Used to inhibit Na v 1.8 pyridine carboxamide compound

Abstract

Disclosed are picolinamide compounds useful for inhibiting NaV1.8 and methods for treating conditions, diseases or disorders associated with increased NaV1.8 activity or expression.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 695,571, filed on July 9, 2018, which is incorporated herein by reference in its entirety.

[0003] background

[0004] The modern pharmacopoeia has a variety of treatments for acute and chronic pain, such as steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs), amine reuptake inhibitors, and opioids (PainMedicine). Everyone has a role to play, and a lot of effort has been made to develop new pain management approaches (Yekkirala et al., 2017), especially in light of the recent epidemic of opioid abuse (Skolnick, 2018). Voltage-gated sodium channels (Na v s)(Catterall 2012) are logical targets for pain management given their important role in neuronal transmission in sensory neurons (Ruiz et al., 2015).

[0005] In total, there are nine known isoforms of the major pore-forming α subunit. v 1.1、Na v 1.2 and Na v The 1.3 subtype is mainly expressed in the central nervous system (CNS), while the Na v 1.4 and Na v 1.5 is abundant in skeletal and cardiac muscle. v 1.6 is expressed in both the peripheral nervous system (PNS) and CNS, while Na v 1.7 Na v 1.8 and Na v 1.9 is generally considered to be limited to the PNS (Yu and Catterall, 2003). Non-selective sodium channel inhibitors are available as antiarrhythmics, anticonvulsants, and local anesthetics, but none are suitable for the general treatment of chronic pain (Eijkelkamp et al., 2012). v The channel family is highly homologous, and obtaining selective drug-like ligands is a major challenge (Bagal et al., 2014). However, the identification of selective inhibitors (Jukic et al., 2014) or activators (Deuis et al., 2017) of specific isoforms has potential in many disorders.

[0006] Due to Na v 1.7 and Na vBoth 1.8 isoforms are present on pain receptors in the PNS and have attracted considerable attention as targets for the treatment of pain (Jukic et al., 2014). v 1.7 (Bennett and Woods, 2014) and the discovery of a class of selective inhibitors (McCormack et al., 2013), a great deal of effort has been directed at this channel (Vetter et al., 2017). v Human clinical trials of 1.7 inhibitors have been disappointing (Donnell et al., 2018; Zakrzewska et al., 2017), suggesting that Na v 1.8 as an alternative target (Han et al., 2016).

[0007] Na v The pore-forming α subunit of the 1.8 sodium channel is encoded by the SCN10A gene and is expressed primarily (but not exclusively) in dorsal root ganglion (DRG) neurons and in trigeminal and nodose ganglion neurons (Akopian et al., 1996; Shields et al., 2012). These neurons mediate most of the inward sodium current during the depolarizing phase of the neuronal action potential, which is essential for the propagation and repetitive firing of action potentials (Akopian et al., 1999). Rodent SCN10A gene knockout and knockdown studies indicate that Na v 1.8 is involved in inflammatory pain and neuropathic pain (Dong et al., 2007). Heterozygous gain-of-function mutations in SCN10A cause abnormal firing of DRG neurons and are associated with painful small fiber neuropathy in humans, further implicating Na v 1.8 is associated with pain-receptor neuronal function (Faber et al., 2012).

[0008] In addition to treating pain, Na v There are also opportunities for 1.8 inhibitors. More and more evidence indicates that Na v 1.8 is expressed in the brain (Lu et al., 2015) and is involved in the pathogenesis of multiple sclerosis (MS). Several reports have shown that Na v 1.8 is ectopically expressed in cerebellar Purkinje neurons of mice with experimental autoimmune encephalomyelitis (EAE) (Black et al., 2000) and patients with MS (Damarjian et al., 2004). vEctopic expression of 1.8 results in abnormal firing patterns of cerebellar Purkinje cells and motor coordination deficits in the absence of overt signs of ataxia in mouse models (Shields et al., 2012).

[0009] Importantly, using Na v Treatment with the 1.8 blocker N-methyl-6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-carboxamide (PF01247324) reversed cerebellar defects in a mouse model of MS, establishing a potential new approach to treating MS (Shields et al., 2015). Data from an in vitro cortical development model in which transcription factor 4 (TCF4) disrupts cortical neuronal physiology show in vivo evidence that TCF4 normally suppresses expression of the SCN10A gene in the CNS. In an in vitro cell model and in two independent rodent models of a genetic form of autism known as Pitt Hopkins syndrome (PTHS), which is defined by TCF4 haploinsufficiency (Sweatt, 2013), TCF4 deficiency was shown to produce an abnormal electrophysiological phenotype characterized by a significant reduction in action potential output, and these phenotypes were associated with increased SCN10A (Na v 1.8) expression (Rannals et al., 2016). In addition, it has been shown in these PTHS models that Na v 1.8 inhibitors, such as N-[6-amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (PF 4531083) and 5-4-(chlorophenyl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (A-803467), can rapidly reverse some of the excitatory phenotypes. These results suggest that the normal peripheral limiting sodium channel Na v Ectopic expression of 1.8 in the brain may drive some symptoms of PTHS, and Na v An inhibitor of 1.8 would be of therapeutic value for patients suffering from PTHS.

[0010] Na v 1.8 channels are also expressed in dorsal-related structures (Bucknill et al., 2002) and in the dental pulp (Renton et al., 2005), and there is a v Evidence for a role of 1.8 channels in burning pain (Shembalkar et al., 2001) and inflammatory bowel conditions (Beyak and Vanner 2005).

[0011] Na v1.8 is significantly different from most other members of the voltage-gated ion channel family in that it is "resistant" to inhibition by the classical sodium channel inhibitor tetrodotoxin, which inhibits most other members of the family (Cestele and Catterall, 2000). v 1.8 Inhibitors such as N-methyl-6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-carboxamide (PF 01247324) (Bagal et al., 2015), 5-4-(chlorophenyl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (A-803467) (Kort et al., 2008) and 5-(4-butoxy-3-chlorophenyl)-N-[[2-(4-morpholinyl)-3-pyridinyl]methyl-3-pyridinecarboxamide (A-887826) (Zhang et al., 2010) are known in the literature (see Figure 1 (prior art)). The efficacy in various pain models was examined by the effects observed in both inflammatory pain rodent models and neuropathic pain rodent models (Jarvis et al., 2007; Payne et al., 2015). These compounds, and compounds like them, have a number of disadvantages, including selectivity relative to other ion channels and poor pharmacokinetics.

[0012] Overview

[0013] In some aspects, the presently disclosed subject matter provides compounds of formula (I):

[0014]

[0015] in:

[0016] X is -CH- or nitrogen;

[0017] Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;

[0018] R1 is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is unsubstituted or substituted by one or more groups selected from the group consisting of a monohalogenated C1-C4 hydrocarbon group, a dihalogenated C1-C4 hydrocarbon group and a trihalogenated C1-C4 hydrocarbon group, a substituted or unsubstituted C1-C8 hydrocarbon group, a C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, sulfanyl, trifluoromethylsulfanyl and arylalkoxy;

[0019] R2 is selected from the group consisting of aryl, heteroaryl and heterocyclic, wherein aryl, heteroaryl and heterocyclic are unsubstituted or substituted by one or more groups selected from the group consisting of monohalogenated C1-C4 hydrocarbon group, dihalogenated C1-C4 hydrocarbon group and trihalogenated C1-C4 hydrocarbon group, substituted or unsubstituted C1-C8 hydrocarbon group, C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, arylalkoxy, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;

[0020] R3, when Y is carbon, is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy, C3-C8 cycloalkyl, -NO2, -N + (=O)-O - , and is absent when Y is nitrogen;

[0021] R4 is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy and morpholinyl, with the proviso that R3 and R4 are not hydrogen at the same time; or

[0022] R3 and R4 together form a C3-C5 carbocyclic ring including the carbon atoms to which R3 and R4 are attached;

[0023] and pharmaceutically acceptable salts thereof.

[0024] In certain aspects of the compounds of formula (I):

[0025] X is -CH- or nitrogen;

[0026] Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;

[0027] R1 is selected from the group consisting of phenyl or pyridyl, wherein the phenyl or pyridyl is unsubstituted or substituted by one or more groups selected from the group consisting of: substituted or unsubstituted C1-C8 hydrocarbon; halogen; -O-R5, wherein R5 is selected from the group consisting of C1-C8 hydrocarbon, -CF3, -CHF2 and -(CH2) p-CF3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; and -S-CF3;

[0028] R2 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl, wherein phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl are unsubstituted or substituted with one or more groups selected from the group consisting of unsubstituted or substituted C1-C8 hydrocarbon group; halogen; cyano; oxo; -O-R5, wherein R5 is selected from the group consisting of C1-C8 hydrocarbon group, -CF3 and -CHF2; -(CH2) q -OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; morpholinyl; oxazolyl; -C(=O)-R8, wherein R8 is selected from the group consisting of -NR6R7 and C1-C4 hydrocarbon groups, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group, provided that when Y is nitrogen and R2 is phenyl or pyridyl, R8 cannot be -NR6R7;

[0029] R3, when Y is carbon, is selected from the group consisting of hydrogen, cyano, halogen, -CF3, C1-C8 alkoxy, -O-CH(F)2, substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, -NO2, and is absent when Y is nitrogen;

[0030] R4 is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, -CF3, substituted or unsubstituted C1-C8 alkyl and morpholinyl, provided that R3 and R4 are not hydrogen at the same time; or

[0031] R3 and R4 together form a C3-C5 carbocyclic ring including the carbon atoms to which R3 and R4 are attached;

[0032] and pharmaceutically acceptable salts thereof.

[0033] In certain further aspects of the compound of formula (I), the compound has the following structure:

[0034]

[0035] in:

[0036] X is -CH- or nitrogen;

[0037] Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;

[0038] R2 is selected from the group consisting of aryl, heteroaryl and heterocyclic, wherein aryl, heteroaryl and heterocyclic are unsubstituted or substituted by one or more groups selected from the group consisting of monohalogenated C1-C4 hydrocarbon group, dihalogenated C1-C4 hydrocarbon group and trihalogenated C1-C4 hydrocarbon group, substituted or unsubstituted C1-C8 hydrocarbon group, C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, arylalkoxy, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;

[0039] R3, when Y is carbon, is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalo, dihalo and trihalo C1-C4 alkoxy, monohalo, dihalo and trihalo C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy, C3-C8 cycloalkyl, -NO2, and is absent when Y is nitrogen;

[0040] R4 is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy and morpholinyl, with the proviso that R3 and R4 are not hydrogen at the same time; or

[0041] R3 and R4 together form a C3-C5 carbocyclic ring including the carbon atoms to which R3 and R4 are attached;

[0042] n is an integer selected from 0, 1, 2, 3, 4 and 5;

[0043] Each R 24 independently selected from the group consisting of monohalogenated C1-C4 hydrocarbon groups, dihalogenated C1-C4 hydrocarbon groups and trihalogenated C1-C4 hydrocarbon groups, substituted or unsubstituted C1-C8 hydrocarbon groups, C3-C10 Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, sulfanyl, trifluoromethylsulfanyl and arylalkoxy;

[0044] and pharmaceutically acceptable salts thereof.

[0045] In particular aspects of the compounds of formula (I'), R2 is selected from the group consisting of:

[0046]

[0047] in:

[0048] m is an integer selected from the group consisting of 0, 1, 2, 3 and 4;

[0049] R 25 Selected from the group consisting of: H; morpholinyl; oxazolyl; halogen; cyano; -(CH2) q -OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -C(=O)-R8, wherein R8 is selected from the group consisting of -NR6R7 and C1-C4 hydrocarbon groups, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group, provided that when Y is nitrogen and R2 is phenyl or pyridyl, R8 cannot be -NR6R7;

[0050] R 26 is a halogen or a cyano group;

[0051] Each R 27 are independently selected from the group consisting of: H, halogen, C1-C8 alkoxy, cyano, and -NR6R7; and

[0052] Each R 28 are independently H or a C1-C4 hydrocarbon group.

[0053] In other aspects, the subject matter disclosed herein provides a method for regulating Na v 1.8 A method for regulating sodium ion channels, which comprises administering an effective amount of a compound of formula (I) to a subject in need thereof.

