NAV1.7- and / or NAV1.8-inhibiting hydroxamates, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits

Abstract

The present invention relates to Nav 1.7 and / or Nav 1.8 blocking hydroxamates. More specifically, the present invention is related to hydroxamates comprising the Formula (I), in which the substituents R1 to R10, as well as their derivatives R11 to R20, are selected independently of the groups defined in the specification, as well as their preparation processes, compositions comprising at least one of these compounds, uses, treatment methods to treat or prevent pain-related pathologies and kits. The present invention belongs to the fields of medicinal chemistry, organic synthesis, as well as the treatment of pain-related diseases.

Description

(19) *EP004660184A1* (11) EP 4 660 184 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 153(4) EPC (43) Date of publication: 10.12.2025 Bulletin 2025 / 50 (21) Application number: 24749440.4 (22) Date of filing: 26.01.2024 (51) International Patent Classification (IPC): C07C 233 / 64 (2006.01) C07C 15 / 00 (2006.01) C07C 15 / 12 (2006.01) C07D 213 / 00 (2006.01) C07D 401 / 00 (2006.01) C07D 403 / 00 (2006.01) A61K 31 / 166 (2006.01) A61K 31 / 435 (2006.01) A61K 31 / 495 (2006.01) A61K 31 / 609 (2006.01) A61P 25 / 02 (2006.01) A61P 25 / 04 (2006.01) A61P 29 / 00 (2006.01) (52) Cooperative Patent Classification (CPC): A61K 31 / 166; A61K 31 / 435; A61K 31 / 495; A61K 31 / 609; A61P 25 / 02; A61P 25 / 04; A61P 29 / 00; C07C 15 / 00; C07C 15 / 12; C07C 233 / 64; C07D 213 / 00; C07D 401 / 00; C07D 403 / 00 (86) International application number: PCT / BR2024 / 050027 (87) International publication number: WO 2024 / 159287 (08.08.2024 Gazette 2024 / 32) (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR Designated Extension States: BA Designated Validation States: GE KH MA MD TN (30) Priority: 30.01.2023 US 202363482216 P (71) Applicants: • Eurofarma Laboratórios S.A. 06696‑000 São Paulo - SP (BR) • Universidade Federal Do Rio De Janeiro - UFRJ 21941‑853 Rio de Janeiro ‑RJ (BR) (72) Inventors: • BARREIRO, Gabriela SP 04514‑032 São Paulo (BR) • SANT’ANA, Danilo Pereira De SP 06709‑320 São Paulo (BR) • MONTEIRO, Júlia Lammoglia SP 06704175 São Paulo (BR) • GAMBA, Luis Eduardo Reina SP 06404‑326 São Paulo (BR) • FRAGA, Carlos Alberto Manssour (deceased) (BR) • BARREIRO, Eliezer Jesus De Lacerda (deceased) (BR) • LIMA, Lídia Moreira RJ 21931‑220 Rio de Janeiro (BR) (74) Representative: Engelhard, Markus Boehmert & Boehmert Anwaltspartnerschaft mbB Pettenkoferstrasse 22 80336 München (DE) (54) NAV1.7‑ AND / OR NAV1.8‑INHIBITING HYDROXAMATES, PROCESSES FOR THE PREPARATION THEREOF, COMPOSITIONS, USES, METHODS FOR TREATMENT USING SAME, AND KITS (57) The present invention relates to Nav 1.7 and / or Nav 1.8 blocking hydroxamates. More specifically, the present invention is related to hydroxamates comprising the Formula (I), in which the substituents R1 to R10, as well as their derivatives R11 to R20, are selected inde- pendently of the groups defined in the specification, as well as their preparation processes, compositions com- prising at least one of these compounds, uses, treatment methods to treat or prevent pain-related pathologies and kits. The present invention belongs to the fields of med- icinal chemistry, organic synthesis, as well as the treat- ment of pain-related diseases. EP 4 66 0 18 4 A 1 Processed by Luminess, 75001 PARIS (FR) (Cont. next page) 2 EP 4 660 184 A1 Description FIELD OF INVENTION

[0001] The present invention refers to Nav 1.7 and / or Nav 1.8 blocking hydroxamates, their preparation processes, compositions containing these, uses, kits and treatment methods to treat or prevent pain-related pathologies. The present invention belongs to the fields of medicinal chemistry, organic synthesis, as well as the treatment of pain-related diseases. BACKGROUND OF INVENTION

[0002] Physiological pain is an important protective mechanism designed toalert the body to real orpotential injuries that can put the integrity thereof at risk. Broadly speaking, physiological pain can be classified into nociceptive pain and inflammatory pain. Nociceptive pain is characterized by having a high activation threshold, which remains until the stimulus that generated it is eliminated. Inflammatory pain, which arises as a response to tissue damage, is characterized by having a low activation threshold and is a consequence of the activity of molecular mediators of the inflammatory process in sensitizing nociceptors (Schaible. Langenbecks Arch. Surg. 2004, 389, 237). When these nociceptive processes remain in the absence of noxious stimuli or in response to não noxious stimuli, the protective and repair role of pain loses its functionality, configuring a maladaptive picture of neural plasticity and, as a consequence, a pathological state of chronic pain. Among the syndromes included in this classification, neuropathic pain has a high prevalence and impact today (Smith. Pain. 2020, 161, 1:S127; Cavalli. Int. J. Immunopathol. Pharmacol. 2019, 33:2058738419838383; Bouhassira. Rev Neurol (Paris). 2019, 175(1‑2):16; Scholz. Nature Neurosci., 2002, 5,1062; Costigan. Annu. Rev. Neurosci., 2009, 32, 1).

[0003] Neuropathic pain is defined by the International Association for the Study of Pain (IASP) as pain initiated or caused by a primary dysfunction or injury in the central and / or peripheral nervous system (Dworkin. Clin. J. Pain, 2002, 18(6), 343). Central neuropathic pain comes from spinal cord injuries or central nervous system diseases such as multiple sclerosis or Parkinson’s disease (Ducreux. Brain, 2006, 129, 963). Peripheral neuropathic pain, on the other hand, can be caused by trauma, metabolic disorders, chemical neurotoxicity, infection, or tumor invasion, among others. Among the most common syndromes of neuropathic pain are chemotherapy-induced neuropathic pain, complex regional pain, neuropathy related to viral infection, neuropathy secondary to tumor infiltration, diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, and postsurgical neuralgia (Pak. Curr. Pain Headache Rep., 2018, 22(2), 9).

[0004] Currently, there is no specific treatment for the control of pathologies related to neuropathic pain, however, the first-line alternative consists of the use of opioid analgesics, and - as adjuvants - local anesthetics, anticonvulsants and antidepressants. However, the adverse effects and low efficacy drastically limit the use of these agents in the control of various pain-related pathologies (Kushnarev. Expert Opin. Investig. Drugs, 2020, 29(3), 259; Emery. Expert Opin. Ther. Targets, 2016, 20(8), 975).

[0005] Voltage-gated sodium channels (Nav) play a key role in the transmission of pain-related stimuli. These channels are activated in response to membrane depolarization, allowing the generation and propagation of action potentials in neurons (and other electrically excitable cells), by controlling the flow of sodium ions through the membranes. Structurally, voltage-gated sodium channels are heteromeric transmembrane proteins consisting of one α subunit and two β helper subunits. The α subunit is organized into four homologous domains (I-IV), each with six transmembrane segments (S1- S6). The S4 segment of each domain is characterized by presenting a conserved region of arginine residues, which act as sensors of the intra‑and extracellular electrical environment of the neuron. This mechanism makes it possible to transform changes in the cellular electric field into specific conformational changes that, in turn, regulate the activation, deactivation and inactivation of voltage-gated sodium channels (Catterall. Nat. Chem. Biol., 2020, 16, 1314; Wisedchaisri. Cell., 2019, 178(4), 993; Clairfeuille. Science, 2019, 363, 1302).

[0006] In mammals, nine subunits α (Nav 1.1 - Nav 1.9) and four auxiliary subunits β (β1-β4) have been identified. The α subunits can also be classified according to their susceptibility to blocking by tetrodotoxin (TTX), being classified as sensitive to tetrodotoxin (Nav 1.1, Nav 1.2, Nav 1.3, Nav 1.4, Nav 1.6 and Nav 1.7) or resistant to tetrodotoxin (Nav 1.5, Nav 1.8 and Nav 1.9) (Lera-Ruiz. J. Med. Chem., 2015, 58(18), 7093; Bagal. J. Med. Chem., 2013, 56(3), 593). Each of these subunitsαhas a different profile of expression and function, so that some of them are essential for the proper functioning of organs such as the heart and / or brain. Thus, the non-selective blockage of these channels is related to several types of adverse effects, such as migraine, epilepsy, paralysis and muscle and cardiac syndromes, among others (Bagal. J. Med. Chem., 2013, 56(3), 593; Bagal. Channels, 2015, 9(6), 360).

[0007] Broadly speaking, sodium channels are distributed mainly in the central and peripheral nervous system, in neurons and glia. Nav channels 1.1, 1.2, and 1.3 are primarily expressed in the brain. The Nav 1.4 and Nav 1.5 channels are found primarily in skeletal and cardiac muscles, respectively. Nav 1.6 channels are expressed in the central and peripheral nervous systems, while Nav 1.9 channels are selectively expressed in C-type nociceptive fibers in the dorsal root ganglion. On the other hand, the Nav 1.7 and Nav 1.8 channels are mainly found in the peripheral nervous system and 3 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 are directly related to the processes of pain transmission (Law. Drug Discovery Today, 2019, 24(7), 1389; Bagal. Channels (Austin), 2015, 9(6), 360; Lera-Ruiz. J. Med. Chem., 2015, 58 (18), 7093).

[0008] Nav 1.7 sodium channels are expressed broadly in the olfactory epithelium, sympathetic ganglion, and dorsal root ganglion, predominantly in nociceptive fibers C and Aδ. A large amount of evidence supports the important role of Nav 1.7 sodium channels in pain transmission processes. For example, gain-of-function related mutations in the gene (SCN9A), which encodes sodium channel Nav 1.7, are associated with extreme pain disorders such as congenital pain insensitivity, paroxysmal extreme pain disorder, and primary erythromelalgia. On the other hand, mutations related to loss of gene function (SCN9A) are related to congenital insensitivity to pain in individuals who, in general terms, are free of motor or cognitive impairment (Vetter. Pharmacology & Therapeutics, 2017, 172, 73; Ahuja. Science, 2015, 350(6267), 1491; Kingwell. Nat. Rev. Drug Discov., 2019, 18, 321; Safina. J. Med. Chem., 2021, 64, 2953; Luo. J. Med. Chem., 2019, 62, 831; Bankar. Cell Reports, 2018, 24, 3133).

[0009] Nav 1.8 sodium channels are most expressed in the peripheral nervous system, widely (but not exclusively) in C- type nociceptive fibers in the dorsal root ganglion. Recent evidence including elevated expression levels of Nav 1.8 in chronic pain states, data with Nav 1.8 knockout animals, and analgesic activity of Nav 1.8-specific desensitizing oligodeoxynucleotides, among others (Brown. Bioorg. Med. Chem., 2019, 27(1), 230; Payne. Br. J. Pharmacol., 2015, 172(10), 2654; Bagal. Med. Chem. Lett. 2015, 6(6) 650; Kort. J. Med. Chem. 2008, 51, 407; Zhang. Neuropharmacology, 2010, 59, 201 and 207), support the role of the sodium channel Nav 1.8 in the development and process of pain-related pathologies (Kingwell. Nat. Rev. Drug Discov., 2019, 18, 321; Law. Drug Discovery Today, 2019, 24(7), 1389; Bagal. Channels (Austin), 2015, 9(6), 360; Lera-Ruiz. J. Med. Chem., 2015, 58(18), 7093).

[0010] Thus, the voltage-gated sodium channels Nav 1.7 and Nav 1.8 are considered promising therapeutic targets for the treatment of neuropathic pain-related dysfunctions (Kornecook. J. Pharmacol. Exp. Ther., 2017, 362, 146; Kingwell. Nat. Rev. Drug Discov., 2019, 18, 321; Bagal. Channels (Austin), 2015, 9(6), 360; Lera-Ruiz. J. Med. Chem., 2015, 58(18), 7093; Deuis. Neuropharmacology, 2017, 127, 87 and 108; Kushnarev. Expert Opin. Investig. Drugs, 2020, 29(3), 259; McKerrall. Bioorganic & Medicinal Chemistry Lett., 2018, 28, 3141; Emery. Expert Opin. Ther. Targets, 2016, 20(8), 975; Bagal. Bioorganic & Medicinal Chemistry Lett., 2014, 24, 3690).

[0011] A large number of compounds have been described in the literature for their ability to act as blockers of Nav 1.7 and 1.8 sodium channels, however, they present a great structural diversity, a fact that does not allow the establishment of a common pharmacophoric group.

[0012] The patent literature contains several examples of compounds that act as sodium channel blockers. In particular, Nav 1.7 selective sodium channel blockers are described in US10550080, US9765029, and US10000475. Additionally, some documents describe selective blockers of Nav 1.8 sodium channels such as WO2020261114, WO2020092667, US9163042, WO2014120808, WO2014120815, WO2018213426, WO2019014352, WO2015006280, and US7928107. These documents reveal compounds with different structures from the present invention.

[0013] In addition, there are patent documents that describe dual Nav blockers 1.7 and 1.8, including WO2018235851, US8629149, JP2017001991 that reveal, respectively, pyridyl amines, oxopiperazine derivatives and benzoxazolons. However, all these documents reveal compounds with structures and physicochemical characteristics different from the present invention.

[0014] In this context, it is advantageous to develop new alternatives of compounds that can act as Nav 1.7 and / or Nav 1.8 blockers that have adequate pharmacological action and, preferably, provide mitigated adverse effects. Therefore, the present invention refers to hydroxamates as an alternative and / or complement to the treatment of pain-related diseases. SUMMARY OF THE INVENTION

[0015] The present invention discloses hydroxamates with blocking activity of Nav 1.7 and / or 1.8 channels, against pain-related pathologies, as well as related compositions, uses, kits, treatment methods and preparation processes.

[0016] The present invention refers to compound(s) of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, ester and isomer thereof, wherein: - X1, X2, X3, and X4 are independently selected from the group consisting of carbon, CH, COH, or nitrogen; wherein 4 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 - when at least one of the substituents X2, X4 is nitrogen or CH, the corresponding R (R2, R3) is null. - R1 is: wherein: - X5, X6, X7, X8, and X9 are independently selected from the group consisting of carbon, CH, or nitrogen; wherein: - when at least one of the substituents X5‑X9 is nitrogen or CH, the corresponding R (R8‑R12) is null; and - R8, R9, R10, R11, and R12 are independently selected from the group consisting of hydrogen, halogen, linear or branched C1‑C6 alkyl, C1‑C6 linear or branched alkoxy, hydroxy, haloalkoxy C1‑C6 linear or branched, azetidinyloxy, azetidinylalkoxy C1‑C6, alkylazetidinyloxy C1‑C6, alkylazetidinylalkoxy C1‑C6, alkylsulfinyl C1‑C6, alkoxy C1‑C6 containing one or more isotopically enriched atoms such as hydrogen isotope 2H but not limited to same; - R2 and R3 are independently selected from the group consisting of hydrogen, halogen, amine, hydroxy, alkoxy C1‑C6 linear or branched, alkyl C1‑C6 linear or branched; - R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, haloalkyl C1‑C6 linear or branched, alkyl C1‑C6 linear or branched; - R6 is selected from the group consisting of aryl, pyridinyl, or substituted pyridinyl, or R13 or R14: - R13 is: wherein: - X10, X11, X12, X13 and X14 are independently selected from the group consisting of carbon, CH or nitrogen, wherein: - when at least one of the substituents X10‑X14 is nitrogen or CH, the corresponding R (R15‑R19) is null, - R15 R16, R17, R18, and R19 are independently selected from the group consisting of hydrogen, halogen, hydroxy, linear or branched C1‑C6 alkyl, cycloalkyl C3‑C6, C1 ‑C6 alkoxy linear or branched, cycloalkoxy C3‑C6, hydroxyalkyl C1-C4 linear or branched, aminoalkyl C1‑C6 linear or branched, alkoxy C1‑C6 containing one or more isotopically enriched atoms, such as hydrogen isotope 2H, but not limited to the same. - R14 is selected from the group consisting of: 5 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 wherein R20 is independently selected from the group consisting of hydrogen, halogen, hydroxy, hydroxyalkyl C1-C4 linear or branched, alkyl C1‑C6 linear or branched, alkoxy C1‑C4 linear or branched, cycloalkoxy C3‑C7, haloalkoxy, nitrile, carboxyl, carboxyalkyl ester C1‑C3, amine, N-alkylamine, N,N- dialkylamine, aminoalkyl C1-C6 linear or branched, sulfonamide, alkylsulfonylamide C1‑C6, N,N-dia- lkylsulfonylamide C1‑C6, sulfonyl, alkylsulfonyl C1‑C6, sulfinyl, alkyl sulfinyl C1‑C6, azetidiniloxy, aze- tidinylalkoxy C1‑C3, alkoxy C1‑C2 linear or branched, hydroxyazetidinyl. - R7, is independently selected from the group consisting of hydrogen and alkyl C1‑C6 linear or branched.

[0017] Additionally, the present invention further refers to compositions comprising one or more compound(s) of Formula (I) or a salt, hydrate, solvate and pharmaceutically acceptable isomer thereof; and one or more pharmaceutically acceptable excipients.

[0018] In addition, kits in accordance with this invention may comprise such compositions and application devices, which may include ampoules, syringes and others. Alternatively, the kits according to this invention comprise more than one compound of Formula (I) arranged in one or more dosage forms, including without limitation, tablets, accompanied by administration instructions.

[0019] The present invention further refers to methods of treatment, prevention, relief, suppression and / or control of diseases related to neuropathic pain. Uses of Formula (I) compound(s) to prepare a drug for the treatment of pathologies related to neuropathic pain are also taught. Finally, the present invention teaches processes for obtaining compound(s) of Formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention presents, in a first embodiment, the compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, ester and isomer thereof, wherein: - X1, X2, X3, and X4 are independently selected from the group consisting of carbon, CH, COH, or nitrogen; wherein: - when at least one of the substituents X2, X4 is nitrogen or CH, the corresponding R (R2, R3) is null. - R1 is: 6 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 wherein: - X5, X6, X7, X8, and X9 are independently selected from the group consisting of carbon, CH, or nitrogen; wherein: - when at least one of the substituents X5‑X9 is N or CH, the corresponding R (R8‑R12) is null; and R8, R9, R10, R11, and R12 are independently selected from the group consisting of hidrogen, halogen, alkyl C1‑C6 linear or branched, alkoxy C1‑C6 linear or branched, azetidinyloxy, azetidinylalkoxy C1‑C6, alkylazetidiniloxy C1‑C6, alkylazetidinylalkoxy C1‑C6, alkylsulfinyl C1‑C6, trifluoromethoxy, hydroxy, difluoromethoxy, alkoxy C1‑C6 containing one or more isotopically enriched atoms such as hydrogen isotope 2H, but not limited to the same. - R2 and R3 are independently selected from the group consisting of hydrogen, halogen, amine, hydroxy, alkoxy C1‑C6 linear or branched, alkyl C1‑C6 linear or branched; - R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, haloalkyl C1‑C6 linear or branched, alkyl C1‑C6 linear or branched; - R6 is selected from the group consisting of aryl, pyridinyl, or substituted pyridinyl, or R13 or R14; - R13 is: wherein: - X10, X11, X12, X13 and X14 are independently selected from the group consisting of carbon, CH or nitrogen, wherein: - when at least one of the substituents X10‑X14 is nitrogen or CH, the corresponding R (R15‑R19) is null; and - R15 R16, R17, R18, and R19 are independently selected from the group consisting of hydrogen, halogen, hydroxy, linear or branched alkyl C1‑C6, cycloalkyl C3‑C6, saturated or unsaturated cycloalkoxy-C3‑C6, alkoxy C1‑C6 linear or branched, hydroxyalkyl C1‑C6 linear or branched, C1-C6 linear or branched aminoalkyl, alkoxy C1‑C6 containing one or more isotopically enriched atoms, such as hydrogen isotope 2H, but not limited to the same; - R14 is selected from the group consisting of: wherein R20 is independently selected from the group consisting of hydrogen, halogen, hydroxy, hydro- xyalkyl C1-C4 linear orbranched, alkyl C1‑C6 linear or branched, alkoxy C1‑C6 linear or branched, cycloalkoxy C3‑C7, haloalkoxy, nitrile, carboxyl, carboxyalkyl ester C1‑C6, amine, N-alkylamine, N,N-dialkylamine, 7 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 aminoalkyl C1-C6 linear or branched, sulfonamide, alkylsulfonylamide C1‑C6, N,N-dialkylsulfonylamide C1‑C6, sulfonyl, alkylsulfonyl C1‑C6, sulfinyl, alkylsulfinyl C1‑C6, azetidiniloxy, azetidinylalkoxy C1‑C6, linear or branched alkoxy C1‑C6, hydroxyazetidinyl. - R7, is independently selected from the group consisting of hydrogen and alkyl C1‑C6 linear or branched.

[0021] As described herein, the compounds of the present invention comprise multiple variable groups (R, X1, etc.). As a person skilled in the art will recognize, the group combinations contemplated by this invention are those combinations that result in the formation of stable or chemically viable compounds.

[0022] The term "stable" in this context refers to compounds that are not substantially altered when subjected to conditions that allow their production, detection and preferably their recovery, purification and use for one or more of the purposes disclosed herein.

[0023] In some embodiments, a stable compound or chemically viable compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least one week.

[0024] In addition, some compounds described in this invention may exist as tautomers, so the individual tautomers, as well as their mixtures, are included in the compounds with structural formula I. EMBODIMENTS

[0025] In an embodiment, X1, X2, X3, and X4 are independently selected from the group consisting of carbon, CH, COH, or nitrogen, where when at least one of the substituents X2, X4 is nitrogen, CH, or COH, the corresponding R (R2, R3) is null; R1 is where X5, X6, X7, X8, and X9 are independently selected from the group consisting of carbon, CH, or nitrogen, where when at least one of the substituents X5‑X9 is nitrogen or CH, the corresponding R (R8‑R12) is null; R8, R9, R10, R11, R12 are independently selected from the groups consisting of hydrogen, halogen, linear or branched C1‑C6 alkyl, alkoxy C1‑C6 linear or branched, haloalkoxy C1‑C6 linear or branched, hydroxy, azetidinyloxy, azetidinylalkoxy C1‑C6, alkylazetidiny- lalkoxy C1‑C6, alkylsulfinyl C1‑C6, alkoxy C1‑C2 containing one or more isotopically enriched atoms such as hydrogen isotopes 2H, but not limited to the same.

[0026] In an embodiment, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, amine, hydroxy, linear or branched C1‑C6 alkyl, linear or branched C1‑C6 alkoxy.

[0027] In an embodiment, R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, linear or branched C1‑C6haloalkyl, alkyl C1‑C6 linear or branched.

[0028] In an embodiment, R6 is selected from the group consisting of aryl, pyridinyl, or substituted pyridinyl, or R13 or R14, where R13 is wherein X10, X11, X12, X13, and X14 are independently selected from the group consisting of carbon, CH, or nitrogen; when at least one of the substituents X10‑X14 is nitrogen or CH, the corresponding R (R15‑R19) is null.

[0029] In an embodiment R15, R16, R17, R18 and R19 are independently selected from the group consisting of hydrogen, halogen, hydroxy, linear or branched C1‑C6 alkyl, cycloalkyl C3‑C7 saturated or unsaturated, linear or branched C1‑C6 alkoxy, C3‑C7 cycloalkoxy, C1‑C6 linear or branched hydroxyalkyl, C1‑C6aminoalkyl, linear or branched, C1‑C2 alkoxy containing one or more isotopically enriched atoms, such as hydrogen isotope 2H, but not limited to the same. 8 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55

[0030] In an embodiment R14 is selected from the group consisting of: where R20 is selected from the group consisting of hydrogen, halogen, hydroxy, hydroxyalkyl C1‑C6 linear or branched, alkyl C1‑C6 linear or branched, alkoxy C1‑C6 linear or branched, cycloalkoxy C >53‑C7 saturated or unsaturated, haloalkoxy C1‑C6 linear or branched, nitrile, carboxyl, carboxyalkyl ester C1‑C6, amine, N-alkylamine, N,N-dialkylamine, linear or branched C1‑C6 aminoalkyl, sulfonamide, alkylsulfonylamide C1‑C6, N,N-dialkylsulfonylamide C1‑C6, sulfonyl, alkylsul- finyl C1‑C6, sulfinyl, alkyl sulfinyl C1‑C6, azetidinyloxy, azetidinylalkoxy C1‑C6, alkoxy C1‑C6 linear or branched, hydro- xyazetidinyl.

[0031] In an embodiment, R7 is selected from the group consisting of hydrogen and alkyl C1‑C6 linear or branched.

[0032] In an embodiment, X1, X2, and X4 are carbon or nitrogen. In a preferred embodiment, X3 is carbon, COH, or nitrogen.

[0033] In an embodiment, R1 is

[0034] In an embodiment, X5, X6, X7, X8, and X9 are independently selected from the group consisting of carbon, CH, and nitrogen. Preferably, X5, X7, and X9 are carbon. Preferably X6 and X8 are carbon or nitrogen.

[0035] In a preferred embodiment, R8 is hydrogen or hydroxy.

[0036] In a preferred embodiment, R9 is hydrogen, hydroxy, or null when X6 is nitrogen.

[0037] In an embodiment, R10 is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, azetidinyloxy, azetidinylmethoxy, azetidinylethoxy, azetidinylpropoxy, 1-methylazetidine‑3-ylmethoxy, 2-methylazeti- dine3-ylmethoxy, 1-ethylazetidine‑3-ylmethoxy, 2-ethylazedine‑3-ylmethoxy, 1-methylazetidine3-ylmethoxy, 2-methyla- zetidine3-ylmetoxy, 1-methylazetine‑3-ylpropoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylsulfinyl, ethylsulfinyl, methoxy-d1, methoxy-d2, methoxy-d3, ethoxy‑1-d1, ethoxy‑2-d1, ethoxy‑1,1-d2, ethoxy‑1,1-d, ethoxy‑1,2-d2, ethoxy‑2,2-d2, ethoxy‑1,1,1-d3, ethoxy‑1,1,2-d3, ethoxy‑1,2,2-d3, ethoxy‑2,2,2-d3, ethoxy‑1,1,2,2-d4, ethoxy‑1,2,2,2-d4, ethoxy-d5. Preferably, R10 is selected from the group consisting of hydroxy, methoxy, ethoxy, isopropoxy, azetidinyloxy, azetidinylmethoxy, 1-methylazetidine‑3-yl- methoxy, 1-methylazetidine3-ylethoxy, methylsulfinyl, ethoxy-d5, ethoxy‑1,1-d2, ethoxy‑2,2,2-d3, trifluoromethoxy, and difluoromethoxy.

[0038] In an embodiment, R11 is hydrogen or null when X8 is nitrogen.

[0039] In an embodiment, R12 is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. In a preferred embodiment, R12 is selected from the group consisting of hydrogen, hydroxy, methyl, and methoxy.

[0040] In an embodiment, R2 is hydrogen, hydroxy, amine, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, 9 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy, or null when X2 is nitrogen. In a preferred embodiment, R2 is hydrogen, hydroxy, amine, fluorine, or null when X2 is nitrogen.

[0041] In an embodiment, R3 is hydrogen, hydroxy, amine, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or null when X4 is nitrogen. In a preferred embodiment, R3 is hydrogen, hydroxy, amine, fluorine, or null when X4 is nitrogen.

[0042] In an embodiment, R4 is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert- butyl. In a preferred embodiment, R4 is hydrogen, deuterium, or methyl.

[0043] In an embodiment, R5 is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert- butyl. In a preferred embodiment, R5 is hydrogen, deuterium, or methyl.

[0044] In an embodiment, R6 is aryl, pyridinyl, substituted pyridinyl, R13, or R14. Preferably, R6 is R13 or R14.

