene (15.0 mL). The reaction was purged and placed under a nitrogen atmosphere. The reaction was set to stir at RT and then heated to 80°C. The reaction was stirred at 80°C for 72 h. The reaction mixture was allowed to cool to RT and concentrated in vacuo. 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, gradient elution) to afford the title compound (410 mg, 87%). LC / MS (Table 1, Method A)R t =1.74 min;MS m / z:288[M+H] +.

[0168] (iii) (2-morpholino-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine 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 protocol 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). This afforded the title compound (465 mg, quantitative). LC / MS (Table 1, Method D)R t = 1.35 min; MS m / z: 292 [M−H] + .

[0169] (iv) 1-((2-morpholino-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate starting materials, (2-morpholino-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (compound 26, step (iii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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 give an off-white solid (116 mg, 47%). 1H 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). LC / MS (Table 1, Method E)R t =4.77 min;MS m / z:471[M+H] + .

[0170] compound 27 1-((2-((4-fluorobenzyl)oxy)-6-morpholinopyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting material following a reaction protocol 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, steps (i-iii). The title compound was purified by reverse-phase HPLC (Table 2, Method 2) to give an off-white solid (27 mg, 29%). 1H 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). LC / MS (Table 1, Method A)R t =5.21 min;MS m / z:497[M+H] + .

[0171] compound 28 (±)-1-((2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) (±)-2-(3-fluoropiperidin-1-yl)isonicotinonitrile A reaction vessel was charged with 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), and solvated in EtOH (10.0 mL) under a nitrogen atmosphere. Triethylamine (1.9 mL, 13.8 mmol) was added. The reaction was set to stir at RT and then heated to 70 °C. The reaction was stirred at 70 °C for 18 h. The reaction mixture was allowed to cool to RT and then partitioned between DCM and distilled water. 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 afford the title compound (730 mg, 64%). LC / MS (Table 1, Method C)R t =1.78 min;MS m / z:206[M+H] + .

[0172] (ii) (±)-(2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methanamine 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] 90:10, gradient elution) to give the title compound (520 mg, 70%). LC / MS (Table 1, Method D)R t =1.30 min;MS m / z:210[M+H] + .

[0173] (iii) (±)-1-((2-(3-fluoropiperidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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, nonlinear gradient from 5% to 60% MeCN) to give a white solid (63 mg, 34%). 1H 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). LC / MS (Table 1, Method E)R t =4.17 min;MS m / z:389[M+H] + .

[0174] compound 29 1-((2-(3-(difluoromethyl)azetidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate starting materials, (2-(3-(difluoromethyl)azetidin-1-yl)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol similar 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 similarly prepared from the appropriate commercially available starting materials following a reaction protocol similar 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 give a white solid (22 mg, 35%). 1H 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). LC / MS (Table 1, Method A)R t =3.01 min;MS m / z:393[M+H] + .

[0175] compound 30 1-((4-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (56 mg, 40%). 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). LCMS (Table 1, Method E)R t =4.18min MS, m / z:387[M+H] + .

[0176] compound 31 1-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (77 mg, 47%). 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). LCMS (Table 1, Method A)R t =4.87min MS, m / z:386[M+H] + .

[0177] compound 32 1-((2-chloro-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following 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)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 give a white solid (63 mg, 56%). 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). LCMS (Table 1, Method F)R t =4.92min MS, m / z:420[M+H] + .

[0178] compound 33 1-(4,4,4-trifluoro-3-hydroxy-3-methylbutyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared from the appropriate commercially available starting material, (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), using a reaction protocol 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 give a white solid (57 mg, 35%). 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). LCMS (Table 1, Method E)R t =3.95min MS, m / z:390[M+H] + .

[0179] compound 34 (±)-1-((2-(3-fluoropyrrolidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following a reaction protocol similar 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 give a white solid (52 mg, 28%). 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). LC / MS (Table 1, Method A)R t =2.90 min;MS m / z:375[M+H] + .

[0180] compound 35 1-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-((1-(trifluoromethyl)cyclopropyl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (65 mg, 53%). 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). LCMS (Table 1, Method A)R t =4.57min MS, m / z:372[M+H] + .

[0181] compound 36 1-(cyclohexylmethyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (35 mg, 30%). 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). LCMS (Table 1, Method E)R t =4.72min MS, m / z:346[M+H] + .

[0182] compound 37 1-(2-methylbenzyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (47 mg, 42%). 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). LCMS (Table 1, Method A)R t =4.64 min MS, m / z:354[M+H] + .

[0183] compound 38 1-((6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following a reaction protocol 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 DCM:MeOH [2M NH3] 90:10, gradient elution) to give a white solid (37 mg, 40%). 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). LCMS (Table 1, Method B)R t =4.16min MS, m / z:387[M+H] + .

[0184] compound 39 1-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) 1-((2-chloro-6-methylpyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate commercially available starting materials, (2-chloro-6-methyl-4-pyridyl)methanamine dihydrochloride (CAS: 1909336-63-5) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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 give the title compound (103 mg, 70%). LC / MS (Table 1, Method A)R t =1.46 min;MS m / z:336[M+H] + .

[0185] (ii) 1-((2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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) 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 title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford an off-white solid (84 mg, 67%). 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). LC / MS (Table 1, Method F)R t =4.79 min;MS m / z:400[M+H] + .

[0186] compound 40 1-(3-fluorobenzyl)-3-((2-((2-fluorobenzyl)oxy)pyridin-4-yl)methyl)urea The title compound was prepared from the appropriate starting materials, (2-((2-fluorobenzyl)oxy)pyridin-4-yl)methanamine and 3-fluorobenzylamine (CAS: 100-82-3), using a reaction protocol 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 similarly prepared from the appropriate commercially available starting materials following 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)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by flash column chromatography (DCM to EtOAc, gradient elution) to give a white solid (15 mg, 37%). 1H 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). LCMS (Table 1, Method F)R t =4.46min MS, m / z:384[M+H] + .