[0054] In other aspects, the subject matter disclosed herein provides a method for inhibiting Na v 1.8 The method comprises administering to a subject in need thereof an inhibitory effective amount of a compound of formula (I).

[0055] In yet other aspects, the subject matter disclosed herein provides a method for treating and increasing Na v 1.8 A method for treating a condition, disease or disorder associated with the activity or expression of said protein, which method comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I).

[0056] In certain aspects, with increased Na v 1.8 The activity or expression-associated condition, disease or disorder is selected from the group consisting of pain, respiratory disease, neurological disorder and psychiatric disease and combinations thereof.

[0057] Having set forth above certain aspects of the subject matter disclosed herein, which in whole or in part are embodied thereby, other aspects will become apparent as the description proceeds when taken in conjunction with the accompanying embodiments as best described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Having thus described the subject matter disclosed herein in general terms, reference will now be made to the accompanying drawings, which are not necessarily drawn to scale, and in which:

[0060] Figure 1 is a diagram of preclinical and clinical Na v 1.8 Representatives of inhibitors.

[0061] Detailed Description

[0062] The subject matter disclosed herein will now be described more fully below. The subject matter disclosed herein may be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein; rather, these embodiments are provided so that the present disclosure will satisfy applicable legal requirements. In fact, many modifications and other embodiments of the subject matter disclosed herein set forth herein will come to mind as would be expected by a person skilled in the art to which the subject matter disclosed herein belongs, with the benefit of the teachings presented in the previous description. Therefore, it should be understood that the subject matter disclosed herein is not limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims.

[0063] I. Used to inhibit Na v 1.8 pyridine carboxamide compound

[0064] The presently disclosed subject matter provides sodium channel inhibitors and their use in treating v 1.8 Use for conditions, diseases or disorders related to activity or expression.

[0065] In some embodiments, the presently disclosed subject matter provides a compound of formula (I):

[0066]

[0067] in:

[0068] X is -CH- or nitrogen;

[0069] Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;

[0070] R1 is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is unsubstituted or substituted by one or more groups selected from the group consisting of a monohalogenated C1-C4 hydrocarbon group, a dihalogenated C1-C4 hydrocarbon group and a trihalogenated C1-C4 hydrocarbon group, a substituted or unsubstituted C1-C8 hydrocarbon group, a C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, sulfanyl, trifluoromethylsulfanyl and arylalkoxy;

[0071] R2 is selected from the group consisting of aryl, heteroaryl and heterocyclic, wherein aryl, heteroaryl and heterocyclic are unsubstituted or substituted by one or more groups selected from the group consisting of monohalogenated C1-C4 hydrocarbon group, dihalogenated C1-C4 hydrocarbon group and trihalogenated C1-C4 hydrocarbon group, substituted or unsubstituted C1-C8 hydrocarbon group, C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, arylalkoxy, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;

[0072] R3, when Y is carbon, is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalo, dihalo and trihalo C1-C4 alkoxy, monohalo, dihalo and trihalo C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy, C3-C8 cycloalkyl, -NO2, and is absent when Y is nitrogen;

[0073] R4 is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy and morpholinyl, with the proviso that R3 and R4 are not hydrogen at the same time; or

[0074] R3 and R4 together form a C3-C5 carbocyclic ring including the carbon atoms to which R3 and R4 are attached;

[0075] and pharmaceutically acceptable salts thereof.

[0076] In some embodiments of compounds of Formula (I):

[0077] X is -CH- or nitrogen;

[0078] Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;

[0079] R1 is phenyl or pyridyl, wherein phenyl or pyridyl is unsubstituted or substituted by one or more groups selected from the group consisting of: substituted or unsubstituted C1-C8 hydrocarbon group; halogen; -O-R5, wherein R5 is selected from C1-C8 hydrocarbon group, -CF3, -CHF2 and -(CH2) p -CF3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; and -S-CF3;

[0080] R2 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl, wherein phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl are unsubstituted or substituted with one or more groups selected from the group consisting of unsubstituted or substituted C1-C8 hydrocarbon group; halogen; cyano; oxo; -O-R5, wherein R5 is selected from the group consisting of C1-C8 hydrocarbon group, -CF3 and -CHF2; -(CH2) q -OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; morpholinyl; oxazolyl; -C(=O)-R8, wherein R8 is selected from the group consisting of -NR6R7 and C1-C4 hydrocarbon groups, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group, provided that when Y is nitrogen and R2 is phenyl or pyridyl, R8 cannot be -NR6R7;

[0081] R3, when Y is carbon, is selected from the group consisting of hydrogen, cyano, halogen, -CF3, C1-C8 alkoxy, -O-CH(F)2, substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, -NO2, and is absent when Y is nitrogen;

[0082] R4 is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, -CF3, substituted or unsubstituted C1-C8 alkyl and morpholinyl, provided that R3 and R4 are not hydrogen at the same time; or

[0083] R3 and R4 together form a C3-C5 carbocyclic ring including the carbon atoms to which R3 and R4 are attached;

[0084] and pharmaceutically acceptable salts thereof.

[0085] In certain embodiments of the compound of formula (I), the compound has the following structure:

[0086]

[0087] in:

[0088] X is -CH- or nitrogen;

[0089] Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;

[0090] R2 is selected from the group consisting of aryl, heteroaryl and heterocyclic, wherein aryl, heteroaryl and heterocyclic are unsubstituted or substituted by one or more groups selected from the group consisting of monohalogenated C1-C4 hydrocarbon group, dihalogenated C1-C4 hydrocarbon group and trihalogenated C1-C4 hydrocarbon group, substituted or unsubstituted C1-C8 hydrocarbon group, C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, arylalkoxy, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;

[0091] R3, when Y is carbon, is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalo, dihalo and trihalo C1-C4 alkoxy, monohalo, dihalo and trihalo C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy, C3-C8 cycloalkyl, -NO2, and is absent when Y is nitrogen;

[0092] R4 is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy and morpholinyl, with the proviso that R3 and R4 are not hydrogen at the same time; or

[0093] R3 and R4 together form a C3-C5 carbocyclic ring including the carbon atoms to which R3 and R4 are attached;

[0094] n is an integer selected from 0, 1, 2, 3, 4 and 5;

[0095] Each R 24 independently selected from the group consisting of monohalogenated C1-C4 hydrocarbon groups, dihalogenated C1-C4 hydrocarbon groups and trihalogenated C1-C4 hydrocarbon groups, substituted or unsubstituted C1-C8 hydrocarbon groups, C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, sulfanyl, trifluoromethylsulfanyl and arylalkoxy;

[0096] and pharmaceutically acceptable salts thereof.

[0097] In certain embodiments of the compounds of formula (I'), R2 is selected from the group consisting of:

[0098]

[0099] in:

[0100] m is an integer selected from the group consisting of 0, 1, 2, 3 and 4;

[0101] R 25 Selected from the group consisting of: H; morpholinyl; oxazolyl; halogen; cyano; -(CH2) q-OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -C(=O)-R8, wherein R8 is selected from the group consisting of -NR6R7 and C1-C4 hydrocarbon groups, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group, provided that when Y is nitrogen and R2 is phenyl or pyridyl, R8 cannot be -NR6R7;

[0102] R 26 is a halogen or a cyano group;

[0103] Each R 27 are independently selected from the group consisting of: H, halogen, C1-C8 alkoxy, cyano, and -NR6R7; and

[0104] Each R 28 are independently H or a C1-C4 hydrocarbon group.

[0105] In some embodiments, the compound of formula (I) is a compound of formula (IF):

[0106]

[0107] in:

[0108] R2 is selected from the group consisting of aryl and heteroaryl, wherein the aryl or heteroaryl is optionally substituted by a substituent group selected from the group consisting of: cyano, heterocycloalkyl, -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group;

[0109] R 12 is a halogen; and

[0110] R 13 It is a C1-C4 hydrocarbon group.

[0111] In some embodiments of the compound of Formula (IF), the aryl and heteroaryl groups are selected from the group consisting of phenyl, benzothiazolyl, pyridyl, pyridyl N-oxide, and pyrimidinyl, each of which is optionally substituted with a substituent group selected from the group consisting of cyano, heterocycloalkyl, -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon, -CF3 or -NR6R7, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group;

[0112] R 12 is fluorine; and

[0113] R 13 It's methyl.

[0114] In certain embodiments of the compound of Formula (IF), R2 is selected from the group consisting of: 1,3-benzothiazol-6-yl, 3-morpholinophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-pyridinyl, 4-pyridinyl, 6-cyano-3-pyridinyl, 3-methylsulfinylphenyl, 3-oxazol-5-ylphenyl, 3-dimethylsulfamoylphenyl, 1,3-benzothiazol-2-yl, pyrimidin-4-yl, (trifluorosulfonyl)phenyl, 3-(methylsulfonylimino)phenyl, 2-methoxy-4-pyridinyl, 3-(N,S-dimethylsulfonylimino)phenyl, 2-methyl-4-pyridinyl, 6-methyl-3-pyridinyl, pyridazin-4-yl, and dimethyl(oxo)-λ 6 -sulfanyl]amino]phenyl.

[0115] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IG):

[0116]

[0117] in:

[0118] R1 is phenyl substituted by one or more of C1-C8 hydrocarbyl, halogen and C1-C8 hydrocarbyloxy, and wherein the C1-C8 hydrocarbyloxy is optionally substituted by one or more halogen; and

[0119] R 14 It is a C1-C4 hydrocarbon group.

[0120] In some embodiments of the compound of Formula (IG), R1 is selected from the group consisting of 2,4-dichlorophenyl, 2,4-dimethylphenyl, 2-chloro-4-methoxyphenyl, 2-propylphenyl, 2-methoxy-4-methylphenyl, 2-methoxy-4-chlorophenyl, 2-isopropoxyphenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2-chloro-4-methoxyphenyl, 3,4-difluorophenyl and 2-chloro-4-fluorophenyl.

[0121] In some embodiments of the compound of formula (I), the compound is a compound of formula (IHi):

[0122]

[0123] in:

[0124] R1 is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazol-4-yl, wherein phenyl and pyridyl may be unsubstituted or substituted by one or more of the following: halogen; C1-C8 hydrocarbon group; -O-R5, wherein R5 is selected from the group consisting of C1-C8 hydrocarbon group, -CF3, -CHF2 and -(CH2) p -CF3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -S-CF3; -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups;

[0125] R3 and R4 are H or -CF3, provided that if R3 is H, then R4 is -CF3, and if R4 is H, then R3 is -CF3;

[0126] R 14 is a C1-C4 hydrocarbon group; and

[0127] R 15 Is O or NR 10 , where R 10 It is H or C1-C4 hydrocarbon group.

[0128] In some embodiments of the compound of Formula (IHi), R1 is selected from the group consisting of phenyl, 4-fluorophenyl, 4-fluoro-2-methoxyphenyl, 2-chloro-4-fluorophenyl, 2-methyl-4-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, difluoromethoxyphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3-fluorophenyl, 2,5-difluorophenyl, 4-methylphenyl, 3-chloro-5-fluorophenyl, 2-isopropylphenyl, 3,4-difluorophenyl, 2, 4-difluorophenyl, 3,5-difluorophenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(trifluoromethylsulfanyl)phenyl, 2-dimethylaminophenyl, 2-trifluoromethylphenyl, 2,4-dimethoxyphenyl, 3,4,5-trifluorophenyl, 3,5-dichlorophenyl, 6-trifluoromethyl-3-pyridyl, 1,3-benzothiazol-4-yl, 4-difluoromethoxyphenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methoxyphenyl and 2-chlorophenyl.

[0129] In some embodiments of the compound of formula (I), the compound is a compound of formula (IH-ii):

[0130]

[0131] in:

[0132] R1 is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazol-4-yl, wherein phenyl or pyridyl may be unsubstituted or substituted by one or more of the following: halogen; C1-C8 hydrocarbon group; -O-R5, wherein R5 is selected from the group consisting of C1-C8 hydrocarbon group, -CF3, -CHF2 and -(CH2) p -CF3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -S-CF3; -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; and

[0133] R3 and R4 are H or -CF3, provided that if R3 is H then R4 is -CF3, and if R4 is H then R3 is -CF3.