[0045] In a preferred embodiment, R13 is

[0046] In an embodiment, X10, X11, X12, and X13 are carbon, CH, or nitrogen. Preferably, they are carbon or nitrogen, wherein, when they are nitrogen, their respective R (R15, R16, R17, R18) is null.

[0047] In an embodiment X14 is carbon, CH, or nitrogen. Preferably, X14 is carbon.

[0048] In an embodiment, R15 is hydrogen or null when X10 is nitrogen.

[0049] In an embodiment, R16 is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert}‑butoxy, methylamine, ethylamine, propyla- mine, dimethylamine, diethylamine, dipropylamine, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, methoxy-d1, methoxy-d2, methoxy-d3, ethoxy‑1-d1, ethoxy‑2-d1, ethoxy‑1,1-d2, ethoxy‑1,2-d2, ethoxy‑2,2-d2, ethoxy‑1,1,1-d3, ethoxy‑1,1,2-d3, ethoxy‑1,2,2-d3, ethoxy‑2,2,2-d3, ethoxy‑1,1,2,2-d4, ethoxy‑1,2,2,2-d4, ethoxy-d5 or null when X11 is nitrogen. In a preferred embodiment, R16 is hydrogen, hydroxy, methoxy, isopropoxy, ethylamine, dimethylamine, methyl, cyclobutoxy, methoxy-d3, or null when X11 is nitrogen.

[0050] In an embodiment R17 is hydrogen or null when X12 is nitrogen.

[0051] In an embodiment R18 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or null when X13 is nitrogen. In a preferred embodiment, R18 is hydrogen, methyl, methoxy, or null when X13 is nitrogen.

[0052] In an embodiment, R19 is hydrogen, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cycloheptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cycloheptenyl, cyclobute- nyl, cyclopropenyl, cyclohexenyl, or null when X14 is nitrogen. In a preferred embodiment, R19 is hydrogen, fluorine, chlorine, hydroxy, methyl, cyclopropyl, or null when X14 is nitrogen.

[0053] In an embodiment, R14 is

[0054] In an embodiment, R20 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, nitrile, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy. In a preferred embodiment, R20 is nitrile, methoxy, 10 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 methyl, ethyl, isopropyl.

[0055] In an implementation of the first embodiment, the Formula (I) compound(s) is selected from the group(s) consisting of: N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4-hydroxyphenyl)pyrazine‑2-carboxamide (Compound 1); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4-methoxyphenyl)pyrazine‑2-carboxamide (Compound 2); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4-isopropoxyphenyl)pyrazine‑2-carboxamide (Compound 3); 6‑(4-ethoxyphenyl)‑N‑((2-fluorobenzyl)oxy)pyrazine‑2-carboxamide (Compound 4); 6‑(4-ethoxyphenyl)‑N‑((3-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 5); 6‑(4-ethoxyphenyl)‑N‑((2-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 6); 6‑(4-ethoxyphenyl)‑N‑((3-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 7); 6‑(4-ethoxyphenyl)‑N‑((5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 8); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 9); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-isopropoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 10); N‑((2-chloro‑5-methoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 11); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 12); 6‑(4-ethoxyphenyl)‑N‑((5-fluoro‑2-methoxypyridine‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 13); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 14); N‑((2-cyclopropyl‑5-methoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 15); 6‑(4-ethoxyphenyl)‑N‑((2-hydroxy‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 16); N‑((5‑(1-aminoethyl)‑2-fluorobenzyl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 17); 6‑(4-ethoxyphenyl)‑N‑((5-methoxy‑2-methylpyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 18); 6‑(4-ethoxyphenyl)‑N‑((5-methoxy‑2-methylbenzyl)oxy)pyrazine‑2-carboxamide (Compound 19); N‑((3,5-dimethoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 20); N‑((3,5-dimethylbenzyl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 21); 6‑(4‑(azetidin‑3-yloxy)phenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 22); 6‑(4‑(azetidine‑3-ylmethoxy)phenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 23); 6‑(4‑(2‑(azetidine‑3-yl)ethoxy)phenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 24); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑((1-methylazetidine‑3-yl)oxy)phenyl)pyrazine‑2-carboxamide (Compound 25); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑((1-methylazetidine‑3-yl)methoxy)phenyl)pyrazine‑2-carboxamide (Com- pound 26); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑(2‑(1-methylazetidine‑3-yl)ethoxy)phenyl)pyrazine‑2-carboxamide (Com- pound 27); 6‑(4‑(difluoromethoxy)phenyl)‑N‑((5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 28); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑(methylsulfinyl)phenyl)pyrazine‑2-carboxamide (Compound 29); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6-methoxypyridine‑3-yl)pyrazine‑2-carboxamide (Compound 30); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6-isopropoxypyridine‑3-yl)pyrazine‑2-carboxamide (Compound 31); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluorobenzyl)oxy)pyrazine‑2-carboxamide (Compound 32); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 33); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 34); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 35); 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 36); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 37); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 38); 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-fluoro‑2-methoxypyridine‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 39); N‑((5‑(dimethylamino)‑2-fluorobenzyl)oxy)‑6‑(6-ethoxypyridine‑3-yl)pyrazine‑2-carboxamide (Compound 40); N‑((5‑(dimethylamino)‑2-fluoropyridine‑3-yl)methoxy)‑6‑(6-ethoxypyridine‑3-yl)pyrazine‑2-carboxamide (Com- pound 41); N‑((5‑(dimethylamino)‑2-fluoropyridine‑3-yl)methoxy)‑6‑(6-ethoxypyridine‑3-yl)pyrazine‑2-carboxamide (Com- pound 42); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 43); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-hydroxy‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 44); N‑((5‑(1-aminoethyl)‑2-fluorobenzyl)oxy)‑6‑(6-ethoxypyridine‑3-yl)pyrazine‑2-carboxamide (Compound 45); 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methoxy‑2-methylpyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 46); 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methoxy‑2-methylbenzyl)oxy)pyrazine‑2-carboxamide (Compound 47); 6‑(6‑(ethoxy-d5)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 48); 6‑(6‑(ethoxy‑2,2,2-d3)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 49); 11 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 6‑(6‑(ethoxy‑1,1-d2)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 50); 6‑(6‑(ethoxy‑1,1-d2)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 51); 6‑(6‑(ethoxy‑2,2,2-d3)pyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)benzyl)oxy)pyrazine‑2-carboxamide (Compound 52); 6‑(6‑(ethoxy-d5)pyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)benzyl)oxy)pyrazine‑2-carboxamide (Compound 53); 6‑(6‑(ethoxy-d5)pyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)phenyl)methoxy-d2)pyrazine‑2-carboxamide (Com- pound 54); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)benzyl)oxy)pyrazine‑2-carboxamide (Compound 55); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)benzyl)oxy)pyrazine‑2-carboxamide (Compound 56); 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methyloxazole‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 57); 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methyloxazole‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 58); 6‑(6-ethoxypyridine‑3-yl)‑N‑((4-methyl‑1H-imidazole‑5-yl)methoxy)pyrazine‑2-carboxamide (Compound 59); 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-methyl‑1H-pyrrole‑2-yl)methoxy)pyrazine‑2-carboxamide (Compound 60); 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-ethyl‑1H-imidazole‑2-yl)methoxy)pyrazine‑2-carboxamide (Compound 61); 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-ethyl‑1H-pyrazole‑5-yl)methoxy)pyrazine‑2-carboxamide (Compound 62); 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-ethyl‑1H-pyrazole‑5-yl)methoxy)pyrazine‑2-carboxamide (Compound 63); 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-ethyl‑1H-pyrazole‑5-yl)methoxy)pyrazine‑2-carboxamide (Compound 64); 6‑(6-ethoxypyridine‑3-yl)‑N‑((4-methyloxazole‑5-yl)methoxy)pyrazine‑2-carboxamide (Compound 65); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methoxyfuran‑2-yl)methoxy)pyrazine‑2-carboxamide (Compound 66); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methyl‑1H-pyrrole‑2-yl)methoxy)pyrazine‑2-carboxamide (Compound 67); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methyl‑1H-pyrrole‑2-yl)methoxy)pyrazine‑2-carboxamide (Compound 68); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methyl‑1H-pyrazole‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 69); N‑((2-fluorobenzyl)oxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 70); N‑((3-methoxybenzyl)oxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 71); N‑(pyridine‑2-ylmethoxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 72); N‑(pyridine‑3-ylmethoxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 73); N‑(pyridine‑4-ylmethoxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 74); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 75); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 76); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 77); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((5-fluoro‑2-methoxypyridine‑4-yl)methoxy)pyrazine‑2-carboxamide (Com- pound 78); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((5-fluoro‑2-methoxypyridine‑4-yl)methoxy)pyrazine‑2-carboxamide (Com- pound 79); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((5‑(dimethylamino)‑2-fluorobenzyl)oxy)pyrazine‑2-carboxamide (Com- pound 80); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((3‑(1-hydroxyethyl)benzyl)oxy)pyrazine‑2-carboxamide (Compound 81); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)benzyl)oxy)pyrazine‑2-carboxamide (Compound 82); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6‑(methylsulfinyl)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 83); 6‑(4-ethoxy‑2-hydroxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 84); 6‑(4-ethoxy‑3-hydroxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 85); 6‑(6-ethoxy‑4-hydroxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 86); 6‑(6-ethoxy‑2-oxo‑1,2-dihydropyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Com- pound 87); N‑((3,5-dimethoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)‑5-hydroxypyrazine‑2-carboxamide (Compound 88); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑5-hydroxypyrazine‑2-carboxamide (Compound 89); N‑((3,5-dimethoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)‑3-hydroxypyrazine‑2-carboxamide (Compound 90); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑3-hydroxypyrazine‑2-carboxamide (Compound 91); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑5-hydroxypyrazine‑2-carboxamide (Compound 92); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑3-hydroxypyrazine‑2-carboxamide (Compound 93); 5-amino‑6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 94); 3-amino‑6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 95); 6‑(6-ethoxypyridine‑3-yl)‑5-fluoro-N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 96); 6‑(6-ethoxypyridine‑3-yl)‑3-fluoro-N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 97); 6’-ethoxy-N‑((2-fluoro‑5-methoxybenzyl)oxy)‑[2,3’-bipyridine]‑6-carboxamide (Compound 98); 6’-ethoxy-N‑((2-fluoro‑5-methoxypyridin‑3-yl)methoxy)‑[2,3’-bipyridine]‑6-carboxamide (Compound 99); 6’-ethoxy-N‑((2-fluoro‑5-methoxybenzyl)oxy)‑[3,3’-bipyridine]‑5-carboxamide (Compound 100); 12 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 2‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrimidine‑4-carboxamide (Compound 101); 2‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridin‑3-yl)methoxy)pyrimidine‑4-carboxamide (Compound 102); 4‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrimidine‑2-carboxamide (Compound 103); 4‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrimidine‑2-carboxamide (Compound 104); 4‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrimidine‑2-carboxamide (Compound 105); 6’‑(difluoromethoxy)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑[2,3’-bipyridine]‑6-carboxamide (Compound 106); 6’‑(difluoromethoxy)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑[2,3’-bipyridine]‑6-carboxamide (Compound 107); 6’‑(difluoromethoxy)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑[2,3’-bipyridine]‑6-carboxamide (Compound 108); 6’‑(difluoromethoxy)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑[3,3’-bipyridine]‑5-carboxamide (Compound 109); 2‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrimidine‑4-carboxamide (Compound 110); 2‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrimidine‑4-carboxamide (Compound 111); 2‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrimidine‑4-carboxamide (Compound 112); 3-amino‑6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxa- mide (Compound 113); 3-amino‑6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxa- mide (Compound 114); 5-amino‑6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Com- pound 115); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑3-fluoro-N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Com- pound 116); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑5-fluoro-N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Com- pound 117); 3‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑1,2,4-triazine‑5-carboxamide (Compound 118); 5‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑1,2,4-triazine‑3-carboxamide (Compound 119); N‑((2‑(3,5-dimethoxyphenyl)propan‑2-yl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 120); N‑(1‑(3,5-dimethoxyphenyl)cyclopropoxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 121); (R)‑N‑(1‑(3,5-dimethoxyphenyl)ethoxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 122); (S)‑N‑(1‑(3,5-dimethoxyphenyl)ethoxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 123); (S)‑N‑(1‑(3,5-dimethoxyphenyl)ethoxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 124); (R)‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 125); (S)‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 126); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxyphenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 127); (R)‑6‑(4-ethoxyphenyl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 128); (S)‑6‑(4-ethoxyphenyl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 129); 6‑(4-ethoxyphenyl)‑N‑((3-methoxyphenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 130); (R)‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 131); (S)‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 132); 6‑(4-ethoxyphenyl)‑N‑((2-fluorophenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 133); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)phenyl)methoxy-d2)pyrazine‑2-carboxamide (compound 134); (R)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 135); (S)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 136); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2‑(2-fluoro‑5-methoxyphenyl)propan‑2-yl)oxy)pyrazine‑2-carboxamide (Compound 137); 6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)cyclopropoxy)pyrazine‑2-carboxamide (Compound 138); 6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)cyclopropoxy)pyrazine‑2-carboxamide (Compound 139); (R)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 140); (S)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 141); 13 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methoxyphenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 142); (R)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 143); (S)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 144); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluorophenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 145); (R)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy‑2,2,2-d3)pyrazine‑2-carboxamide (Com- pound 146); (S)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy‑2,2,2-d3)pyrazine‑2-carboxamide (Com- pound 147); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑N-methylpyrazine‑2-carboxamide (Compound 148); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑N-methylpyrazine‑2-carboxamide (Com- pound 149); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑N-methylpyrazine‑2-carboxamide (Com- pound 150); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑N-methylpyrazine‑2-carboxa- mide (Compound 151); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methoxyphenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 152); (R*)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 153); (S*)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 154); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluorophenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 155); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑N-methylpyrazine‑2-carboxamide (Compound 156); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑N-methylpyrazine‑2-carboxamide (Com- pound 157); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑N-methylpyrazine‑2-carboxamide (Com- pound 158); and 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑N-methylpyrazine‑2-carboxa- mide (Compound 159).

[0056] In an implementation of the first embodiment, the Formula (I) compound(s) are voltage-gated sodium channel blockers Nav 1.7 and / or Nav 1.8. In a preferred embodiment, the Formula (I) compound(s)are dual voltage-gated sodium channel blockers Nav 1.7 and Nav 1.8.

[0057] In an implementation of the first embodiment, the compound(s) of Formula (I) may have a basic nature and, consequently, pharmaceutically acceptable salts may be obtained by the addition of organic or inorganic acids. Non- limiting examples of organic acids that can be used are fumaric, maleic, benzoic, lactic acids, among others. Among the inorganic acids, we can mention hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, nitric acid, among others.

[0058] In an implementation of the first embodiment, the compound(s) of Formula (I) can be obtained in the form of crystals, which can be optionally presented as pharmaceutically acceptable solvates, in which the solvent is incorporated in stoichiometric proportions or not into the crystal lattice. In further embodiments, the crystallization solvent is water, resulting in pharmaceutically acceptable hydrates.

[0059] Finally, in an implementation of the first embodiment the Formula (I) compound(s) may present more than one isomer, including without limitation, spatial isomerism, such as geometric and optical isomerism. DEFINITIONS:

[0060] In order to clarify or elucidate the terms used in this invention, the following definitions are presented, whereby the scope is not limited thereto.

[0061] The term "halogen" refers to the elements of the 7th family of the periodic table, which are: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At) and tennessine (Ts).

[0062] The term "linear or branched C1‑C6 alkyl" refers to saturated hydrocarbon groups of linear or branched chain, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, but not limited to the same.

[0063] The term "linear or branched C1‑C6 alkoxy" refers to alkyl groups attached to an oxygen radical, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, but not limited to the same.

[0064] The term "linear or branched haloalkoxy C1‑C6" refers to alkyl groups attached to a root oxygen and at least one halogen, such as, but not limited to, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0065] The term "linear or branched C1‑C6" refers to saturated, linear or branched alkyl groups replaced with at least one hydroxyl, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 2-hydroxypropyl, isopropoxy, but not limited to the same. 14 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55

[0066] The term "COH" refers to a carbon atom bonded to a hydroxyl by means of a single bond.

[0067] The term "azetidinylalkoxy C1‑C3" refers to the azetidinyl groups attached to an "alkoxy C1‑C3" group, e.g., azetidinylmethoxy, azetidinylethoxy, azetidinylpropoxy, and azetidinylbutoxy.

[0068] The term "C1‑C6 alkylsulfinyl" refers to the sulfinyl groups (R2S=O) attached to the C1‑C6 alkyl group, e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, sec-butylsulfinyl, and tert-butylsulfinyl.

[0069] The term "alkylazetidinylalkoxy C1‑C6" refers to azetidinylalkoxy groups linked to "alkyl C1‑C6" groups, such as, for example, 1-methylazetidine‑3-ylmetoxy, 2-methylazetidine‑3-ylethoxy, 1-methylazetidine‑3-ylpropoxy, but not being limited thereto.

[0070] The term "C1‑C2 containing one or more isotopically enriched atoms such as hydrogen isotope 2H" refers to exemplified species such as , methoxy-d1, methoxy-d2, methoxy-d3, ethoxy‑1-d1, ethoxy‑2-d1, ethoxy‑1, 1-d2, ethoxy‑1,2- d2, ethoxy‑2,2-d2, ethoxy‑1,1,1-d3, ethoxy‑1,1,2-d3, ethoxy‑1,2,2-d3, ethoxy‑2,2,2-d3, ethoxy‑1,1,2,2-d4, ethoxy‑1,2,2,2- d4, ethoxy-ds, but not limited to these.

[0071] The term "saturated or unsaturated C3‑C7 cycloalkyl" refers to alkyl cycle groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, but not being limited thereto.

[0072] The term "cycloalkoxy C3‑C7" refers to, but is not limited to, the alkyl cycle groups attached to an oxygen radical, such as cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0073] The term "linear or branched C1‑C6 aminoalkyl" refers to amines that are attached to one or two linear or branched alkyl groups by means of single bonds such as, but not limited to, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine.

[0074] In a second embodiment, the present invention presents a composition comprising a therapeutically effective amount of compound(s) of Formula (I) of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof; and one or more pharmaceutically acceptable excipients.

[0075] Pharmaceutically acceptable excipients are any substance, other than the active pharmaceutical ingredient, that has been evaluated for its safety and that is intentionally added to the dosage form. Such excipients are selected according to the pharmaceutical dosage form of interest, the route of administration thereof, physicochemical compatibility with the active ingredient, and the effect on efficacy.

[0076] In addition, these excipients are widely known in the state of the art and are classified according to their function, including without limitation diluents, binders, disintegrants or disaggregators, lubricants, suspending agents, thickeners, solvents, surfactants, sliders, anti-caking agents or flow agents, glazing agents, plasticizers, sweeteners, isotonicity agents, dyes and pigments, preservatives, antioxidants, modifying agents or pH control, complexing agents, chelating agents, flavorings, viscosity modifying agents, opacifiers, permeation promoters, among others.

[0077] In an implementation of the second embodiment, the pharmaceutical compositions of the present invention can be administered by several routes including oral, sublingual, nasal, parenteral, injectable, submuscular, topical, trans- dermal, ocular, rectal, but not limited thereto.

[0078] In a third embodiment, the present invention presents the use of compound(s) of Formula (I) or a salt, hydrate, solvate and pharmaceutically acceptable isomer thereof to prepare a drug to treat pathologies related to neuropathic pain.

[0079] In an implementation of the third embodiment, said pathologies are selected from the group consisting of peripheral neuropathic pain, chemotherapy-induced neuropathy, complex regional pain, neuropathy related to viral infection, neuropathy secondary to tumor infiltration, diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia and postsurgical neuralgia.

[0080] In a fourth embodiment, the present invention presents a method of treatment, prevention, relief, suppression and / or control of pathologies related to neuropathic pain comprising the administration of an effective amount of Formula (I) compound(s) or a salt, hydrate, solvate and pharmaceutically acceptable isomer thereof.

[0081] In an implementation of the fourth embodiment, the method is for the treatment, prevention, relief, suppression and / or control of peripheral neuropathic pain, chemotherapy-induced neuropathy, complex regional pain, neuropathy related to viral infection, neuropathy secondary to tumor infiltration, diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia and postsurgical neuralgia.

[0082] In another implementation of the fourth embodiment, the administration of at least one Formula (I) compound is selected from the group comprising oral, sublingual, nasal, parenteral, injectable, submuscular, topical, transdermal, ocular and rectal routes.

[0083] In a fifth embodiment of the invention, processes for obtaining Formula (I) compounds are presented, comprising the following steps: (a) Formation of the Formula III intermediate: 15 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 from the hydrolysis reaction of a Formula IV intermediate: (b) obtaining Formula I compound; from the reaction with the Formula II intermediates: and Formula III with or without the presence of a catalyst and a suitable solvent; wherein, - X1, X2, X3, and X4 are independently selected from the group consisting of carbon, CH, COH, or nitrogen; wherein: - when at least one of the substituents X2, X4 is nitrogen or CH, the corresponding R (R2, R3) is null. - R1 is: wherein: 16 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 - X5, X6, X7, X8, and X9 are independently selected from the group consisting of carbon, CH, or nitrogen; wherein: - when at least one of the substituents X5‑X9 is nitrogen or CH, the corresponding R (R8‑R12) is null; and R8, R9, R10, R11, and R12 are independently selected from the group consisting of hydrogen, halogen, C1‑C6 alkyl linear or branched, alkoxy C1‑C6 linear or branched, haloalkoxy C1‑C6 linear or branched, hydroxy, azetidinyloxy, azetidinylalkoxy C1‑C3, alkylazetidiniloxy C1‑C6, alkylazetidinylalkoxy C1‑C6, alkylsulfinyl C1‑C6, C1‑C2 alkoxy containing one or more isotopically enriched atoms such as, but not limited to, the hydrogen isotope 2H. - R2 and R3 are independently selected from the group consisting of hydrogen, halogen, amine, hydroxy, C1‑C6 alkoxy linear or branched, alkyl C1‑C6 linear or branched; - R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, haloalkyl C1‑C6 linear or branched, alkyl C1‑C6 linear or branched; - R6 is selected from the group consisting of aryl, pyridinyl, or substituted pyridinyl, or R13 or R14, wherein: - R13 is: wherein: - X10, X11, X12, X13 and X14 are independently selected from the group consisting of carbon, CH, or nitrogen; wherein: - when at least one of the substituents X10‑14 is nitrogen or CH, the corresponding R (R15‑R19) is null; and - R15 R16, R17, R18 and R19 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl linear or branched C1‑C6, cycloalkyl C3‑C7, C1‑C6 alkoxy linear or branched, cycloalkoxy C3‑C7, hydroxyalkyl C1-C6 linear or branched, aminoalkyl C1‑C6 linear or branched, alkoxy C1‑C2 containing one or more isotopically enriched atoms, such as hydrogen isotope 2H, but not limited to the same. - R14 is selected from the group consisting of: wherein R20 is independently selected from the group consisting of hydrogen, halogen, hydroxy, hydroxyalkyl C1‑C6 linear or branched, alkyl C1‑C6 linear or branched, alkoxy 17 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 C1‑C6 linear or branched, cycloalkyl C3‑C7, haloalkoxy C1‑C6 linear or branched, nitrile, carboxyl, carboxyalkyl ester C1‑C6, amine, N-alkylamine, N,N-dialkylamine, aminoalkyl C1‑C4 linear or branched, sulfonamide, alkylsulfonylamide C1‑C6, N,N-dialkylsulfonylamide C1‑C6, sulfonyl, alkylsulfonyl C1‑C6, sulfinyl, alkyl sulfinyl C1‑C6, azetidiniloxy, azetidinylalkoxy C1‑C6, linear or branched alkoxy C1‑C6, hydroxyazetidinyl. - R7, is independently selected from the group consisting of hydrogen and alkyl C1‑C6 linear or branched.

[0084] In an implementation of the fifth embodiment, the process additionally comprises a step (c) of formation of compound(s) of Formula (I) in which R7 is linear or branched C1‑C6 alkyl from the nucleophilic substitution reaction of a compound obtained in step (b), with linear or branched C1-C6 alkyl halides in the presence of inorganic base and polar aprotic solvents.

[0085] In an implementation of the fifth embodiment step (b) the coupling agent is selected from T3P or combination between TCFH and NMI or suitable coupling agents and said solvent selected is dichloromethane or classical aprotic solvents.

[0086] In a sixth embodiment, the present invention presents kits comprising a pharmaceutical composition of the present invention and an application device.

[0087] In an implementation of the sixth embodiment the kits of the present invention may comprise such compositions and application devices, which may include ampoules, syringes and others. Alternatively, the kits of this invention comprise more than one compound of Formula (I) arranged in one or more dosage forms, including without limitation, tablets, accompanied by administration instructions.

[0088] The compound(s) of Formula (I) of this invention have been prepared from the synthetic route described in General Scheme 1. However, those skilled in the art will readily notice that additional detailing and / or modifications to the arrangement of one or more steps can be accomplished without departing from the processes taught here. Such variations can be, without limitation, combinations of solvents and catalysts, including stereoselective ones, protective groups, among others.

[0089] In the following General Scheme 1, the formation of the Formula II, III and IV intermediates is described, in addition to the formation of the Formula (I) compound(s).