[0187] compound 41 1-(4,4,4-trifluoro-3,3-dimethylbutyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea 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 4,4,4-trifluoro-3,3-dimethylbutan-1-amine hydrochloride (CAS: 1454690-74-4), using a reaction protocol 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 give an off-white solid (89 mg, 69%). 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). LCMS (Table 1, Method A)R t =4.83min MS, m / z:388[M+H] + .

[0188] compound 42 1-(3-Fluorobenzyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea 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 protocol 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 give an off-white solid (42 mg, 37%). 1 H 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). LCMS (Table 1, Method B)R t =4.28min MS, m / z:358[M+H] + .

[0189] compound 43 1-Cyclohexyl-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea 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 protocol 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 give an off-white solid (75 mg, 71%). 1H 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). LCMS (Table 1, Method F)R t =4.38min MS, m / z:332[M+H] + .

[0190] compound 44 1-((2-(3-(trifluoromethyl)azetidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate starting materials, (2-(3-(trifluoromethyl)azetidin-1-yl)pyridin-4-yl)methanamine and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol similar 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 similarly prepared from the appropriate commercially available starting materials following a reaction protocol similar 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 give a white solid (118 mg, 60%). 1H 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). LCMS (Table 1, Method A)R t =3.18 min MS, m / z:411[M+H] + .

[0191] compound 45 1-((2-(3-fluoroazetidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) 2-(3-fluoroazetidin-1-yl)isonicotinonitrile The title compound was prepared 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 protocol 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 give the title compound (387 mg, 68%). LC / MS (Table 1, Method C)R t =1.16 min;MS m / z:178[M+H] + .

[0192] (ii) (2-(3-fluoroazetidin-1-yl)pyridin-4-yl)methanamine The title compound was prepared from the appropriate starting material, 2-(3-fluoroazetidin-1-yl)isonicotinonitrile (Compound 45, step (i)), using a reaction protocol 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 give the title compound (94 mg, 46%). LC / MS (Table 1, Method G)R t =1.01 min;MS m / z:182[M+H] + .

[0193] (iii) 1-((2-(3-fluoroazetidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate starting materials, (2-(3-fluoroazetidin-1-yl)pyridin-4-yl)methanamine (compound 45, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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 give an off-white solid (84 mg, 45%). 1 H 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). LC / MS (Table 1, Method A)R t =2.84 min;MS m / z:361[M+H] + .

[0194] compound 46 1-(o-Tolyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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%). 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). LC / MS (Table 1, Method F)R t =4.39min;MS m / z:340[M+H] + .

[0195] compound 47 (S)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-3-((2-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting material following 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)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse-phase HPLC (Table 2, Method 3, nonlinear gradient from 40% to 100% MeCN) to afford an off-white solid (108 mg, 45%). 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). LC / MS (Table 1, Method E)R t =4.80 min;MS m / z:400[M+H] + .

[0196] compound 48 1-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea (i) tert-butyl (2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate 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) under a nitrogen atmosphere at 0° C. was added sodium hydride (60%, 93 mg, 2.33 mmol). The reaction was allowed to warm to RT and then heated to 60° C. for 18 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 (MgSO), and concentrated in vacuo to give the title compound (327 mg, 86%). 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).

[0197] (ii) 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethan-1-amine hydrochloride The title compound was prepared from the appropriate starting tert-butyl (2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)carbamate ((Compound 48, step (i)) using a reaction protocol 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). Trituration of the compound with diethyl ether gave the title compound (216 mg, 86%). 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).

[0198] (iii) 1-(2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared from the 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)ethan-1-amine hydrochloride (compound 48, step (ii)), using a reaction protocol 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%). 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). LCMS (Table 1, Method F)R t =4.47min MS, m / z:404[M+H] + .

[0199] compound 49 1-((2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) (2-chloropyrimidin-4-yl)methyl 4-methylbenzenesulfonate To a solution of (2-chloropyrimidin-4-yl)methanol (CAS: 34953-87-2, 397 mg, 2.75 mmol), p-toluenesulfonyl chloride (628 mg, 3.30 mmol) in THF (15.0 mL) at 0 °C, triethylamine (0.51 mL, 3.65 mmol) was added. The reaction was stirred at 0 °C for 3 h. The reaction was allowed to warm to RT and stirred at RT 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 give the title compound (570 mg, 69%). The product was carried on to step (ii) without characterization.

[0200] (ii) tert-butyl (tert-butoxycarbonyl)((2-chloropyrimidin-4-yl)methyl)carbamate The title compound was prepared from the appropriate starting material, (2-chloropyrimidin-4-yl)methyl 4-methylbenzenesulfonate (compound 49, step (i)), using a reaction protocol 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 give the title compound (638 mg, quantitative). LC / MS (Table 1, Method C)R t =1.88 min;MS m / z:366[M+H] + .

[0201] (iii) tert-butyl ((2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)carbamate 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 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 (cyclohexane to EtOAc, gradient elution) to give the title compound (47 mg, 8%). LC / MS (Table 1, Method C)R t =1.61 min;MS m / z:308[M+H] + .

[0202] (iv) (2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methanamine hydrochloride 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 protocol 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 (38 mg, quantitative). LC / MS (Table 1, Method A)R t =0.92 min;MS m / z:208[M+H] + .

[0203] (v) 1-((2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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 give an off-white solid (33 mg, 54%). 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). LCMS (Table 1, Method F)R t =4.12min MS, m / z:387[M+H] + .

[0204] compound 50 1-((6-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following a reaction protocol similar 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%). 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). LCMS (Table 1, Method F)R t =4.31min MS, m / z:401[M+H] + .