[0134] In some embodiments of the compound of Formula (IH-ii), R1 is selected from the group consisting of 2,4-dichlorophenyl, 4-difluoromethoxyphenyl, and 2-chloro-4-methoxyphenyl.

[0135] In some embodiments of the compound of formula (I), the compound is a compound of formula (II):

[0136]

[0137] in:

[0138] R2 is selected from the group consisting of phenyl, pyridazinyl and pyridinyl, wherein the phenyl group may be substituted by one or more of the following: halogen, -S(=O)-R9, -S(=O)2-R9 and -S(=O)(=NR 10 )-R 11 , wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group;

[0139] R 16 is a halogen; and

[0140] R 17 It is a C1-C4 hydrocarbon group.

[0141] In some embodiments of the compound of Formula (II), R2 is selected from the group consisting of 3-methylsulfinylphenyl, 2-fluoro-5-methylsulfonylphenyl, 3-(N,S-dimethylsulfonylimino)phenyl, pyridazinyl, and pyridinyl.

[0142] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IJ):

[0143]

[0144] in:

[0145] R2 is selected from the group consisting of phenyl and pyridyl, wherein the phenyl is substituted by one or more of the following: halogen; -C(=O)-R8, wherein R8 is a C1-C4 hydrocarbon group; -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon, -CF3 or -NR6R7, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group; and

[0146] R 18 It's a halogen.

[0147] In some embodiments of the compound of Formula (IJ), R2 is selected from the group consisting of: 3-methylsulfonylphenyl, 3-methylsulfinylphenyl, 3-(dimethylsulfamoyl)phenyl, 2-fluoro-5-methylsulfonylphenyl, 3-(methylsulfonylimino)phenyl, 3-carbamoylphenyl, 3-(N,S-dimethylsulfonylimino)phenyl, 3-pyridyl and 4-pyridyl.

[0148] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IK):

[0149]

[0150] in:

[0151] R1 is phenyl substituted by one or more of the following: halogen; C1-C8 hydrocarbon group; -O-R5, wherein R5 is selected from C1-C8 hydrocarbon group, -CF3, -CHF2 and -(CH2) p -CF3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8.

[0152] In some embodiments of the compound of Formula (IK), R1 is selected from the group consisting of 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,4-difluorophenyl, and 3,4-difluorophenyl.

[0153] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IL):

[0154]

[0155] wherein R2 is selected from the group consisting of phenyl, pyridyl and pyridazin-4-yl, wherein the phenyl group is substituted by: -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently a C1-C4 hydrocarbon group or -NR6R7, wherein R6 and R7 are each H, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group. In a specific embodiment, R2 is 3-(N,S-dimethylsulfonylimino)phenyl.

[0156] In some embodiments of the compound of formula (I), the compound is a compound of formula (IMi):

[0157]

[0158] in:

[0159] R2 is 3-(N,S-dimethylsulfonylimino)phenyl or pyridazin-4-yl;

[0160] R 16 is a halogen; and

[0161] R 19 It is a C1-C4 hydrocarbon group.

[0162] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IM-ii):

[0163]

[0164] wherein R1 is selected from the group consisting of 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl.

[0165] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IM-iii):

[0166]

[0167] in:

[0168] R1 is selected from the group consisting of 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl;

[0169] R 20 is a C1-C4 hydrocarbon group; and

[0170] R 21 It is H or C1-C4 hydrocarbon group.

[0171] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IM-iv):

[0172]

[0173] wherein R1 is selected from the group consisting of 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl.

[0174] In some embodiments of the compound of formula (I), the compound is a compound of formula (IN):

[0175]

[0176] in:

[0177] R2 is selected from the group consisting of 3-(N,S-dimethylsulfonylimino)phenyl, 3-(methylsulfonylimino)phenyl and pyridazin-4-yl;

[0178] R 16 is a halogen; and

[0179] R 19 It is a C1-C4 hydrocarbon group.

[0180] In some embodiments of the compound of formula (I), the compound is a compound of formula (IO):

[0181]

[0182] wherein R2 is selected from the group consisting of phenyl, pyridyl and pyridazin-4-yl, wherein the phenyl group is substituted by: -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently a C1-C4 hydrocarbon group or -NR6R7, wherein R6 and R7 are each H, R 10 is H or a C1-C4 hydrocarbon group, and R 11 It is a C1-C4 hydrocarbon group.

[0183] In some embodiments of the compound of formula (I), the compound is a compound of formula (IP):

[0184]

[0185] wherein R1 is selected from the group consisting of 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl, 2,4-difluorophenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2-chloro-4-methoxyphenyl, 3,4-difluorophenyl and 2-chloro-4-fluorophenyl.

[0186] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IQ):

[0187]

[0188] in:

[0189] R2 is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiadiazolyl, pyrazolyl and 1,2,4-triazolyl;

[0190] in:

[0191] The phenyl group is substituted by one or more groups selected from the group consisting of: unsubstituted or substituted C1-C8 hydrocarbon group; halogen; cyano; oxo; -O-R5, wherein R5 is selected from the group consisting of C1-C8 hydrocarbon group, -CF3 and -CHF2; -(CH2) q -OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; morpholinyl; oxazolyl; -C(=O)-R8, wherein R8 is selected from the group consisting of -NR6R7 and C1-C4 hydrocarbon groups, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group;

[0192] Pyridyl is unsubstituted or substituted by C1-C8 alkyl, oxo, C1-C8 alkoxy and halogen; and

[0193] R 18 It's a halogen.

[0194] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IR):

[0195]

[0196] in:

[0197] R2 is 3-(methylsulfonylimino)phenyl or pyridazin-4-yl; and

[0198] R 22 and R 23 Each is a C1-C4 hydrocarbon group.

[0199] In some embodiments of the compound of formula (I), the compound is a compound of formula (IS):

[0200]

[0201] in:

[0202] R2 is 3-(methylsulfonylimino)phenyl or pyridazin-4-yl; and

[0203] R16 and R 18 Each is a halogen.

[0204] In some embodiments of the compound of Formula (I), the compound of Formula (I) is selected from the group consisting of:

[0205] 6-Chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (Intermediate 3);

[0206] N-(1,3-Benzothiazol-6-yl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (1);

[0207] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-morpholinophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (2);

[0208] N-(3-cyanophenyl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (3);

[0209] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (4);

[0210] N-(4-cyanophenyl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (5);

[0211] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (6);

[0212] N-(6-cyano-3-pyridinyl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (7);

[0213] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfinylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (8);

[0214] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-oxazol-5-ylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (9);

[0215] N-[3-(Dimethylsulfamoyl)phenyl]-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (10);

[0216] N-(1,3-Benzothiazol-2-yl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (11);

[0217] 2-(4-Fluoro-2-methoxy-phenoxy)-N-pyrimidin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (12);

[0218] 2-(4-Fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)-N-[3-(trifluoromethylsulfonyl)phenyl]pyridine-3-carboxamide (13);

[0219] 2-(4-Fluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (14);

[0220] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (15);

[0221] N-[3-(N,S-dimethylsulfonylimino)phenyl]-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (16);

[0222] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(2-methyl-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (17);

[0223] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(6-methyl-3-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (18);

[0224] 2-(4-Fluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (19);

[0225] N-[3-[[dimethyl(oxy)-λ 6 -sulfanyl]amino]phenyl]-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (20);

[0226] 2-(2,4-Dichlorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (21);

[0227] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-morpholinophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (22);

[0228] 2-(2-Chloro-4-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (23);

[0229] N-(3-methylsulfonylphenyl)-2-(2-propylphenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (24);

[0230] 2-(2-Methoxy-4-methyl-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (25);

[0231] 2-(4-Chloro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (26);

[0232] 2-(2-Isopropoxyphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (27);

[0233] 2-(4-(difluoromethoxy)phenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (28);

[0234] 2-(2,4-dimethoxyphenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (29);

[0235] 2-(2-Chloro-4-methoxyphenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (30);

[0236] 2-(3,4-difluorophenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (31);

[0237] 2-(2-Chloro-4-fluorophenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (32);

[0238] 2-(2,6-Dimethylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (33);

[0239] 2-(4-Fluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (34);

[0240] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (35);

[0241] 2-(2-Chloro-4-fluoro-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (36);

[0242] N-(3-Methylsulfonylphenyl)-2-[2-methyl-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (37);

[0243] N-(3-Methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (38);

[0244] 2-[4-(Difluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (39);

[0245] 2-[3-Fluoro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (40);

[0246] N-(3-Methylsulfonylphenyl)-2-phenoxy-5-(trifluoromethyl)pyridine-3-carboxamide (41);

[0247] 2-(3-Fluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (42);

[0248] 2-(2,5-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (43);

[0249] 2-(4-Methylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (44);

[0250] 2-(3-Chloro-5-fluoro-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (45);

[0251] 2-(2-Isopropylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (46);

[0252] 2-(3,4-Difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (47);

[0253] 2-(2,4-Difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (48);

[0254] 2-(3,5-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (49);

[0255] N-(3-Methylsulfonylphenyl)-2-[4-(2,2,2-trifluoroethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (50);

[0256] N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-[4-(trifluoromethylsulfanyl)phenoxy]pyridine-3-carboxamide (51);

[0257] 2-[2-(Dimethylamino)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (52);

[0258] N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-[2-(trifluoromethyl)phenoxy]pyridine-3-carboxamide (53);

[0259] 2-(2,4-Dimethoxyphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (54);

[0260] N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-(3,4,5-trifluorophenoxy)pyridine-3-carboxamide (55);

[0261] 2-(3,5-Dichlorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (56);

[0262] N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-[[6-(trifluoromethyl)-3-pyridinyl]oxy]pyridine-3-carboxamide (57);

[0263] 2-(1,3-Benzothiazol-4-yloxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (58);

[0264] 2-[4-(Difluoromethoxy)phenoxy]-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (59);

[0265] 2-(2-Chloro-4-fluoro-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (60);

[0266] 2-(2-Chloro-4-methoxy-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (61);

[0267] 2-(2-Chlorophenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (62);

[0268] 2-(2,4-Dichlorophenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (63);

[0269] 2-[4-(Difluoromethoxy)phenoxy]-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (64);

[0270] 2-(2-Chloro-4-methoxy-phenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (65);

[0271] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (66);

[0272] 4-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (67);

[0273] 4-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfinylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (68);

[0274] 4-(4-Fluoro-2-methoxy-phenoxy)-N-(2-fluoro-5-methylsulfonyl-phenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (69);

[0275] N-[3-(N,S-dimethylsulfonylimino)phenyl]-4-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxamide (70);

[0276] 4-(4-Fluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (71);

[0277] 4-(4-Fluoro-2-methoxy-phenoxy)-N-(4-pyridinyl)-6-(trifluoromethyl)pyridine-3-carboxamide (72);

[0278] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[2-(dimethylamino)-4-pyridinyl]-6-(trifluoromethyl)pyridine-3-carboxamide (73);

[0279] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (74);

[0280] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfinylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (75);

[0281] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethylsulfamoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (76);

[0282] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro-5-methylsulfonyl-phenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (77);

[0283] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-pyridinyl)-6-(trifluoromethyl)pyridine-3-carboxamide (78);

[0284] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(4-pyridinyl)-6-(trifluoromethyl)pyridine-3-carboxamide (79);

[0285] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (80);

[0286] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(N,S-dimethylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (82);

[0287] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (83);

[0288] 4-(4-Fluoro-2-methoxy-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (84);

[0289] 4-(4-Fluoro-2-methyl-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (85);

[0290] 4-[4-(Difluoromethoxy)phenoxy]-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (86);

[0291] N-(1-Oxopyridin-1-ium-3-yl)-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (87);

[0292] 4-(2,4-Dimethoxyphenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (88);

[0293] 4-(2,4-Difluorophenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (89);

[0294] 3-(4-(3,4-difluorophenoxy)-6-(trifluoromethyl)nicotinylamino)pyridine-1-oxide (90);

[0295] N-[3-(Methylsulfonylimino)phenyl]-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (91);

[0296] N-[3-(N,S-dimethylsulfonylimino)phenyl]-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (92);