[0090] As illustrated in General Scheme 1, Formula Ia compounds can be prepared from amide coupling reactions between Formula III intermediates with Formula II intermediates in the presence of coupling agents in suitable solvents such as DCM or other aprotic solvents such as DMF. In turn, Formula III intermediates can be prepared by hydrolysis reaction from the corresponding esters (Formula IV) obtained following various methods. Formula II intermediates can be prepared from the corresponding reagents following different methods, some of which can be obtained commercially. The intermediaries obtained by such methodologies are described below. FORMULA IV INTERMEDIATES:

[0091] Following General Scheme 1, the methods from IV-A to IV-E for the formation of formula IV intermediates are presented, however, these methods are not exhaustive. METHOD IV-A 18 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 INTERMEDIATES IV‑1 TO IV‑42:

[0092]

[0093] In a round-bottomed flask containing methyl 6-chloropyrazine‑2-carboxylate (11.6 mmol) in dioxane (50.0 mL) and H2O (10.0 mL), (4-hydroxyphenyl)boronic acid (12.8 mmol), NaHCO3 (17.4 mmol), and Pd(dppf)Cl2 (579 µmol) was added under N2 atmosphere. The reaction mixture was kept under agitation at 70 °C for 12 hours. After full consumption of the starting reagent (monitored by CCD), the mixture was concentrated under reduced pressure to remove the solvent. The residue obtained was diluted with H2O (100 mL) and extracted with AcOEt (100 mL x 3). The organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether / AcOEt: 50 / 1 → 0 / 1). 1.5 g (56% yield) of the corresponding ester were obtained in the form of a white solid. This procedure is used to obtain the intermediates of Table 1. TABLE 1. INTERMEDIATES OBTAINED FROM THE CORRESPONDING REAGENTS FOLLOWING METHOD IV- A. Intermediate Structure Intermediate Structure IV‑1 IV‑21 IV‑2 IV‑22 IV‑3 IV‑23 IV‑4 IV‑24 IV‑5 IV‑25 IV‑6 IV‑26 IV‑7 IV‑27 19 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Intermediate Structure Intermediate Structure IV‑8 IV‑28 IV‑9 IV‑29 IV‑10 IV‑30 IV‑11 IV‑31 IV‑12 IV‑32 IV‑13 IV‑33 IV‑14 IV‑34 IV‑15 IV‑35 IV‑16 IV‑36 IV‑17 IV‑37 IV‑18 IV‑40 20 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Intermediate Structure Intermediate Structure IV‑19 IV‑41 IV‑20 IV‑42 METHOD IV-B STEP IV-B-I: PRECURSORS IV‑43I TO IV‑46I:

[0094]

[0095] In a round-bottomed flask containing 4‑(4,4,5,5-tetramethyl‑1,3,2-dioxaborolan‑2-yl)phenol (4.54 mmol) in DMF (15 mL) at 0 °C, K2CO3 (9.09 mmol) and tert-butyl 3-iodoazetidin‑1-carboxylate (5.45 mmol) were added. The reaction mixture was kept under agitation at 80 °C for 12 hours. After total consumption of the starting reagent (monitored by CCD), the mixture was diluted with H2O (100 mL) and extracted with AcOEt (100 mL x 2). The organic phase was washed with saturated sodium chloride solution (brine) (5.0 mL x 1), dried under Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography. 1.1 g (38.4% yield) of the product of interest were obtained in the form of a brown solid. TABLE 2. PRECURSORS OBTAINED FROM THE CORRESPONDING REACTANTS FOLLOWING STEP IV-B-I. Intermediate Structure IV‑43i IV‑44i IV‑45i 21 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Intermediate Structure IV‑46i STEP IV-B-II: INTERMEDIATES IV‑43 TO IV‑46:

[0096]

[0097] In a round-bottomed flask containing 3‑(4‑(4,4,5,5-tetramethyl‑1,3,2-dioxaborolan‑2-yl)phenoxy)tert-butyl aze- tidin‑1-carboxylate (2.40 mmol) and methyl 6-chloropyrazine‑2-carboxylate (3.12 mmol) in DMF (20 mL), Cs2CO3 (4.80 mmol) was added, and the mixture was de-gasified for 30 minutes. Next, Pd(dppf)Cl2 (0.19 mmol) was added under inert atmosphere. The reaction mixture was kept under agitation at 55 °C for 12 hours. After total consumption of the starting reagent (monitored by CCD), the mixture was diluted with H2O (100.0 mL) and extracted with AcOEt (100.0 mL x 2). The organic phase was washed with saturated sodium chloride solution (brine), dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography. 510 mg (34.2% yield) of the product of interest were obtained in the form of a white solid. TABLE 3. PRECURSORS OBTAINED FROM THE CORRESPONDING REAGENTS FOLLOWING STEP IV-B-II. Intermediate Structure IV‑43 IV‑44 IV‑45 IV‑46 METHOD IV-C

[0098] 22 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55

[0099] In a round-bottomed flask containing methyl 6‑(4‑(methylthio)phenyl)pyrazine‑2-carboxylate (1.15 mmol) in H2O (10 mL), sodium periodate (1.09 mmol) was added at 25 °C. The reaction mixture was kept under agitation at 55 °C for 3 hours. After total consumption of the starting reagent (monitored by CCD), the mixture was diluted with H2O (20 mL) and extracted with AcOEt (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (brine), dried under Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography. 311 mg (80% yield) of the product of interest were obtained in the form of a white solid. TABLE 4. PRECURSORS OBTAINED FROM THE CORRESPONDING REAGENTS FOLLOWING METHOD C. Intermediate Structure IV‑47 IV‑48 METHOD IV-D STEP IV-D-I: PRECURSOR IV‑49I:

[0100]

[0101] In a round-bottomed flask containing MOMCl (79.4 mmol) in acetone (30.0 mL), 4-bromobenzene‑1,3-diol (79.4 mmol) and K2CO3 (119 mmol) in acetone (100 mL) at 20‑30 °C under N2 atmosphere was added. The reaction mixture remained at 60 °C for 12 hours under an atmosphere of N2. After total consumption of the starting reagent (monitored by CCD), the mixture was cooled to 20‑30 °C and filtered. The residue was washed with AcOEt (60.0 mL). The resulting filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / AcOEt: 50 / 1 → 5 / 1). 10 g (51.73% yield) of the product of interest were obtained in the form of a yellow solid. STEP IV-D-II: PRECURSOR IV‑49II:

[0102] 23 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55

[0103] In a round-bottomed flask containing 4-bromo‑3‑(methoxymethoxy)phenol (42.9 mmol) and K2CO3 (64.39 mmol) in MeCN (70.0 mL), iodoethane (55.8 mmol) was added at 20‑30 °C under an atmosphere of N2. The reaction mixture was kept under agitation at 80 °C for 12 hours. After total consumption of the starting reagent (monitored by LC-MS and CCD), the mixture was filtered, and the residue was washed with AcOEt (20.0 mL x 2). The organic phase obtained was concentrated under reduced pressure and purified by column chromatography (petroleum ether / AcOEt: 50 / 1 → 5 / 1). 7.9 g (70.51% yield) of the product of interest were obtained in the form of a yellow solid. STEP II-D-III: PRECURSOR IV‑49III:

[0104]

[0105] In a round-bottomed flask containing 4-bromo‑3‑(methoxymethoxy)phenol (21.5 mmol) in THF (40.0 mL), n-BuLi (2.50 M, 17.2 mL) was added at ‑70 °C under N2 atmosphere. The reaction mixture was kept under agitation at ‑70 °C for 1 hour. Next, trimethylborate (85.8 mmol) was added at ‑70 °C. The mixture was kept under agitation at 20 °C for 1 hour. After total consumption of the starting reagent (monitored by LC-MS), the mixture was diluted with H2O (10.0 mL) at 0 °C and extracted with AcOEt (10.0 mL x 3). The organic phase obtained was concentrated under reduced pressure. 4.80 g (99.0% yield) of the product of interest were obtained in the form of a brown oil. STEP II-D-IV: PRECURSOR IV‑49IV:

[0106]

[0107] In a round-bottomed flask containing methyl 6-chloropyrazine‑2-carboxylate (21.2 mmol), (4-ethoxy‑2‑(methox- ymethoxy)phenyl)boronic acid (12.7 mmol), and NaHCO3 (31.8 mmol) in dioxane (20.0 mL) and H2O (4.00 mL), Pd(dppf) Cl2 (1.06 mmol) was added at 20‑30 °C under N2 atmosphere. The reaction mixture remained at 60 °C for 12 hours under an atmosphere of N2. After total consumption of the starting reagent (monitored by CCD and LC-MS), the mixture was concentrated under reduced pressure. The residue obtained was diluted with H2O (20.0 mL) and extracted with AcOEt (20.0 mL x 3). The organic phase was washed with saturated sodium chloride solution (brine) (20.0 mL), dried on anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 0 / 1). 3.50 g (51.7% yield) of the product of interest were obtained in the form of a yellow solid. 24 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 STEP II-D-V:

[0108]

[0109] In a round-bottomed flask containing methyl 6‑(4-ethoxy‑2‑(methoxymethoxy)phenyl)pyrazine‑2-carboxylate (11.0 mmol), in DCM (20.0 mL), HCl / dioxane (54.8 mmol) was added. The reaction mixture remained under agitation at 30 °C for 1 hour. After total consumption of the starting reagent (monitored by CCD and LC-MS), the mixture was concentrated under reduced pressure. 3.00 g (99.5% yield) of the product of interest were obtained in the form of an orange solid, which was used in the next step without further purification. METHOD IV-E STEP IV-E-I: IV‑50I - IV‑56I PRECURSORS:

[0110]

[0111] In a round-bottomed flask containing 1-bromo‑4-ethoxy‑2-methylbenzene (2.32 mmol) and 4,4,4’,4’,5,5,5’,5’- octamethyl‑2,2’-bi(1,3,2-dioxaborlan) (3.48 mmol) in 1,4-dioxane (7.5 mL), potassium acetate (5.81 mmol) was added at room temperature and the mixture was purged with N2 for 10 minutes. Next, Pd(dppf)Cl2 / DCM (0.23 mmol) was added. The reaction mixture was kept under agitation at 80 °C for 2 hours. After total consumption of the starting reagent, the mixture was filtered with celite. The filtrate was diluted with H2O (50 mL) and extracted with n-hexane (50 mL x 3). The organic phase was washed with H2O (25 mL), dried on Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography (100% n-hexane). 460 mg (37.74% yield) of the product of interest were obtained in the form of a yellow oil. TABLE 5. PRECURSORS OBTAINED FROM THE CORRESPONDING REAGENTS FOLLOWING STEP IV-E-I: Intermediate Structure IV‑50 IV‑51 25 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Intermediate Structure IV‑52 IV‑53 IV‑54 IV‑55 IV‑56 STEP IV-E-II: IV‑50 - IV‑56 INTERMEDIATES:

[0112]

[0113] In a round-bottomed flask containing 2‑(4-ethoxy‑2-methylphenyl)‑4,4,5,5-tetramethyl‑1,3,2-dioxaborolan (1.75 mmol) and methyl 6-bromopyrazine‑2-carboxylate (1.75 mmol) in 1,4-dioxane (5 mL), a solution of Na2CO3 (2M, 5 mL) was added at room temperature and the mixture was purged with N2 for 10 minutes. Next, Pd(dppf)Cl2 / DCM (0.17 mmol) was added. The reaction mixture was kept under agitation at 50 °C for 1 hour. After total consumption of the starting reagent, the mixture was filtered with celite. The filtrate was diluted with H2O (50 mL) and extracted with n-hexane (50 mL x 3). The organic phase was washed with H2O (25 mL), dried on Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography (n-hexane / AcOEt: 99 / 1). 330 mg (69.07% yield) of the product of interest were obtained in the form of a yellow oil. 26 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 TABLE 6. PRECURSORS OBTAINED FROM THE CORRESPONDING REAGENTS FOLLOWING STEP IV-E-II Intermediate Structure IV‑50 IV‑51 IV‑52 IV‑53 IV‑54 IV‑55 IV‑56 FORMULA III INTERMEDIATES:

[0114] Following General Scheme 1, the intermediates of Formula III are presented

[0115] In a round-bottomed flask containing methyl 6‑(4-hydroxyphenyl)pyrazine‑2-carboxylate (3.65 mmol) and in MeOH (10.0 mL), NaOH (7.29 mmol) and H2O (2.00 mL) were added. The reaction mixture remained at 20 °C for 3 hours. After total consumption of the starting reagent (monitored by LC-MS and HPLC), the mixture was concentrated under reduced pressure and the pH of the residue obtained was adjusted to 5 with HCl solution (2 N). The mixture was then filtered and purified by preparative HPLC ([H2O (HCl) / ACN] 25% → 55% B) . 200 mg (21.0% yield) of the compound of interest (Table 7) were obtained in the form of a yellow solid. 27 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 TABLE 7. INTERMEDIATES OBTAINED FROM THE CORRESPONDING REAGENTS FOLLOWING THE METHOD DESCRIBED IN OBTAINING THE COMPOUNDS OF FORMULA III. Intermediate Structure Intermediate Structure III‑1 III‑27 III‑2 III‑28 III‑3 III‑29 III‑4 III‑30 III‑5 III‑31 III‑6 III‑32 III‑7 III‑33 III‑8 III‑34 III‑9 III‑35 III‑10 III‑36 III‑11 III‑37 28 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Intermediate Structure Intermediate Structure III‑12 III‑38 III‑13 III‑39 III‑14 III‑40 III‑15 III‑41 III‑16 III‑42 III‑17 III‑43 III‑18 III‑44 III‑19 III‑45 III‑20 III‑46 III‑21 III‑47 III‑22 III‑48 29 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Intermediate Structure Intermediate Structure III‑23 III‑49 III‑24 III‑50 III‑25 III‑51 III‑26 III‑52 OBTAINING FORMULA II COMPOUNDS

[0116] Following General Scheme 1, the example methods II-A to II-X, for the formation of formula II intermediates are presented without limitation below. METHOD II-A STEP II-A-I: PRECURSOR II‑1I:

[0117]

[0118] TBSCl (45.0 mmol) at 0‑10 °C was added to a round-bottomed flask containing 2-hydroxybenzaldehyde (40.9 mmol) and imidazole (49.1 mmol) in anhydrous DCM (30.0 mL). Subsequently, the reaction mixture was kept under agitation at 20‑30 °C for 2 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was diluted with H2O (30.0 mL) and extracted with DCM (20.0 mL x 2). Subsequently, the organic phase was concentrated under reduced pressure. 10 g of the product of interest were obtained in the form of a colorless oil. STEP II-A-II: PRECURSOR II‑1II:

[0119] 30 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55

[0120] In a round-bottomed flask containing 2‑((tert-butyldimethylsilyl)oxy)benzaldehyde (42.3 mmol) in MeOH (70.0 mL), NaBH4 (36.0 mmol) was added slowly, under an atmosphere of N2 at 0‑20 °C. Subsequently, the reaction mixture was kept under agitation at 20‑30 °C for 1 hour. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was cooled to 0‑10 °C and slowly diluted with acetone (10.0 mL). The mixture was kept under agitation at 0‑10 °C for 30 minutes. Subsequently, the mixture was concentrated, and the residue was diluted with H2O (50.0 mL) and extracted with AcOEt (50.0 mL x 3). The organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether / AcOEt: 100 / 1 → 5 / 1). 5.90 g (55.4 % yield) of the product of interest were obtained in the form of a yellow oil. STEP II-A-III: PRECURSOR II‑1III:

[0121]

[0122] In a flask containing (2‑((tert-butyldimethylsilyl)oxy)phenyl)methanol (21.8 mmol), 2-hydroxysoindoline‑1,3- dione (28.36 mmol) and PPh3 (32.7 mmol) in anhydrous THF (30.0 mL) DEAD (32.7 mmol) at 0‑10 °C was added. Subsequently, the reaction mixture was keptunder agitation at 20‑30 °C for 16 hours. After total consumption of the starting reagent (monitored by CCD and LC-MS), the mixture was concentrated and purified by column chromatography (petroleum ether / AcOEt: 100 / 1 → 5 / 1). 5.30 g (63.3% yield) of the product of interest were obtained in the form of a white solid. STEP II-A-IV:

[0123]

[0124] In a round-bottomed flask containing 2‑((2‑((tert-butyldimethylsilyl)oxy)benzyl)oxy)oxy)isoindoline‑1,3-dione (5.47 mmol) in EtOH (36.0 mL), NH2NH2H2O (8.20 mmol) was added. Subsequently, the reaction mixture was kept under agitation at 90 °C for 2 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 1 / 1). 0.99 g (72.8% yield) of the product of interest were obtained in the form of a colorless oil. METHOD B STEP II-B-I: 31 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 PRECURSOR II‑2I:

[0125]

[0126] In a round-bottomed flask containing methyl 2-fluoro‑5-hydroxybenzoate (11.7 mmol) in MeCN (12.0 mL), 2- iodopropane (23.5 mmol) and K2CO3 (23.5 mmol) were added. Subsequently, the reaction mixture was kept under agitation at 80 °C for 16 hours. After total consumption of the starting reagent (monitored by LC-MS), the reaction mixture was cooled to 25 °C and diluted with H2O (10.0 mL) and extracted with AcOEt (8.00 mL x 2). Subsequently, the organic phase was dried on anhydrous sodium sulfate, filtered and concentrated under reduced pressure. 2.10 g (84.1% yield) of the product of interest were obtained in the form of a yellow oil, which was used for the next step without further purification. STEP II-B-II: PRECURSOR II‑2II:

[0127]

[0128] In a round-bottomed flask containing methyl 2-fluoro‑5-isopropoxybenzoate (8.81 mmol) in THF (15.0 mL), LiAlH4 (2.50 M, 10.5 mL) was added at 0 °C under N2 atmosphere. Subsequently, the reaction mixture was kept in agitation at 0‑20 °C for 2 hours. After total consumption of the starting reagent (monitored by LC-MS), Na2SO4·10H2O (1.50 g) were added at 0 °C. The mixture was then filtered and concentrated under reduced pressure. 1.56 g (96.1% yield) of the product of interest were obtained in the form of a colorless oil, which was used for the next step without further purification. STEP II-B-III: PRECURSOR II‑2III:

[0129]

[0130] In a round-bottomed flask containing (2-fluoro‑5-isopropoxyphenyl)methanol (9.23 mmol) in THF (17.0 mL), 2- hydroxysoindoline‑1,3-dione (10.1 mmol), PPh3 (13.8 mmol) and DIAD (13.8 mmol) were added at 0 °C. Subsequently, the reaction mixture was kept under agitation at 20 °C for 16 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered. The residue was purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 1 / 1). 1.8 g (59.23% yield) of the product of interest were obtained in the form of a white solid. STEP II-B-IV:

[0131] 32 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55

[0132] In a round-bottomed flask containing 2‑((2-fluoro‑5-isopropoxybenzyl)oxy)isoindoline‑1,3-dione (5.47 mmol) in EtOH (36.0 mL), NH2NH2H2O (8.20 mmol) was added. Subsequently, the reaction mixture was kept under agitation at 90 °C for 2 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 1 / 1). 0.99 g (72.8% yield) of the product of interest were obtained in the form of a colorless oil. METHOD C STEP II-C-I: PRECURSOR II‑3I:

[0133]

[0134] In a round-bottomed flask containing methyl 2-chloro‑5-methoxybenzoate (5.98 mmol) in THF (3.00 mL), LiAlH4 (2.50 M, 7.18 mL) was added at 0 °C. Subsequently, the reaction mixture was kept in agitation at 25 °C for 2 hours. After full consumption of the starting reagent (monitored by CCD), Na2SO4·10H was added to the reaction mixture 2O (1.50 g) at 0 °C. The mixture was then filtered and concentrated under reduced pressure. 1.02 g (98.7% yield) of the product of interest were obtained in the form of a colorless oil, which was used for the next step without further purification. STEP II-C-II: PRECURSOR II‑3II:

[0135]

[0136] In a round-bottomed flask containing (2-chloro‑5-methoxyphenyl)methanol (5.91 mmol) in THF (15.0 mL), 2- hydroxysoindoline‑1,3-dione (6.50 mmol), PPh3 (8.86 mmol), and DIAD (8.86 mmol) were added at 0 °C. Subsequently, the reaction mixture was kept under agitation at 20 °C for 16 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered. The residue was purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 1 / 1). 1.2 g (63.91% yield) of the product of interest were obtained in the form of a white solid. STEP II-C-III:

[0137] 33 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55

[0138] In a round-bottomed flask containing 2‑((2-chloro‑5-methoxybenzyl)oxy)isoindoline‑1,3-dione (3.78 mmol) in EtOH (24.0 mL), NH2NH2H2O (5.67 mmol) was added. Subsequently, the reaction mixture was kept under agitation at 90 °C for 2 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 3 / 1). 680 mg (83.2% yield) of the product of interest were obtained in the form of a colorless oil. METHOD D STEP II-D-I:

[0139]

[0140] In a round-bottomed flask containing methyl 2-bromo‑5-methoxybenzoate (20.4 mmol) in dioxane (17.0 mL), cyclopropylboronic acid (61.2 mmol), H2O (102 mmol), NaHCO3 (40.8 mmol), and Pd(dppf)Cl2 (2.04 mmol) was added under N2 atmosphere. Subsequently, the reaction mixture was kept under agitation at 80 °C for 16 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was diluted in H2O (20.0 mL) and extracted with AcOEt (15.0 mL x 2). Subsequently, the organic phase was concentrated under reduced pressure and purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 2 / 1). 2.00 g (30.1% yield) of the product of interest were obtained in the form of a white solid. STEP II-D-II:

[0141]

[0142] In a round-bottomed flask containing methyl 2-cyclopropyl‑5-methoxybenzoate (7.27 mmol) in THF (10.0 mL), LiAlH4 (2.50 M, 3.49 mL) was added at 0 °C under an atmosphere of N2. Subsequently, the reaction mixture was kept in agitation at 20 °C for 2 hours. After full consumption of the starting reagent (monitored by CCD), Na2SO4·10H was added to the reaction mixture 2O (5.00 g) at 0 °C. The mixture was then filtered and concentrated under reduced pressure. 1.23 g (94.8% yield) of the product of interest were obtained in the form of a colorless oil, which was used for the next step without further purification. STEP II-D-III:

[0143] 34 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55

[0144] In a round-bottomed flask containing (2-cyclopropyl‑5-methoxyphenyl)methanol (6.90 mmol) in THF (10.0 mL), 2-hydroxysoindoline‑1,3-dione (7.59 mmol), DEAD (10.3 mmol), and PPh3 (10.3 mmol) were added at 0 °C. Subse- quently, the reaction mixture was kept under agitation at 20 °C for 16 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered. The residue was purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 1 / 1). 1.20 g (53.7% yield) of the product of interest were obtained in the form of a white solid. STEP II-D-IV:

[0145]

[0146] In a round-bottomed flask containing 2‑((2-cyclopropyl‑5-methoxybenzyl)oxy)isoindoline‑1,3-dione (3.71 mmol) in EtOH (7.50 mL), NH2NH2H2O (5.57 mmol) was added. Subsequently, the reaction mixture was kept under agitation at 90 °C for 2 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 1 / 1). 630 mg (87.8% yield) of the product of interest were obtained in the form of a colorless oil. METHOD E STEP II-E-I: PRECURSOR II‑5I:

[0147]

[0148] In a round-bottomed flask containing (3,5-dimethylphenyl)methanol (7.34 mmol) in THF (10.0 mL), 2-hydro- xysoindoline‑1,3-dione (8.08 mmol), PPh3 (11.0 mmol), and DIAD (11.0 mmol) were added at 0 °C. Subsequently, the reaction mixture was kept under agitation at 20 °C for 16 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered. The residue was purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 1 / 1). 1.50 g (72.6% yield) of the product of interest were obtained in the form of a white solid. STEP II-AND-II: 35 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 INTERMEDIATE II‑5II:

[0149]

[0150] In a round-bottomed flask containing 2‑((3,5-dimethylbenzyl)oxy)isoindoline‑1,3-dione (3.78 mmol) in EtOH (24.0 mL), NH2NH2H2O (5.67 mmol) was added. Subsequently, the reaction mixture was kept under agitation at 90 °C for 2 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 1 / 1). 700 mg (83.2% yield) of the product of interest were obtained in the form of a colorless oil. METHOD F STEP II-F-I: PRECURSOR II‑6I:

[0151]

[0152] In a round-bottomed flask containing 5-methoxniycotineldehyde (7.29 mmol) in MeOH (10.0 mL), NaBH4 (7.40 mmol) was added slowly at 0 °C. Subsequently, the reaction mixture was kept in agitation at 25 °C for 0.5 hours. After total consumption of the starting reagent (monitored by CCD and LC-MS), the mixture was cooled to 0‑10 °C and diluted in acetone (10.0 mL) slowly. The mixture was placed under agitation at 0‑10 °C for 30 minutes and subsequently concentrated. The residue was diluted in H2O (50.0 mL) and extracted with AcOEt (50.0 mL x 3). The organic phase was concentrated under reduced pressure. 1.00 g (98.5% yield) of the product of interest were obtained in the form of a yellow oil, which was used for the next step without further purification. STEP II-F-II: PRECURSOR II‑6II:

[0153]

[0154] In a round-bottomed flask containing (5-methoxypyridine‑3-yl)methanol (33.7 mmol), PPh3 (50.7 mmol) in THF (25.0 mL), DEAD (9.21 mmol) was added at 0 °C under N2 atmosphere. Subsequently, the reaction mixture was kept under 36 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 agitation at 30 °C for 16 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was concentrated under reduced pressure. The residue was placed under agitation with MeOH (20.0 mL) at 30 °C for 30 minutes. 7.20 g (74.9% yield) of the product of interest were obtained in the form of a white solid. STEP II-F-III:

[0155]

[0156] In a round-bottomed flask containing 2‑((5-methoxypyridine‑3-yl)methoxy)isoindoline‑1,3-dione (29.2 mmol) in EtOH (50.0 mL), NH2NH2H2O (35.8 mmol) was added. Subsequently, the reaction mixture was kept under agitation at 90 °C for 2 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered and washed with EtOH (10.0 mL x 3). The residue was purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 0 / 1). 4.00 g (88.9% yield) of the product of interest were obtained in the form of a yellow oil. METHOD G STEP II-G-I: PRECURSOR II‑7I:

[0157]

[0158] In a round-bottomed flask containing 2-fluoro‑5-methoxypyridine (39.3 mmol) in THF (30.0 mL), a solution of LDA (2 M, 29.5 mL) was added dropwise at ‑60 °C. The reaction mixture remained at ‑60 °C under agitation for 2 hours. After total consumption of the starting reagent (monitored by CCD), an HCl solution (2N, 50.0 mL) at 0 °C was added. Subsequently, the reaction mixture was extracted with AcOEt (50.0 mL x 3). The organic phase was washed with saturated sodium chloride solution (brine) (50.0 mL), dried on anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / AcOEt: 100 / 1 → 10 / 1). 6.00 g (89.1% yield) of the product of interest were obtained in the form of a brown solid. STEP II-G-II: PRECURSOR II‑7II:

[0159]

[0160] In a round-bottomed flask containing 2-fluoro‑5-methoxynicotinic acid (35.1 mmol) in THF (60.0 mL), BH3MeS (10 M, 17.5 mL) was added dropwise at 0 °C. The reaction mixture remained at 20 °C under agitation for 16 hours. After 37 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 total consumption of the starting reagent (monitored by LC-MS), MeOH (50.0 mL) was added slowly at 0 °C and the reaction mixture was concentrated. Subsequently, 1-butanol (50.0 mL) was added, the reaction mixture was kept under agitation at 110 °C for 12 hours, and then concentrated. 5.50 g (99.8% yield) of the product of interest were obtained in the form of a brown oil, which was used in the next step without further purification. STEP II-G-III: PRECURSOR II‑7III:

[0161]

[0162] In a round-bottomed flask containing (2-fluoro‑5-methoxypyridin‑3-yl)methanol (35.0 mmol), 2-hydroxysoindo- line‑1,3-dione (42.0 mmol), and PPh3 (52.5 mmol) in THF (35.0 mL), DEAD (52.5 mmol) was added at 0 °C. Subsequently, the reaction mixture was kept under agitation at 20 °C for 16 hours. After total consumption of the starting reagent (monitored by LC-MS), the reaction mixture was diluted in H2O (50.0 mL) and extracted with AcOEt (30.0 mL x 3). Subsequently, the organic phase was washed with saturated sodium chloride solution (brine) (50.0 mL), dried on anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / AcOEt: 100 / 1 → 10 / 1). 5.20 g (78.6% yield) of the product of interest were obtained in the form of a white solid. STEP II-G-IV:

[0163]

[0164] In a round-bottomed flask containing 2‑((2-fluoro‑5-methoxypyridin‑3-yl)methoxy)isoindoline‑1,3-dione (4.30 mmol) in EtOH (10.0 mL), NH2NH2H2O (12.0 mmol) was added. Subsequently, the reaction mixture was kept under agitation at 90 °C for 2 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered and washed with EtOH (5.00 mL x 3). The residue was purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 0 / 1). 700 mg (94.5% yield) of the product of interest were obtained in the form of a yellow oil. METHOD H STEP II-H-I: PRECURSOR II‑8I:

[0165] 38 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55

[0166] In a round-bottomed flask containing 5-fluoro‑2-methoxysonicotinic acid (11.69 mmol, 2.00 g) in THF (10.0 mL), BH3MeS (10 M, 5.84 mL) was added dropwise at 0 °C. The reaction mixture remained at 0‑20 °C under agitation for 16 hours. After total consumption of the starting reagent (monitored by LC-MS), MeOH (50.0 mL) was added slowly at 0 °C and the reaction mixture was concentrated. Subsequently, 1-butanol (50.0 mL) was added, the reaction mixture was kept under agitation at 110 °C for 12 hours, and then concentrated. 1.80 g (98.0% yield) of the product of interest were obtained, which was used in the next step without further purification. STEP II-H-II: PRECURSOR II‑8II:

[0167]

[0168] In a round-bottomed flask containing (5-fluoro‑2-methoxypyridin‑4-yl)methanol (11.45 mmol, 1.80 g), 2-hydro- xysoindoline‑1,3-dione (13.73 mmol, 2.24 g), and PPh3 (17.19 mmol, 4.51 g) in THF (10.0 mL), DEAD (17.17 mmol, 2.99 g) was added at 0 °C. Subsequently, the reaction mixture was kept under agitation at 0‑20 °C for 16 hours. After total consumption of the starting reagent (monitored by LC-MS), the reaction mixture was diluted in H2O (50.0 mL) and extracted with AcOEt (30.0 mL x 3). Subsequently, the organic phase was washed with saturated sodium chloride solution (brine) (50.0 mL), dried on anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / AcOEt: 100 / 1 → 10 / 1). 1.60 g (33.0% yield) of the product of interest were obtained. STEP II-H-III: INTERMEDIATE II‑8:

[0169]

[0170] In a round-bottomed flask containing 2‑((5-fluoro‑2-methoxypyridin‑4-yl)methoxy)isoindoline‑1,3-dione (5.29 mmol, 1.60 g) in EtOH (10.0 mL), NH2NH2H2O (6.39 mmol, 0.320 g) was added. Subsequently, the reaction mixture was kept under agitation at 90 °C for 2 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered and washed with EtOH (5.00 mL x 3). The residue was purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 0 / 1). 750 mg (82.3% yield) of the product of interest were obtained in the form of a yellow oil. METHOD I STEP II-I-I: 39 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 PRECURSORS II‑9I - II‑20I:

[0171]

[0172] In a round-bottomed flask containing 2‑((5-fluoro‑2-methoxypyridin‑4-yl)methoxy)isoindoline‑1,3-dione (1.80 mmol, 6.11 g) in THF (10.0 mL), LiNH4 (8.83e‑1 eq, 2.70 g) was added. Subsequently, the reaction mixture was kept under agitation at 60 °C for 2 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered and extracted with AcOEt (20.0 mL x3). Theorganic phase was washedwith anhydroussodium sulfate, filtered and concentrated at reduced pressure. 1.70 g of the product of interest were obtained in the form of a colorless oil, which was used in the next step for further purification. TABLE 8. PRECURSORS OBTAINED FROM THE CORRESPONDING REAGENTS FOLLOWING STEP II-I-I Intermediate Structure II‑9i II‑10i II‑11i II‑12i II‑13i II‑14i II‑15i II‑16i II‑17i 40 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Intermediate Structure II‑18i II‑19i II‑20i STEP II-I-II: PRECURSORS II‑9II - II‑20II:

[0173]

[0174] In a flask containing 2‑(hydroxymethyl)‑1‑((2‑(trimethylsilyl)ethoxy)methyl)‑1H-pyrrole‑3-carbonitrile (6.34 mmol), 2-hydroxysoindoline‑1,3-dione (8.24 mmol) and PPh3 (9.51 mmol) in THF (20.0 mL) was added DEAD (9.51 mmol) dropwise under an atmosphere of N2 at 0‑10 °C. Subsequently, the reaction mixture was kept under agitation at 20‑30 °C for 16 hours. After total consumption of the starting reagent (monitored by LC-MS), the reaction mixture was diluted with H2O (30.0 mL) and extracted with AcOEt (30.0 mL x 3). The organic phase was dried on anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was placed under agitation with MeOH (2.00 mL) at 0‑10 °C for 30 minutes. The mixture was filtered and washed with MeOH (2.00 mL). 1.60 g (63.4% yield) of the product of interest were obtained in the form of a white solid. TABLE 9. PRECURSORS OBTAINED FROM THE CORRESPONDING REAGENTS FOLLOWING STEP II-I-II. Intermediate Structure II‑9ii II‑10ii 41 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Intermediate Structure II‑11ii II‑12ii II‑13ii II‑14ii II‑15ii II‑16ii II‑17ii II‑18ii II‑19ii 42 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Intermediate Structure II‑20ii STEP II-I-III:

[0175]

[0176] In a round-bottomed flask containing 2‑(((1,3-dioxoisoindoline‑2-yl)oxy)methyl)‑1‑((2‑(trimethylsilyl)ethoxy) methyl)‑1H-pyrrole‑3-carbonitrile (2.16 mmol) in EtOH (10.0 mL), NH2NH2H2O (5.59 mmol) was added. Subsequently, the reaction mixture was keptunder agitationat 90 °C for 2 hours.After total consumption of the starting reagent (monitored by CCD), the reaction mixture was cooled to 20‑30 °C, filtered, washed with EtOH (10.0 mL) and concentrated. 570 mg (98.5% yield) of the product of interest were obtained in the form of a colorless oil, which was used in the next step without further purification. TABLE 10. PRECURSORS OBTAINED FROM THE CORRESPONDING REAGENTS FOLLOWING STEP II-I-III. Intermediate Structure II‑9 II‑10 II‑11 II‑12 II‑13 II‑14 43 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Intermediate Structure II‑15 II‑16 II‑17 II‑18 II‑19 II‑20 J METHOD STEP II-J-I: PRECURSOR II‑21I:

[0177]

[0178] In a round-bottomed flask containing 1‑(2-fluoro‑5-methoxyphenyl)etan‑1-one (10.7 mmol) in THF (90.0 mL), NaBH4 (15.9 mmol) at 0 °C was added. Subsequently, the reaction mixture was kept in agitation at 25 °C for 1 hour. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was diluted in H2O (50.0 mL), AcOEt (40.0 mL) at 0 °C and extracted with AcOEt (40.0 mL x 3). The organic phase was washed with saturated sodium chloride solution (brine) (20.0 mL x 2), dried in anhydrous sodium sulfate, filtered and concentrated under reduced pressure. 1.75 g (96.1% yield) of the product of interest were obtained in the form of a white oil, which was used for the next step without further purification. STEP II-J-II: PRECURSOR II‑21II:

[0179] 44 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55

[0180] In a round-bottomed flask containing 1‑(2-fluoro‑5-methoxyphenyl)etan‑1-ol (8.23 mmol) in DCM(20 mL), SOCl2 (16.4 mmol) was added at 0 °C. Subsequently, the reaction mixture was kept in agitation at 25 °C for 16 hours. After full consumption of the starting reagent (monitored by CCD), the concentrated reaction mixture under reduced pressure. 1.50 g (96.7% yield) of the product of interest were obtained in the form of a brown oil, which was used for the next step without further purification. STEP II-J-III: PRECURSOR II‑21III:

[0181]

[0182] In a round-bottomed flask containing 2‑(1-chloroethyl)‑1-fluoro‑4-methoxybenzene (11.9 mmol) and compound 7-b (7.95 mmol) in DMF (15.0 mL), TEA (15.9 mmol) was added at 25 °C. Subsequently, the reaction mixture was kept in agitation at 60 °C for 12 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was diluted with H2O (5.00 mL) at 0‑10 °C and AcOEt (5.00 mL) was added. The mixture was extracted with AcOEt (5.00 mL x 2). The organic phase was washed with saturated sodium chloride solution (brine) (5.00 mL x 2), dried in anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / AcOEt: 10 / 1 → 0 / 1). 1.80 g (71.79% yield) of the product of interest were obtained in the form of a white solid. STEP II-J-III:

[0183]

[0184] In a round-bottomed flask containing 2‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy)isoindoline‑1,3-dione (5.71 mmol) in EtOH (20.0 mL), NH2NH2H2O (8.56 mmol) at 25 °C was added. Subsequently, the reaction mixture was kept under agitation at 90 °C for 2 hours. After total consumption of the starting reagent (monitored by CCD), the reaction mixture was filtered, washed with EtOH (30 mL x 3) and concentrated under reduced pressure. 950 mg (89.8% yield) of the product of interest were obtained in the form of a yellow oil. EXAMPLES

[0185] The following examples, described in detail, serve to illustrate the embodiments of this invention without, however, having any limitation character to the scope of protection thereof. 45 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55

[0186] The General Formula I compound(s) of this invention were obtained from the amide coupling between the Formula III intermediates with the Formula II intermediates described above, synthesized according to the various methodologies, described above and schematized in General Scheme 1, but not limited to these. EXAMPLE 1. N‑((2-FLUORO‑5-METHOXYBENZYL)OXY)‑6‑(4-HYDROXYPHENYL)PYRAZINE‑2-CARBOXAMIDE

[0187]

[0188] In a round-bottomed flask, 6‑(4-hydroxyphenyl)pyrazine‑2-carboxylic acid (768 µmol), O‑[(2-fluoro‑5-methoxy- phenyl)methyl]hydroxylamine (768 µmol), T3P (3.87 mmol, 50% purity), DIEA (1.15 mmol) in DCM (10 mL) were added. The reaction mixture was kept under agitation for 16 hours at 20 °C. Upon conclusion of the reaction, the mixture was diluted with water and poured with DCM (3 x 10 mL). The organic phases were washed with anhydrous Na2SO4 and concentrated under reduced pressure. The product was crushed with methanol (10 mL) at 20oC for 20 min. The product of interest 1 was obtained in the form of a yellow solid.