[0205] compound 51 (R)-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-3-((2-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting material following 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)cyclopropyl)ethyl)urea, steps (i-ii). The title compound was purified by reverse-phase HPLC (Table 2, Method 2) to give an off-white solid (67 mg, 55%). 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). LC / MS (Table 1, Method A)R t = 4.99 min; MS m / z: 400 [M+H] + .

[0206] compound 52 1-((5-methyl-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following 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)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%). 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). LCMS (Table 1, Method F)R t =4.75min MS, m / z:400[M+H] + .

[0207] compound 53 1-((6-(2,2,2-trifluoroethoxy)pyridazin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol 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 similarly prepared from the appropriate commercially available starting materials following a reaction protocol 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%). 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). LCMS (Table 1, Method F)R t =4.11min MS, m / z:387[M+H] + .

[0208] compound 54 1-((2-((3-fluoropyridin-2-yl)methoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate starting materials according to 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)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%). 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). LCMS (Table 1, Method F)R t =4.05min MS, m / z:413[M+H] + .

[0209] compound 55 1-((2-(pyrimidin-2-ylmethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) 2-(pyrimidin-2-ylmethoxy)isonicotinonitrile The title compound was prepared 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 protocol 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 give the title compound (889 mg, 79%). LCMS (Table 1, Method D)R t =1.03min MS, m / z:213[M+H] + .

[0210] (ii) (2-(pyrimidin-2-ylmethoxy)pyridin-4-yl)methanamine 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) at 0 °C under a nitrogen atmosphere. The reaction was allowed to warm to RT and stirred at RT 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 (NaSO) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to DCM:MeOH [2M NH] 90:10, gradient elution) to give the title compound (71 mg, 35%). LCMS (Table 1, Method D)R t =0.76min MS, m / z:217[M+H] + .

[0211] (iii) 1-((2-(pyrimidin-2-ylmethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate starting materials, (2-(pyrimidin-2-ylmethoxy)pyridin-4-yl)methanamine (compound 55, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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%). 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). LCMS (Table 1, Method F)R t =3.42min MS, m / z:396[M+H] + .

[0212] compound 56 1-((2-(3,3-difluoroazetidin-1-yl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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), using a reaction protocol similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (2-(3,3-difluoroazetidin-1-yl)pyridin-4-yl)methanamine was similarly prepared according to a reaction protocol similar 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 give an off-white solid (55 mg, 53%). 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). LCMS (Table 1, Method E)R t =3.99min MS, m / z:379[M+H] + .

[0213] compound 57 1-(2-hydroxy-2-methylpropyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give the title compound as a white solid (68 mg, 67%). 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). LCMS (Table 1, Method F)R t =3.28min MS, m / z:322[M+H] + .

[0214] compound 58 1-((1S,2R)-2-Hydroxycyclohexyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (60 mg, 54%). 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). LC / MS (Table 1, Method F)R t =3.65 min;MS m / z:348[M+H] + .

[0215] compound 59 (R)-2-Methyl-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)morpholine-4-carboxamide The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (75 mg, 69%). 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). LC / MS (Table 1, Method F)R t =3.71 min;MS m / z:334[M+H] + .

[0216] compound 60 (S)-2-Methyl-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)morpholine-4-carboxamide The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (79 mg, 73%). 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). LC / MS (Table 1, Method F)R t =3.70 min;MS m / z:334[M+H] + .

[0217] compound 61 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)acetamide (i) tert-butyl ((5-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)carbamate 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) under a nitrogen atmosphere at 0 °C. The reaction was set to stir at 0 °C, and sodium borohydride (465 mg, 12.3 mmol) was added portionwise. The reaction was allowed to warm to RT, and the reaction was stirred at RT for 1 h. The reaction mixture was quenched by the addition of diethylenetriamine (0.19 mL, 1.76 mmol), and the reaction was stirred at RT for 30 min. The reaction was then partitioned between DCM and saturated aqueous sodium bicarbonate. 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 afford the title compound (513 mg, 83%). LC / MS (Table 1, Method C) Rt=1.49 min; MS m / z:307[M+H] + .

[0218] (ii) (5-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine dihydrochloride 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 protocol 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). LC / MS (Table 1, Method C)R t =0.25 min;MS m / z:207[M+H] + .

[0219] (iii) 2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)acetamide The title compound was prepared 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)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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] 90:10, gradient elution) followed by flash column chromatography (DCM to MeOH, gradient elution) to afford a white solid (128 mg, 50%). 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). LCMS (Table 1, Method F)R t =3.87min MS, m / z:386[M+H] + .

[0220] compound 62 1-((1R,2S)-2-Hydroxycyclohexyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (33 mg, 28%). 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). LC / MS (Table 1, Method F)R t =3.64 min;MS m / z:348[M+H] + .

[0221] compound 63 1-((1S,2S)-2-Hydroxycyclohexyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared from the appropriate commercially available starting materials, (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (1S,2S)-2-aminocyclohexan-1-ol (CAS: 74111-21-0), using a reaction protocol 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 give the title compound as a white solid (62 mg, 57%). 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). LC / MS (Table 1, Method F)R t =3.79 min;MS m / z:348[M+H] + .

[0222] compound 64 1-((1R,2R)-2-hydroxycyclohexyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared from the appropriate commercially available starting materials, (2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine (CAS: 561297-93-6) and (1R,2R)-2-aminocyclohexan-1-ol (CAS: 931-16-8), using a reaction protocol 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 give the title compound as a white solid (64 mg, 59%). 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). LC / MS (Table 1, Method F)R t =3.79 min;MS m / z:348[M+H] + .

[0223] compound 65 (R)-1-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) N-Methoxy-N-methyl-2-(2,2,2-trifluoroethoxy)isonicotinamide A reaction vessel was charged with 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) and solvated in DCM (50.0 mL). N,N-Diisopropylethylamine (4.0 mL, 22.7 mmol) was added, and the reaction was stirred at RT 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 give the title compound (2.26 g, 94%). LC / MS (Table 1, Method C)R t =1.52 min;MS m / z:265[M+H] + .