[0297] 4-(4-Fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (93);

[0298] N-[3-(N,S-dimethylsulfonylimino)phenyl]-4-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxamide (94);

[0299] 4-(4-Fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (95);

[0300] N-pyridazin-4-yl-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (96);

[0301] 4-[4-(Difluoromethoxy)phenoxy]-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (97);

[0302] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (98);

[0303] 4-(2,4-Dimethoxyphenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (99);

[0304] 4-(2,4-Difluorophenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (100);

[0305] 4-[4-(Difluoromethoxy)phenoxy]-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (101);

[0306] 4-(2,4-Dimethoxyphenoxy)-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (102);

[0307] 4-(2,4-Difluorophenoxy)-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (103);

[0308] 4-(4-(difluoromethoxy)phenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl)nicotinamide (104);

[0309] N-(Pyridin-3-yl)-4-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)nicotinamide (105)

[0310] 4-(2-Chloro-4-(trifluoromethoxy)phenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl)nicotinamide (106);

[0311] 4-(2,4-dimethoxyphenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl)nicotinamide (107);

[0312] 4-(2,4-difluorophenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl)nicotinamide (108);

[0313] 2-(4-Fluoro-2-methyl-phenoxy)-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (109);

[0314] 2-(4-Fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (110);

[0315] 5-Bromo-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (111);

[0316] 5-Cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (112);

[0317] 2-(4-Fluoro-2-methyl-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (113);

[0318] N-[3-(N,S-dimethylsulfonylimino)phenyl]-2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (114);

[0319] 2-(4-Fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (115);

[0320] 2-(4-Fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (116);

[0321] 2-(4-Fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (117);

[0322] 2-(4-Fluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (118);

[0323] 5-Chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (119);

[0324] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (120);

[0325] N-(3-Methylsulfinylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (121);

[0326] N-(3-sulfamoylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (122);

[0327] N-[3-(Methylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (123);

[0328] N-[3-(N,S-dimethylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (124);

[0329] N-(3-ethylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (125);

[0330] N-(3-pyridinyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (126);

[0331] N-(4-pyridinyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (127);

[0332] N-pyridazin-4-yl-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (128);

[0333] N-[3-[[dimethyl(oxy)-λ 6 -sulfanyl]amino]phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (129);

[0334] N-[3-(Methylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide, Enantiomer A (130);

[0335] N-[3-(Methylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide, enantiomer B (131);

[0336] N-(1-Oxopyridin-1-ium-3-yl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (132);

[0337] 2-(4-Fluoro-2-methyl-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (133);

[0338] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (134);

[0339] 2-(2,4-Difluorophenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (135);

[0340] 3-(2-(4-(difluoromethoxy)phenoxy)-5-(trifluoromethyl)nicotinoylamino)pyridine 1-oxide (136);

[0341] 3-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)nicotinylamino)pyridine 1-oxide (137);

[0342] 3-(2-(2-chloro-4-methoxyphenoxy)-5-(trifluoromethyl)nicotinylamino)pyridine 1-oxide (138);

[0343] 3-(2-(3,4-difluorophenoxy)-5-(trifluoromethyl)nicotinylamino)pyridine 1-oxide (139);

[0344] 2-(2-Chloro-4-fluoro-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (140);

[0345] N-(1-Oxidopyridin-1-ium-4-yl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (141);

[0346] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (142);

[0347] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-ethylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (143);

[0348] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(N,S-dimethylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (144);

[0349] 4-Pyridinyl 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)picolinate (145);

[0350] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-cyanophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (146);

[0351] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (147);

[0352] N-(3-Carbamoylphenyl)-2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (148);

[0353] N-(3-Acetylphenyl)-2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (149);

[0354] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methyl-2-oxo-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (150);

[0355] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethylcarbamoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (151);

[0356] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(4-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (152);

[0357] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(4-methylsulfinylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (153);

[0358] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethylsulfamoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (154);

[0359] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3,4-difluorophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (155);

[0360] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(6-methoxy-3-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (156);

[0361] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-pyrimidin-5-yl-5-(trifluoromethyl)pyridine-3-carboxamide (157);

[0362] N-(2-chloro-4-pyridinyl)-2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (158);

[0363] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(6-fluoro-3-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (159);

[0364] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(hydroxymethyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (160);

[0365] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (161);

[0366] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro-5-methylsulfonyl-phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (162);

[0367] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-fluorophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (163);

[0368] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (164);

[0369] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (165);

[0370] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (166);

[0371] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methylpyrazol-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (167);

[0372] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-5-methylsulfonyl-phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (168);

[0373] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (169);

[0374] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methyl-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (170);

[0375] 2-(2,4-Dimethoxyphenoxy)-N-[3-(N,S-dimethylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (171);

[0376] 2-(2,4-Dimethoxyphenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (172);

[0377] 2-(2,4-Dimethoxyphenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (173);

[0378] 2-(2,4-Difluorophenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (174);

[0379] 2-(2,4-Difluorophenoxy)-N-[3-(N,S-dimethylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (175);

[0380] 2-(2,4-Difluorophenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (176);

[0381] 5-Cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (177);

[0382] 5-Fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (178);

[0383] 5-(Difluoromethoxy)-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (179);

[0384] N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (180); and

[0385] 5-Chloro-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (181).

[0386] B. Methods for treating conditions, diseases or disorders associated with increased NAV1.8 activity or expression

[0387] In some embodiments, the subject matter disclosed herein provides a method for regulating Na v1.8 A method for regulating sodium ion channels, which comprises administering an effective amount of a compound of formula (I) to a subject in need thereof.

[0388] In other embodiments, the subject matter disclosed herein provides a method for inhibiting Na v 1.8 The method comprises administering to a subject in need thereof an inhibitory effective amount of a compound of formula (I).

[0389] As used herein, the term "inhibit" and its grammatical derivatives refer to the compounds disclosed herein, such as the compounds of Formula (I) disclosed herein, blocking, partially blocking, interfering with, reducing or decreasing Na in a subject. v 1.8 activity or expression. Therefore, it will be understood by those of ordinary skill in the art that the term "inhibit" encompasses a complete and / or partial reduction in channel function, such as a reduction of at least 10%, in some embodiments, a reduction of at least 20%, 30%, 50%, 75%, 95%, 98% and up to and including 100%.

[0390] In certain embodiments, the subject matter disclosed herein provides a method for treating a condition associated with increased Na v 1.8 activity or expression of conditions, diseases or disorders. In more specific embodiments, with increased Na v 1.8 The condition, disease or disorder associated with activity or expression is selected from the group consisting of: pain, in particular inflammatory pain, visceral pain and neuropathic pain; neurological disorders, in particular multiple sclerosis; autism, in particular Pitt Hopkins syndrome; and psychiatric disorders, and combinations thereof, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0391] In a specific embodiment, the disease or condition is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, post-surgical pain, labor pain, labor pain, neurogenic bladder disorder, ulcerative colitis, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, or a combination thereof.

[0392] In other embodiments, the disease or condition is selected from the group consisting of: pain associated with HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome, Crohn's disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, depression, anxiety, schizophrenia, sodium channel toxin-related disorders, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, partial and generalized tonic seizures, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection in ischemic conditions caused by stroke or neurotrauma, tachyarrhythmias, atrial fibrillation, and ventricular fibrillation.

[0393] In some embodiments, the disease or condition is Pitt Hopkins syndrome (PTHS).

[0394] The disclosed subject matter also includes compounds of formula (I) for use in the manufacture of a method for treating a patient suffering from increased Na v 1.8 Use in a medicament for treating a condition, disease or disorder associated with the activity or expression of such disorder in a subject.

[0395] A "subject" treated by the methods disclosed herein, in many of their embodiments, is desirably a human subject, although it is understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term "subject." Thus, a "subject" may include a human subject used for medical purposes, such as for treatment of an existing condition or disease or for prophylactic treatment to prevent the onset of a condition or disease, or an animal subject used for medical purposes, veterinary purposes, or developmental purposes. Suitable animal subjects include mammals, including but not limited to primates, such as humans, monkeys, apes, etc.; bovines, such as cattle, oxen, etc.; ovines, such as sheep, etc.; caprines, such as goats, etc.; porcines, such as pigs, hogs, etc.; equines, such as horses, donkeys, zebras, etc.; felines, including wild cats and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, etc.; and rodents, including mice, rats, etc. Animals can be transgenic animals. In some embodiments, the subject is a human, including but not limited to fetuses, newborns, infants, adolescents, and adult subjects. In addition, "subjects" may include patients suffering from or suspected of having a condition or disease. Therefore, the terms "subject" and "patient" are used interchangeably herein. The term "subject" also refers to an organism, tissue, cell, or collection of cells from a subject.

[0396] Typically, an "effective amount" of an active agent or drug delivery device refers to the amount necessary to elicit a desired biological response. As will be appreciated by one of ordinary skill in the art, the effective amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue, etc.

[0397] The term "combination" is used in its broadest sense and means that a subject is administered at least two agents, more particularly a compound of formula (I) and at least one analgesic; and optionally one or more analgesics. More particularly, the term "in combination" refers to the concomitant administration of two (or more) active agents for the treatment of, for example, a single disease state. As used herein, the active agents may be combined and administered in a single dosage form, may be administered simultaneously as separate dosage forms, or may be administered as separate dosage forms administered alternately or sequentially on the same or separate days. In one embodiment of the subject matter disclosed herein, the active agents are combined and administered in a single dosage form. In another embodiment, the active agents are administered in separate dosage forms (e.g., where it is desirable to vary the amount of one but not the other). A single dosage form may include additional active agents for the treatment of a disease state.

[0398] In addition, the compounds of formula (I) described herein can be administered alone or in combination with adjuvants, which are alone or in combination with one or more analgesics, enhance the stability of the compounds of formula (I), facilitate the administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunctive therapy, etc., including other active ingredients. Advantageously, such combination therapies use lower doses of conventional therapeutic agents, thus avoiding possible toxicity and adverse side effects caused when those agents are used as monotherapy.

[0399] The administration time of the compound of formula (I) and at least one other therapeutic agent can be changed, as long as the beneficial effect of the combination of these agents is realized. Therefore, the wording "combined with ... " refers to the administration of the compound of formula (I) and at least one other therapeutic agent simultaneously, sequentially or in combination thereof. Therefore, the subject of the combination of the compound of formula (I) and at least one other therapeutic agent administered can accept the compound of formula (I) and at least one other therapeutic agent simultaneously (that is, simultaneously) or at different times (that is, on the same day or on different days, in any order, sequentially), as long as the effect of the combination of two agents is realized in the subject.

[0400] When administered sequentially, the agents may be administered within 1 minute, 5 minutes, 10 minutes, 30 minutes, 60 minutes, 120 minutes, 180 minutes, 240 minutes or longer of each other. In other embodiments, the agents administered sequentially may be administered within 1 day, 5 days, 10 days, 15 days, 20 days or more of each other. In the case where a compound of formula (I) and at least one additional therapeutic agent are administered simultaneously, they may be administered to a subject as separate pharmaceutical compositions, each of which comprises a compound of formula (I) or at least one additional therapeutic agent, or they may be administered to a subject as a single pharmaceutical composition comprising two agents.

[0401] When administered in combination, the effective concentration of each of the agents that elicit a particular biological response can be less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be required if the agent were administered as a single agent. The effects of multiple agents can be, but need not be, additive or synergistic. An agent can be administered multiple times.

[0402] In some embodiments, when used in combination, two or more agents may have a synergistic effect. As used herein, the terms "synergy", "synergistic", "synergistically" and their derivatives, such as in "synergy" or "synergistic combination" or "synergistic composition", refer to situations where the biological activity of the combination of a compound of formula (I) and at least one other therapeutic agent is greater than the sum of the biological activities of the respective agents when used individually.

[0403] Synergy can be expressed in terms of a "synergy index (SI)", which can generally be determined by the method described by FC Kull et al., Applied Microbiology 9, 538 (1961), from the ratio determined by:

[0404] Q a / Q A +Q b / Q B =Synergy Index (SI)

[0405] in:

[0406] Q A is the concentration of component A acting alone that produces an endpoint with respect to component A;

[0407] Q a is the concentration of component A in the mixture that produces an endpoint;

[0408] Q B is the concentration of Component B, acting alone, which produces an endpoint with respect to Component B; and

[0409] Q b is the concentration of component B in the mixture that produces an endpoint.