[0189] The compounds 2 ‑156, as shown in table 11, are obtained by the procedure described for example 1 (compound 1), changing the corresponding intermediates II and III. TABLE 11. COMPOUNDS OBTAINED FROM THE CORRESPONDING REACTANTS FOLLOWING METHOD I-A. Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 1 N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4-hydroxyphenyl) pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.31 (s, 1H), 10.15 - 9.96 (m, 1H), 9.41 (s, 1H), 9.00 (s, 1H), 8.31 (br d, J = 8.6 Hz, 2H), 7.27 - 7.16 (m, 2H), 7.08 - 6.93 (m, 3H), 5.10 (br s, 2H), 3.82 (s, 3H). [M+H]+: 370.1 2 N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4-methoxyphenyl) pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.30 (s, 1H), 9.42 (s, 1H), 8.98 (s, 1H), 8.36 (d, J = 8.80 Hz, 2H), 7.20 to 7.12 (m, 2H), 7.11 to 7.09 (m, 2H), 7.00 to 6.95 (m, 1H), 5.05 (s, 2H), 3.86 (s, 3H), 3.76 (s, 3H). [M+H]+: 384.1. 3 N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4-isopropoxyphenyl) pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.30 (s, 1H), 9.41 (s, 1H), 8.98 (s, 1H), 8.34 (d, J = 8.80 Hz, 2H), 7.20 to 7.16 (m, 2H), 7.15 (d, J = 3.60 Hz, 2H), 7.09 to 7.00 (m, 1H), 5.05 (s, 2H), 4.79 to 4.76 (m, 1H), 3.76 (s, 3H), 1.32 (d, J = 6.00 Hz, 6H). [M+H]+: 412.1. 46 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 4 6‑(4-ethoxyphenyl)‑N‑((2-fluorobenzyl)oxy)pyrazine‑2-car- boxamide 1H-NMR, 400 MHz, Methanol-d4 δ = 9.24 (s, 1H), 8.99 (s, 1H), 8.26 - 8.06 (m, 2H), 7.61 (dt, J = 1.7, 7.5 Hz, 1H), 7.48 - 7.34 (m, 1H), 7.24 - 7.18 (m, 1H), 7.13 (t, J = 8.9 Hz, 1H), 7.09 - 6.99 (m, 2H), 5.14 (s, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H). [M+H]+: 368.1. 5 6‑(4-ethoxyphenyl)‑N‑((3-methoxybenzyl)oxy)pyrazine‑2- carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.28 (s, 1H), 9.52 - 9.37 (m, 1H), 9.09 - 8.94 (m, 1H), 8.35 (d, J = 8.8 Hz, 2H), 7.36 - 7.29 (m, 1H), 7.13 - 7.04 (m, 4H), 6.94 (dd, J = 2.0, 8.3 Hz, 1H), 4.98 (s, 2H), 4.14 (q, J = 7.0 Hz, 2H), 3.78 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H). [M+H]+: 380.2. 6 6‑(4-ethoxyphenyl)‑N‑((2-hydroxybenzyl)oxy)pyrazine‑2- carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.31 - 12.10 (m, 1H), 9.49 (br d, J = 3.3 Hz, 1H), 9.20 (s, 1H), 8.78 (s, 1H), 8.15 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 6.5 Hz, 1H), 7.02 - 6.93 (m, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.68 - 6.55 (m, 2H), 4.77 (s, 2H), 3.91 (q, J = 6.9 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H). [M+H]+: 366.1. 7 6‑(4-ethoxyphenyl)‑N‑((3-hydroxybenzyl)oxy)pyrazine‑2- carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.27 (s, 1H), 9.48 (s, 1H), 9.42 (s, 1H), 8.99 (s, 1H), 8.36 (d, J = 8.8 Hz, 2H), 7.19 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.94 - 6.88 (m, 2H), 6.78 - 6.72 (m, 1H), 4.90 (s, 2H), 4.13 (q, J = 6.9 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H). [M+H]+: 366.1. 8 6‑(4-ethoxyphenyl)‑N‑((5-methoxypyridine‑3-yl)methoxy) pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 1.37 (t, J=6.94 Hz, 3 H) 3.85 (s, 3 H) 4.13 (q, J=6.96 Hz, 2 H) 5.05 (s, 2 H) 7.09 (d, J=8.88 Hz, 2 H) 7.54 (s, 1 H) 8.25 - 8.38 (m, 4 H) 8.98 (s, 1 H) 9.42 (s, 1 H) 12.32 (s, 1 H). [M+H]+: 381.2. 9 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyr- azine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.30 (s, 1H), 9.42 (s, 1H), 8.98 (s, 1H), 8.35 (dd, J = 2.00, 7.00 Hz, 1H), 7.20‑7.14 (m, 2H), 7.10‑7.08 (m, 2H), 6.99‑6.97 (m, 1H), 5.04 (s, 2H), 4.14 (q, J = 6.80 Hz, 2H), 3.76 (s, 3H), 1.37 (t, J = 6.80 Hz, 3H). [M+H]+: 398.5. 47 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 10 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-isopropoxybenzyl)oxy) pyrazi ne‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.28 (s, 1H), 9.41 (s, 1H), 8.96 (s, 1H), 8.34 (d, J = 8.8 Hz, 2H), 7.17 - 7.04 (m, 4H), 6.98 - 6.91 (m, 1H), 5.02 (s, 2H), 4.54 (td, J = 6.1, 12.1 Hz, 1H), 4.13 (q, J = 6.9 Hz, 2H), 1.37 (t, J = 6.9 Hz, 3H), 1.21 (d, J = 6.0 Hz, 6H). [M+H]+: 426.1. 11 N‑((2-chloro‑5-methoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)pyr- azine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.33 (s, 1H), 9.41 (s, 1H), 8.98 (s, 1H), 8.34 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 3.1 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.97 (dd, J = 3.2, 8.8 Hz, 1H), 5.10 (s, 2H), 4.13 (q, J = 7.0 Hz, 2H), 3.78 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H). [M+H]+: 414.0. 12 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl) methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.32 (s, 1H), 9.42 (s, 1H), 8.97 (s, 1H), 8.34 (br d, J = 8.8 Hz, 2H), 7.96 - 7.90 (m, 1H), 7.78 (dd, J = 3.0, 7.6 Hz, 1H), 7.09 (d, J = 8.9 Hz, 2H), 5.05 (s, 2H), 4.14 (q, J = 6.9 Hz, 2H), 3.84 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H). [M+H]+: 399.1. 13 6‑(4-ethoxyphenyl)‑N‑((5-fluoro‑2-methoxypyridine‑4-yl) methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.37 (s, 1H), 9.42 (s, 1H), 8.98 (s, 1H), 8.34 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 1.2 Hz, 1H), 7.14 - 7.03 (m, 3H), 5.11 (s, 2H), 4.14 (q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H). [M+H]+: 399.1. 14 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-hydroxybenzyl)oxy)pyra- zine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.31 (br s, 1H), 9.57 - 9.37 (m, 2H), 8.98 (s, 1H), 8.36 (br d, J = 8.8 Hz, 2H), 7.11 - 7.00 (m, 3H), 6.95 (dd, J = 3.0, 5.8 Hz, 1H), 6.81 - 6.71 (m, 1H), 4.96 (s, 2H), 4.13 (q, J = 6.9 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H). [M+H]+: 384.1. 15 N‑((2-cyclopropyl‑5-methoxybenzyl)oxy)‑6‑(4-ethoxyphe- nyl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.31 (br s, 1H), 9.42 (s, 1H), 9.00 (s, 1H), 8.36 (d, J = 8.9 Hz, 2H), 7.14 - 7.01 (m, 3H), 6.97 - 6.92 (m, 1H), 6.84 (dd, J = 2.8, 8.5 Hz, 1H), 5.16 (s, 2H), 4.14 (q, J = 7.0 Hz, 2H), 3.74 (s, 3H), 2.36 - 2.22 (m, 1H), 1.37 (t, J = 6.9 Hz, 3H), 0.96 - 0.85 (m, 2H), 0.66 - 0.52 (m, 2H). [M+H]+: 420.4. 48 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 16 6‑(4-ethoxyphenyl)‑N‑((2-hydroxy‑5-methoxybenzyl)oxy) pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.83 - 11.99 (m, 1H), 9.77 - 8.89 (m, 2H), 8.37 (d, J = 8.9 Hz, 2H), 7.18 - 6.94 (m, 3H), 6.79 (s, 2H), 4.98 (s, 2H), 4.14 (q, J = 7.0 Hz, 2H), 3.70 (s, 3H), 1.38 (t, J = 6.9 Hz, 3H). [M+H]+: 396.1. 17 N‑((5‑(1-aminoethyl)‑2-fluorobenzyl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide 18 6‑(4-ethoxyphenyl)‑N‑((5-methoxy‑2-methylpyridine‑3-yl)methoxy)pyrazine‑2-carboxamide 19 6‑(4-ethoxyphenyl)‑N‑((5-methoxy‑2-methylbenzyl)oxy)pyrazine‑2-carboxamide 20 N‑((3,5-dimethoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)pyra- zine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.27 (s, 1H), 9.42 (s, 1H), 8.98 (s, 1H), 8.35 (d, J = 8.9 Hz, 2H), 7.19 - 6.93 (m, 2H), 6.67 (d, J = 2.3 Hz, 2H), 6.48 (t, J = 2.2 Hz, 1H), 4.94 (s, 2H), 4.14 (q, J = 6.9 Hz, 2H), 3.75 (s, 6H), 1.37 (t, J = 7.0 Hz, 3H). [M+H]+: 410.1. 21 N‑((3,5-dimethylbenzyl)oxy)‑6‑(4-ethoxyphenyl)pyra- zine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.27 (s, 1H), 9.42 (s, 1H), 8.99 (s, 1H), 8.36 (d, J = 8.8 Hz, 2H), 7.13 - 7.06 (m, 4H), 7.00 (s, 1H), 4.91 (s, 2H), 4.14 (q, J = 7.0 Hz, 2H), 2.29 (s, 6H), 1.37 (t, J = 7.0 Hz, 3H). [M+H]+: 378.1. 22 6‑(4‑(azetidine‑3-yloxy)phenyl)‑N‑((2-fluoro‑5-methoxy- benzyl)oxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 9.42 (s, 1H), 8.99 (s, 1H), 8.35 (d, J = 9.20 Hz, 2H), 7.20‑7.14 (m, 2H), 7.00‑6.96 (m, 3H), 5.12 (t, J = 6.00 Hz, 1H), 5.04 (s, 2H), 3.93‑3.89 (m, 2H), 3.76‑3.75 (m, 3H), 3.63‑3.59 (m, 2H). [M+H]+: 425.2. 23 6‑(4‑(azetidine‑3-ylmethoxy)phenyl)‑N‑((2-fluoro‑5-meth- oxybenzyl)oxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 9.44 (s, 1H), 9.00 (s, 1H), 8.40‑8.38 (m, 2H), 7.20‑7.14 (m, 4H), 7.00‑6.96 (m, 1H), 5.05 (s, 2H), 4.25‑4.24 (m, 2H), 4.03 (t, J = 9.20 Hz, 2H), 3.84‑3.76 (m, 5H), 3.26‑3.21 (m, 1H). [M+H]+: 439.2. 49 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 24 6‑(4‑(2‑(azetidine‑3-yl)ethoxy)phenyl)‑N‑((2-fluoro‑5-meth- oxybenzyl)oxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.30 (s, 1H), 9.43 (s, 1H), 8.61‑8.49 (m, 2H), 8.38‑8.35 (m, 2H), 7.20‑7.15 (m, 2H), 7.09‑7.07 (m, 2H), 7.00‑6.97 (m, 1H), 5.05 (s, 1H), 4.11‑4.01 (m, 4H), 3.82‑3.80 (m, 5H), 3.04‑2.96 (m, 1H), 2.10‑2.06 (m, 2H), 1.51 (s, 1H). [M+H]+: 453.2. 25 N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑((1-methylazeti- dine‑3-yl)oxy)phenyl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 11.68 (s, 1H), 9.41 (s, 1H), 8.98 (s, 1H), 8.35 (d, J = 8.0 Hz, 2H), 7.20 to 7.14 (m, 2H), 7.00 to 6.95 (m, 3H), 5.04 (s, 2H), 4.92 to 4.86 (m, 1H), 3.79 to 3.76 (m, 5H), 3.02 to 2.99 (m, 2H), 2.31 (s, 3H), 1.90 (s, 3H). [M+H]+: 439.2. 26 N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑((1-methylazetidine‑3-yl)methoxy)phenyl)pyrazine‑2-car- boxamide 27 N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑(2‑(1-methylazetidine‑3-yl)ethoxy)phenyl)pyrazine‑2-car- boxamide 28 6‑(4‑(difluoromethoxy)phenyl)‑N‑((5-methoxypyridine‑3-yl) methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.38 (s, 1H), 9.50 (s, 1H), 9.07 (s, 1H), 8.48 (d, J = 8.9 Hz, 2H), 8.30 (d, J = 3.3 Hz, 2H), 7.66 - 7.18 (m, 4H), 5.07 (s, 2H), 3.86 (s, 3H). [M+H]+: 403.4. 29 N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑(methylsulfinyl) phenyl)py razine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.40 (s, 1H), 9.57 (s, 1H), 9.13 (s, 1H), 8.60 (d, J = 8.40 Hz, 2H), 7.89‑7.86 (m, 2H), 7.21‑7.00 (m, 2H), 6.99‑6.97 (m, 1H), 5.06 (s, 2H), 3.76 (s, 3H), 2.83 (s, 3H). [M+H]+: 416.2. 30 N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6-methoxypyri- dine‑3-yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.35 (s, 1H), 9.50 (s, 1H), 9.22 (d, J = 2.00 Hz, 1H), 9.05 (s, 1H), 8.74 to 8.71 (m, 1H), 7.20 to 7.14 (m, 2H), 7.03 to 6.98 (m, 2H), 5.04 (s, 2H), 3.96 (s, 3H), 0.75 (s, 3H). [M+H]+: 385.0. 50 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 31 N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6-isopropoxypyri- dine‑3-yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.34 (s, 1H), 9.48 (s, 1H), 9.21‑9.20 (m, 1H), 9.04 (s, 1H), 8.72‑8.69 (m, 1H), 7.20‑7.14 (m, 2H), 6.99‑6.94 (m, 2H), 5.40‑5.31 (m, 1H), 5.04 (s, 2H), 3.76 (s, 3H), 1.36‑1.34 (m, 6H). [M+H]+: 413.1. 32 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluorobenzyl)oxy)pyrazine ‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.37 (s, 1H), 9.49 (s, 1H), 9.21 (d, J = 2.00 Hz, 1H), 9.04 (s, 1H), 8.74‑8.71 (m, 1H), 7.62‑7.57 (m, 1H), 7.47‑7.43 (m, 1H), 7.28‑7.24 (m, 2H), 7.00‑6.98 (m, 1H), 5.07 (s, 2H), 4.44‑4.38 (m, 2H), 1.38‑1.35 (m, 3H). [M+H]+: 369.4. 33 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methoxybenzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.33 (s, 1H), 9.49 (s, 1H), 9.21‑9.20 (m, 1H), 9.05 (s, 1H), 8.74‑8.71 (m, 1H), 7.35‑7.31 (m, 1H), 7.09‑7.06 (m, 2H), 7.00‑6.95 (m, 2H), 4.99 (s, 2H), 4.41 (q, J = 6.80 Hz, 2H), 3.78 (s, 3H), 1.37 (t, J = 6.80 Hz, 3H). [M+H]+: 381.1. 34 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-hydroxybenzyl)oxy)pyrazine‑2-carboxamide 35 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-hydroxybenzyl)oxy)pyrazine‑2-carboxamide 36 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methoxypyridine‑3-yl)meth- oxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 1.36 (t, J=7.07 Hz, 3 H) 3.85 (s, 3 H) 4.40 (q, J=7.09 Hz, 2 H) 5.05 (s, 2 H) 6.98 (d, J=8.63 Hz, 1 H) 7.53 (dd, J=2.44, 1.81 Hz, 1 H) 8.28 (dd, J=3.75, 2.25 Hz, 2 H) 8.70 (dd, J=8.75, 2.50 Hz, 1 H) 9.04 (s, 1 H) 9.19 (d, J=2.25 Hz, 1 H) 9.48 (s, 1 H) 12.36 (s, 1 H). [M+H]+: 382.4. 37 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl) oxy)pyrazine ‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.36 (s, 1H), 9.40 (s, 1H), 9.15 (d, J = 2.40 Hz, 1H), 9.00 (s, 1H), 8.66 (dd, J = 2.40, 8.60 Hz, 1H), 7.18 to 7.13 (m, 2H), 6.98 to 6.93 (m, 2H), 5.01 (s, 2H), 4.40 (q, J = 6.80 Hz, 2H), 3.75 (s, 3H), 1.36 (t, J = 7.20 Hz, 3H). [M+H]+: 398.5. 51 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 38 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyri- dine‑3-yl)methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.36 (br s, 1H), 9.49 (s, 1H), 9.19 (br d, J = 1.6 Hz, 1H), 9.03 (s, 1H), 8.70 (dd, J = 2.2, 8.7 Hz, 1H), 7.91 (br s, 1H), 7.78 (dd, J = 2.8, 7.7 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 5.05 (s, 2H), 4.41 (q, J = 7.0 Hz, 2H), 3.84 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H). [M+H]+: 400.1. 39 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-fluoro‑2-methoxypyri- dine‑4-yl)methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.41 (s, 1H), 9.50 (s, 1H), 9.20 (d, J = 2.2 Hz, 1H), 9.04 (s, 1H), 8.70 (dd, J = 2.4, 8.7 Hz, 1H), 8.18 (s, 1H), 7.10 (d, J = 4.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 5.11 (s, 2H), 4.41 (q, J = 6.9 Hz, 2H), 3.85 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H). [M+H]+: 400.1. 40 N‑((5‑(dimethylamino)‑2-fluorobenzyl)oxy)‑6‑(6-ethoxypyri- dine‑3-yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.32 (s, 1H), 9.49 (s, 1H), 9.21 (s, 1H), 9.04 (s, 1H), 8.74‑8.71 (m, 1H), 7.00‑6.91 (m, 3H), 6.90‑6.89 (m, 1H), 5.02 (s, 2H), 4.42 (q, J = 7.20 Hz, 2H), 2.87 (s, 6H), 1.37 (t, J = 6.80 Hz, 3H) . [M+H]+: 412.2. 41 N‑((5‑(dimethylamino)‑2-fluoropyridine‑3-yl)methoxy)‑6‑(6- ethoxypyridine‑3-yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.32 (s, 1H), 9.49 (s, 1H), 9.19 (d, J = 2.40 Hz, 1H), 9.03 (s, 1H), 8.72‑8.69 (m, 1H), 7.62‑7.61 (m, 1H), 7.51‑7.48 (m, 1H), 6.98 (d, J = 8.40 Hz, 1H), 5.02 (s, 2H), 4.41 (q, J = 7.20 Hz, 2H), 2.89 (s, 6H), 1.37 (t, J = 7.20 Hz, 3H). [M+H]+: 413.2. 42 N-((5-cyclobutoxy‑2-fluorobenzyl)oxy)‑6‑(6-ethoxypyri- dine‑3-yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.33 (s, 1H), 9.49 (s, 1H), 9.21‑9.20 (m, 1H), 9.05 (s, 1H), 8.74‑8.71 (m, 1H), 7.35‑7.31 (m, 1H), 7.09‑7.06 (m, 2H), 7.00‑6.95 (m, 2H), 4.99 (s, 2H), 4.41 (q, J = 6.80 Hz, 2H), 3.78 (s, 3H), 1.37 (t, J = 6.80 Hz, 3H). [M+H]+: 381.1. 43 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-hydroxybenzyl)oxy)pyrazine‑2-carboxamide 44 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-hydroxy‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide 52 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 45 N‑((5‑(1-aminoethyl)‑2-fluorobenzyl)oxy)‑6‑(6-ethoxypyridine‑3-yl)pyrazine‑2-carboxamide 46 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methoxy‑2-methylpyridine‑3-yl)methoxy)pyrazine‑2-carboxamide 47 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methoxy‑2-methylbenzyl)oxy)pyrazine‑2-carboxamide 48 6‑(6‑(ethoxy‑D5)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxyben- zyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.41 - 12.28 (m, 1H), 9.54 - 8.97 (m, 3H), 8.77 - 8.64 (m, 1H), 7.24 - 7.08 (m, 2H), 7.01 - 6.90 (m, 2H), 5.04 (s, 2H), 3.81 - 3.66 (m, 3H). [M+H]+: 404.1. 49 6‑(6‑(ethoxy‑2,2,2‑d3)pyridine‑3-yl)‑N‑((2-fluoro‑5-methox- ybenzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.34 (s, 1H), 9.48 (s, 1H), 9.20 (d, J = 2.3 Hz, 1H), 9.04 (s, 1H), 8.71 (dd, J = 2.5, 8.8 Hz, 1H), 7.21 - 7.10 (m, 2H), 7.02 - 6.90 (m, 2H), 5.04 (s, 2H), 4.39 (s, 2H), 3.75 (s, 3H). [M+H]+: 402.0. 50 6‑(6‑(ethoxy‑1,1‑d2)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxy- benzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.34 (s, 1H), 9.48 (s, 1H), 9.20 (d, J = 2.1 Hz, 1H), 9.04 (s, 1H), 8.71 (dd, J = 2.5, 8.8 Hz, 1H), 7.21 - 7.10 (m, 2H), 6.97 (br d, J = 8.8 Hz, 2H), 5.04 (s, 2H), 3.75 (s, 3H), 1.34 (s, 3H). [M+H]+: 401.0. 51 6‑(6‑(ethoxy‑1,1‑d2)pyridine‑3-yl)‑N‑((2-fluoro‑5‑(methox- y‑d3)benzyl)oxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.34 (s, 1H), 9.48 (s, 1H), 9.20 (d, J = 2.3 Hz, 1H), 9.04 (s, 1H), 8.71 (dd, J = 2.4, 8.8 Hz, 1H), 7.21 - 7.11 (m, 2H), 7.00 - 6.93 (m, 2H), 5.04 (s, 2H), 1.34 (s, 3H). [M+H]+: 404.1. 52 6‑(6‑(ethoxy‑2,2,2‑d3)pyridine‑3-yl)‑N‑((2-fluor- o‑5‑(methoxy‑d3)benzyl)oxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.34 (s, 1H), 9.48 (s, 1H), 9.19 (d, J = 2.3 Hz, 1H), 9.04 (s, 1H), 8.70 (dd, J = 2.5, 8.8 Hz, 1H), 7.22 - 7.10 (m, 2H), 7.01 - 6.91 (m, 2H), 5.03 (s, 2H), 4.39 (s, 2H). [M+H]+: 405.0. 53 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 53 6‑(6‑(ethoxy‑d5)pyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy‑d3) benzyl)oxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.35 (s, 1H), 9.57 - 8.95 (m, 3H), 8.76 - 8.63 (m, 1H), 7.26 - 7.08 (m, 2H), 7.05 - 6.93 (m, 2H), 5.05 (s, 2H). [M+H]+: 407.5. 54 6‑(6‑(ethoxy‑d5)pyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy‑d3) phenyl)methoxy‑d2)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.33 (s, 1H), 9.48 (s, 1H), 9.20 (s, 1H), 9.07 - 9.01 (m, 1H), 8.71 (dd, J = 2.4, 8.6 Hz, 1H), 7.23 - 7.09 (m, 2H), 7.02 - 6.92 (m, 2H). [M+H]+: 409.5. 55 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy‑d3)ben- zyl)oxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.34 (s, 1H), 9.48 (s, 1H), 9.20 (d, J = 2.4 Hz, 1H), 9.04 (s, 1H), 8.71 (dd, J = 2.5, 8.8 Hz, 1H), 7.20 - 7.12 (m, 2H), 6.99 - 6.93 (m, 2H), 5.04 (s, 2H), 4.40 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H). [M+H]+: 402.0. 56 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-methyl‑1H-midazole‑5-yl) methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.27 (s, 1H), 9.49 (s, 1H), 9.20 (d, J = 2.4 Hz, 1H), 9.04 (s, 1H), 8.72 (dd, J = 2.4, 8.7 Hz, 1H), 7.68 (s, 1H), 7.04 - 6.93 (m, 2H), 4.98 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). [M+H]+: 355.0. 57 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methyloxazole‑4-yl)meth- oxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.27 (s, 1H), 9.48 (s, 1H), 9.20 (d, J = 2.4 Hz, 1H), 9.04 (s, 1H), 8.73 (dd, J = 2.5, 8.8 Hz, 1H), 8.23 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 4.87 (s, 2H), 4.41 (q, J = 7.0 Hz, 2H), 2.36 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H). [M+H]+: 356.0. 58 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-methyl‑1H-pyrazole‑5-yl) methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.37 (s, 1H), 9.49 (s, 1H), 9.20 (d, J = 2.3 Hz, 1H), 9.05 (s, 1H), 8.71 (dd, J = 2.4, 8.7 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 5.05 (s, 2H), 4.41 (q, J = 7.0 Hz, 2H), 4.01 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H). [M+H]+: 355.4. 54 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 59 6‑(6-ethoxypyridine‑3-yl)‑N‑((4-methyl‑1H-imidazole‑5-yl) methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 13.73 (br d, J = 5.0 Hz, 1H), 12.25 (br s, 1H), 9.49 (s, 1H), 9.19 (d, J = 2.3 Hz, 1H), 9.02 (s, 1H), 8.82 - 8.62 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H), 4.99 (s, 2H), 4.41 (q, J = 7.0 Hz, 2H), 2.28 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). [M+H]+: 355.4. 60 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-methyl‑1H-pyrrole‑2-yl)methoxy)pyrazine‑2-carboxamide 61 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-ethyl‑1H-imidazole‑2-yl) methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.62 - 12.17 (m, 1H), 9.50 (s, 1H), 9.21 (d, J = 2.1 Hz, 1H), 9.06 (s, 1H), 8.73 (dd, J = 2.4, 8.7 Hz, 1H), 7.31 (s, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.90 (s, 1H), 5.02 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H), 4.28 (q, J = 7.3 Hz, 2H), 1.39 (td, J = 7.1, 18.3 Hz, 6H). [M+H]+: 369.1. 62 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-ethyl‑1H-pyrazole‑5-yl) methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.40 (s, 1H), 9.50 (s, 1H), 9.21 (d, J = 2.4 Hz, 1H), 9.06 (s, 1H), 8.72 (dd, J = 2.5, 8.8 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 5.04 (s, 2H), 4.40 (qd, J = 7.2, 9.6 Hz, 4H), 1.39 (td, J = 7.1, 19.0 Hz, 6H). [M+H]+: 369.0. 63 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-isopropyl‑1H-imidazole‑5- yl)methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.32 (s, 1H), 9.50 (s, 1H), 9.21 (d, J = 2.3 Hz, 1H), 9.06 (s, 1H), 8.72 (dd, J = 2.5, 8.8 Hz, 1H), 7.90 (d, J = 0.6 Hz, 1H), 7.01 - 6.98 (m, 2H), 4.97 (s, 2H), 4.86 (td, J = 6.7, 13.4 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 1.50 (d, J = 6.8 Hz, 6H), 1.37 (t, J = 7.1 Hz, 3H). [M+H]+: 383.0. 64 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-isopropyl‑1H-pyrazole‑5-yl) methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.41 (s, 1H), 9.50 (s, 1H), 9.21 (d, J = 2.3 Hz, 1H), 9.07 (s, 1H), 8.72 (dd, J = 2.4, 8.7 Hz, 1H), 7.45 (d, J = 1.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.35 (d, J = 1.6 Hz, 1H), 5.17 - 4.96 (m, 3H), 4.41 (q, J = 7.0 Hz, 2H), 1.44 (d, J = 6.5 Hz, 6H), 1.36 (t, J = 7.0 Hz, 3H). [M+H]+: 383.1. 55 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 65 6‑(6-ethoxypyridine‑3-yl)‑N‑((4-methyloxazole‑5-yl)meth- oxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.28 (s, 1H), 9.48 (s, 1H), 9.19 (d, J = 2.4 Hz, 1H), 9.02 (s, 1H), 8.70 (dd, J = 2.5, 8.8 Hz, 1H), 8.31 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 5.03 (s, 2H), 4.40 (q, J = 7.0 Hz, 2H), 2.11 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H). [M+H]+: 356.4. 66 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methoxyfuran‑2-yl)methoxy)pyrazine‑2-carboxamide 67 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methyl‑1H-pyrrole‑2-yl)methoxy)pyrazine‑2-carboxamide 68 N‑((3-cyan‑1H-pyrrole‑2-yl)methoxy)‑6‑(6-ethoxypyri- dine‑3-yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.30 (br s, 1H), 12.11 (br s, 1H), 9.47 (s, 1H), 9.19 (d, J = 2.1 Hz, 1H), 9.03 (s, 1H), 8.70 (dd, J = 2.3, 8.7 Hz, 1H), 7.00 - 6.94 (m, 2H), 6.47 (d, J = 2.6 Hz, 1H), 5.01 (s, 2H), 4.40 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). [M+H]+: 365.4. 69 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methyl‑1H-pyrazole‑4-yl) methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.18 (s, 1H), 9.48 (s, 1H), 9.21 (d, J = 2.0 Hz, 1H), 9.05 (s, 1H), 8.73 (dd, J = 2.5, 8.8 Hz, 1H), 7.59 (s, 1H), 6.99 (d, J = 9.3 Hz, 1H), 4.84 (s, 2H), 4.41 (q, J = 7.1 Hz, 3H), 2.31 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). [M+H]+: 355.4. 70 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-isopropyl‑1H-imidazole‑4- yl)methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.25 (br s, 1H), 9.48 (s, 1H), 9.21 (d, J = 2.3 Hz, 1H), 9.04 (s, 1H), 8.75 (dd, J = 2.5, 8.8 Hz, 1H), 7.71 (d, J = 1.0 Hz, 1H), 7.39 (d, J = 0.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 4.84 (s, 2H), 4.49 - 4.31 (m, 3H), 1.42 - 1.33 (m, 9H). [M+H]+: 383.1. 71 N‑((2-fluorobenzyl)oxy)‑6‑(6‑(trifluoromethoxy)pyridin e‑3- yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.42 (s, 1H), 9.60 (s, 1H), 9.40 (d, J = 2.00 Hz, 1H), 9.15 (s, 1H), 9.02 (dd, J = 2.40, 8.40 Hz, 1H), 7.62‑7.54 (m, 1H), 7.51 (d, J = 0.80 Hz, 1H), 7.48‑7.46 (m, 1H), 7.45‑7.43 (m, 2H), 5.08 (s, 2H), 3.32 (s, 3H). [M+H]+: 409.1. 56 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 72 N‑((3-methoxybenzyl)oxy)‑6‑(6‑(trifluoromethoxy)pyridin e‑3-yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.40 (s, 1H), 9.60 (s, 1H), 9.41 (d, J = 2.40 Hz, 1H), 9.16 (s, 1H), 9.02 (dd, J = 2.40, 8.60 Hz, 1H), 7.53 (d, J = 8.40 Hz, 1H), 7.33 (t, J = 8.00 Hz, 1H), 7.09‑7.06 (m, 2H), 6.94 (dd, J = 2.40, 8.00 Hz, 1H), 4.99 (s, 2H), 3.78 (s, 3H). [M+H]+: 421.1. 73 N‑(pyridine‑2-ylmethoxy)‑6‑(6‑(trifluoromethoxy)pyridin e‑3-yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.49 (s, 1H), 9.60 (s, 1H), 9.46 (t, J = 2.00 Hz, 1H), 9.18 (d, J = 10.40 Hz, 1H), 9.02 (dd, J = 2.40, 8.40 Hz, 1H), 8.58 (d, J = 4.00 Hz, 1H), 7.91‑7.86 (m, 1H), 7.70‑7.68 (m, 1H), 7.53 (d, J = 8.80 Hz, 1H), 7.40 (d, J = 4.80 Hz, 1H), 7.39‑7.37 (m, 1H), 5.12 (s, 2H). [M+H]+: 392.0. 74 N‑(pyridine‑3-ylmetoxy)‑6‑(6‑(trifluoromethoxy)pyridine ‑3- yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.43 (s, 1H), 9.59 (d, J = 9.20 Hz, 1H), 9.40 (d, J = 2.40 Hz, 1H), 9.17 (d, J = 13.60 Hz, 1H), 9.05 to 9.00 (m, 1H), 8.70 (d, J = 1.60 Hz, 1H), 8.58 (dd, J = 1.60, 4.80 Hz, 1H), 7.94 (dd, J = 2.00, Hz, 1H), 7.53 (d, J = 8.80 Hz, 1H), 7.47 to 7.44 (m, 1H), 5.06 (s, 2H). [M+H]+: 392.1. 75 (N‑(pyridine‑4-ylmethoxy)‑6‑(6‑(trifluoromethoxy)pyridine ‑3-yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.48 (s, 1H), 9.59 (s, 1H), 9.39 (d, J = 2.40 Hz, 1H), 9.15 (s, 1H), 9.00 (dd, J = 2.40, 8.40 Hz, 1H), 8.61 (dd, J = 1.60, 4.40 Hz, 1H), 7.54‑7.51 (m, 3H), 5.09 (s, 2H). [M+H]+: 392.2. 76 N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6‑(trifluoromethoxy) pyridine ‑3-yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.42 (s, 1H), 9.60 (s, 1H), 9.40 (d, J = 2.40 Hz, 1H), 9.16 (s, 1H), 9.02 (dd, J = 2.40, 8.40 Hz, 1H), 7.53 (d, J = 8.80 Hz, 1H), 7.20‑7.14 (m, 2H), 6.99 (m, 1H), 5.05 (s, 2H), 3.76 (s, 3H). [M+H]+: 439.1. 77 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2-fluoro‑5-meth- oxybenzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.40 (s, 1H), 9.57 (s, 1H), 9.30 (d, J = 2.00 Hz, 1H), 9.12 (s, 1H), 8.93 (dd, J = 2.40, 8.80 Hz, 1H), 7.83 (t, J = 72.40 Hz, 1H), 7.32 (dd, J = 0.40, 8.60 Hz, 1H), 7.20‑7.14 (m, 2H), 7.00‑6.97 (m, 1H), 5.05 (s, 2H), 3.76 (s, 3H). [M+H]+: 420.1 57 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 78 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2-fluoro‑5-meth- oxypyridine‑3-yl)methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.42 (br s, 1H), 9.57 (s, 1H), 9.29 (br d, J = 1.8 Hz, 1H), 9.11 (s, 1H), 8.92 (dd, J = 2.3, 8.6 Hz, 1H), 8.06 - 7.62 (m, 2H), 7.32 (d, J = 8.6 Hz, 1H), 5.06 (s, 2H), 3.84 (s, 3H). [M+H]+: 422.1. 79 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((5-fluoro‑2-meth- oxypyridine‑4-yl)methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.46 (br s, 1H), 9.57 (br s, 1H), 9.29 (br s, 1H), 9.12 (br s, 1H), 8.91 (br d, J = 8.2 Hz, 1H), 8.17 (s, 1H), 8.02 - 7.62 (m, 1H), 7.32 (br d, J = 8.6 Hz, 1H), 7.10 (br d, J = 3.2 Hz, 1H), 5.11 (br s, 2H), 3.85 (s, 3H). [M+H]+: 422.0. 80 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)-N-((5‑(dimethylami- no)‑2-fluoropyridine‑3-yl)methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.39 (s, 1H), 9.57 (s, 1H), 9.29 (s, 1H), 9.29 (s, 1H), 8.94‑8.91 (m, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.65‑7.62 (m, 1H), 7.51‑7.48 (m, 1H), 5.03 (s, 2H), 2.90 (s, 6H). [M+H]+: 435.1. 81 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)-N-((5‑(dimethylami- no)‑2-fluorobenzyl)oxy)pyrazine ‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.38 (s, 1H), 9.57 (s, 1H), 9.30 (d, J = 2.40 Hz, 1H), 9.12 (s, 1H), 8.96‑8.93 (m, 1H), 7.83 (s, 1H), 7.33‑7.30 (m, 1H), 7.09‑7.05 (m, 1H), 6.91 (m, 1H), 6.78‑6.76 (m, 1H), 5.03 (s, 2H), 2.87 (s, 6H). [M+H]+: 434.2. 82 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((5-methoxypyri- dine‑3-yl)methoxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.42 (br s, 1H), 9.57 (s, 1H), 9.29 (d, J = 2.3 Hz, 1H), 9.12 (s, 1H), 8.93 (dd, J = 2.3, 8.7 Hz, 1H), 8.29 (dd, J = 2.2, 4.2 Hz, 2H), 8.05 - 7.63 (m, 1H), 7.59 - 7.52 (m, 1H), 7.33 (d, J = 8.6 Hz, 1H), 5.06 (s, 2H), 3.86 (s, 3H). [M+H]+: 404.1. 83 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2-fluor- o‑5‑(methoxy‑d3)benzyl)oxy)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.40 (s, 1H), 9.56 (s, 1H), 9.29 (d, J = 2.3 Hz, 1H), 9.11 (s, 1H), 8.93 (dd, J = 2.5, 8.6 Hz, 1H), 7.82 (t, J = 72.5 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.21 - 7.10 (m, 2H), 6.97 (td, J = 3.7, 8.9 Hz, 1H), 5.04 (s, 2H). [M+H]+: 423.9. 58 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 84 N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6‑(methylsulfinyl) pyridine‑3-yl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.45 (s, 1H), 9.67 to 9.64 (m, 2H), 9.18 (s, 1H), 9.09 to 9.07 (m, 1H), 8.10 to 8.08 (m, 1H), 7.21 to 7.14 (m, 2H), 7.00 to 6.97 (m, 1H), 5.06 (s, 2H), 3.76 (s, 3H), 2.88 (s, 3H). [M+H]+: 417.2. 85 6‑(4-ethoxy‑2-hydroxyphenyl)‑N‑((2-fluoro‑5-methoxyben- zyl)oxy)pyrazine ‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.22 (br s, 1H), 11.01 - 10.67 (m, 1H), 9.47 (s, 1H), 8.88 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.20 - 7.07 (m, 2H), 7.00 - 6.90 (m, 1H), 6.63 - 6.47 (m, 2H), 5.02 (s, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.75 (s, 3H), 1.35 (t, J = 6.9 Hz, 3H). [M+H]+: 414.4. 86 6‑(4-ethoxy‑2-methylphenyl)‑N‑((2-fluoro‑5-methoxyben- zyl)oxy)pyrazine ‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.09 (br s, 1H), 9.03 (s, 1H), 8.99 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.17 to 7.11 (m, 2H), 6.97 to 6.90 (m, 3H), 5.00 (s, 2H), 4.12 to 4.07 (q, J = 7.2 Hz, 2H), 3.74 (s, 3H), 2.37 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). [M+H]+: 412.1. 87 6‑(4-ethoxy‑2-methoxyphenyl)‑N‑((2-fluoro‑5-methoxyben- zyl)oxy)pyrazine ‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.22 (s, 1H), 9.31 (s, 1H), 8.93(s, 1H), 8.14 (d, , J = 8.4 Hz, 1H), 7.19 to 7.13 (m, 2H), 6.99 to 6.94 (m, 1H), 6.73 to 6.69 (m, 2H), 5.02 (s, 2H), 4.17 to 4.12 (q, J = 7.2 Hz, 2H), 3.91 (s, 3 H), 3.75 (s, 3H), 1.37 (t, J = 6.8 Hz, 3H). [M+H]+: 428.1. 88 6‑(4‑(difluoromethoxy)‑2-methoxyphenyl)‑N‑((2-fluoro‑5- methoxybenzyl)oxy)pyrazine ‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.26 (s, 1H), 9.33 (s, 1H), 9.01 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 74 Hz, 1H), 7.19 to 7.13 (m, 2H) 7.04 (m, 1H), 6.99 to 6.94 (m, 2H), 5.02 (s, 2H), 3.93 (s, 3H), 3.75 (s, 3H). [M+H]+: 449.9. 89 6‑(4-ethoxy‑3-hydroxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide 90 6‑(6-ethoxy‑4-hydroxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide 59 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 91 6‑(6-ethoxy‑2-hydroxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide 92 6‑(6-ethoxy‑2-methylpyridine‑3-yl)‑N-((2-fluoro‑5-methoxy- benzyl)oxy)pyrazine ‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.15 (s, 1H), 9.06 (s, 2H), 8.01 (d, J = 8.4 Hz, 1H), 7.18‑7.11 (m, 2H), 6.97‑6.95 (m, 1H), 6.81‑6.79 (d, J = 8.4 Hz, 1H), 5.01 (s, 2H), 4.40‑4.34 (q, J = 7.2 Hz, 2H), 3.74 (s, 3H), 2.52‑2.50 (m, 2 H), 1.35 (t, J = 7.2 Hz, 3H). [M+H]+: 413.1. 93 6‑(6-ethoxy‑4-methylpyridine‑3-yl)‑N-((2-fluoro‑5-methoxy- benzyl)oxy)pyrazine ‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.14 (s, 1H), 9.08 (d, J = 6.4 Hz, 2H), 8.40 (s, 1H), 7.17‑7.11 (m, 2H), 6.97‑6.93 (m, 1H), 6.83 (s, 1H), 5.00 (s, 1H), 4.39‑4.34 (q, J = 7.2 Hz, 2H), 3.74 (s, 3H), 2.39 (s, 3H), 1.36‑1.30 (m, 3 H). [M+H]+: 413.1. 94 6‑(6-ethoxy‑2-methoxypyridine‑3-yl)‑N-((2-fluoro‑5-meth- oxybenzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.12 (brs ,1H), 9.44 (s, 1H), 8.96 (s, 1H), 8.75 (d, J = 8.4Hz, 1H), 7.19‑7.13 (m, 2H), 6.99‑6.96 (m, 1H), 6.60 (d, J = 8.4Hz, 1H), 5.03 (s, 2H), 4.45‑4.40 (q, J = 7.2Hz, 2H), 4.05 (s, 3H), 3.75(s, 3H), 1.38 (t, J = 7.2Hz, 3H). [M+H]+: 429.0. 95 6‑(6-ethoxy‑4-methoxypyridine‑3-yl)‑N-((2-fluoro‑5-meth- oxybenzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.18 (s, 1H), 9.13 (s, 2H), 8.22 (d, J = 8.4 Hz, 1H), 7.812 (t, J = 72.8 Hz, 1H), 7.18 to 7.11 (m, 3H), 6.98 to 6.94 (m, 1H), 5.01 (s, 2H), 3.74 (s, 3H), 2.55 (s, 3H), 1.23 (s, 3H). [M+H]+: 435.0. 96 N‑((3,5-dimethoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)‑5-hydro- xypyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.74 (s, 1H), 11.67 (s, 1H), 8.58 (dd, J = 6.8, 2.0 Hz, 2 H), 7.87 (s, 1H), 6.98 (m, 2 H), 6.65 (d, J = 2.0 Hz, 2H), 6.47 (t, J = 2.4 Hz, 1 H), 4.89 (s, 2H), 4.11 (q, J = 7.0 Hz, 2H), 3.76 (s, 6H), 1.37 (t, J = 6.8 Hz, 3H). [M+H]+: 426.1. 60 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 97 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑5- hydroxypyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.77 (s, 1H), 11.70 (s, 1H), 8.57 (m, 2.0 Hz, 2 H), 7.87 (s, 1H), 7.16 (m, 2H), 6.99 (m, 3H), 4.99 (s, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.76 (s, 3H), 1.67 (t, J = 6.8 Hz, 3H). [M+H]+: 412.2. 98 N‑((3,5-dimethoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)‑3-hydro- xypyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 8.39 (s, 1H), 7.79 (m, 2H), 6.94 (dd, J = 6.8, 2.0 Hz, 2H), 6.61 (s, 2H), 6.44 (s, 1H), 4.86 (s, 2H), 4.04 (q, J = 7.2 Hz, 2H), 3.75 (s, 6H), 1.34 (t, J = 7.2 Hz, 3H). [M+H]+: 424.1. 99 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑3- hydroxypyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO‑2 d6 δ = 8.39 (s, 1H), 7.78 (m, 1H), 7.14 (m, 1H), 6.94 (m, 3H), 6.07 (s, 1H), 4.95 (s, 2H), 4.05 (q, J = 6.8 Hz, 2H), 3.75 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H). [M+H]+: 412.1. 100 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl) oxy)‑5-hydroxypyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.90 (s, 1H), 11.79 (s, 1H), 9.42 (s, 1H), 8.87 (m, 1H), 8.82 (s, 1H), 7.92 (s, 1H), 7.15 (m, 1H), 6.98 (m, 1H), 6.95 (d, J = 3.6 Hz, 1H), 4.98 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 3.76 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). [M+H]+: 413.0. 101 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl) oxy)‑3-hydroxypyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 8.78 (s, 1H), 8.34 (s, 1H), 7.16 (m, 1H), 7.12 (m, 1H), 6.97 (m, 1H), 6.88 (m, 1H), 5.01 (s, 2H), 4.34 (q, J = 6.8 Hz, 2H), 3.76 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). [M+H]+: 413.1. 102 5-amino‑6‑(6-ethoxypyridine‑3-yl)‑N-((2-fluoro‑5-methoxy- benzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 11.57 (s, 1 H), 8.59 (d, J = 2.25 Hz, 1 H), 8.44 (s, 1 H) 8.11 (dd, J = 8.63, 2.50 Hz, 1 H), 7.07 - 7.19 (m, 2 H), 6.86 - 7.01 (m, 4 H), 4.95 (s, 2 H), 4.38 (q, J = 7.00 Hz, 2 H), 3.74 (s, 3 H), 1.35 (t, J = 7.07 Hz, 3 H). [M+H]+: 414.1. 61 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 103 3-amino‑6‑(6-ethoxypyridine‑3-yl)‑N-((2-fluoro‑5-methoxy- benzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.02 (s, 1H), 8.96 (d, J = 2.1 Hz, 1H), 8.85 (s, 1H), 8.51 (dd, J = 2.4, 8.6 Hz, 1H), 7.52 (br s, 2H), 7.20 - 7.11 (m, 2H), 7.00 - 6.93 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.00 (s, 2H), 4.35 (q, J = 7.0 Hz, 2H), 3.75 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H). [M+H]+: 414.1. 104 6‑(6-ethoxypyridine‑3-yl)‑5-fluoro-N‑((2-fluoro‑5-methoxy- benzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.31 (s, 1H), 9.03 (s, 1H), 8.74 (d, J = 1.4 Hz, 1H), 8.56 (dd, J = 1.3, 8.9 Hz, 1H), 7.21 - 7.10 (m, 2H), 7.03 - 6.93 (m, 2H), 5.03 (s, 2H), 4.42 (q, J = 7.0 Hz, 2H), 3.75 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H). [M+H]+: 417.0. 105 6‑(6-ethoxypyridine‑3-yl)‑3-fluoro-N‑((2-fluoro‑5-methoxy- benzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.21 (s, 1H), 9.17 - 8.97 (m, 2H), 8.55 (dd, J = 2.3, 8.7 Hz, 1H), 7.22 - 7.08 (m, 2H), 7.02 - 6.93 (m, 2H), 5.02 (s, 2H), 4.39 (q, J = 7.0 Hz, 2H), 3.75 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H). [M+H]+: 417.4. 106 6’-ethoxy-N‑((2-fluoro‑5-methoxybenzyl)oxy)‑[2,3’-bipyri- dine]‑6-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 1.37 (s, 3 H) 3.76 (s, 3 H) 4.40 (q, J=7.05 Hz, 2 H) 5.03 (s, 2 H) 6.86 - 7.01 (m, 2 H) 7.09 - 7.23 (m, 2 H) 7.89 - 7.95 (m, 1 H) 8.06 (t, J=7.82 Hz, 1 H) 8.15 - 8.22 (m, 1 H) 8.67 (dd, J=8.76, 2.50 Hz, 1 H) 9.14 (d, J=2.13 Hz, 1 H) 12.14 (s, 1 H). [M+H]+: 398.4. 107 6’-ethoxy-N‑((2-fluoro‑5-methoxypyridine‑3-yl)meth- oxy)‑[2,3’-bipyridine]‑6-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 1.36 (t, J=7.07 Hz, 3 H) 3.84 (s, 3 H) 4.39 (q, J=7.05 Hz, 2 H) 5.04 (s, 2 H) 6.92 (d, J=8.63 Hz, 1 H) 7.77 (dd, J=7.75, 3.00 Hz, 1 H) 7.86 - 7.94 (m, 2 H) 8.05 (t, J=7.82 Hz, 1 H) 8.12 - 8.23 (m, 1 H) 8.65 (dd, J=8.76, 2.50 Hz, 1 H) 9.13 (d, J=2.25 Hz, 1 H) 12.14 (s, 1 H). [M+H]+: 399.4. 62 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 108 6’-ethoxy-N‑((2-fluoro‑5-methoxybenzyl)oxy)‑[3,3’-bipyri- dine]‑5-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.02 (br s, 1H), 9.04 (d, J = 1.4 Hz, 1H), 8.85 (d, J = 1.4 Hz, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.32 (br s, 1H), 8.07 - 8.15 (m, 1H), 7.08 - 7.20 (m, 2H), 6.91 - 7.02 (m, 2H), 5.00 (s, 2H), 4.36 (q, J = 7.0 Hz, 2H), 3.75 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). [M+H]+: 398.0. 109 2‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl) oxy)pyrimid ine‑4-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.47 (s, 1H), 9.38 (d, J = 2.3 Hz, 1H), 9.10 (d, J = 4.9 Hz, 1H), 8.81 (dd, J = 2.4, 8.8 Hz, 1H), 7.85 (d, J = 5.0 Hz, 1H), 7.21 - 7.10 (m, 2H), 7.01 - 6.91 (m, 2H), 5.04 (s, 2H), 4.41 (q, J = 7.0 Hz, 2H), 3.75 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). [M+H]+: 399.4. 110 2‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyri- dine‑3-yl)methoxy)pyrimidine‑4-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 1.21 - 1.58 (m, 2 H) 1.37 - 1.37 (m, 1 H) 3.77 - 3.88 (m, 3 H) 4.36 - 4.48 (m, 2 H) 5.06 (s, 2 H) 6.83 (d, J=2.38 Hz, 1 H) 7.62 - 8.11 (m, 2 H) 8.59 - 8.93 (m, 1 H) 8.68 - 8.90 (m, 1 H) 8.99 (s, 1 H) 9.51 (s, 1 H) 12.33 - 12.57 (m, 1 H). [M+H]+: 400.0. 111 4‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl) oxy)pyrimid ine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 9.06 (d, J = 2.3 Hz, 1H), 8.96 (br d, J = 5.3 Hz, 1H), 8.53 (dd, J = 2.5, 8.8 Hz, 1H), 8.23 (d, J = 5.4 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 4.40 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). [M+H]+: 398.1. 112 2‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6- hydroxypyrimidine‑4-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.82 (br s, 1H), 12.11 (s, 1H), 8.36 (br d, J = 8.8 Hz, 2H), 7.21 - 6.92 (m, 5H), 6.72 (br s, 1H), 5.00 (s, 2H), 4.14 (q, J = 6.9 Hz, 2H), 3.75 (s, 3H), 1.36 (t, J = 6.9 Hz, 3H). [M+H]+: 414.1. 113 4‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6- hydroxypyrimidine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.83 (br dd, J = 1.9, 9.9 Hz, 1H), 12.11 (s, 1H), 8.36 (br d, J = 8.5 Hz, 2H), 7.21 - 7.10 (m, 2H), 7.05 (d, J = 8.9 Hz, 2H), 6.96 (td, J = 3.7, 8.8 Hz, 1H), 6.71 (br s, 1H), 5.00 (s, 2H), 4.14 (q, J = 6.9 Hz, 2H), 3.75 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H). [M+H]+: 414.1. 63 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 114 6’‑(difluoromethoxy)‑N-((2-fluoro‑5-methoxypyridine‑3-yl) methoxy)‑[2,3’-bipyridine]‑6-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.20 (br s, 1H), 9.23 (d, J = 2.3 Hz, 1H), 8.86 (dd, J = 2.4, 8.7 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.11 (t, J = 7.9 Hz, 1H), 8.00 - 7.95 (m, 1H), 7.93 - 7.88 (m, 1H), 7.81 - 7.74 (m, 1H), 7.62 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 5.05 (s, 2H), 3.84 (s, 3H). [M+H]+: 421.3. 115 6’‑(difluoromethoxy)‑N-((2-fluoro‑5-methoxybenzyl) oxy)‑[2,3’-bipyridine]‑6-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.20 (s, 1H), 9.24 (d, J = 2.3 Hz, 1H), 8.88 (dd, J = 2.4, 8.7 Hz, 1H), 8.27 (dd, J = 0.8, 8.0 Hz, 1H), 8.11 (t, J = 7.8 Hz, 1H), 8.01 - 7.57 (m, 2H), 7.30 - 7.09 (m, 3H), 6.96 (td, J = 3.7, 8.9 Hz, 1H), 5.03 (s, 2H), 3.75 (s, 3H). [M+H]+: 420.3. 116 6’‑(difluoromethoxy)‑N-((2-fluoro‑5-methoxybenzyl) oxy)‑[3,3’-bipyridine]‑5-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 11.93 - 12.12 (m, 1H), 9.09 (s, 1H), 8.89 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.30 - 8.42 (m, 2H), 7.78 (t, J = 72.7 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.07 - 7.22 (m, 2H), 6.91 - 7.02 (m, 1H), 5.01 (s, 2H), 3.75 (s, 3H). [M+H]+: 420.1 117 2‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2-fluoro‑5-meth- oxypyridine‑3-yl)methoxy)pyrimidine‑4-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 3.84 (s, 3 H) 5.06 (s, 2 H) 7.29 (d, J=8.76 Hz, 1 H) 7.62 - 7.69 (m, 1 H) 7.72 - 8.07 (m, 3 H) 9.02 (dd, J=8.63, 2.38 Hz, 1 H) 9.17 (d, J=5.00 Hz, 1 H) 9.45 (d, J=2.13 Hz, 1 H) 12.55 (s, 1 H). [M+H]+: 422.0. 118 2‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2-fluoro‑5-meth- oxybenzyl)oxy)pyrimid ine‑4-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.55 (s, 1H), 9.46 (d, J = 2.0 Hz, 1H), 9.17 (d, J = 4.9 Hz, 1H), 9.04 (dd, J = 2.3, 8.6 Hz, 1H), 8.05 - 7.62 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 7.22 - 7.09 (m, 2H), 7.03 - 6.93 (m, 1H), 5.05 (s, 2H), 3.76 (s, 3H). [M+H]+: 421.4. 119 4‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2-fluoro‑5-meth- oxybenzyl)oxy)pyrimid ine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.31 (s, 1H), 9.28 (d, J = 2.1 Hz, 1H), 9.04 (d, J = 5.3 Hz, 1H), 8.88 (dd, J = 2.4, 8.8 Hz, 1H), 8.32 (d, J = 5.4 Hz, 1H), 7.83 (t, J = 72.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.13 - 7.19 (m, 2H), 6.96 (td, J = 3.7, 8.8 Hz, 1H), 5.03 (s, 2H), 3.75 (s, 3H). [M+H]+: 421.0. 64 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 120 3-amino‑6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2- fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carbox- amide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.20 (s, 1H), 9.24 (d, J = 2.3 Hz, 1H), 8.88 (dd, J = 2.4, 8.7 Hz, 1H), 8.27 (dd, J = 0.8, 8.0 Hz, 1H), 8.11 (t, J = 7.8 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.97 - 7.61 (m, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.96 (td, J = 3.7, 8.9 Hz, 1H), 5.03 (s, 2H), 3.75 (s, 3H). [M+H]+: 437.4. 121 3-amino‑6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2- fluoro‑5-methoxybenzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.09 (s, 1H), 9.07 (d, J = 2.1 Hz, 1H), 8.92 (s, 1H), 8.76 - 8.67 (m, 1H), 7.98 - 7.54 (m, 3H), 7.21 - 7.09 (m, 3H), 7.01 - 6.91 (m, 1H), 5.00 (s, 2H), 3.84 - 3.65 (m, 3H). [M+H]+: 436.4. 122 5-amino‑6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2- fluoro‑5-methoxybenzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 11.61 (s, 1 H), 8.67 (d, J = 2.00 Hz, 1 H), 8.48 (s, 1 H), 8.32 (dd, J = 8.51, 2.50 Hz, 1 H), 7.80 (t, J = 72.73 Hz, 1 H), 7.03 - 7.24 (m, 5 H), 3.74 (s, 3 H), 6.94 (dt, J = 8.82, 3.72 Hz, 1 H), 4.95 (s, 2 H). [M+H]+: 436.0. 123 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑3-fluoro-N‑((2- fluoro‑5-methoxybenzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.26 (br s, 1H), 9.22 - 9.12 (m, 2H), 8.77 (dd, J = 2.4, 8.6 Hz, 1H), 7.82 (t, J = 72.5 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.22 - 7.09 (m, 2H), 6.98 (td, J = 3.6, 8.9 Hz, 1H), 5.02 (s, 2H), 3.75 (s, 3H). [M+H]+: 439.3. 124 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑5-fluoro-N‑((2- fluoro‑5-methoxybenzyl)oxy)pyrazin e‑2-carboxamide 1H-NMR, 400 MHz, Methanol-d4 δ = 9.01 (s, 1H), 8.83 (d, J = 1.6 Hz, 1H), 8.68 - 8.63 (m, 1H), 7.67 (t, J = 72.6 Hz, 1H), 7.19 - 7.13 (m, 2H), 7.07 - 7.00 (m, 1H), 6.92 (td, J = 3.6, 9.0 Hz, 1H), 5.09 (s, 2H), 3.79 (s, 3H). [M+H]+: 439.4. 125 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑5-hydroxypyrazine‑2-car- boxamide 65 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 126 2‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2-fluoro‑5-meth- oxybenzyl)oxy)‑6-hydroxypyrimidine‑4-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 13.34 - 12.96 (m, 1H), 12.22 (br s, 1H), 9.25 (br s, 1H), 8.88 (dd, J = 1.9, 8.7 Hz, 1H), 7.82 (t, J = 72.4 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.23 - 7.08 (m, 2H), 7.01 - 6.80 (m, 2H), 5.00 (s, 2H), 3.75 (s, 3H). [M+H]+: 437.1. 127 4‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2-fluoro‑5-meth- oxybenzyl)oxy)‑6-hydroxypyrimidine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 3.75 (s, 3 H) 5.00 (s, 2 H) 6.85 (s, 1 H) 6.97 (dt, J = 8.88, 3.63 Hz, 1 H) 7.10 - 7.20 (m, 2 H) 7.27 (d, J = 8.76 Hz, 1 H) 7.82 (t, J = 72.35 Hz, 1 H) 8.88 (dd, J = 8.75, 2.38 Hz, 1 H) 9.25 (d, J = 2.00 Hz, 1 H) 12.13 - 12.30 (m, 1 H) 12.77 - 13.43 (m, 1 H). [M+H]+: 437.1. 128 (R*)‑N‑(1‑(3,5-dimethoxyphenyl)ethoxy)‑6‑(4-ethoxyphe- nyl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 11.94 (s, 1H), 9.39 (s, 1H), 8.95 (s, 1H), 8.31 (d, J = 8.80 Hz, 2H), 7.09 to 7.06 (m, 2H), 6.67 (d, J = 2.00 Hz, 2H), 6.43 (s, 1H), 5.14 (q, J = 6.40 Hz, 1H), 4.14 (q, J = 7.20 Hz, 2H), 3.75 (s, 6H), 1.51 (s, 3H), 1.35 (s, 3H). [M+H]+: 424.0. 129 (S*)‑N‑(1‑(3,5-dimethoxyphenyl)ethoxy)‑6‑(4-ethoxyphe- nyl)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 11.93 (s, 1H), 9.39 (s, 1H), 8.95 (s, 1H), 8.31 (d, J = 8.80 Hz, 2H), 7.09 to 7.06 (m, 2H), 6.67 (d, J = 2.00 Hz, 2H), 6.43 (s, 1H), 5.14 (q, J = 6.40 Hz, 1H), 4.14 (q, J = 7.20 Hz, 2H), 3.75 (s, 6H), 1.51 (s, 3H), 1.35 (s, 3H). [M+H]+: 424.0. 130 N‑((3,5-dimethoxyphenyl)methoxy-d2)‑6‑(4-ethoxyphenyl) pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 9.41 (s, 1H), 8.98 (s, 1H), 8.35 (d, J = 9.20 Hz, 2H), 7.09 (d, J = 8.80 Hz, 2H), 6.68 (s, 2H), 6.49 (s, 1H), 4.14 (q, J = 6.80 Hz, 2H), 3.76 (s, 6H), 1.38 (t, J = 7.20 Hz, 3H). [M+H]+: 412.0. 131 (R)*‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide 132 (S*)‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide 66 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 133 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxyphenyl)methoxy‑d2)pyrazine‑2-carboxamide 134 (R*)‑6‑(4-ethoxyphenyl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide 135 (S*)‑6‑(4-ethoxyphenyl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide 136 6‑(4-ethoxyphenyl)‑N‑((3-methoxyphenyl)methoxy‑d2)pyrazine‑2-carboxamide 137 (R*)‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide 138 (S*)‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide 139 6‑(4-ethoxyphenyl)‑N‑((2-fluorophenyl)methoxy‑d2)pyrazine‑2-carboxamide 140 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)-N-((3-methoxyphenyl) methoxy-d2)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.38 (s, 1H), 9.57 (s, 1H), 9.30 (d, J = 2.3 Hz, 1H), 9.12 (s, 1H), 8.94 (dd, J = 2.4, 8.7 Hz, 1H), 7.83 (t, J = 72.5 Hz, 1H), 7.37 - 7.26 (m, 2H), 7.13 - 7.01 (m, 2H), 6.94 (dd, J = 2.3, 8.1 Hz, 1H), 3.77 (s, 3H). [M+H]+: 405.1. 141 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)-N-((2-fluorophenyl) methoxy-d2)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.40 (br s, 1H), 9.56 (s, 1H), 9.30 (d, J = 2.1 Hz, 1H), 9.11 (s, 1H), 8.93 (dd, J = 2.4, 8.6 Hz, 1H), 7.82 (t, J = 72.5 Hz, 1H), 7.59 (dt, J = 1.6, 7.5 Hz, 1H), 7.45 (ddt, J = 1.8, 5.7, 7.7 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.29 - 7.20 (m, 2H). [M+H]+: 393.1. 67 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 142 (R*)‑6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑(1‑(3-methox- yphenyl)ethoxy)pyra zine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.14 - 11.99 (m, 1H) , 9.53 (s, 1H), 9.27 (d, J = 2.3 Hz, 1H), 9.08 (s, 1H), 8.89 (dd, J = 2.4, 8.7 Hz, 1H), 7.82 (t, J = 72.5 Hz, 1H), 7.33 - 7.23 (m, 2H), 7.12 - 7.02 (m, 2H), 6.93 - 6.82 (m, 1H), 5.17 (q, J = 6.4 Hz, 1H), 3.76 (s, 3H), 1.53 (d, J = 6.5 Hz, 3H). [M+H]+: 417.4. 143 (S*)‑6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑(1‑(3-methoxy- phenyl)ethoxy)pyra zine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.06 (br s, 1H) , 9.52 (s, 1H) , 9.26 (d, J = 2.3 Hz, 1H) , 9.07 (s, 1H) , 8.88 (dd, J = 2.4, 8.6 Hz, 1H) , 7.81 (t, J = 72.5 Hz, 1H) , 7.33 - 7.21 (m, 2H) , 7.13 - 6.97 (m, 2H) , 6.87 (dd, J = 1.9, 8.2 Hz, 1H) , 5.16 (q, J = 6.5 Hz, 1H) , 3.76 (s, 3H) , 1.52 (d, J = 6.5 Hz, 3H). [M+H]+: 417.4. 144 (R*)‑6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑(1‑(2-fluoro- phenyl)ethoxy)pyraz ine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.14 (br s, 1H), 9.53 (s, 1H), 9.26 (d, J = 2.3 Hz, 1H), 9.07 (s, 1H), 8.88 (dd, J = 2.4, 8.6 Hz, 1H), 8.02 - 7.62 (m, 2H), 7.42 - 7.13 (m, 4H), 5.48 (q, J = 6.5 Hz, 1H), 1.56 (d, J = 6.5 Hz, 3H). [M+H]+: 405.1. 145 (S*)‑6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑(1‑(2-fluoro- phenyl)ethoxy)pyraz ine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.14 (s, 1H) , 9.52 (s, 1H) , 9.26 (d, J = 2.3 Hz, 1H) , 9.07 (s, 1H) , 8.88 (dd, J = 2.5, 8.6 Hz, 1H) , 8.03 - 7.60 (m, 2H) , 7.42 - 7.12 (m, 4H) , 5.49 (q, J = 6.5 Hz, 1H) , 1.57 (d, J = 6.6 Hz, 3H). [M+H]+: 405.1. 146 6‑(6‑(difluoromethoxy)pyridine ‑3-yl)‑N‑((2-fluor- o‑5‑(methoxy‑d3)phenyl)methoxy‑d2)pyrazine‑2-carboxa- mide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.37 (br s, 1H), 9.54 (s, 1H), 9.27 (d, J = 2.3 Hz, 1H), 9.09 (s, 1H), 8.90 (dd, J = 2.4, 8.7 Hz, 1H), 8.05 - 7.53 (m, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.19 - 7.07 (m, 2H), 6.95 (td, J = 3.8, 8.8 Hz, 1H). [M+H]+: 426.3. 68 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 147 (R*)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxy- phenyl)ethoxy)pyra zine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.09 (s, 1 H), 9.45 (s, 1 H), 9.16 (d, J = 2.13 Hz, 1 H), 9.00 (s, 1 H) 8.66 (dd, J = 8.76, 2.38 Hz, 1 H), 7.24 (dd, J = 5.75, 3.25 Hz, 1 H), 7.09 (t, J = 9.44 Hz, 1 H), 6.96 (d, J = 8.75 Hz, 1 H), 6.88 (dt, J = 8.88, 3.63 Hz, 1 H), 5.46 (q, J = 6.46 Hz, 1 H), 4.40 (q, J = 7.00 Hz, 2 H), 3.78 (s, 3 H), 1.54 (d, J = 6.50 Hz, 3 H), 1.36 (t, J = 7.00 Hz, 3 H) . [M+H]+: 412.15. 148 (S*)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxy- phenyl)ethoxy)pyra zine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 12.09 (s, 1 H), 9.45 (s, 1 H), 9.17 (d, J = 2.25 Hz, 1 H), 9.00 (s, 1 H), 8.66 (dd, J = 8.76, 2.50 Hz, 1 H), 7.24 (dd, J = 5.88, 3.13 Hz, 1 H), 7.09 (t, J = 9.38 Hz, 1 H), 6.97 (d, J = 8.76 Hz, 1 H), 6.88 (dt, J = 9.04, 3.61 Hz, 1 H), 5.46 (d, J = 6.50 Hz, 1 H), 4.40 (q, J = 7.05 Hz, 2 H), 3.78 (s, 3 H), 1.54 (d, J = 6.50 Hz, 3 H), 1.36 (t, J = 7.00 Hz, 3 H) . [M+H]+: 412.15. 149 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxyphenyl) methoxy‑d2)pyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 10.10 (s, 1 H), 9.27 (s, 1 H), 9.14 (s, 1 H), 8.76 (d, J = 2.25 Hz, 1 H), 8.15 (dd, J = 8.69, 2.56 Hz, 1 H), 7.03 - 7.08 (m, 1 H), 6.99 - 7.03 (m, 1 H), 6.84 - 6.91 (m, 2 H), 4.45 (q, J = 7.05 Hz, 2 H), 3.80 (s, 3 H), 1.44 (t, J = 7.07 Hz, 3 H). [M+H]+: 400.15. 150 (R*)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide 151 (S*)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide 152 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methoxyphenyl)methoxy‑d2)pyrazine‑2-carboxamide 153 (R*)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide 69 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Structure 1H-NMR / MS(m / z) [M+H]+ 154 (S*)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide 155 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluorophenyl)methoxy‑d2)pyrazine‑2-carboxamide (R*) (S*) = Relative stereochemistry. COMPOUNDS IN FORMULA IB EXAMPLE 2. 6‑(6-ETHOXYPYRIDINE‑3-IL)‑N‑((2-FLUORO‑5-METHOXYBENZYLOXY-N-METHYLPYRAZINE‑2- CARBOXAMIDE (156)