[0224] (ii) 1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethan-1-one 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) at 0° C. was added 3 M methylmagnesium bromide solution (4.4 mL, 13.2 mmol). The reaction was allowed to warm to RT and the reaction was stirred at RT for 1 h. The reaction mixture was quenched when poured into saturated aqueous sodium bicarbonate solution 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 give the title compound (1.29 g, 97%). LC / MS (Table 1, Method C)R t =1.65 min;MS m / z:220[M+H] + .

[0225] (iii) (R,E)-2-methyl-N-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethylidene)propane-2-sulfinamide A reaction vessel was charged with 1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethan-1-one ((compound 65, step (ii), 370 mg, 1.64 mmol)), (R)-2-methyl-2-propanesulfinamide (218 mg, 1.80 mmol) and solvated in THF (10.0 mL). Titanium(IV) ethoxide (0.69 mL, 3.28 mmol) was added and the reaction was set to stir at RT and then heated to 70° C. The reaction was stirred at 70° C. for 24 h. The reaction was allowed to cool to RT. The reaction mixture was then partitioned between EtOAc and saturated brine. The organic layer was separated. The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the title compound (635 mg, quantitative). LC / MS (Table 1, Method C)R t =1.80 min;MS m / z:323[M+H] + .

[0226] (iv) (R)-2-methyl-N-((R)-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethyl)propane-2-sulfinamide To a solution of (R,E)-2-methyl-N-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethylidene)propane-2-sulfinamide ((compound 65, step (iii), 635 mg, 1.89 mmol)) in THF (10.0 mL) at −78° C. was added 1 M diisobutylaluminum hydride (4.3 mL, 4.26 mmol) dropwise. The reaction was stirred at −78° C. for 18 h. MeOH (5 mL) was added and the reaction was allowed to warm to RT. 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 (MgSO4), and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeOH, gradient elution) to afford the title compound (111 mg, 18%). LC / MS (Table 1, Method F)R t =4.41 min;MS m / z:325[M+H] + .

[0227] (v) (R)-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethan-1-amine hydrochloride 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 protocol 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 (108 mg, quantitative). 1H 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).

[0228] (vi) (R)-1-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (50 mg, 64%). 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). LC / MS (Table 1, Method F)R t =4.66 min;MS m / z:399[M+H] + .

[0229] compound 66 (±)-1-(3-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) S-((6-chloropyridin-3-yl)methyl) O-ethyl carbonodithioate A reaction vessel was charged with 2-chloro-5-(chloromethyl)pyridine (CAS: 70258-18-3, 5.00 g, 30.9 mmol) and solvated in acetone (25.0 mL). Potassium ethoxymethanedithioate (5.44 g, 33.9 mmol) was added portionwise, and the reaction was stirred at RT 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 (NaSO) and concentrated in vacuo to give the title compound (7.27 g, 95%). LC / MS (Table 1, Method D)R t =1.49 min;MS m / z:248[M+H] + .

[0230] (ii) (±)-S-(3-(6-chloropyridin-3-yl)-1-(1,3-dioxoisoindolin-2-yl)propyl)O-ethyl carbonodithioate A reaction vessel was charged with S-((6-chloropyridin-3-yl)methyl) O-ethyl carbonodithioate ((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 RT. The reaction was then heated to reflux. The reaction was stirred at reflux for 13 h while additional lauroyl peroxide (73 mg, 0.183 mmol) was added every hour. The reaction mixture was allowed to cool to RT and then concentrated in vacuo. The residue was directly purified by flash column chromatography (pentane to diethyl ether, gradient elution) to afford the title compound (924 mg, 30%). LC / MS (Table 1, Method D)R t =1.62 min;MS m / z:421[M+H]+ .

[0231] (iii) (±)-2-(3-chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)isoindoline-1,3-dione A reaction vessel was charged with (±)-S-(3-(6-chloropyridin-3-yl)-1-(1,3-dioxoisoindolin-2-yl)propyl)O-ethyl carbonodithioate ((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 RT. The reaction was then heated to reflux. The reaction was stirred at reflux for 5 hours, with additional lauroyl peroxide (172 mg, 0.430 mmol) being added every hour. The reaction mixture was allowed to cool to RT and concentrated in vacuo. The residue was directly purified by flash column chromatography (pentane to diethyl ether, gradient elution) to afford the title compound (119 mg, 19%). LC / MS (Table 1, Method D)R t =1.40 min;MS m / z:299[M+H] + .

[0232] (iv) (±)-2-(3-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)isoindoline-1,3-dione The title compound was prepared from the 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 give the title compound (74 mg, 41%). LC / MS (Table 1, Method D)R t =1.64 min;MS m / z:362[M+H] + .

[0233] (v) (±)-3-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-amine A 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). 1 M 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 RT and concentrated in vacuo. The residue was directly purified by flash column chromatography (DCM to DCM:MeOH [2M NH] 90:10, gradient elution) to afford the title compound (32 mg, 67%). 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).

[0234] (vi) (±)-1-(3-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (25 mg, 42%). 1 H 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). LC / MS (Table 1, Method B)R t =4.76 min;MS m / z:412[M+H] + .

[0235] compound 67 (S)-1-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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), using a reaction protocol similar to that described for compound 1: 1-((2-(benzyloxy)pyridin-4-yl)methyl)-3-(3-fluorophenyl)urea. (S)-1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethan-1-amine hydrochloride was similarly prepared from the appropriate commercially available auxiliary (S)-2-methyl-2-propanesulfinamide (CAS: 343338-28-3) following a reaction protocol similar 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, steps (i-v). The title compound was purified by reverse-phase HPLC (Table 2, Method 7) to give a white solid (45 mg, 58%). 1 H 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). LC / MS (Table 1, Method F)R t =4.66 min;MS m / z:400[M+H] + .