[0410] Usually, when Q a / Q A and Q b / Q BWhen the sum of the SI is greater than 1, antagonism is indicated. When the sum is equal to 1, additivity is indicated. When the sum is less than 1, synergy is demonstrated. The lower the SI, the greater the synergy shown by a particular mixture. Thus, a "synergistic combination" has an activity that is higher than what would be expected based on the activity observed for each component when used alone. In addition, a "synergistically effective amount" of a component refers to the amount of the component necessary to elicit a synergistic effect in, for example, another therapeutic agent present in the composition.

[0411] More specifically, in some embodiments, the methods disclosed herein comprise co-administering to a subject a compound of formula (I) and / or a pharmaceutically acceptable salt thereof and one or more compounds selected from the group consisting of one or more of the following:

[0412] Nonsteroidal anti-inflammatory drugs (NSAIDs), including but not limited to aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufensal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, and zomepirac;

[0413] Opioid analgesics, including, but not limited to, morphine, heroin, hydromorphone, oxymorphone, hydroxymethyllevomorphan, levorphanol, methadone, pethidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorfen, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, and pentazocine;

[0414] Barbiturates, including but not limited to amobarbital, aprobarbital, butabarbital, butalbital, methylphenobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiopental, and thiopental;

[0415] Benzodiazepines, including but not limited to clodiazepine, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, and triazolam;

[0416] Histamine H1 antagonists, including but not limited to diphenhydramine, mepyramine, promethazine, chlorpheniramine, and chlorcyclizine;

[0417] Sedatives, including but not limited to glutethimide, meprobamate, methaqualone, and chloralphenazone;

[0418] Skeletal muscle relaxants, including but not limited to baclofen, carantamid, chlorzoxazone, cyclobenzaprine, methocarbamol, and orphrenadine;

[0419] NMDA receptor antagonists, including but not limited to dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinolinequinine, cis-4-(phosphonomethyl)-2-piperidinic acid, budipine, EN-3231 (a combination preparation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel, including NR2B antagonists such as ifenprodil, traxoprodil and (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

[0420] Transient receptor potential ion channel antagonists;

[0421] α-adrenergics, including but not limited to doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5-methane-sulfonylamino-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline;

[0422] tricyclic antidepressants, including but not limited to desipramine, imipramine, amitriptyline, and nortriptyline;

[0423] Anticonvulsants, including but not limited to carbamazepine Lamotrigine, topiramate, lacosamide and valproate;

[0424] Tachykinin antagonists, particularly NK-3, NK-2 or NK-1 antagonists, include but are not limited to (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazacyclooctatetraeno[2,1-g][1,7]-naphthyridine-6,13-dione (TAK-637), 5-[[(2 R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholino]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanapitant, dapitant, and 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

[0425] Muscarinic antagonists, including but not limited to oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine, and ipratropium;

[0426] Cyclooxygenase-2 selective (COX-2) inhibitors, including but not limited to celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib;

[0427] Coal tar analgesics, including but not limited to acetaminophen;

[0428] Neuroleptics, including but not limited to droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eliserin, oxanetant, rimonabant, meclinertant, and Shalizotan;

[0429] Vanilloid receptor agonists, including but not limited to resinferatoxin or civamide;

[0430] Vanilloid receptor antagonists, including but not limited to capsazepine or GRC-15300;

[0431] beta-adrenergic agents, including but not limited to propranolol;

[0432] Local anesthetics, including but not limited to mexiletine;

[0433] Corticosteroids, including but not limited to dexamethasone and prednisone;

[0434] 5-HT receptor agonists or antagonists, especially 5-HT 1B / 1D agonists, including but not limited to eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan;

[0435] 5-HT2A receptor antagonists, including but not limited to R(+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenethyl)]-4-piperidinol (MDL-100907), eliserin, ketanserin, and pimavanserin;

[0436] Cholinergic (nicotinic) analgesics, including but not limited to isopycylamine (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), and nicotine;

[0437] α2δ ligands, including but not limited to gabapentin Gabapentin GR Gabapentin Pregabalin 3-Methylgabapentin (1[α],3[α],5[α])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-amino methyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

[0438] Cannabinoid receptor ligands, including but not limited to cannabidiol, KHK-6188;

[0439] Metabotropic glutamate subtype 1 receptor antagonist;

[0440] Serotonin reuptake inhibitors, including but not limited to sertraline, sertraline metabolite desmethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cefotaxime, and trazodone;

[0441] Noradrenaline (norepinephrine) reuptake inhibitors, including but not limited to maprotiline, lofepramine, mirtazapine, hydroxyprotriptyline, fezopramine, atomoxetine, mianserin, baprotriptyline, baprotriptyline metabolite hydroxybaprotriptyline, nomifensine, and viloxazine In particular, selective norepinephrine reuptake inhibitors such as reboxetine, in particular (S,S)-reboxetine;

[0442] Dual serotonin-norepinephrine reuptake inhibitors, including but not limited to venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine Milnacipran and imipramine;

[0443] Rho kinase inhibitors;

[0444] Inducible nitric oxide synthase (iNOS) inhibitors include, but are not limited to, S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-S-chloro-S-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-S-chloro-S-pyridinecarbonitrile, 3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolylbutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl)thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboximidamide, NXN-462 and guanidinoethyl disulfide;

[0445] Acetylcholinesterase inhibitors, including but not limited to donepezil;

[0446] Prostaglandin E2 subtype 4 antagonists, including but not limited to N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide, and 4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

[0447] Leukotriene B4 antagonists, including but not limited to 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-pentanoic acid (ONO-4057), and DPC-11870;

[0448] 5-lipoxygenase inhibitors, including but not limited to zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), and 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504);

[0449] Sodium channel blockers, including but not limited to lidocaine, lidocaine plus tetracaine cream (ZRS-201), and eslicarbazepine acetate;

[0450] 5-HT3 antagonists, including but not limited to ondansetron;

[0451] N-methyl-D-aspartate receptor antagonist;

[0452] Voltage-gated calcium channel blockers (e.g., N-type and T-type), including but not limited to ziconotide, Z-160, (R)-2-(4-cyclopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;

[0453] KCNQ openers (e.g. KCNQ2 / 3 (K v 7.2 / 3));

[0454] TPRV1 receptor agonists, including but not limited to capsaicin and pharmaceutically acceptable salts and solvates thereof;

[0455] Nicotinic receptor antagonists, including but not limited to varenicline;

[0456] Nerve growth factor antagonists, including but not limited to tanezumab;

[0457] Endopeptidase stimulators, including but not limited to senrebotase;

[0458] Angiotensin II antagonists, including but not limited to EMA-401;

[0459] Tramadol ER Tapentadol ER

[0460] PDE5 inhibitors, including but not limited to 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyridin- [3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dione Hydrogen-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one pyrimidine-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

[0461] Na v1.7 Blockers, including but not limited to XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893, and those disclosed in WO2011 / 140425, WO2012 / 106499, WO2012 / 112743, WO2012 / 125613, WO2012 / 116440, WO2011026240, U.S. Pat. Nos. 8,883,840 or 8,466,188, or PCT / US2013 / 21535, the entire contents of each of which are hereby incorporated by reference; and

[0462] Na v1.7 Blockers, including but not limited to (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4-diphenylmethylpiperazine- 1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridinyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl] -yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidinyl]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidinyl]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidinyl]-6-yl]ethanone, 2,2,2-trifluoro-1- [1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-1-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[ 1,2-a]pyrazine-1,4'-piperidin]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 1-[1'-[4-methoxy-3-(trifluoromethyl)benzoyl]- 2-Methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine oxazine-1,4'-piperidinyl]-1'-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidinyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidinyl]-1'-yl]methanone.

[0463] In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein in combination with a second therapeutic agent selected from the group consisting of acetaminophen, an NSAID, an opioid analgesic, and combinations thereof, with or without a pharmaceutically acceptable carrier.

[0464] In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt in combination with one or more additional therapeutic agents for treating pain, with or without a pharmaceutically acceptable carrier. In one embodiment, the additional therapeutic agent is selected from the group consisting of acetaminophen, NSAIDs (such as aspirin, ibuprofen, and naproxen), and opioid analgesics. In another embodiment, the additional therapeutic agent is acetaminophen. In another embodiment, the additional therapeutic agent is an NSAID. In another embodiment, the additional therapeutic agent is an opioid analgesic.

[0465] C. Pharmaceutical Compositions and Administration

[0466] In another aspect, the present disclosure provides a pharmaceutical composition comprising a single compound of formula (I) mixed with a pharmaceutically acceptable excipient or a compound of formula (I) in combination with one or more additional therapeutic agents. One of ordinary skill in the art will recognize that the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound described above. Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art and include salts of active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituent moieties present on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (pure or in a suitable inert solvent), or by ion exchange, whereby one basic counterion (base) in the ionic complex replaces another basic counterion (base). Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts or magnesium salts, or similar salts.

[0467] When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (either neat or in a suitable inert solvent), or by ion exchange whereby one acidic counterion (acid) replaces another acidic counterion (acid) in an ionic complex. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and the like; as well as salts derived from relatively nontoxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine salts and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities, which allow the compounds to be converted into either base or acid addition salts.

[0468] Thus, pharmaceutically acceptable salts suitable for use with the subject matter disclosed herein include, for example, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsylate, carbonate, citrate, edetate, edisylate, etopoate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolyllarsanilate, hexanesulfonate, Pharmaceutically acceptable salts include, but are not limited to, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, mucate, naphthylsulfonate, nitrate, pamoate (pamoate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate or theoclorate. Other pharmaceutically acceptable salts can be found in, for example, Remington: The Science and Practice of Pharmacy (20th Edition) Lippincott, Williams & Wilkins (2000).

[0469] In therapeutic and / or diagnostic applications, the compounds of the present disclosure may be formulated for a variety of modes of administration, including systemic administration and topical or localized administration. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).

[0470] Depending on the specific conditions treated, such agents can be formulated into liquid dosage forms or solid dosage forms, and are administered systemically or topically. Agents can be delivered, for example, in the form of timed slow release or sustained slow release known to those skilled in the art. The technology for preparation and application can be found in Remington: The Science and Practice of Pharmacy (20th edition) Lippincott, Williams & Wilkins (2000). Suitable routes can include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intraventricular, intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal or intraocular injection or other delivery modes.

[0471] For injection, the agents of the present disclosure can be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0472] The use of pharmaceutically acceptable inert carriers for preparing the compounds disclosed herein for practicing the present disclosure into dosages suitable for systemic administration is within the scope of the present disclosure. With appropriate selection of carriers and suitable manufacturing practices, the compositions of the present disclosure, particularly those formulated as solutions, can be administered parenterally, such as by intravenous injection. The compounds can be easily formulated into dosages suitable for oral administration using pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the present disclosure to be formulated into tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like for oral ingestion by a subject to be treated (e.g., a patient).

[0473] For nasal or inhaled delivery, the agents of the present disclosure may also be formulated by methods known to those of ordinary skill in the art, and may include, for example, but not limited to, solubilizing, diluting, or dispersing substances such as saline; preservatives such as benzyl alcohol; absorption enhancers; and examples of fluorocarbons.

[0474] Pharmaceutical compositions suitable for use in the present disclosure include compositions in which the active ingredient is contained in an effective amount to achieve its intended purpose. The determination of the effective amount is fully within the capabilities of those skilled in the art, particularly in light of the detailed disclosure provided herein. Typically, compounds according to the present disclosure are effective over a wide dosage range. For example, in the treatment of adults, dosages from 0.01 mg to 1000 mg, from 0.5 mg to 100 mg, from 1 mg to 50 mg, and from 5 mg to 40 mg per day are examples of dosages that can be used. A non-limiting dose is 10 mg to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, the bioavailability of one or more compounds, the adsorption, distribution, metabolism and excretion (ADME) toxicity of one or more compounds, and the preference and experience of the attending physician.