[0190]

[0191] In a flask containing 3.57 mmol of 6‑(6-ethoxypyridin‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑N-methylpyra- zine‑2-carboxamide, dissolved in 50 mL DMF, 4.28 mmol NaH (60% purity) at 0 °C were added. The mixture was heated to 20 °C for 2 hours, and then 9.86 mmol of iodomethane was added. Subsequently, the reaction mixture was kept in agitation at 20 °C for 2 hours. After total consumption of the starting reagent (monitored by CCF), the reaction mixture was diluted with a solution of NH4Cl. The product was filtered and washed with ethanol (10 mL). 440 mg (30% yield) of the product of interest were obtained. COMPOUNDS ‑156 - 159

[0192] TABLE 12. COMPOUNDS OBTAINED FROM THE CORRESPONDING REACTANTS FOLLOWING THE METHOD IN EXAMPLE 2. Compound No. Structure 1H-NMR / MS (m / z) [M+H]+ 156 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxy- benzyl)oxy)‑N-methylpyrazine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 9.33 (s, 1H), 8.93 (d, J = 1.8 Hz, 1H), 8.65 (br s, 1H), 8.37 (dd, J = 2.1, 8.7 Hz, 1H), 6.96 (br d, J = 8.7 Hz, 2H), 6.77 (br s, 1H), 6.67 - 6.46 (m, 1H), 4.99 (br s, 2H), 4.39 (q, J = 7.0 Hz, 2H), 3.55 (br s, 3H), 3.42 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H). [M+H]+: 413.1. 70 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound No. Structure 1H-NMR / MS (m / z) [M+H]+ 157 6‑(6-ethoxypyridine‑3-yl)‑N-((2-fluoro‑5-methoxy- pyridine‑3-yl)methoxy)‑N-methylpyrazine‑2-carbox- amide 1H-NMR, 400 MHz, DMSO-d6 δ = 9.33 (s, 1H), 8.91 (d, J = 1.3 Hz, 1H), 8.67 (br s, 1H), 8.36 (dd, J = 1.6, 8.7 Hz, 1H), 7.80 - 7.54 (m, 1H), 7.45 - 7.15 (m, 1H), 6.96 (d, J = 8.6 Hz, 1H), 5.01 (s, 2H), 4.40 (q, J = 7.0 Hz, 2H), 3.67 (br s, 3H), 3.43 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). [M+H]+: 414.1. 158 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5- methoxybenzyl)oxy)‑N-methylpyrazine‑2-carboxa- mide 1H-NMR, 400 MHz, DMSO-d6 δ = 9.40 (s, 1H), 9.00 (d, J = 2.1 Hz, 1H), 8.72 (br s, 1H), 8.57 (dd, J = 2.3, 8.6 Hz, 1H), 7.81 (t, J = 72.5 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.03 - 6.51 (m, 3H), 4.98 (br s, 2H), 3.55 (br s, 3H), 3.43 (s, 3H). [M+H]+: 435.1. 159 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5- methoxypyridine‑3-yl)methoxy)‑N-methylpyra- zine‑2-carboxamide 1H-NMR, 400 MHz, DMSO-d6 δ = 9.41 (s, 1H), 8.99 (d, J = 1.9 Hz, 1H), 8.75 (br s, 1H), 8.56 (dd, J = 2.0, 8.6 Hz, 1H), 8.04 - 7.76 (m, 1H), 7.63 (s, 1H), 7.28 (d, J = 8.6 Hz, 2H), 5.00 (br s, 2H), 3.67 (br s, 3H), 3.44 (s, 3H). [M+H]+: 436.1. EXAMPLE 3. TESTS IN VITRO:

[0193] Biological assays were performed on Chinese hamster ovary (CHO) cells that express human sodium channels Nav 1.8 or Nav 1.7 in a stable manner.

[0194] The experimental protocol voltage-clamp using the whole cell configuration was established on the automated ScreenPatch® 384P platform (SP384PE, Nanion Technologies, Livingston, NJ) and the results were recorded with a Nanion 384-well Patch Clamp chip (NPC) (Nanion Technologies, Livingston, NJ).

[0195] Formula I compounds were diluted in eight concentrations in the extracellular solution composed of saline saline solution, buffered with HEPES (mM): NaCl, 137; KCl, 4; CaCl2, 3,8; MgCl2, 1; HEPES, 10; Glucose, 10; pH 7.4. The extracellular solution is composed of (mM) CsCl, 50; CsF, 90; MgCl2, 5; EGTA, 5; HEPES, 10; pH 7.2. The duration of exposure of each compound with cells expressing Nav 1.7 or Nav 1.8 was at least five minutes and the assays were performed at room temperature.

[0196] The measurements of the sodium currents of Nav 1.8 and Nav 1.7 were obtained using the voltage protocol described below.

[0197] A holding voltage of ‑100 mV was established followed by an inactivation voltage step at ‑40 mV for 8 seconds, followed by a step of ‑100 mV for 20 ms, followed by a 20 ms step for 10 mV for Nav 1.8 or 0 mV for Nav 1.7 (TP1A) before returning to the holding voltage of ‑100 mV.

[0198] The protocol was repeated at a frequency of 0.05 Hz and the amplitude of the current was quantified throughout the recording of the TP1A phase. The variation in the amplitude of the peak current was evaluated according to the formula described below, after exposing the cells expressing the channels to each concentration of the different compounds: wherein ITP1A,basal and ITP1A,molecule represent the peaks of sodium current input into TP1A before exposure to the compound and in the presence of the compound, respectively.

[0199] The decrease in the amplitude of the peak current, after the exposure of the cells to the compounds, was used to calculate the percentage of relative blockage of the channels in relation to the positive control according to the formula below: 71 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 wherein %Vand %CP represent the means of the values of current inhibition with a vehicle (DMSO) and positive controls, respectively. The sodium currents of the positive control were considered as 100%. wherein [Test] represents the concentration of the molecule evaluated, IC50 is the concentration of the compound that generates half of the maximum inhibition, N is the Hill coefficient, and % Blockage’ is the percentage of sodium channel current (Nav 1.8 and Nav 1.7) blocked at each concentration of the molecule evaluated. Data were obtained by nonlinear regression (nonlinear least squares) with XLfit for Excel (Microsoft, Redmond, WA).

[0200] The compounds were tested in at least one assay to obtain the value of CI50. For compounds that were tested in two or more assays, the results are described as the mean of the CI50 values.