[0236] compound 68 1-((2-(methyl(2,2,2-trifluoroethyl)amino)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) 2-(methyl(2,2,2-trifluoroethyl)amino)isonicotinonitrile The title compound was prepared from the appropriate commercially available starting materials, 4-cyano-2-fluoropyridine (CAS: 3939-14-8) and 2,2,2-trifluoro-N-methyl-ethanamine hydrochloride (CAS: 2730-52-1), using a reaction protocol 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 give the title compound (187 mg, 38%). LC / MS (Table 1, Method H)R t =1.72 min;MS m / z:216[M+H] + .

[0237] (ii) 4-(aminomethyl)-N-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine 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 protocol 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] 90:10, gradient elution) to give the title compound (100 mg, 52%). LC / MS (Table 1, Method D)R t =1.13 min;MS m / z:220[M+H] + .

[0238] (iii) 1-((2-(methyl(2,2,2-trifluoroethyl)amino)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate starting materials, 4-(aminomethyl)-N-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine (compound 68, step (ii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2), using a reaction protocol 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%). 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). LC / MS (Table 1, Method F)R t =3.22 min;MS m / z:399[M+H] + .

[0239] compound 69 1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-3-((2-(trifluoromethyl)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (79 mg, 72%). 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). LC / MS (Table 1, Method F)R t =4.19 min;MS m / z:356[M+H] + .

[0240] compound 70 1-((4,4-difluorocyclohexyl)methyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (38 mg, 36%). 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). LC / MS (Table 1, Method F)R t =4.32 min;MS m / z:382[M+H] + .

[0241] compound 71 1-(4,4-difluorocyclohexyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (53 mg, 52%). 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). LC / MS (Table 1, Method F)R t=4.22 min;MS m / z:368[M+H] + .

[0242] compound 72 6-Fluoro-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)indoline-1-carboxamide (i) 6-Fluoroindoline-1-carbonyl chloride To a solution of 6-fluoroindoline hydrochloride (250 mg, 1.44 mmol) and pyridine (0.23 mL, 2.88 mmol) in DCM (5.0 mL) at 0° C. was added triphosgene (214 mg, 0.720 mmol) dropwise. The reaction was allowed to warm to RT and stirred at RT for 18 h. The reaction mixture was quenched by the addition of 1 M aqueous HCl and then partitioned with DCM. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo to give the title compound (358 mg, quantitative). LC / MS (Table 1, Method D)R t =1.55 min;MS m / z:200[M+H] + .

[0243] (ii) 6-fluoro-N-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)indoline-1-carboxamide 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)methanamine (CAS: 561297-93-6, 100 mg, 0.485 mmol) in DCM (2.0 mL) at 0 °C under nitrogen. The reaction was allowed to warm to RT and stirred at RT 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 (NaSO), and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford the title compound as an off-white solid (105 mg, 57%). 1 H 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). LC / MS (Table 1, Method F)R t =4.82 min;MS m / z:370[M+H] + .

[0244] compound 73 (R)-1-(2-hydroxy-3,3-dimethylbutyl)-3-((2-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)methyl)urea (i) 2-(2,2,3,3,3-pentafluoropropoxy)isonicotinonitrile 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 protocol 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 give the title compound (420 mg, 46%). LC / MS (Table 1, Method D)R t =1.58 min;MS m / z:253[M+H] + .

[0245] (ii) (2-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)methanamine 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 protocol similar to that described for compound 11: 1-((6-(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, step (ii). This gave the title compound (350 mg, 65%). The product was carried on to step (iii) without characterization.

[0246] (iii) (R)-1-(2-hydroxy-3,3-dimethylbutyl)-3-((2-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)methyl)urea The title compound was prepared from the 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), using a reaction protocol 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 give a white solid (97 mg, 69%). 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). LC / MS (Table 1, Method F)R t=4.40min;MS m / z:400[M+H] + .

[0247] compound 74 1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-3-((2-(3,3,3-trifluoropropoxy)pyridin-4-yl)methyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting material following a reaction protocol similar 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, nonlinear gradient from 5% to 60% MeCN) to afford an off-white solid (90 mg, 65%). 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). LC / MS (Table 1, Method A)R t =4.64 min;MS m / z:400[M+H] + .

[0248] compound 75 1-(2-chlorobenzyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared from the 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), using a reaction protocol 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, nonlinear gradient from 40% to 100% MeOH) followed by reverse-phase HPLC (Table 2, Method 3) to afford an off-white solid (38 mg, 41%). 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). LC / MS (Table 1, Method E)R t =4.58 min;MS m / z:374[M+H] + .

[0249] compound 76 1-(3-Fluorobenzyl)-3-((6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methyl)urea The title compound was prepared from the appropriate commercially available starting materials, (6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)methanamine dihydrochloride and 3-fluorobenzylamine (CAS: 100-82-3), using a reaction protocol similar 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 dihydrochloride was similarly prepared according to a reaction protocol similar 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 give an off-white solid (22 mg, 17%). 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). LC / MS (Table 1, Method A)R t =4.10 min;MS m / z:359[M+H] + .

[0250] compound 77 1-(3-chloro-5-fluorophenyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (17 mg, 16%). 1 H 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). LC / MS (Table 1, Method B)R t =4.98 min;MS m / z:378[M+H] + .

[0251] compound 78 (R)-1-(2-hydroxy-3,3-dimethylbutyl)-3-((2-(3,3,3-trifluoropropoxy)pyridin-4-yl)methyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting material following a reaction protocol similar 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 give an off-white solid (45 mg, 70%). 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). LC / MS (Table 1, Method F)R t =4.03min;MS m / z:364[M+H] + .

[0252] compound 79 1-((3,3-difluorocyclohexyl)methyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (61 mg, 63%). 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). LC / MS (Table 1, Method F)R t =4.36 min;MS m / z:382[M+H] + .