[0475] In addition to the active ingredient, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers, including excipients and adjuvants, which assist in processing the active compound into a preparation that can be used pharmaceutically. Preparations formulated for oral administration may be in the form of tablets, dragees, capsules or solutions.

[0476] Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture and, if desired, processing the mixture of granules after adding suitable auxiliaries, to obtain tablets or dragee cores. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC) and / or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt of alginic acid such as sodium alginate may be added.

[0477] The dragee core is provided with a suitable coating. For this purpose, concentrated sugar solutions can be used, which can optionally comprise gum arabic, talcum powder (talc), polyvinyl pyrrolidone, carbomer gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. Dye or pigment can be added to tablet or dragee coating for identification or characterization of the different combinations of active compound dosage.

[0478] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient mixed with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or a liquid polyethylene glycol (PEG). In addition, stabilizers may be added.

[0479] II. Definitions

[0480] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter described herein belongs.

[0481] Although the following terms with respect to compounds of formula (I) are considered to be well understood by those of ordinary skill in the art, the following definitions are set forth to help explain the subject matter disclosed herein. These definitions are intended to supplement and illustrate, rather than exclude, definitions that would be obvious to those of ordinary skill in the art after reviewing the present disclosure.

[0482] As used herein, whether or not there is the term "optionally" in front, the term substituted (substituted) and substituent (substituent) refer to the ability of changing a functional group on a molecule to another functional group as understood by those skilled in the art, provided that the valence of all atoms is maintained. When more than one position in any given structure can be substituted by more than one substituent selected from a particular group, the substituent can be the same or different at each position. Substituents can also be further substituted (for example, aryl group substituents can be substituted by another substituent, such as another aryl group, which is further substituted at one or more positions).

[0483] Where substituent groups or linking groups are specified by their conventional chemical formula written from left to right, they also encompass chemically identical substituents that would result from writing the structure from right to left, for example, -CH2O- is equivalent to -OCH2-; -C(=O)O- is equivalent to -OC(=O)-; -OC(=O)NR- is equivalent to -NRC(=O)O-, and so on.

[0484] When the term "independently selected" is used, the substituents referred to (e.g., R groups such as groups R1, R2, etc., or variables such as "m" and "n") can be the same or different. For example, both R1 and R2 can be substituted hydrocarbyl, or R1 can be hydrogen and R2 can be substituted hydrocarbyl, etc.

[0485] When referring to a group of substituents herein, the term "a", "an" or "a(n)" means at least one. For example, in the case where a compound is substituted with "an" hydrocarbyl or aryl, the compound is optionally substituted with at least one hydrocarbyl and / or at least one aryl. In addition, in the case where a portion is substituted with an R substituent, the group may be referred to as "R-substituted". In the case where a portion is R-substituted, the portion is substituted with at least one R substituent and each R substituent is optionally different.

[0486] A named "R" or group will generally have a structure recognized in the art as corresponding to the group having that name, unless otherwise specified herein. For purposes of illustration, certain representative "R" groups as set forth above are defined below.

[0487] The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art. Thus, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to conform to the principles of chemical bonding and to give compounds that are not inherently unstable and / or that would be known to one of ordinary skill in the art to be potentially unstable under environmental conditions such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl group is attached to the remainder of the molecule via a ring heteroatom in compliance with the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0488] Unless expressly defined otherwise, a "substituent group" as used herein includes a functional group selected from one or more of the following moieties defined herein:

[0489] As used herein, the term hydrocarbon refers to any chemical group comprising hydrogen and carbon. Hydrocarbons may be substituted or unsubstituted. As will be known to those skilled in the art, all valences must be satisfied when any substitution is made. Hydrocarbons may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic or heterocyclic. Illustrative hydrocarbons are further defined below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl and the like.

[0490] Unless otherwise stated, the term "alkyl" by itself or as part of another substituent means a straight chain (i.e., unbranched) or branched, acyclic or cyclic hydrocarbon group, or combinations thereof, which may be fully saturated, monounsaturated or polyunsaturated, and may include divalent and polyvalent groups, having a specified number of carbon atoms (i.e., C 1-10 means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 carbons). In certain embodiments, the term "alkyl" refers to a C 1-20 (including C1 and C 20 ), including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbon linear (i.e., "straight chain"), branched or cyclic, saturated or at least partially unsaturated, and in some cases fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon groups derived from a hydrocarbon moiety containing between 1 and 20 carbon atoms by the removal of a single hydrogen atom.

[0491] Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers thereof.

[0492] "Branched" refers to a hydrocarbyl group in which a lower hydrocarbyl group such as methyl, ethyl or propyl is attached to a linear hydrocarbyl chain. "Lower hydrocarbyl" refers to a hydrocarbyl group having from 1 to about 8 carbon atoms, for example, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., C 1- C8 alkyl). "Higher alkyl" refers to an alkyl group having from about 10 to about 20 carbon atoms, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. In certain embodiments, "alkyl" specifically refers to C 1- In other embodiments, "alkyl" refers specifically to C 1- C8 branched chain hydrocarbon group.

[0493] The hydrocarbyl group may optionally be substituted with one or more hydrocarbyl group substituents ("substituted hydrocarbyl") which may be the same or different. The term "hydrocarbyl group substituent" includes, but is not limited to, hydrocarbyl, substituted hydrocarbyl, halogen, arylamino, acyl, hydroxyl, aryloxy, hydrocarbyloxy, hydrocarbylthio, arylthio, arylalkyloxy, arylalkylthio, carboxyl, hydrocarbyloxycarbonyl, oxo, and cycloalkyl. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms (wherein the nitrogen substituent is hydrogen, a lower hydrocarbyl (also referred to herein as "hydrocarbylaminohydrocarbyl")), or aryl may be optionally inserted along the hydrocarbyl chain.

[0494] Thus, as used herein, the term "substituted alkyl" includes alkyl groups as defined herein, wherein one or more atoms or functional groups of the alkyl group are replaced by another atom or functional group, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxy, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.

[0495] Unless otherwise stated, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched chain or cyclic hydrocarbon group of from 1 to 20 carbon atoms or heteroatoms, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen atoms, phosphorus atoms and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The one or more heteroatoms O, N, P and S and Si may be located at any interior position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0496] As described above, heteroalkyl groups as used herein include those groups attached to the remainder of the molecule through a heteroatom, such as -C(O)NR', ​​-NR'R", -OR', -SR, -S(O)R and / or -S(O2)R'. Where "heteroalkyl" is recited, followed by a specific heteroalkyl group (such as -NR'R" or a similar group), it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for added clarity. Therefore, the term "heteroalkyl" should not be interpreted herein to exclude specific heteroalkyl groups, such as -NR'R" or a similar group.

[0497] "Cyclic" and "cycloalkyl" refer to non-aromatic monocyclic or polycyclic ring systems of about 3 to about 10 carbon atoms, for example, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Cycloalkyl groups may optionally be partially unsaturated. Cycloalkyl groups may also optionally be substituted with alkyl group substituents, oxo and / or alkylene as defined herein. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be optionally inserted along the cyclic alkyl chain, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl or substituted aryl, thereby providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl and cycloheptyl. Polycyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl, as well as fused ring systems such as dihydronaphthalene and tetrahydronaphthalene, and the like.

[0498] As used herein, the term "cycloalkylalkyl" refers to a cycloalkyl group as defined above separated by an alkylene moiety, such as C 1-20 The alkylene moiety is attached to the parent molecular moiety.Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[0499] The term "cycloheteroalkyl" or "heterocycloalkyl" refers to a non-aromatic ring system, an unsaturated or partially unsaturated ring system, such as a 3- to 10-membered substituted or unsubstituted cycloalkyl ring system, which includes one or more heteroatoms which may be the same or different and are selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P) and silicon (Si), and optionally may include one or more double bonds.

[0500] Cycloheteroalkyl rings may optionally be fused or otherwise attached to other cycloheteroalkyl rings and / or non-aromatic hydrocarbon rings. Heterocyclic rings include those rings having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the term heterocycle refers to a non-aromatic 5-, 6-, or 7-membered ring or polycyclic group in which at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including but not limited to bicyclic groups or tricyclic groups, including fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may be optionally quaternized, and (iv) any of the above heterocycles may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinyl, tetrahydrofuranyl, and the like.

[0501] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms represent cyclic forms of "alkyl" and "heterocycloalkyl", respectively. In addition, for heterocycloalkyl, heteroatoms can occupy the position where the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The terms "cycloalkylene" and "heterocycloalkylene" refer to divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.

[0502] Unsaturated hydrocarbons have one or more double bonds or triple bonds. Examples of unsaturated hydrocarbyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher homologues and isomers. Hydrocarbyl groups limited to hydrocarbyl groups are referred to as "homoalkyl".

[0503] More specifically, the term "alkenyl" as used herein refers to a group derived from C having at least one carbon-carbon double bond by removing a single hydrogen molecule. 2-20 (including C2 and C 20 ). Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-butene-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.

[0504] As used herein, the term "cycloalkenyl" refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

[0505] As used herein, the term "alkynyl" refers to a straight or branched C-chain radical derived from a specified number of carbon atoms containing at least one carbon-carbon triple bond. 2-20 A monovalent group of a hydrocarbon. Examples of the "alkynyl group" include an ethynyl group, a 2-propynyl (propargyl) group, a 1-propynyl group, a pentynyl group, a hexynyl group, a heptynyl group, and the like.

[0506] The term "alkylene" by itself or as part of another substituent refers to a straight or branched divalent aliphatic hydrocarbon group derived from a hydrocarbon group having from 1 to about 20 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The hydrocarbon group can be straight, branched or cyclic. The hydrocarbon group can also be optionally unsaturated and / or substituted with one or more "hydrocarbyl group substituents". One or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "hydrocarbylaminohydrocarbyl") can be optionally inserted along the hydrocarbon group, wherein the nitrogen substituent is a hydrocarbon group as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexylene (-C6H 10 -); -CH=CH-CH=CH-; -CH=CH-CH2-; -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2CsCCH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2) q -N(R)-(CH2) r-, wherein each of q and r is independently an integer from 0 to about 20, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and R is hydrogen or a lower alkyl; methylenedioxy (-O-CH2-O-); and ethylenedioxy (-O-(CH2)2-O-). The alkylene group can have from about 2 to about 3 carbon atoms and can also have 6-20 carbons. Typically, the alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being some embodiments of the present disclosure. "Lower alkyl" or "lower alkylene" is a shorter chain alkyl group or alkylene group, typically having 8 or fewer carbon atoms.

[0507] The term "heteroalkylene" by itself or as part of another substituent means a divalent group derived from a heteroalkyl group, exemplified, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also occupy either or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.

[0508] Unless otherwise stated, the term "aryl" means an aromatic hydrocarbon substituent which may be a single ring or multiple rings (such as from 1 to 3 rings) fused together or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing from 1 to 4 heteroatoms selected from N, O and S (in each individual ring in the case of multiple rings), wherein the nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. The heteroaryl group may be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl , 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents for each of the above-mentioned aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms "arylene" and "heteroarylene" refer to the divalent forms of aryl and heteroaryl, respectively.

[0509] For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthiooxy, arylalkyl), includes both aryl and heteroaryl rings as defined above. Thus, the terms "arylalkyl" and "heteroarylalkyl" are intended to include those groups in which an aryl group or a heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furanylmethyl, and the like), including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced, for example, by an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like). However, the term "haloaryl" as used herein is intended to encompass only aryl groups substituted by one or more halogens.

[0510] In cases where the heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (eg, "3- to 7-membered"), the term "member" refers to a carbon or heteroatom.

[0511] Additionally, as used herein, structures generally represented by the formula:

[0512]

[0513] Refers to a ring structure comprising a substituent R group, such as, but not limited to, aliphatic and / or aromatic cyclic compounds of 3-carbon, 4-carbon, 5-carbon, 6-carbon, 7-carbon and similar structures, including saturated ring structures, partially saturated ring structures and unsaturated ring structures, wherein the R group may be present or absent, and when present, one or more R groups may be substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and the number of the R group are determined by the value of the variable "n", which is an integer generally having a range from 0 to the value of the number of carbon atoms that can be used for substitution on the ring. If the R group is more than one, each R group is substituted on the available carbon of the ring structure rather than being substituted on another R group. For example, the structure above wherein n is 0 to 2 will include such a compound group, which includes but is not limited to:

[0514]

[0515] and the like.