[0201] Table 5 shows the efficacy in vitro of selected compounds against Nav1.8 and Nav1.7. CI50 values less than 500 nM are represented with the legend (+++); CI50 values between 500 nM and 1000 nM are represented with the legend (++), CI50 values greater than 1000 nM are demonstrated with the symbology (+). TABLE 13. CI50 VALUES OF THE COMPOUNDS OF THIS INVENTION IN NAV 1.8 AND NAV 1.7 CHANNELS. Compound Nº Nav1.8 IC50 (nM) Nav1.7 IC50 (nM) 1 + + 2 +++ + 3 +++ +++ 4 +++ ++ 5 +++ + 6 + + 7 + + 8 + + 9 +++ + 10 +++ + 11 +++ ++ 12 +++ + 13 +++ + 14 +++ + 15 +++ +++ 16 + + 17 +++ + 18 +++ ++ 19 + + 20 + + 21 + + 22 + + 23 + + 24 + + 25 ++ + 26 +++ ++ 27 +++ + 72 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Nav1.8 IC50 (nM) Nav1.7 IC50 (nM) 28 +++ + 29 + + 30 +++ + 31 ++ + 32 ++ + 33 +++ + 34 + + 35 +++ + 36 +++ + 37 +++ + 38 +++ + 39 +++ + 40 +++ + 41 +++ + 42 +++ + 43 + + 44 + + 45 + + 46 + + 47 + + 48 + + 49 + + 50 + + 51 + + 52 + + 53 + + 54 + + 55 +++ ++ 56 +++ ++ 57 + + 58 + + 59 + + 60 +++ ++ 61 +++ + 62 + + 63 + + 64 + + 65 + + 66 + + 73 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Nav1.8 IC50 (nM) Nav1.7 IC50 (nM) 67 +++ + 68 + + 69 + + 70 +++ ++ 71 +++ +++ 72 +++ +++ 73 +++ + 74 +++ + 75 +++ +++ 76 +++ ++ 77 + + 78 + + 79 + + 80 ++ + 81 + + 82 + + 83 + + 84 +++ + 85 + + 86 +++ + 87 +++ + 88 + + 89 +++ + 90 ++ + 91 + + 92 +++ + 93 + + 94 + + 95 ++ + 96 +++ +++ 97 +++ + 98 + + 99 +++ + 100 +++ + 101 + + 102 +++ + 103 ++ + 104 +++ + 105 ++ + 74 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (continued) Compound Nº Nav1.8 IC50 (nM) Nav1.7 IC50 (nM) 106 + + 107 + + 108 + + 109 +++ + 110 +++ ++ 111 + + 112 +++ + 113 +++ + 114 ++ + 115 + + 116 +++ + 117 + + 118 +++ + 119 +++ + 120 + + 121 +++ + 122 + + 123 + + 124 + + 125 + +

[0202] From these results, the blocking activity of Nav 1.7 and / or 1.8 is proven, whose application is readily performed by those versed in the technique in pharmaceutical compositions, which may comprise one or more of the aforementioned Formula I compounds, kits, in addition to uses in the treatment of pain-related pathologies.

[0203] In particular, these results indicate the possibility of using Formula (I) compounds in the preparation of drugs for the treatment of conditions such as peripheral neuropathic pain, chemotherapy-induced neuropathy, complex regional pain, neuropathy related to viral infection, neuropathy secondary to tumor infiltration, diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, and postsurgical neuralgia.

[0204] It should be understood that the embodiments described above are merely illustrative and that several modifications can be made by a person skilled in the art without departing from the scope of this invention. Consequently, the present invention should not be regarded as limited to the illustrative specifications described in this application. Claims 1. COMPOUND, characterized by being of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, ester and isomer thereof, wherein: 75 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 - X1, X2, X3, and X4 are independently selected from the group consisting of carbon, CH, COH, or nitrogen wherein - when at least one of the substituents X2, X4 is nitrogen or CH, the corresponding R (R2, R3) is null, - R1 is: wherein - X5, X6, X7, X8, and X9 are independently selected from the group consisting of carbon, CH, or nitrogen, wherein - when at least one of the substituents X5‑X9 is nitrogen or CH, the corresponding R (R8‑R12) is null, - R8, R9, R10, R11, and R12 are independently selected from the group consisting of hydrogen, halogen, linear or branched C1‑C6 alkyl, linear or branched C1‑C6 alkoxy, haloalkoxy C1‑C6 linear or branched, hydroxy, azetidinyloxy, azetidinylalkoxy C1‑C3, alkylazetidinyloxy C1‑C6, alkylazetidinylalkoxy C1‑C6, alkylsulfinyl C1‑C6, alkoxy C1‑C2 containing but not limited to one or more isotopically enriched atoms such as hydrogen isotope 2H; - R2 and R3 are independently selected from the group consisting of hydrogen, halogen, amine, hydroxy, C1‑C6 alkoxy linear or branched, alkyl C1‑C6 linear or branched; - R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, haloalkyl C1‑C6 linear or branched, alkyl C1‑C6 linear or branched; - R6 is selected from the group consisting of aryl, pyridinyl, or substituted pyridinyl, or R13, or R14, wherein - R13 is: wherein: - X10, X11, X12, X13 and X14 are independently selected from the group consisting of carbon, CH or nitrogen; - when at least one of the substituents X10‑X14 is nitrogen or CH, the corresponding R (R13‑R19) is null, - R13 R16, R17, R18, and R19 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl linear or branched C1‑C4, cycloalkyl C3‑C7, C1‑C6 alkoxy linear or branched, cycloalkoxy C3‑C6, hydroxyalkyl C1-C6 linear or branched, aminoalkyl C1‑C6 linear or branched, alkoxy C1‑C2 containing one or more isotopically enriched atoms, such as hydrogen isotope 2H, but not limited to the same; - R14 is selected from the group consisting of: 76 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 wherein R20 is independently selected from the group consisting of hydrogen, halogen, hydroxy, hydroxyalkyl C1-C6 linear or branched, alkyl C1‑C6 linear or branched, alkoxy C1‑C6 linear or branched, cycloalkoxy C3‑C7 saturated or unsaturated, haloalkoxy C1‑C6 linear or branched, nitrile, carboxyl, carboxyalkyl ester C1‑C6, amine,N-alkylamine,N,N-dialkylamine, aminoalkyl C1-C6 linear or branched, sulfonamide, alkylsulfonylamide C1‑C6, N,,N-dialkylsulfonylamide C1‑C6, sulfonyl, alkylsulfonyl C1‑C6, sulfinyl, alkylsulfinyl C1‑C6, azetidiniloxy, azetidinylalkoxy C1‑C6, linear or branched alkoxy C1‑C6, hydroxyazetidinyl; - R7, is independently selected from the group consisting of hydrogen and alkyl C1‑C6 linear or branched. 2. COMPOUND in accordance with claim 1, characterized by be selected from the group consisting of: N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4-hydroxyphenyl)pyrazine‑2-carboxamide (Compound 1); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4-methoxyphenyl)pyrazine‑2-carboxamide (Compound 2); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4-isopropoxyphenyl)pyrazine‑2-carboxamide (Compound 3); 6‑(4-ethoxyphenyl)‑N‑((2-fluorobenzyl)oxy)pyrazine‑2-carboxamide (Compound 4); 6‑(4-ethoxyphenyl)‑N‑((3-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 5); 6‑(4-ethoxyphenyl)‑N‑((2-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 6); 6‑(4-ethoxyphenyl)‑N‑((3-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 7); 6‑(4-ethoxyphenyl)‑N‑((5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 8); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 9); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-isopropoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 10); N‑((2-chloro‑5-methoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 11); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 12); 6‑(4-ethoxyphenyl)‑N‑((5-fluoro‑2-methoxypyridine‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 13); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 14); N‑((2-cyclopropyl‑5-methoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 15); 6‑ (4-ethoxyphenyl)‑N‑((2-hydroxy‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 16); N‑((5‑(1-aminoethyl)‑2-fluorobenzyl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 17); 6‑(4-ethoxyphenyl)‑N‑((5-methoxy‑2-methylpyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 18); 6‑(4-ethoxyphenyl)‑N‑((5-methoxy‑2-methylbenzyl)oxy)pyrazine‑2-carboxamide (Compound 19); N‑((3,5-dimethoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 20); N‑((3,5-dimethylbenzyl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 21); 6‑(4‑(azetidine‑3-yloxy)phenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 22); 6‑(4‑(azetidine‑3-ylmethoxy)phenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 23); 6‑(4‑(2‑(azetidine‑3-yl)ethoxy)phenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 24); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑((1-methylazetidine‑3-yl)oxy)phenyl)pyrazine‑2-carboxamide (Com- pound 25); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑((1-methylazetidine‑3-yl)methoxy)phenyl)pyrazine‑2-carboxamide (Compound 26); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑(2‑(1-methylazetidine‑3-yl)ethoxy)phenyl)pyrazine‑2-carboxamide (Compound 27); 6‑(4‑(difluoromethoxy)phenyl)‑N‑((5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 28); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(4‑(methylsulfinyl)phenyl)pyrazine‑2-carboxamide (Compound 29); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6-methoxypyridine‑3-yl)pyrazine‑2-carboxamide (Compound 30); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6-isopropoxypyridine‑3-yl)pyrazine‑2-carboxamide (Compound 31); 77 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluorobenzyl)oxy)pyrazine‑2-carboxamide (Compound 32); 6‑(6-ethoxypyridine‑3-yl)‑N-((3-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 33); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 34); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 35); 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 36); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 37); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 38); 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-fluoro‑2-methoxypyridine‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 39); N‑((5‑(dimethylamino)‑2-fluorobenzyl)oxy)‑6‑(6-ethoxypyridine‑3-yl)pyrazine‑2-carboxamide (Compound 40); N‑((5‑(dimethylamino)‑2-fluoropyridine‑3-yl)methoxy)‑6‑(6-ethoxypyridine‑3-yl)pyrazine‑2-carboxamide (Com- pound 41); N‑((5‑(dimethylamino)‑2-fluoropyridine‑3-yl)methoxy)‑6‑(6-ethoxypyridine‑3-yl)pyrazine‑2-carboxamide (Com- pound 42); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-hydroxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 43); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-hydroxy‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 44); N‑((5‑(1-aminoethyl)‑2-fluorobenzyl)oxy)‑6‑(6-ethoxypyridine‑3-yl)pyrazine‑2-carboxamide (Compound 45); 6‑(6-ethoxypyridin‑3-yl)‑N‑((5-methoxy‑2-methylpyridine‑3-yl)methoxy)pyrazine‑2-carboxamide (Compound 46); 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methoxy‑2-methylbenzyl)oxy)pyrazine‑2-carboxamide (Compound 47); 6‑(6‑(ethoxy-d5)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 48); 6‑(6‑(ethoxy‑2,2,2-d3)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 49); 6‑(6‑(ethoxy‑1,1-d2)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound50); 6‑(6‑(ethoxy‑1,1-d2)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound51); 6‑(6‑(ethoxy‑2,2,2-d3)pyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)benzyl)oxy)pyrazine‑2-carboxamide (Com- pound 52); 6‑(6‑(ethoxy-d5)pyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)benzyl)oxy)pyrazine‑2-carboxamide (Compound 53); 6‑(6‑(ethoxy-d5)pyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)phenyl)methoxy-d2)pyrazine‑2-carboxamide (Com- pound 54); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)benzyl)oxy)pyrazine‑2-carboxamide (Compound 55); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)benzyl)oxy)pyrazine‑2-carboxamide (Compound 56); 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methyloxazole‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 57); 6‑(6-ethoxypyridine‑3-yl)‑N‑((5-methyloxazole‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 58); 6‑(6-ethoxypyridine‑3-yl)‑N‑((4-methyl‑1H-imidazole‑5-yl)methoxy)pyrazine‑2-carboxamide (Compound 59); 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-methyl‑1H-pyrrole‑2-yl)methoxy)pyrazine‑2-carboxamide (Compound 60); 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-ethyl‑1H-imidazole‑2-yl)methoxy)pyrazine‑2-carboxamide (Compound 61); 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-ethyl‑1H-pyrazole‑5-yl)methoxy)pyrazine‑2-carboxamide (Compound 62); 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-ethyl‑1H-pyrazole‑5-yl)methoxy)pyrazine‑2-carboxamide (Compound 63); 6‑(6-ethoxypyridine‑3-yl)‑N‑((1-ethyl‑1H-pyrazole‑5-yl)methoxy)pyrazine‑2-carboxamide (Compound 64); 6‑(6-ethoxypyridine‑3-yl)‑N‑((4-methyloxazole‑5-yl)methoxy)pyrazine‑2-carboxamide (Compound 65); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methoxyfuran‑2-yl)methoxy)pyrazine‑2-carboxamide (Compound 66); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methyl‑1H-pyrrole‑2-yl)methoxy)pyrazine‑2-carboxamide (Compound 67); 6‑(6-ethoxypyridine‑3-yl)-N‑((3-methyl‑1H-pyrrole‑2-yl)methoxy)pyrazine‑2-carboxamide (Compound 68); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methyl‑1H-pyrazole‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 69); N‑((2-fluorobenzyl)oxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 70); N‑((3-methoxybenzyl)oxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 71); N‑(pyridine‑2-ylmethoxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 72); N‑(pyridine‑3-ylmethoxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 73); N‑(pyridine‑4-ylmethoxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 74); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6‑(trifluoromethoxy)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 75); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 76); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 77); 78 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((5-fluoro‑2-methoxypyridine‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 78); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((5-fluoro‑2-methoxypyridin‑4-yl)methoxy)pyrazine‑2-carboxamide (Compound 79); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((5‑(dimethylamino)‑2-fluorobenzyl)oxy)pyrazine‑2-carboxamide (Com- pound 80); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((3‑(1-hydroxyethyl)benzyl)oxy)pyrazine‑2-carboxamide (Compound 81); 6‑(6‑(difluoromethoxy)pyridin‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)benzyl)oxy)pyrazine‑2-carboxamide (Com- pound 82); N‑((2-fluoro‑5-methoxybenzyl)oxy)‑6‑(6‑(methylsulfinyl)pyridine‑3-yl)pyrazine‑2-carboxamide (Compound 83); 6‑(4-ethoxy‑2-hydroxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 84); 6‑(4-ethoxy‑3-hydroxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 85); 6‑(6-ethoxy‑4-hydroxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 86); 6‑(6-ethoxy‑2-oxo‑1,2-dihydropyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 87); N‑((3,5-dimethoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)‑5-hydroxypyrazine‑2-carboxamide (Compound 88); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑5-hydroxypyrazine‑2-carboxamide (Compound 89); N‑((3,5-dimethoxybenzyl)oxy)‑6‑(4-ethoxyphenyl)‑3-hydroxypyrazine‑2-carboxamide (Compound 90); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑3-hydroxypyrazine‑2-carboxamide (Compound 91); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑5-hydroxypyrazine‑2-carboxamide (Compound 92); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑3-hydroxypyrazine‑2-carboxamide (Compound 93); 5-amino‑6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 94); 3-amino‑6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 95); 6‑(6-ethoxypyridine‑3-yl)‑5-fluoro-N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 96); 6‑(6-ethoxypyridine‑3-yl)‑3-fluoro-N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 97); 6’-ethoxy-N‑((2-fluoro‑5-methoxybenzyl)oxy)‑[2,3’-bipyridine]‑6-carboxamide (Compound 98); 6’-ethoxy-N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑[2,3’-bipyridine]‑6-carboxamide (Compound 99); 6’-ethoxy-N‑((2-fluoro‑5-methoxybenzyl)oxy)‑[3,3’-bipyridine]‑5-carboxamide (Compound 100); 2‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrimidine‑4-carboxamide (Compound 101); 2‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrimidine‑4-carboxamide (Compound 102); 4‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrimidine‑2-carboxamide (Compound 103); 4‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrimidine‑2-carboxamide (Compound 104); 4‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrimidine‑2-carboxamide (Compound 105); 6’‑(difluoromethoxy)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑[2,3’-bipyridine]‑6-carboxamide (Com- pound 106); 6’‑(difluoromethoxy)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑[2,3’-bipyridine]‑6-carboxamide (Com- pound 107); 6’‑(difluoromethoxy)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑[2,3’-bipyridine]‑6-carboxamide (Com- pound 108); 6’‑(difluoromethoxy)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑[3,3’-bipyridine]‑5-carboxamide (Compound 109); 2‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrimidine‑4-carboxamide (Compound 110); 2‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrimidine‑4-carboxamide (Compound 111); 2‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrimidine‑4-carboxamide (Compound 112); 3-amino‑6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-car- boxamide (Compound 113); 3-amino‑6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)pyrazine‑2-car- boxamide (Compound 114); 5-amino‑6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide 79 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (Compound 115); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑3-fluoro-N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 116); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑5-fluoro-N‑((2-fluoro‑5-methoxybenzyl)oxy)pyrazine‑2-carboxamide (Compound 117); 3‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑1,2,4-triazine‑5-carboxamide (Com- pound 118); 5‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑1,2,4-triazine‑3-carboxamide (Com- pound 119); N‑((2‑(3,5-dimethoxyphenyl)propan‑2-yl)oxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 120); N‑(1‑(3,5-dimethoxyphenyl)cyclopropoxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 121); (R)‑N‑(1‑(3,5-dimethoxyphenyl)ethoxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 122); (S)‑N‑(1‑(3,5-dimethoxyphenyl)ethoxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 123); (S)‑N‑(1‑(3,5-dimethoxyphenyl)ethoxy)‑6‑(4-ethoxyphenyl)pyrazine‑2-carboxamide (Compound 124); (R)‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 125); (S)‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 126); 6‑(4-ethoxyphenyl)‑N‑((2-fluoro‑5-methoxyphenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 127); (R)‑6‑(4-ethoxyphenyl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 128); (S)‑6‑(4-ethoxyphenyl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 129); 6‑(4-ethoxyphenyl)‑N‑((3-methoxyphenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 130); (R)‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 131); (S)‑6‑(4-ethoxyphenyl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 132); 6‑(4-ethoxyphenyl)‑N‑((2-fluorophenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 133); 6‑(6‑(difluoromethoxy)pyridin‑3-yl)‑N‑((2-fluoro‑5‑(methoxy-d3)phenyl)methoxy-d2)pyrazine‑2-carboxamide (compound 134); (R)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 135); (S)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 136); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2‑(2-fluoro‑5-methoxyphenyl)propan‑2-yl)oxy)pyrazine‑2-carboxamide (Com- pound 137); 6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)cyclopropoxy)pyrazine‑2-carboxamide (Compound 138); 6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)cyclopropoxy)pyrazine‑2-carboxamide (Compound 139); (R)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 140); (S)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(3-methoxyphenyl)ethoxy)pyrazine‑2-carboxamide (Compound 141); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methoxyphenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 142); (R)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 143); (S)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 144); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluorophenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 145); (R)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy‑2,2,2-d3)pyrazine‑2-carboxamide (Com- pound 146); (S)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluoro‑5-methoxyphenyl)ethoxy‑2,2,2-d3)pyrazine‑2-carboxamide (Com- pound 147); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑N-methylpyrazine‑2-carboxamide (Compound 148); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑N-methylpyrazine‑2-carboxamide (Compound 149); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑N-methylpyrazine‑2-carboxamide (Compound 150); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑N-methylpyrazine‑2-car- boxamide (Compound 151); 6‑(6-ethoxypyridine‑3-yl)‑N‑((3-methoxyphenyl)methoxy‑d2)pyrazine‑2-carboxamide (Compound 152); (R*)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 153); (S*)‑6‑(6-ethoxypyridine‑3-yl)‑N‑(1‑(2-fluorophenyl)ethoxy)pyrazine‑2-carboxamide (Compound 154); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluorophenyl)methoxy-d2)pyrazine‑2-carboxamide (Compound 155); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑N-methylpyrazine‑2-carboxamide (Compound 80 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 156); 6‑(6-ethoxypyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridin‑3-yl)methoxy)‑N-methylpyrazine‑2-carboxamide (Compound 157); 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxybenzyl)oxy)‑N-methylpyrazine‑2-carboxamide (Compound 158); and 6‑(6‑(difluoromethoxy)pyridine‑3-yl)‑N‑((2-fluoro‑5-methoxypyridine‑3-yl)methoxy)‑N-methylpyrazine‑2-car- boxamide (Compound 159). 3. COMPOUND, according to claim 1 or 2, characterized by being a blocker of voltage-gated sodium channels Nav 1.7 and / or Nav 1.8. 4. PHARMACEUTICAL COMPOSITION, characterized by comprising a therapeutically effective amount of one or more compounds of Formula (I) or of a pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof, as defined in any of claims 1 to 3, and one or more pharmaceutically acceptable excipients. 5. PHARMACEUTICAL COMPOSITION, according to claim 4, characterized by being formulated as an oral, sub- lingual, nasal, parenteral, injectable, submuscular, topical, transdermal, ocular, or rectal composition. 6. USE OF FORMULA (I) COMPOUND(S), as defined in any of claims 1 to 3, characterized by being to prepare a drug to treat pathologies related to neuropathic pain. 7. USE, according to claim 6, characterized by said pathologies being selected from the group consisting of peripheral neuropathic pain, chemotherapy-induced neuropathy, complex regional pain, neuropathy related to viral infection, neuropathy secondary to tumor infiltration, diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, and postsurgical neuralgia. 8. METHOD OF TREATMENT, PREVENTION, RELIEF, SUPPRESSION AND / OR CONTROL of pathologies related to neuropathic pain characterized by the administration of an effective amount of at least one compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate and isomer thereof, as defined in any of claims 1 to 3. 9. METHOD, according to claim 8, characterized by being for the treatment or prophylaxis of peripheral neuropathic pain, chemotherapy-induced neuropathy, complex regional pain, neuropathy related to viral infection, neuropathy secondary to tumor infiltration, diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, and postsurgical neuralgia. 10. METHOD, according to claim 8 or 9, characterized by administration of at least one compound of Formula (I) being selected from the group comprising oral, sublingual, nasal, parenteral, injectable, submuscular, topical, transdermal, ocular, and rectal routes. 11. PROCESS OF OBTAINING GENERAL FORMULA COMPOUND (I), as defined in any of the claims 1 to 3, characterized by comprising the steps: (a) formation of the Formula III intermediate: from the hydrolysis reaction of a Formula IV intermediate: 81 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 (b) obtaining Formula I compound; from the reaction with the Formula II intermediates: and Formula III, with or without the presence of a catalyst and a suitable solvent; wherein, - X1, X2, X3, and X4 are independently selected from the group consisting of carbon, CH, COH, or nitrogen; wherein: - when at least one of the substituents X2, X4 is nitrogen or CH, the corresponding R (R2, R3) is null, - R1 is: wherein: - X5, X6, X7, X8, and X9 are independently selected from the group consisting of carbon, CH, or nitrogen; wherein: - when at least one of the substituents X5‑X9 is nitrogen or CH, the corresponding R (R8‑R12) is null; and - R8, R9, R10, R11, and R12 are independently selected from the group consisting of hydrogen, halogen, C1‑C6 linear or branched alkyl, C1‑C6 linear or branched alkoxy, hydroxy, haloalkoxy C1‑C6 linear or branched, azetidinyloxy, azetidinylalkoxy C1‑C6, alkylazetidinyloxy C1‑C6, alkylsulfinyl, alkoxy C1‑C2 containing one or more isotopically enriched atoms, such as hydro- gen isotopes 2H, but not limited to the same; - R2 and R3 are independently selected from the group consisting of hydrogen, halogen, amine, hydroxy, C1‑C6 alkoxy, and C1‑C4 alkyl - R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, haloalkyl C1‑C6 linear or branched, alkyl C1‑C6 linear or branched; - R6 is selected from the group consisting of aryl, pyridinyl, or substituted pyridinyl, or R13 or R14: - R13 is: 82 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 wherein: - X10, X11, X12, X13, and X14 are independently selected from the group consisting of carbon, CH, or nitrogen; wherein: - when at least one of the substituents X10‑X14 is N or CH, the corresponding R (R15‑R19) is null; and - R15, R16, R17, R18, and R19 are independently selected from the group consisting of hydrogen, halogen, hydroxy, linear or branched C1‑C6 alkyl, cycloalkyl C3‑C7, alkoxy C1‑C6 linear or branched, C3‑C6 cycloalkoxy, hydroxyalkyl C1-C6 linear or branched, C1‑C6 aminoalkyl linear or branched, alkoxy C1‑C2 containing one or more isotopically enriched atoms, such as hydrogen isotope 2H, but not limited to the same; - R14 is selected from the group consisting of: wherein R20 is independently selected from the group consisting of hydrogen, halogen, hydroxy, hydroxyalkyl C1-C6 linear or branched, alkyl C1‑C6 linear or branched, alkoxy C1‑C6 linear or branched, cycloalkoxy C3‑C7 saturated or unsaturated, haloalkoxy C1‑C6 linear or branched, nitrile, carboxyl, carboxyalkyl ester C1‑C6, amine, N-alkylamine, N,N-dialkylamine, aminoalkyl C1-C6 linear or branched, sulfonamide, alkylsulfonylamide C1‑C6, N,N-dialkylsulfonylamide C1‑C6, sulfonyl, alkyl sulfonyl C1‑C6, sulfinyl, alkyl sulfinyl C1‑C6, azetidinyloxy, azetidinylalkoxy C1‑C3, linear or branched alkoxy C1‑C6, hydroxyzetidinyl; and - R7, is independently selected from the group consisting of hydrogen and alkyl C1‑C6 linear or branched. 12. PROCESS, according to claim 11, characterized by further comprising a compound formation step (c) of Formula (I) where R7 is linear or branched C1-C6 alkyl from the nucleophilic substitution reaction of a compound obtained in step (b), with linear or branched C1- C6 alkyl halides in the presence of inorganic base and polar aprotic solvents. 13. PROCESS, according to any of claims 11 to 12, characterized by in step (b) said catalyst being selected from concentrated hydrochloric acid, acetic acid, trifluoroacetic acid, formic acid, or combinations of these and said solvent being selected from dimethylformamide, dimethylsulfoxide, alcohols, or combinations thereof. 83 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 14. PROCESS, according to any of claims 12 to 13, characterized by in step (c) said inorganic base being selected from K2CO3 or NaH. 15. KIT, characterized by comprising a pharmaceutical composition as defined in claim 4 and an application device. 84 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 85 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 86 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 87 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 88 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 89 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 90 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 91 EP 4 660 184 A1 5 10 15 20 25 30 35 40 45 50 55 92 EP 4 660 184 A1 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • US 10550080 B

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[0010] 摘要 本发明涉及 Nav 1.7 和 / 或 Nav 1.8 阻断性羟肟酸酯。更具体地，本发明涉及包含式(I)的羟肟 酸酯，其中取代基 R1 至 R10 以及它们的衍生物 R11 至 R20 独立地选自说明书中所定义的基 团，以及它们的制备工艺、包含至少一种所述化合物的组合物、用途、用于治疗或预防疼痛 相关病理状态的治疗方法以及试剂盒。本发明属于药物化学、有机合成以及疼痛相关疾病治 疗领域。

Claims

1. COMPOUND, characterized by being of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, ester and isomer thereof, wherein: - X1, X2, X3, and X4 are independently selected from the group consisting of carbon, CH, COH, or nitrogen wherein - when at least one of the substituents X2, X4 is nitrogen or CH, the corresponding R (R2, R3) is null, - R1 is: wherein - X5, X6, X7, X8, and X9 are independently selected from the group consisting of carbon, CH, or nitrogen, wherein - when at least one of the substituents X5-X9 is nitrogen or CH, the corresponding R (R8-R12) is null, - R8, R9, R10, R11, and R12 are independently selected from the group consisting of hydrogen, halogen, linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy, haloalkoxy C1-C6 linear or branched, hydroxy, azetidinyloxy, azetidinylalkoxy C1-C3, alkylazetidinyloxy C1-C6, alkylazetidinylalkoxy C1-C6, alkylsulfinyl C1-C6, alkoxy C1-C2 containing but not limited to one or more isotopically enriched atoms such as hydrogen isotope 2H; - R2 and R3 are independently selected from the group consisting of hydrogen, halogen, amine, hydroxy, C1-C6 alkoxy linear or branched, alkyl C1-C6 linear or branched; - R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, haloalkyl C1-C6 linear or branched, alkyl C1-C6 linear or branched; - R6 is selected from the group consisting of aryl, pyridinyl, or substituted pyridinyl, or R13, or R14, wherein - R13 is: wherein: - X10, X11, X12, X13 and X14 are independently selected from the group consisting of carbon, CH or nitrogen; - when at least one of the substituents X10-X14 is nitrogen or CH, the corresponding R (R13-R19) is null, - R13 R16, R17, R18, and R19 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl linear or branched C1-C4, cycloalkyl C3-C7, C1-C6 alkoxy linear or branched, cycloalkoxy C3-C6, hydroxyalkyl C1-C6 linear or branched, aminoalkyl C1-C6 linear or branched, alkoxy C1-C2 containing one or more isotopically enriched atoms, such as hydrogen isotope 2H, but not limited to the same; - R14 is selected from the group consisting of: wherein R20 is independently selected from the group consisting of hydrogen, halogen, hydroxy, hydroxyalkyl C1-C6 linear or branched, alkyl C1-C6 linear or branched, alkoxy C1-C6 linear or branched, cycloalkoxy C3-C7 saturated or unsaturated, haloalkoxy C1-C6 linear or branched, nitrile, carboxyl, carboxyalkyl ester C1-C6, amine, N-alkylamine, N,N-dialkylamine, aminoalkyl C1-C6 linear or branched, sulfonamide, alkylsulfonylamide C1-C6, N,,N-dialkylsulfonylamide C1-C6, sulfonyl, alkylsulfonyl C1-C6, sulfinyl, alkylsulfinyl C1-C6, azetidiniloxy, azetidinylalkoxy C1-C6, linear or branched alkoxy C1-C6, hydroxyazetidinyl; - R7, is independently selected from the group consisting of hydrogen and alkyl C1-C6 linear or branched.