[0253] compound 80 1-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (18 mg, 18%). 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). LC / MS (Table 1, Method A)R t =4.61 min;MS m / z:386[M+H] + .

[0254] compound 81 (±)-1-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (51 mg, 54%). 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). LC / MS (Table 1, Method F)R t =4.57 min;MS m / z:384[M+H] + .

[0255] compound 82 1-((2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following a reaction protocol 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 MeOH, gradient elution) to give an off-white solid (51 mg, 31%). 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). LC / MS (Table 1, Method F)R t =5.11 min;MS m / z:454[M+H] + .

[0256] compound 83 (R)-1-(2-hydroxy-3,3-dimethylbutyl)-3-((2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyridin-4-yl)methyl)urea The title compound was prepared from the 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 protocol similar 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 similarly prepared from the appropriate commercially available starting materials following a reaction protocol 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 reverse-phase HPLC (Table 2, Method 3, non-linear gradient from 40% to 100% MeCN) to give an off-white solid (41 mg, 51%). 1H 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). LC / MS (Table 1, Method A)R t =4.80 min;MS m / z:418[M+H] + .

[0257] compound 84 (R)-N-(2-hydroxy-3,3-dimethylbutyl)-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (i) tert-butyl 6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate The title compound, compound 21: 1-(3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroisoquinolin-5-yl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea, 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 protocol similar to that described for step (iv). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound (187 mg, 80%). 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).

[0258] (ii) 6-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine 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) at 0 °C was added trifluoroacetic acid (0.45 mL, 5.88 mmol). The reaction was allowed to warm to RT and stirred at RT for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by SCX-2 column chromatography (DCM to DCM:MeOH [2M NH] 90:10, gradient elution) to afford the title compound (106 mg, 83%). LC / MS (Table 1, Method D)R t =1.00 min;MS m / z:219[M+H] + .

[0259] (iii) 6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carbonyl chloride 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 protocol similar 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%). LC / MS (Table 1, Method D)R t =1.68 min;MS m / z:281[M+H] + .

[0260] (iv) (R)-N-(2-hydroxy-3,3-dimethylbutyl)-6-(2,2,2-trifluoroethoxy)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (31 mg, 33%). 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). LC / MS (Table 1, Method F)R t =4.07 min;MS m / z:362[M+H] + .

[0261] compound 85 1-(2-chloro-5-fluorobenzyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give an off-white solid (5.9 mg, 6%). 1 H 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). LC / MS (Table 1, Method B)R t =4.64 min;MS m / z:392[M+H] + .

[0262] compound 86 (R)-1-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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, nonlinear gradient from 30% to 95% MeCN) to give a white solid (49 mg, 52%). 1H 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). LC / MS (Table 1, Method F)R t =4.61 min;MS m / z:384[M+H] + .

[0263] compound 87 1-((5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea (i) tert-butyl ((2-chloro-5-fluoropyridin-4-yl)methyl)carbamate The title compound was prepared from the appropriate commercially available starting material, 2-chloro-5-fluoro-pyridine-4-carbonitrile (CAS: 1057319-20-6), using a reaction protocol similar 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, step (i). The compound was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound (266 mg, 23%). LC / MS (Table 1, Method D)R t =1.57 min;MS m / z:261[M+H] + .

[0264] (ii) tert-butyl((5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)carbamate The title compound was prepared from the 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 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 (cyclohexane to EtOAc, gradient elution) to give the title compound (76 mg, 76%). LC / MS (Table 1, Method D)R t =1.78 min;MS m / z:325[M+H] + .

[0265] (iii) (5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine hydrochloride 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 protocol 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). Trituration of the compound with diethyl ether afforded the title compound (52 mg, 85%). LC / MS (Table 1, Method D)R t =1.12 min;MS m / z:225[M+H] + .

[0266] (iv) 1-((5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-3-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)urea The title compound was prepared from the appropriate starting materials (5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine hydrochloride (compound 87, step (iii)) and 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-amine hydrochloride (CAS: 1454690-80-2) using a reaction protocol 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 give a white solid (27 mg, 37%). 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). LC / MS (Table 1, Method B)R t =4.71 min;MS m / z:404[M+H] + .

[0267] compound 88 1-((3,3-difluorocyclopentyl)methyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)urea The title compound was prepared 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), using a reaction protocol 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 give a white solid (54 mg, 52%). 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). LC / MS (Table 1, Method F)R t =4.20 min;MS m / z:368[M+H] + .

[0268] Example 2 K V 7.2 / K V 7.3 Evaluation of in vitro efficacy against channels Automated patch clamp assays on a Sophion Qube 384 were performed using heteromeric K V 7.2 / K V It was developed for potency testing to identify small molecule activators of 7.3 channels (KCNQ2, Uniprot ID O43526; KCNQ3, Uniprot O43525).

[0269] The cell line used constitutively expresses K V 7.2 / K V The cell line was a stably transfected CHO-K1 cell line expressing 7.3.

[0270] CHO-K1 / Kv7.2 / Kv7.3 cells were maintained in the following culture medium: DMEM / F-12 with GlutaMAX™ (Gibco 31331-028), ·10% Fetal clone 2 serum (Perbio Science SH30066.03), 1 mg / ml Geneticin™ selective antibiotic (G418, Invitrogen 1013027), and · 5 μg / ml Blasticidin S HCl (Invivogen Ant-bl-5).

[0271] On the day of the experiment, cells were resuspended in serum-free medium, counted, and measured at 3.5 × 10 cells per ml of medium. 6 Diluted to final cell concentration.

[0272] The cells were then placed in a Sophion Qube 384 and allowed to settle for a minimum of 1 hour.