[0516] A dotted line representing a bond in a ring structure indicates that the bond may or may not be present in the ring. That is, a dotted line representing a bond in a ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

[0517] symbol Represents the point of attachment of the moiety to the rest of the molecule.

[0518] When a named atom of an aromatic ring or a heterocyclic aromatic ring is defined as "absent", the named atom is replaced by a direct bond.

[0519] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," and "heterocycloalkyl," "aryl," "heteroaryl," "phosphonate," and "sulfonate," and divalent derivatives thereof) is intended to include both substituted and unsubstituted forms of the indicated radical. Optional substituents for each type of radical are provided below.

[0520] Substituents for the monovalent derivatives and divalent derivatives of hydrocarbon, heterohydrocarbon, cycloalkyl, heterocycloalkyl groups (including those groups commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl groups) may be one or more of a variety of groups selected from, but not limited to, the following in a number ranging from zero to (2m'+1): -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, - SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R' ", -NR"C(O)OR', -NR-C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -CN, CF3, fluorinated C 1-4 Hydrocarbyl and -NO2, where m' is the total number of carbon atoms in such a group. R', R", R'"' and R"" can each independently refer to hydrogen, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted cyclohydrocarbyl, substituted or unsubstituted heterocyclohydrocarbyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted hydrocarbyl, hydrocarbyloxy or thiohydrocarbyloxy groups, or arylhydrocarbyl groups. As used herein, a "hydrocarbyloxy" group is a hydrocarbyl group attached to the remainder of the molecule via a divalent oxygen. When a compound of the present disclosure includes more than one R group, for example, each of the R groups is independently selected, as are each R', R", R'"' and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-membered ring, a 5-membered ring, a 6-membered ring, or a 7-membered ring. For example, -NR'R" is meant to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of ordinary skill in the art will understand that the term "hydrocarbyl" is meant to include groups containing carbon atoms bonded to groups other than hydrogen groups, such as halogenated hydrocarbyl groups (e.g., -CF3 and -CH2CF3) and acyl groups (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0521] Similar to the substituents described above for the hydrocarbyl groups, exemplary substituents for aryl and heteroaryl groups (and their divalent derivatives) are different and are selected in numbers ranging from zero to the total number of open valences on the aromatic ring system, for example: halogen, -OR', -NR'R", -SR', -SiR'R"R'", -OC(O)R', -C(O)R', -C02R', -C(O)NR'R", -OC(O)R', -C02R', -C(O)NR'R", -OC(O)R', -C02R', -C(O)NR'R", -OC(O)R', -C02R', -C(O)NR'R", -OC(O) C(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R'", -NR"C(O)OR', -NR-C(NR'R"R'")=NR"", -NR-C(NR 'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -CN and -NO2, -R', -N3, -CH(Ph)2, fluoro(C 1-4 ) oxy- and fluoro-(C 1-4 ) alkyl; and wherein R', R", R"' and R"" can be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the present disclosure includes more than one R group, for example, each of the R groups is independently selected, as are each R', R", R"' and R"" group when more than one of these groups is present.

[0522] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a group of the formula -TC(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by the formula -A-(CH2) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 4.

[0523] One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by a double bond of the formula -(CRR') s -X'-(C"R'") d-substituted by a substituent of, wherein s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2- or -S(O)2NR'-. The substituents R, R', R" and R'"' may be independently selected from hydrogen, substituted or unsubstituted hydrocarbon, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0524] As used herein, the term "acyl" refers to an organic acid group in which the -OH of the carboxyl group has been replaced by another substituent and has the general formula RC(=O)-, wherein R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a carbocyclic group, a heterocyclic group, or an aromatic heterocyclic group as defined herein. Therefore, the term "acyl" particularly includes aryl acyl groups such as 2-(furan-2-yl)acetyl) groups and 2-phenylacetyl groups. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups are also intended to include amides-RC(=O)NR', ​​esters-RC(=O)OR', ketones-RC(=O)R', and aldehydes-RC(=O)H.

[0525] The terms "alkoxyl" or "alkoxy" are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms "alkyl", "alkenyl" and "alkynyl" are as previously described and may include C 1-20 (including C1 and C 20 ) of a linear, branched or cyclic, saturated or unsaturated oxyhydrocarbon chain, including, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy and n-pentoxy, neopentoxy, n-hexoxy and the like.

[0526] As used herein, the term "alkoxyalkyl" refers to an alkyl-O-alkyl ether, for example, a methoxyethyl group or an ethoxymethyl group.

[0527] "Aryloxy" refers to an aryl-O-group, wherein the aryl group is as previously described, including substituted aryl groups. As used herein, the term "aryloxy" may refer to phenyloxy or hexyloxy, and phenyloxy or hexyloxy substituted with alkyl, substituted alkyl, halogen or alkyloxy.

[0528] "Arylalkyl" refers to an aryl-alkyl-group in which the aryl and alkyl are as previously described, and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0529] "Aryloxy" refers to an aryl-O- group, wherein the aryl group is as previously described. An exemplary aryloxy group is benzyloxy, i.e., C6H5-CH2-O-. The aryloxy group may be optionally substituted.

[0530] "Hydroxycarbonyl" refers to a hydrocarbyl-OC(=O)- group. Exemplary hydrocarbyloxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, and tert-butoxycarbonyl.

[0531] "Aryloxycarbonyl" refers to an aryl-OC(=O)- group. Exemplary aryloxycarbonyl groups include phenoxy-carbonyl and naphthoxy-carbonyl.

[0532] "Aryloxycarbonyl" refers to an aryl-OC(=O)- group. An exemplary aryloxycarbonyl group is benzyloxycarbonyl.

[0533] "Carbamoyl" refers to an amide group of the formula -C(=O)NH2. "Alkylcarbamoyl" refers to an R'RN-C(=O)- group, wherein one of R and R' is hydrogen and the other of R and R' is a hydrocarbyl and / or substituted hydrocarbyl as previously described. "Dihydrocarbylcarbamoyl" refers to an R'RN-C(=O)- group, wherein each of R and R' is independently a hydrocarbyl and / or substituted hydrocarbyl as previously described.

[0534] The term carbonyldioxy as used herein refers to a carbonate group of formula -OC(=O)-OR.

[0535] "Acyloxy" means an acyl-O- group in which the acyl group is as previously described.

[0536] The term "amino" refers to a -NH2 group, and also refers to a nitrogen-containing group as known in the art derived from ammonia by replacing one or more hydrogen groups with an organic group. For example, the terms "acylamino" and "hydrocarbylamino" refer to specific N-substituted organic groups with acyl and hydrocarbyl substituent groups, respectively.

[0537] As used herein, "aminoalkyl" refers to an amino group covalently bonded to an alkylene linker. More specifically, the terms alkylamino, dialkylamino and trialkylamino, as used herein, refer to one, two or three alkyl groups as previously defined, respectively, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR', wherein R' is a alkyl group as previously defined; while the term dialkylamino refers to a group having the structure -NR'R", wherein R' and R" are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR'R"R"', wherein R', R" and R"' are each independently selected from the group consisting of alkyl groups. In addition, R', R" and / or R"' together may optionally be -(CH2) k -, wherein k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino.

[0538] An amino group is -NR'R", wherein R' and R" are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0539] The terms alkylthioether and thioalkyloxy refer to saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) groups attached to the parent molecular moiety through a sulfur atom. Examples of thioalkyloxy moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio and the like.

[0540] "Acylamino" refers to an acyl-NH- group in which the acyl group is as previously described. "Aroylamino" refers to an aroyl-NH- group in which the aroyl group is as previously described.

[0541] The term "carbonyl" refers to a -C(=O)- group, and may include an aldehyde group represented by the general formula RC(=O)H.

[0542] The term "carboxyl" refers to a -COOH group. Such groups are also referred to herein as "carboxylic acid" moieties.

[0543] The term "cyano" refers to a -C≡N group.

[0544] As used herein, the term "halo", "halide" or "halogen" refers to fluoro, chloro, bromo and iodo groups. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1-4 )alkyl" is meant to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.

[0545] The term "hydroxy" refers to an -OH group.

[0546] The term "hydroxyalkyl" refers to an alkyl group substituted with an -OH group.

[0547] The term "mercapto" refers to a -SH group.

[0548] As used herein, the term "oxo" means an oxygen atom double bonded to a carbon atom or another element, including double bonded to the nitrogen of a pyridine ring to prepare a pyridine N-oxide.

[0549] The term "nitro" refers to the -NO2 group, which can also be represented as -N + (=O)-O - .

[0550] The term "thio" refers to compounds previously described herein wherein a carbon atom or an oxygen atom is replaced by a sulfur atom.

[0551] The term "sulfate" refers to a -SO4 group.

[0552] As used herein, the term thiol or thiol refers to a group of formula -SH.

[0553] More particularly, the term "sulfide" refers to a compound having a group of formula -SR.

[0554] The term "sulfone" refers to a compound having a sulfonyl group -S(O2)R'.

[0555] The term "sulfoxide" refers to a compound having a sulfinyl group -S(O)R.

[0556] The term urea refers to a urea group of the formula -NH-CO-NH2.

[0557] "-S(=O)(=NR 10 )-R 11" group is described, for example, in Frings et al., Sulfoximines from a Medicinal Chemist's Perspective: Physicochemical and in vitro Parameters Relevant for Drug Discovery, European Journal of Medicinal Chemistry 126 (2017) 225e245, which is incorporated herein by reference in its entirety.

[0558] Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.

[0559] Certain compounds of the present disclosure may have asymmetric carbon or sulfur atoms (optical centers or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined as (R)- or (S)- or as D- or L- for amino acids in terms of absolute stereochemistry, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those compounds known in the art that are too unstable to be synthesized and / or separated. The present disclosure is intended to include compounds in racemic, non-racemic (scalemic) and optically pure forms. Optically active (R)- and (S)-isomers or D- and L-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0560] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structures; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the present disclosure.

[0561] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure. As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0562] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in the replacement of hydrogen with deuterium or tritium or in the replacement of 13 C- or 14 Compounds having the present structures with a C-enriched carbon in the place of carbon are within the scope of this disclosure.

[0563] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that make up such compounds. For example, the compounds may be substituted with radioactive isotopes such as, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeled. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0564] The compounds of the present disclosure may exist as salts. The present disclosure includes such salts. Examples of suitable salt forms include hydrochlorides, hydrobromides, sulfates, mesylates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts or magnesium salts, or similar salts. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (neat or in a suitable inert solvent), or by ion exchange. Examples of acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid and the like; and salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like. Also included are salts of amino acids such as arginine salts and the like and organic acids such as glucuronic acid or galacturonic acid and the like. Certain specific compounds of the present disclosure contain both basic and acidic functional groups, which allow the compound to be converted into base addition salts or acid addition salts.

[0565] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0566] Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms (including hydrated forms). Typically, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in polymorphic forms or amorphous forms. Typically, all physical forms are equivalent and intended to be within the scope of the present disclosure for the intended use of the present disclosure.

[0567] In addition to salt forms, the present disclosure provides compounds in the form of prodrugs. The prodrugs of the compounds described herein are those compounds that are easily subjected to chemical changes under physiological conditions to provide compounds of the present disclosure. In addition, the prodrugs can be converted into compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, the prodrugs can be slowly converted into compounds of the present disclosure when placed in a transdermal patch reservoir (transdermal patch reservoir) with a suitable enzyme or chemical reagent.

[0568] The term "blocking group" refers to some or all reactive parts of a closed compound and prevents such part from participating in a chemical reaction until the chemical part of the blocking group is removed, for example, at TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, those parts listed and described in the 3rd edition. John Wiley & Sons (1999). It can be advantageous that, when different blocking groups are adopted, each (different) blocking group is removable by different means. The blocking group that is cleaved under completely different reaction conditions allows the difference of such blocking group to be removed. For example, the blocking group can be removed by acid, base and hydrogenolysis. The group such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl is acid-labile, and in the presence of an amino group protected by the unstable Fmoc group of a Cbz group (which is removable by hydrogenolysis) and a base, can be used to protect carboxyl and hydroxyl reactive parts. Carboxylic acid and hydroxy reactive moieties can be blocked with base labile groups such as, but not limited to, methyl, ethyl and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.