2. COMPOUND in accordance with claim 1, <b>characterized by be selected from the group consisting of: N-((2-fluoro-5-methoxybenzyl)oxy)-6-(4-hydroxyphenyl)pyrazine-2-carboxamide (Compound 1); N-((2-fluoro-5-methoxybenzyl)oxy)-6-(4-methoxyphenyl)pyrazine-2-carboxamide (Compound 2); N-((2-fluoro-5-methoxybenzyl)oxy)-6-(4-isopropoxyphenyl)pyrazine-2-carboxamide (Compound 3); 6-(4-ethoxyphenyl)-N-((2-fluorobenzyl)oxy)pyrazine-2-carboxamide (Compound 4); 6-(4-ethoxyphenyl)-N-((3-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 5); 6-(4-ethoxyphenyl)-N-((2-hydroxybenzyl)oxy)pyrazine-2-carboxamide (Compound 6); 6-(4-ethoxyphenyl)-N-((3-hydroxybenzyl)oxy)pyrazine-2-carboxamide (Compound 7); 6-(4-ethoxyphenyl)-N-((5-methoxypyridine-3-yl)methoxy)pyrazine-2-carboxamide (Compound 8); 6-(4-ethoxyphenyl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 9); 6-(4-ethoxyphenyl)-N-((2-fluoro-5-isopropoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 10); N-((2-chloro-5-methoxybenzyl)oxy)-6-(4-ethoxyphenyl)pyrazine-2-carboxamide (Compound 11); 6-(4-ethoxyphenyl)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)pyrazine-2-carboxamide (Compound 12); 6-(4-ethoxyphenyl)-N-((5-fluoro-2-methoxypyridine-4-yl)methoxy)pyrazine-2-carboxamide (Compound 13); 6-(4-ethoxyphenyl)-N-((2-fluoro-5-hydroxybenzyl)oxy)pyrazine-2-carboxamide (Compound 14); N-((2-cyclopropyl-5-methoxybenzyl)oxy)-6-(4-ethoxyphenyl)pyrazine-2-carboxamide (Compound 15); 6- (4-ethoxyphenyl)-N-((2-hydroxy-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 16); N-((5-(1-aminoethyl)-2-fluorobenzyl)oxy)-6-(4-ethoxyphenyl)pyrazine-2-carboxamide (Compound 17); 6-(4-ethoxyphenyl)-N-((5-methoxy-2-methylpyridine-3-yl)methoxy)pyrazine-2-carboxamide (Compound 18); 6-(4-ethoxyphenyl)-N-((5-methoxy-2-methylbenzyl)oxy)pyrazine-2-carboxamide (Compound 19); N-((3,5-dimethoxybenzyl)oxy)-6-(4-ethoxyphenyl)pyrazine-2-carboxamide (Compound 20); N-((3,5-dimethylbenzyl)oxy)-6-(4-ethoxyphenyl)pyrazine-2-carboxamide (Compound 21); 6-(4-(azetidine-3-yloxy)phenyl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 22); 6-(4-(azetidine-3-ylmethoxy)phenyl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 23); 6-(4-(2-(azetidine-3-yl)ethoxy)phenyl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 24); N-((2-fluoro-5-methoxybenzyl)oxy)-6-(4-((1-methylazetidine-3-yl)oxy)phenyl)pyrazine-2-carboxamide (Compound 25); N-((2-fluoro-5-methoxybenzyl)oxy)-6-(4-((1-methylazetidine-3-yl)methoxy)phenyl)pyrazine-2-carboxamide (Compound 26); N-((2-fluoro-5-methoxybenzyl)oxy)-6-(4-(2-(1-methylazetidine-3-yl)ethoxy)phenyl)pyrazine-2-carboxamide (Compound 27); 6-(4-(difluoromethoxy)phenyl)-N-((5-methoxypyridine-3-yl)methoxy)pyrazine-2-carboxamide (Compound 28); N-((2-fluoro-5-methoxybenzyl)oxy)-6-(4-(methylsulfinyl)phenyl)pyrazine-2-carboxamide (Compound 29); N-((2-fluoro-5-methoxybenzyl)oxy)-6-(6-methoxypyridine-3-yl)pyrazine-2-carboxamide (Compound 30); N-((2-fluoro-5-methoxybenzyl)oxy)-6-(6-isopropoxypyridine-3-yl)pyrazine-2-carboxamide (Compound 31); 6-(6-ethoxypyridine-3-yl)-N-((2-fluorobenzyl)oxy)pyrazine-2-carboxamide (Compound 32); 6-(6-ethoxypyridine-3-yl)-N-((3-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 33); 6-(6-ethoxypyridine-3-yl)-N-((2-hydroxybenzyl)oxy)pyrazine-2-carboxamide (Compound 34); 6-(6-ethoxypyridine-3-yl)-N-((3-hydroxybenzyl)oxy)pyrazine-2-carboxamide (Compound 35); 6-(6-ethoxypyridine-3-yl)-N-((5-methoxypyridine-3-yl)methoxy)pyrazine-2-carboxamide (Compound 36); 6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 37); 6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)pyrazine-2-carboxamide (Compound 38); 6-(6-ethoxypyridine-3-yl)-N-((5-fluoro-2-methoxypyridine-4-yl)methoxy)pyrazine-2-carboxamide (Compound 39); N-((5-(dimethylamino)-2-fluorobenzyl)oxy)-6-(6-ethoxypyridine-3-yl)pyrazine-2-carboxamide (Compound 40); N-((5-(dimethylamino)-2-fluoropyridine-3-yl)methoxy)-6-(6-ethoxypyridine-3-yl)pyrazine-2-carboxamide (Compound 41); N-((5-(dimethylamino)-2-fluoropyridine-3-yl)methoxy)-6-(6-ethoxypyridine-3-yl)pyrazine-2-carboxamide (Compound 42); 6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-hydroxybenzyl)oxy)pyrazine-2-carboxamide (Compound 43); 6-(6-ethoxypyridine-3-yl)-N-((2-hydroxy-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 44); N-((5-(1-aminoethyl)-2-fluorobenzyl)oxy)-6-(6-ethoxypyridine-3-yl)pyrazine-2-carboxamide (Compound 45); 6-(6-ethoxypyridin-3-yl)-N-((5-methoxy-2-methylpyridine-3-yl)methoxy)pyrazine-2-carboxamide (Compound 46); 6-(6-ethoxypyridine-3-yl)-N-((5-methoxy-2-methylbenzyl)oxy)pyrazine-2-carboxamide (Compound 47); 6-(6-(ethoxy-d5)pyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 48); 6-(6-(ethoxy-2,2,2-d3)pyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 49); 6-(6-(ethoxy-1,1-d2)pyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 50); 6-(6-(ethoxy-1,1-d2)pyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 51); 6-(6-(ethoxy-2,2,2-d3)pyridine-3-yl)-N-((2-fluoro-5-(methoxy-d3)benzyl)oxy)pyrazine-2-carboxamide (Compound 52); 6-(6-(ethoxy-d5)pyridine-3-yl)-N-((2-fluoro-5-(methoxy-d3)benzyl)oxy)pyrazine-2-carboxamide (Compound 53); 6-(6-(ethoxy-d5)pyridine-3-yl)-N-((2-fluoro-5-(methoxy-d3)phenyl)methoxy-d2)pyrazine-2-carboxamide (Compound 54); 6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-(methoxy-d3)benzyl)oxy)pyrazine-2-carboxamide (Compound 55); 6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-(methoxy-d3)benzyl)oxy)pyrazine-2-carboxamide (Compound 56); 6-(6-ethoxypyridine-3-yl)-N-((5-methyloxazole-4-yl)methoxy)pyrazine-2-carboxamide (Compound 57); 6-(6-ethoxypyridine-3-yl)-N-((5-methyloxazole-4-yl)methoxy)pyrazine-2-carboxamide (Compound 58); 6-(6-ethoxypyridine-3-yl)-N-((4-methyl-1H-imidazole-5-yl)methoxy)pyrazine-2-carboxamide (Compound 59); 6-(6-ethoxypyridine-3-yl)-N-((1-methyl-1H-pyrrole-2-yl)methoxy)pyrazine-2-carboxamide (Compound 60); 6-(6-ethoxypyridine-3-yl)-N-((1-ethyl-1H-imidazole-2-yl)methoxy)pyrazine-2-carboxamide (Compound 61); 6-(6-ethoxypyridine-3-yl)-N-((1-ethyl-1H-pyrazole-5-yl)methoxy)pyrazine-2-carboxamide (Compound 62); 6-(6-ethoxypyridine-3-yl)-N-((1-ethyl-1H-pyrazole-5-yl)methoxy)pyrazine-2-carboxamide (Compound 63); 6-(6-ethoxypyridine-3-yl)-N-((1-ethyl-1H-pyrazole-5-yl)methoxy)pyrazine-2-carboxamide (Compound 64); 6-(6-ethoxypyridine-3-yl)-N-((4-methyloxazole-5-yl)methoxy)pyrazine-2-carboxamide (Compound 65); 6-(6-ethoxypyridine-3-yl)-N-((3-methoxyfuran-2-yl)methoxy)pyrazine-2-carboxamide (Compound 66); 6-(6-ethoxypyridine-3-yl)-N-((3-methyl-1H-pyrrole-2-yl)methoxy)pyrazine-2-carboxamide (Compound 67); 6-(6-ethoxypyridine-3-yl)-N-((3-methyl-1H-pyrrole-2-yl)methoxy)pyrazine-2-carboxamide (Compound 68); 6-(6-ethoxypyridine-3-yl)-N-((3-methyl-1H-pyrazole-4-yl)methoxy)pyrazine-2-carboxamide (Compound 69); N-((2-fluorobenzyl)oxy)-6-(6-(trifluoromethoxy)pyridine-3-yl)pyrazine-2-carboxamide (Compound 70); N-((3-methoxybenzyl)oxy)-6-(6-(trifluoromethoxy)pyridine-3-yl)pyrazine-2-carboxamide (Compound 71); N-(pyridine-2-ylmethoxy)-6-(6-(trifluoromethoxy)pyridine-3-yl)pyrazine-2-carboxamide (Compound 72); N-(pyridine-3-ylmethoxy)-6-(6-(trifluoromethoxy)pyridine-3-yl)pyrazine-2-carboxamide (Compound 73); N-(pyridine-4-ylmethoxy)-6-(6-(trifluoromethoxy)pyridine-3-yl)pyrazine-2-carboxamide (Compound 74); N-((2-fluoro-5-methoxybenzyl)oxy)-6-(6-(trifluoromethoxy)pyridine-3-yl)pyrazine-2-carboxamide (Compound 75); 6-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 76); 6-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 77); 6-(6-(difluoromethoxy)pyridine-3-yl)-N-((5-fluoro-2-methoxypyridine-4-yl)methoxy)pyrazine-2-carboxamide (Compound 78); 6-(6-(difluoromethoxy)pyridine-3-yl)-N-((5-fluoro-2-methoxypyridin-4-yl)methoxy)pyrazine-2-carboxamide (Compound 79); 6-(6-(difluoromethoxy)pyridine-3-yl)-N-((5-(dimethylamino)-2-fluorobenzyl)oxy)pyrazine-2-carboxamide (Compound 80); 6-(6-(difluoromethoxy)pyridine-3-yl)-N-((3-(1-hydroxyethyl)benzyl)oxy)pyrazine-2-carboxamide (Compound 81); 6-(6-(difluoromethoxy)pyridin-3-yl)-N-((2-fluoro-5-(methoxy-d3)benzyl)oxy)pyrazine-2-carboxamide (Compound 82); N-((2-fluoro-5-methoxybenzyl)oxy)-6-(6-(methylsulfinyl)pyridine-3-yl)pyrazine-2-carboxamide (Compound 83); 6-(4-ethoxy-2-hydroxyphenyl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 84); 6-(4-ethoxy-3-hydroxyphenyl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 85); 6-(6-ethoxy-4-hydroxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 86); 6-(6-ethoxy-2-oxo-1,2-dihydropyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 87); N-((3,5-dimethoxybenzyl)oxy)-6-(4-ethoxyphenyl)-5-hydroxypyrazine-2-carboxamide (Compound 88); 6-(4-ethoxyphenyl)-N-((2-fluoro-5-methoxybenzyl)oxy)-5-hydroxypyrazine-2-carboxamide (Compound 89); N-((3,5-dimethoxybenzyl)oxy)-6-(4-ethoxyphenyl)-3-hydroxypyrazine-2-carboxamide (Compound 90); 6-(4-ethoxyphenyl)-N-((2-fluoro-5-methoxybenzyl)oxy)-3-hydroxypyrazine-2-carboxamide (Compound 91); 6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)-5-hydroxypyrazine-2-carboxamide (Compound 92); 6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)-3-hydroxypyrazine-2-carboxamide (Compound 93); 5-amino-6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 94); 3-amino-6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 95); 6-(6-ethoxypyridine-3-yl)-5-fluoro-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 96); 6-(6-ethoxypyridine-3-yl)-3-fluoro-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 97); 6'-ethoxy-N-((2-fluoro-5-methoxybenzyl)oxy)-[2,3'-bipyridine]-6-carboxamide (Compound 98); 6'-ethoxy-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)-[2,3'-bipyridine]-6-carboxamide (Compound 99); 6'-ethoxy-N-((2-fluoro-5-methoxybenzyl)oxy)-[3,3'-bipyridine]-5-carboxamide (Compound 100); 2-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrimidine-4-carboxamide (Compound 101); 2-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)pyrimidine-4-carboxamide (Compound 102); 4-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrimidine-2-carboxamide (Compound 103); 4-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrimidine-2-carboxamide (Compound 104); 4-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrimidine-2-carboxamide (Compound 105); 6'-(difluoromethoxy)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)-[2,3'-bipyridine]-6-carboxamide (Compound 106); 6'-(difluoromethoxy)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)-[2,3'-bipyridine]-6-carboxamide (Compound 107); 6'-(difluoromethoxy)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)-[2,3'-bipyridine]-6-carboxamide (Compound 108); 6'-(difluoromethoxy)-N-((2-fluoro-5-methoxybenzyl)oxy)-[3,3'-bipyridine]-5-carboxamide (Compound 109); 2-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)pyrimidine-4-carboxamide (Compound 110); 2-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)pyrimidine-4-carboxamide (Compound 111); 2-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)pyrimidine-4-carboxamide (Compound 112); 3-amino-6-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)pyrazine-2-carboxamide (Compound 113); 3-amino-6-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)pyrazine-2-carboxamide (Compound 114); 5-amino-6-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 115); 6-(6-(difluoromethoxy)pyridine-3-yl)-3-fluoro-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 116); 6-(6-(difluoromethoxy)pyridine-3-yl)-5-fluoro-N-((2-fluoro-5-methoxybenzyl)oxy)pyrazine-2-carboxamide (Compound 117); 3-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)-1,2,4-triazine-5-carboxamide (Compound 118); 5-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)-1,2,4-triazine-3-carboxamide (Compound 119); N-((2-(3,5-dimethoxyphenyl)propan-2-yl)oxy)-6-(4-ethoxyphenyl)pyrazine-2-carboxamide (Compound 120); N-(1-(3,5-dimethoxyphenyl)cyclopropoxy)-6-(4-ethoxyphenyl)pyrazine-2-carboxamide (Compound 121); (R)-N-(1-(3,5-dimethoxyphenyl)ethoxy)-6-(4-ethoxyphenyl)pyrazine-2-carboxamide (Compound 122); (S)-N-(1-(3,5-dimethoxyphenyl)ethoxy)-6-(4-ethoxyphenyl)pyrazine-2-carboxamide (Compound 123); (S)-N-(1-(3,5-dimethoxyphenyl)ethoxy)-6-(4-ethoxyphenyl)pyrazine-2-carboxamide (Compound 124); (R)-6-(4-ethoxyphenyl)-N-(1-(2-fluoro-5-methoxyphenyl)ethoxy)pyrazine-2-carboxamide (Compound 125); (S)-6-(4-ethoxyphenyl)-N-(1-(2-fluoro-5-methoxyphenyl)ethoxy)pyrazine-2-carboxamide (Compound 126); 6-(4-ethoxyphenyl)-N-((2-fluoro-5-methoxyphenyl)methoxy-d2)pyrazine-2-carboxamide (Compound 127); (R)-6-(4-ethoxyphenyl)-N-(1-(3-methoxyphenyl)ethoxy)pyrazine-2-carboxamide (Compound 128); (S)-6-(4-ethoxyphenyl)-N-(1-(3-methoxyphenyl)ethoxy)pyrazine-2-carboxamide (Compound 129); 6-(4-ethoxyphenyl)-N-((3-methoxyphenyl)methoxy-d2)pyrazine-2-carboxamide (Compound 130); (R)-6-(4-ethoxyphenyl)-N-(1-(2-fluorophenyl)ethoxy)pyrazine-2-carboxamide (Compound 131); (S)-6-(4-ethoxyphenyl)-N-(1-(2-fluorophenyl)ethoxy)pyrazine-2-carboxamide (Compound 132); 6-(4-ethoxyphenyl)-N-((2-fluorophenyl)methoxy-d2)pyrazine-2-carboxamide (Compound 133); 6-(6-(difluoromethoxy)pyridin-3-yl)-N-((2-fluoro-5-(methoxy-d3)phenyl)methoxy-d2)pyrazine-2-carboxamide (compound 134); (R)-6-(6-ethoxypyridine-3-yl)-N-(1-(2-fluoro-5-methoxyphenyl)ethoxy)pyrazine-2-carboxamide (Compound 135); (S)-6-(6-ethoxypyridine-3-yl)-N-(1-(2-fluoro-5-methoxyphenyl)ethoxy)pyrazine-2-carboxamide (Compound 136); 6-(6-ethoxypyridine-3-yl)-N-((2-(2-fluoro-5-methoxyphenyl)propan-2-yl)oxy)pyrazine-2-carboxamide (Compound 137); 6-(6-ethoxypyridine-3-yl)-N-(1-(2-fluoro-5-methoxyphenyl)cyclopropoxy)pyrazine-2-carboxamide (Compound 138); 6-(6-ethoxypyridine-3-yl)-N-(1-(2-fluoro-5-methoxyphenyl)cyclopropoxy)pyrazine-2-carboxamide (Compound 139); (R)-6-(6-ethoxypyridine-3-yl)-N-(1-(3-methoxyphenyl)ethoxy)pyrazine-2-carboxamide (Compound 140); (S)-6-(6-ethoxypyridine-3-yl)-N-(1-(3-methoxyphenyl)ethoxy)pyrazine-2-carboxamide (Compound 141); 6-(6-ethoxypyridine-3-yl)-N-((3-methoxyphenyl)methoxy-d2)pyrazine-2-carboxamide (Compound 142); (R)-6-(6-ethoxypyridine-3-yl)-N-(1-(2-fluorophenyl)ethoxy)pyrazine-2-carboxamide (Compound 143); (S)-6-(6-ethoxypyridine-3-yl)-N-(1-(2-fluorophenyl)ethoxy)pyrazine-2-carboxamide (Compound 144); 6-(6-ethoxypyridine-3-yl)-N-((2-fluorophenyl)methoxy-d2)pyrazine-2-carboxamide (Compound 145); (R)-6-(6-ethoxypyridine-3-yl)-N-(1-(2-fluoro-5-methoxyphenyl)ethoxy-2,2,2-d3)pyrazine-2-carboxamide (Compound 146); (S)-6-(6-ethoxypyridine-3-yl)-N-(1-(2-fluoro-5-methoxyphenyl)ethoxy-2,2,2-d3)pyrazine-2-carboxamide (Compound 147); 6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)-N-methylpyrazine-2-carboxamide (Compound 148); 6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)-N-methylpyrazine-2-carboxamide (Compound 149); 6-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)-N-methylpyrazine-2-carboxamide (Compound 150); 6-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)-N-methylpyrazine-2-carboxamide (Compound 151); 6-(6-ethoxypyridine-3-yl)-N-((3-methoxyphenyl)methoxy-d2)pyrazine-2-carboxamide (Compound 152); (R*)-6-(6-ethoxypyridine-3-yl)-N-(1-(2-fluorophenyl)ethoxy)pyrazine-2-carboxamide (Compound 153); (S*)-6-(6-ethoxypyridine-3-yl)-N-(1-(2-fluorophenyl)ethoxy)pyrazine-2-carboxamide (Compound 154); 6-(6-ethoxypyridine-3-yl)-N-((2-fluorophenyl)methoxy-d2)pyrazine-2-carboxamide (Compound 155); 6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)-N-methylpyrazine-2-carboxamide (Compound 156); 6-(6-ethoxypyridine-3-yl)-N-((2-fluoro-5-methoxypyridin-3-yl)methoxy)-N-methylpyrazine-2-carboxamide (Compound 157); 6-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxybenzyl)oxy)-N-methylpyrazine-2-carboxamide (Compound 158); and 6-(6-(difluoromethoxy)pyridine-3-yl)-N-((2-fluoro-5-methoxypyridine-3-yl)methoxy)-N-methylpyrazine-2-carboxamide (Compound 159).

3. COMPOUND, according to claim 1 or 2, characterized by being a blocker of voltage-gated sodium channels Nav 1.7 and / or Nav 1.8.

4. PHARMACEUTICAL COMPOSITION, characterized by comprising a therapeutically effective amount of one or more compounds of Formula (I) or of a pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof, as defined in any of claims 1 to 3, and one or more pharmaceutically acceptable excipients.

5. PHARMACEUTICAL COMPOSITION, according to claim 4, characterized by being formulated as an oral, sublingual, nasal, parenteral, injectable, submuscular, topical, transdermal, ocular, or rectal composition.

6. USE OF FORMULA (I) COMPOUND(S), as defined in any of claims 1 to 3, characterized by being to prepare a drug to treat pathologies related to neuropathic pain.

7. USE, according to claim 6, characterized by said pathologies being selected from the group consisting of peripheral neuropathic pain, chemotherapy-induced neuropathy, complex regional pain, neuropathy related to viral infection, neuropathy secondary to tumor infiltration, diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, and postsurgical neuralgia.

8. METHOD OF TREATMENT, PREVENTION, RELIEF, SUPPRESSION AND / OR CONTROL of pathologies related to neuropathic pain characterized by the administration of an effective amount of at least one compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate and isomer thereof, as defined in any of claims 1 to 3.

9. METHOD, according to claim 8, characterized by< / b> being for the treatment or prophylaxis of peripheral neuropathic pain, chemotherapy-induced neuropathy, complex regional pain, neuropathy related to viral infection, neuropathy secondary to tumor infiltration, diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, and postsurgical neuralgia.

10. METHOD, according to claim 8 or 9, characterized by administration of at least one compound of Formula (I) being selected from the group comprising oral, sublingual, nasal, parenteral, injectable, submuscular, topical, transdermal, ocular, and rectal routes.

11. PROCESS OF OBTAINING GENERAL FORMULA COMPOUND (I), as defined in any of the claims 1 to 3, <b>characterized by comprising the steps: (a) formation of the Formula III intermediate: from the hydrolysis reaction of a Formula IV intermediate: (b) obtaining Formula I compound; from the reaction with the Formula II intermediates: and Formula III, with or without the presence of a catalyst and a suitable solvent; wherein, - X1, X2, X3, and X4 are independently selected from the group consisting of carbon, CH, COH, or nitrogen; wherein: - when at least one of the substituents X2, X4 is nitrogen or CH, the corresponding R (R2, R3) is null, - R1 is: wherein: - X5, X6, X7, X8, and X9 are independently selected from the group consisting of carbon, CH, or nitrogen; wherein: - when at least one of the substituents X5-X9 is nitrogen or CH, the corresponding R (R8-R12) is null; and - R8, R9, R10, R11, and R12 are independently selected from the group consisting of hydrogen, halogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, hydroxy, haloalkoxy C1-C6 linear or branched, azetidinyloxy, azetidinylalkoxy C1-C6, alkylazetidinyloxy C1-C6, alkylsulfinyl, alkoxy C1-C2 containing one or more isotopically enriched atoms, such as hydrogen isotopes 2H, but not limited to the same; - R2 and R3 are independently selected from the group consisting of hydrogen, halogen, amine, hydroxy, C1-C6 alkoxy, and C1-C4 alkyl - R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, haloalkyl C1-C6 linear or branched, alkyl C1-C6 linear or branched; - R6 is selected from the group consisting of aryl, pyridinyl, or substituted pyridinyl, or R13 or R14: - R13 is: wherein: - X10, X11, X12, X13, and X14 are independently selected from the group consisting of carbon, CH, or nitrogen; wherein: - when at least one of the substituents X10-X14 is N or CH, the corresponding R (R15-R19) is null; and - R15, R16, R17, R18, and R19 are independently selected from the group consisting of hydrogen, halogen, hydroxy, linear or branched C1-C6 alkyl, cycloalkyl C3-C7, alkoxy C1-C6 linear or branched, C3-C6 cycloalkoxy, hydroxyalkyl C1-C6 linear or branched, C1-C6 aminoalkyl linear or branched, alkoxy C1-C2 containing one or more isotopically enriched atoms, such as hydrogen isotope 2H, but not limited to the same; - R14 is selected from the group consisting of: wherein R20 is independently selected from the group consisting of hydrogen, halogen, hydroxy, hydroxyalkyl C1-C6 linear or branched, alkyl C1-C6 linear or branched, alkoxy C1-C6 linear or branched, cycloalkoxy C3-C7 saturated or unsaturated, haloalkoxy C1-C6 linear or branched, nitrile, carboxyl, carboxyalkyl ester C1-C6, amine, N-alkylamine, N,N-dialkylamine, aminoalkyl C1-C6 linear or branched, sulfonamide, alkylsulfonylamide C1-C6, N,N-dialkylsulfonylamide C1-C6, sulfonyl, alkyl sulfonyl C1-C6, sulfinyl, alkyl sulfinyl C1-C6, azetidinyloxy, azetidinylalkoxy C1-C3, linear or branched alkoxy C1-C6, hydroxyzetidinyl; and - R7, is independently selected from the group consisting of hydrogen and alkyl C1-C6 linear or branched.

12. PROCESS, according to claim 11, characterized by further comprising a compound formation step (c) of Formula (I) where R7 is linear or branched C1-C6 alkyl from the nucleophilic substitution reaction of a compound obtained in step (b), with linear or branched C1- C6 alkyl halides in the presence of inorganic base and polar aprotic solvents.

13. PROCESS, according to any of claims 11 to 12, characterized by in step (b) said catalyst being selected from concentrated hydrochloric acid, acetic acid, trifluoroacetic acid, formic acid, or combinations of these and said solvent being selected from dimethylformamide, dimethylsulfoxide, alcohols, or combinations thereof.

14. PROCESS, according to any of claims 12 to 13, characterized by in step (c) said inorganic base being selected from K2CO3 or NaH.

15. KIT, characterized by comprising a pharmaceutical composition as defined in claim 4 and an application device.