[0273] The following solutions were used for recording: Extracellular solution (mM): 145 NaCl, 4 KCl, 1 MgCl2, 2 CaCl2, 10 HEPES, 10 glucose, pH 7.4, 315-320 mOsm. · Intracellular solution (mM): 120 KCl, 5.74 CaCl2, 1.75 MgCl2, 10 EGTA, 10 HEPES, 5 Na2ATP, pH 7.2, adjusted to 315 mOsm with sucrose.

[0274] After establishing the whole-cell configuration, cells were held at -80 mV throughout the experiment. A current-voltage (IV) protocol was applied, measuring Kv7.2 / Kv7.3 currents by stepping from -100 mV to +20 mV for 1 s, with each step followed by a 200 ms pulse to 0 mV to measure tail currents. From the IV protocol, a Boltzmann fit was applied to generate activation curves. Data were sampled at 25 kHz and filtered at 5 kHz (Bessel). Data were generated using a multihole QChip. The IV protocol was applied several times to establish responses under control conditions (typically 0.3% DMSO) and in the presence of test compound.

[0275] To ensure quality, data were reviewed in Sophion Analyser version 6.5.2 (Sophion Bioscience) and filters were applied to remove failed wells. Leak subtraction was applied to all recordings. Unless otherwise specified, data filters for the multi-hole QChip were typically: seal resistance >4 MΩ, capacitance >20 pF, baseline VHalf between 0 and -40 mV, baseline holding current between -2 and 2 nA, and baseline steady-state current >4 nA at 20 mV.

[0276] K V 7.4 Evaluation of in vitro efficacy against channels Homomer K V A counter-screening assay for the 7.4 channel (KCNQ4, Uniprot ID P56696) was also developed in Qube. The cell line used was a constitutively K 7.4 channel (KCNQ4, Uniprot ID P56696) supplied by Charles River Laboratories. V The cells were stably transfected CHO-K1 expressing 7.4.

[0277] K V CHO-K1 cells stably expressing the 7.4 channel were maintained in the following culture medium: hams F-12 containing GlutaMAX™ (Life Technologies 31765027), 10% Fetal clone 2 serum (Perbio Science SH30066.03), and ·250μg / ml Geneticin™ Selective Antibiotic (G418, Invitrogen 1013-027).

[0278] Cell maintenance, preparation, recording conditions and voltage protocols were all identical to those described above.

[0279] K V 7.3 / K V 7.5 Evaluation of in vitro efficacy against channels Counter-screening of heteromeric K V 7.3 / K V The cell lines used were constitutively K 7.5 channels (KCNQ3, Uniprot ID O43525; KCNQ5, Uniprot ID Q9NR82O43525) supplied by Charles River Laboratories. V 7.3, which is induced by tetracycline. V 7.5-expressing stably transfected HEK293 cell line.

[0280] Cells were maintained in the following culture media: DMEM / F-12 with GlutaMAX™ (Life Technologies 31331-028), ·10% Tet Systems FCS (Clonetech 631106), ·500 μg / ml Geneticin™ selective antibiotic (G418, Invitrogen 1013-027), 5 μg / ml blasticidin S HCl (InvivoGen ant-bl-5), and ·100μg / ml Zeocin (InvivoGen:ant-zn-5).

[0281] Cell maintenance, preparation, recording conditions and voltage protocols were all identical to those described above.

[0282] Analysis of data to assess efficacy Ten concentrations of test compound were applied to individual wells in quadruplicate to assess potency as a 3-fold dilution series from a top concentration of 30 μM. The half-activation voltage (V half ) to generate a concentration-response curve fitted with a four-parameter logistic model, and the EC 50 and V from the apex of the curve half The maximum shift of

[0283] The results are summarized in Table 3 below. EC 50 The lower the value, the more potent the compound analyzed. Selectivity criteria are assigned based on the maximum shift in Vhalf at 30 μM. Selective compounds exhibit a Kv7.4 and / or Kv7.3 / 7.5 ΔV of 15 mV or less. 1 / 2 (Table 3, letter A). Non-selective compounds exhibited a Kv7.4 and / or Kv7.3 / 7.5 ΔV higher than 15 mV. 1 / 2 (Letter B in Table 3). In Table 3, ND means that the selectivity was not determined.

[0284] [Table 5-1]

[0285] [Table 5-2]

[0286] [Table 5-3]

[0287] [Table 5-4]

[0288] [Table 5-5]

[0289] [Table 5-6]

[0290] [Table 5-7]

[0291] [Table 5-8]

[0292] [Table 5-9]

[0293] The obtained EC50 values ​​indicated that all tested compounds had the ability to activate Kv7.2 / 7.3 potassium channels, most of which were also selective for Kv7.4 and / or Kv7.3 / 7.5 potassium channels.

Claims

1. 1. A Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder modulated by the Kv7.2 / Kv7.3 potassium channel, the compound having the following general formula (I): 【Chemistry 1】 (In the formula, R1 is represented by -L1-A1; L1 is a bond or a straight or branched C1-C6 alkyl chain, which may be substituted with one or more halogen atoms or hydroxyl groups and which may contain an oxy (—O—) group within the alkyl chain or at any terminus thereof; A1 is a hydrogen atom, or (i) A 3- to 6-membered aromatic or aliphatic ring, which may contain one or more heteroatoms selected from the group consisting of N, O, and S, and which is unsubstituted or substituted with halogen, hydroxyl, methoxy, CN, CF ３ , a C1-C3 alkyl chain optionally substituted with one or more halogen atoms, and AR, where AR may contain one or more heteroatoms selected from the group consisting of N, O and S, and is unsubstituted or substituted with halogen, hydroxyl, methoxy, CN, CF ３ and a C1-C3 alkyl chain optionally substituted with one or more halogen atoms; or (ii) 5-12 membered fused or bridged bicyclic rings, which may contain one or more heteroatoms selected from the group consisting of N, O and S, and are unsubstituted or substituted with halogen, hydroxyl, methoxy, CN, CF ３ , O-Gr, and C1-C3 alkyl optionally substituted with one or more halogen atoms, wherein Gr is a 3- to 6-membered aliphatic ring that may contain one or more heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or substituted with one or more heteroatoms selected from the group consisting of halogen, hydroxyl, methoxy, CN, CF ３ a fused or bridged bicyclic ring, which is an aliphatic ring, substituted with one or more substituents selected from the group consisting of a C1-C3 alkyl chain optionally substituted with one or more halogen atoms; and R2 is hydrogen or a C1-C3 alkyl chain; R3 is hydrogen or an aliphatic ring, optionally containing a C1-C3 alkyl chain substituted with a hydroxyl group, or one or more heteroatoms selected from the group consisting of N, O and S, unsubstituted or selected from halogen, hydroxyl, methoxy, CN, and CF ３ an aliphatic ring substituted with one or more substituents selected from the group consisting of: R4 is represented by -L2-A2; L2 is a bond or a C1-C3 alkyl chain; A2 is a 6-membered aromatic ring containing 1 or 2 nitrogen atoms, said aromatic ring being optionally fused with an aliphatic ring having 5 or 6 carbon atoms, said aromatic ring being (i) a halogen atom, (ii) a C1-C3 alkyl chain optionally substituted with one or more halogen atoms; (iii) a 4- to 6-membered aliphatic ring containing one or more heteroatoms selected from O and N, optionally substituted with one or more halogen atoms or a C1-C3 alkyl chain optionally substituted with one or more halogens or hydroxyls; 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) a 3- to 6-membered aliphatic or aromatic ring, which may contain one or more heteroatoms selected from O and N, and which may be substituted with a halogen atom or a C1-C3 alkyl chain, which may be substituted with one or more halogens, hydroxyl, or CN; or (b) a C1-C3 alkyl chain optionally substituted with one or more halogen atoms; is) and is substituted with one or more substituents selected from: R5 is hydrogen or a C1-C3 alkyl chain; or R4 taken together with R2 or R3, and / or R5 taken together with R1, and / or R3 taken together with R2 form a 5- to 6-membered aliphatic ring optionally substituted with an alkyl chain having 1 to 3 carbon atoms, a halogen atom, or a hydroxyl group, which may contain an oxygen atom and which may be fused to or substituted with a benzene or pyridine ring, said benzene or pyridine ring optionally substituted with a halogen, or an alkyl or alkoxy chain having 1 to 3 carbon atoms, said chain optionally substituted with one or more halogen atoms; provided that R2, R3 and R5 are hydrogen atoms, and R4 is 【Chemistry 2】 When R1 is 【Transformation 3】 wherein R6 is H or OH. Unlike, provided that when L1 is a bond, A1 is not a substituted or unsubstituted cyclobutane ring.

10. A Kv7.2 / 7.3 potassium channel activator compound having the formula:

2. A1 is hydrogen, or (i) Halogen, hydroxyl, methoxy, CN, CF ３ an aromatic or aliphatic ring selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, optionally substituted with one or more substituents selected from the group consisting of a C1-C3 alkyl chain optionally substituted with one or more halogen atoms; or (ii) halogen, hydroxyl, methoxy, CN, CF ３ , C1-C3 alkyl chains optionally substituted with one or more halogen atoms, bicyclic[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), coumaran (2,3-dihydro-1-benzofuran), tetralin (1,2,3 a bicyclic ring selected from the group consisting of 5,6-dihydro-4H-cyclopenta[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; 2. The Kv7.2 / 7.3 potassium channel activator compound for use according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

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

4. 2. The 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 the group consisting of azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, oxazetidine, oxazolidine, or morpholine, optionally substituted with one or more halogen atoms or a C1-C3 alkyl chain optionally substituted with one or more halogen atoms.

5. 2. The Kv7.2 / 7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, for use according to claim 1, wherein A3 is a 3- to 6-membered aliphatic ring or a 5- or 6-membered aromatic ring, which may contain one or more heteroatoms selected from O and N and may be substituted with a halogen atom or a C1-C3 alkyl chain optionally substituted with one or more halogens, hydroxyl, CN.

6. 2. 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, tetrahydropyran.

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

8. 8. The 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 the group consisting of salts with organic acids, preferably oxalic acid, maleic acid, methanesulfonic acid, paratoluenesulfonic acid, succinic acid, citric acid, malic acid, tartaric acid and lactic acid, salts with organic bases, preferably tromethamine, lysine, arginine, glycine, alanine and ethanolamine, salts with inorganic acids, preferably hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and salts with inorganic bases, preferably hydroxides or carbonates of alkali or alkaline earth metals, such as sodium, potassium and calcium.

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

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

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

12. The compounds of Tables A and B below Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 or a pharmaceutically acceptable salt thereof.

13. 13. The Kv7.2 / 7.3 potassium channel activator compound of claim 12, wherein the pharmaceutically acceptable salt is selected from the group consisting of salts with organic acids, preferably oxalic acid, maleic acid, methanesulfonic acid, paratoluenesulfonic acid, succinic acid, citric acid, malic acid, tartaric acid and lactic acid; salts with organic bases, preferably tromethamine, lysine, arginine, glycine, alanine and ethanolamine; salts with inorganic acids, preferably hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid; and salts with inorganic bases, preferably hydroxides or carbonates of alkali or alkaline earth metals, such as sodium, potassium and calcium.

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

15. A pharmaceutical composition for use in the treatment of a disorder modulated by KV7.2 / KV7.3 potassium channels, comprising: (i) a Kv7.2 / KV7.3 potassium channel activating compound described in any one of claims 1 to 7; and (ii) at least one pharmaceutically acceptable excipient.

16. 15. 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. 17. The pharmaceutical composition of claim 16 for use in the treatment of a disorder modulated by KV7.2 / KV7.3 potassium channels.

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

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

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

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

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