[0569] Carboxylic acid and hydroxyl reactive moieties may also be blocked with hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of acid hydrogen bonding may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be blocked with fluoride-labile silylcarbamates.

[0570] Allyl blocking groups are useful in the presence of acid protecting groups and base protecting groups, because the former is stable and can be removed by metal or π-acid catalysts subsequently. For example, the carboxylic acid of allyl blocking can be deprotected by palladium (0) catalyzed reaction in the presence of acid-unstable tert-butyl carbamate or base-unstable acetamine blocking groups. Another form of blocking group is that a compound or intermediate can be attached to its resin. As long as the residue is attached to the resin, the functional group is blocked and cannot react. After releasing from the resin, the functional group can be used to react.

[0571] Typical blocking / protecting groups include, but are not limited to, the following:

[0572]

[0573] In accordance with long-standing patent law practice, when used in this application, including the claims, the terms "a," "an," and "the" mean "one or more." Thus, for example, reference to "a subject" includes more than one subject unless the context clearly indicates otherwise (e.g., more than one subject), etc.

[0574] Throughout this specification and claims, the terms "comprise," "comprises," and "comprising" are used in a non-exclusive sense, except where the context requires otherwise. Likewise, the term "include" and its grammatical variations are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.

[0575] For purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing amounts, sizes, dimensions, ratios, shapes, formulations, parameters, percentages, quantities, characteristics, and other numerical values ​​used in the specification and claims are to be understood in all instances as modified by the term "about", even though the term "about" may not explicitly appear with a value, amount, or range. Therefore, unless otherwise indicated, the numerical parameters set forth in the following specification and the appended claims are not exact and need not be exact, but may be approximate and / or larger or smaller as desired, reflecting tolerances, conversion factors, rounding, measurement errors, etc., and other factors known to those of ordinary skill in the art, depending on the desired properties sought to be obtained by the subject matter disclosed herein. For example, the term "about" when referring to a value may be intended to encompass variations from the specified amount by ±100%, in some embodiments ±50%, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1%, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.

[0576] In addition, when used in conjunction with one or more numbers or numerical ranges, the term "about" should be understood to refer to all such numbers, including all numbers within the range and modifications of the range by extending the boundaries to above and below the numerical values ​​recited. Numerical ranges recited by endpoints include all numbers within the range, such as all integers, including fractions thereof (e.g., the description of 1 to 5 includes 1, 2, 3, 4 and 5, and fractions thereof such as 1.5, 2.25, 3.75, 4.1 and the like) and any range within the range. Example

[0577] The following examples have been included to provide guidance to those of ordinary skill in the art for practicing representative embodiments of the subject matter disclosed herein. Based on the present disclosure and the general level of those skilled in the art, the skilled person will appreciate that the following examples are intended to be exemplary only, and that many variations, modifications, and changes may be employed without departing from the scope of the subject matter disclosed herein. The following synthetic descriptions and specific examples are intended only for illustrative purposes and should not be construed as limiting in any way the compounds of the present disclosure prepared by other methods.

[0578] Synthesis Procedure

[0579] Exemplary compounds are prepared via several general synthetic routes as described in the examples below. Any of the disclosed compounds of the present invention can be prepared according to one or more of these synthetic routes or specific examples, or via modifications thereof as would be expected by one of ordinary skill in the art.

[0580] Intermediate 1: 2-(4-Fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid

[0581] Method A

[0582]

[0583] A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (500mg, 2.22mmol), 4-fluoro-2-methoxyphenol (278μL, 2.44mmol) and cesium carbonate (1806mg, 5.54mmol) in MeCN (5mL) was stirred at 80°C for 18h. After cooling, the content was diluted with 20mL water and acidified to pH 5 via careful addition of 2N HCl, then stirred for 2h. The precipitate was collected by filtration, washed with water and dried under vacuum to give 2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (695mg, 2.10mmol, 94.6% yield) as a beige solid. MS, ES + m / z 332.0[M+H]+.

[0584] 1 H-NMR(400MHz,DMSO-d6)δ13.74(br.s.,1H),8.67(br.s.,1H),8.50(s,1H),7.22(dd, J=8.97,5.68Hz,1H),7.10(dd,J=11.12,2.78Hz,1H),6.79-6.86(m,1H),3.70(s,3H).

[0585] Intermediate 2: 2-(Benzotriazol-1-yloxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine- 3-Formamide

[0586] Method B

[0587]

[0588] A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (508 mg, 2.25 mmol), 3-methylsulfonylaniline (424 mg, 2.48 mmol), HBTU (854 mg, 2.25 mmol) and DIPEA (981 μL, 5.63 mmol) in chloroform (10 mL) was stirred at room temperature for 40 h. The solvent was removed under N2 flow, and the residue was treated with water / MeOH (5: 1). The mixture was sonicated briefly and then stirred at room temperature for 24 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 2-(benzotriazole-1-yloxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (665 mg, 1.39 mmol, 61.9% yield) as a beige solid. MS, ES+m / z 448.0[M+H]+.

[0589] 1H-NMR (400MHz, DMSO-d6) δ11.37(s,1H),8.88(d,J=2.27Hz,1H),8.72(d,J=1.01Hz,1H),8.43(s,1H),8.20(d ,J=8.59Hz,1H),8.03-8.07(m,1H),7.83(d,J=8.59Hz,1H),7.67-7.77(m,3H),7.54-7.58(m,1H),3.25(s,3H).

[0590] Intermediate 3: 6-Chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxylate amine

[0591]

[0592] Step 1: Synthesis of 2,6-dichloro-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0593] Method C

[0594]

[0595] A mixture of 2,6-dichloropyridine-3-carbonyl chloride (200 mg, 0.950 mmol), 3-methylsulfonylaniline (179 mg, 1.05 mmol) and DIPEA (414 μL, 2.38 mmol) in chloroform (5 mL) was stirred at room temperature for 24 h. The contents were treated with 10% NaCO, extracted with CHCl (3×), and the solvent was removed in vacuo to give 2,6-dichloro-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (378 mg, 1.10 mmol, 115% yield) as a yellow foam, which was used without further purification. MS, ES+m / z 344.9[M+H]+.

[0596] Step 2: Synthesis of 6-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0597] Method D

[0598]

[0599] By crude 2,6-dichloro-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (276mg, 0.800mmol), 4-fluoro-2-methoxyphenol (91.1μL, 0.800mmol) and cesium carbonate (273mg, 0.840mmol) in MeCN (2mL) mixture stirred at room temperature for 23h. The content was diluted with 20mL water and stirred at room temperature for 2h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 6-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (242mg, 0.536mmol, 67.0% yield) as a white solid. MS, ES+m / z 451.1[M+H]+.

[0600] 1 H-NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.41(s,1H),8.19(d,J=7.83Hz,1H),7.96(d,J=7.58Hz,1H),7.63-7.71(m ,2H),7.32-7.39(m,2H),7.12(dd,J=10.74,2.91Hz,1H),6.86(td,J=8.46,2.78Hz,1H),3.73(s,3H),3.22(s,3H).

[0601] Intermediate 4: 2-Chloro-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide

[0602] Method E

[0603]

[0604] A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carbonyl chloride (250mg, 1.02mmol), 3-methylsulfonylaniline (193mg, 1.13mmol) and DIPEA (446μL, 2.56mmol) in chloroform (5mL) was stirred at room temperature for 24h. The content was treated with 10% Na2CO3, extracted with CHCl3 (3×), and the solvent was removed in a vacuum to give a yellow foam, which was ground with MeOH / 2% Na2CO3 (1:10). The solid was collected by filtration, washed with water and dried under vacuum to give 2-chloro-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (175mg, 0.462mmol, 45.1% yield) as a beige solid. MS, ES+m / z 379.0[M+H]+. 1 H-NMR (400MHz, DMSO-d6) δ11.17(s,1H),9.04(s,1H),8.72(d,J=2.27Hz,1H),8.35(s,1H),7.94(d,J=7.83Hz,1H),7.67-7.76(m,2H),3.25(s,3H).

[0605] Example 1: N-(1,3-benzothiazol-6-yl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyrrolidone Pyridine-3-carboxamide

[0606] Method F

[0607]

[0608] A mixture of 2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (Intermediate 1) (30.0 mg, 0.090 mmol), 1,3-benzothiazole-6-amine (15.0 mg, 0.100 mmol), HBTU (37.8 mg, 0.100 mmol) and DIPEA (29.3 mg, 39.4 μL, 0.230 mmol) in chloroform (2 mL) was stirred at room temperature for 20 h. The solvent was removed under a stream of N2, and the residue was treated with water / MeOH (3: 1). The mixture was sonicated briefly and then stirred at room temperature for 3 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give N-(1,3-benzothiazol-6-yl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (35.4 mg, 0.0764 mmol, 84.3% yield) as a beige solid. MS, ES+ m / z 464.0[M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.32(s,1H),8.70(d,J=2.02Hz,1H),8.66-8.68(m,1H),8.53(d,J=2.53Hz,1H),8.09(d,J=8.84Hz,1 H), 7.75 (dd, J=8.84, 2.02Hz, 1H), 7.35 (dd, J=8.84, 5.81Hz, 1H), 7.11 (dd, J=10.74, 2.91Hz, 1H), 6.85 (td, J=8.53, 2.91Hz, 1H), 3.72 (s, 3H).

[0609] The following compounds have been synthesized according to Method F:

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619] Example 21: 2-(2,4-dichlorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3- Formamide

[0620] Method G

[0621]

[0622] A mixture of 2-(benzotriazol-1-yloxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (Intermediate 2) (50.0 mg, 0.100 mmol), 2,4-dichlorophenol (20.5 mg, 0.130 mmol) and cesium carbonate (102 mg, 0.310 mmol) in MeCN (3 mL) was stirred at 50 °C for 1 h. The solvent was removed under a stream of N2, and the residue was treated with water / MeOH (4:1). The mixture was sonicated briefly and then stirred at room temperature for 24 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 2-(2,4-dichlorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (43.6 mg, 0.0863 mmol, 82.4% yield) as an off-white solid. MS, ES + m / z 505.0[M+H] + .

[0623] 1 H-NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.71-8.73 (m, 1H), 8.63 (d, J = 2.53Hz, 1H), 8.39-8.42 ( m,1H),7.97-8.01(m,1H),7.82-7.84(m,1H),7.66-7.74(m,2H),7.53-7.60(m,2H),3.24(s,3H).

[0624] The following compounds have been synthesized according to Method G:

[0625]

[0626]

[0627]

[0628]

[0629] The following compounds have been synthesized according to Method G:

[0630]

[0631]

[0632]

[0633]

[0634] Example 33: 2-(2,6-dimethylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine- 3-Formamide

[0635] Method H

[0636]

[0637] A mixture of 2-chloro-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (Intermediate 4) (59 mg, 0.160 mmol), 2,6-dimethylphenol (20.9 mg, 0.170 mmol) and cesium carbonate (152 mg, 0.470 mmol) in MeCN (2 mL) was stirred at room temperature for 18 h. The contents were diluted with EtOAc, washed with water (3×), brine (1×), dried over MgSO, filtered and the solvent removed in vacuo to give a residue which was purified by automated normal phase chromatography (0%-100% EtOAc / heptane, 4 g silica gel cartridge) to give 2-(2,6-dimethylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (32.6 mg, 0.0702 mmol, 45.1% yield) as a white foam. MS,ES + m / z 465.0[M+H] + .

[0638] 1 H-NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.64(dd,J=2.53,1.01Hz,1H),8.59(d,J=2.53Hz,1H),8.42-8.4 4(m,1H),7.98(dt,J=7.58,1.89Hz,1H),7.66-7.73(m,2H),7.08-7.16(m,3H),3.23(s,3H),2.07(s,6H).

[0639] The following compounds have been synthesized according to Method H:

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650] The following compounds have been synthesized according to Method H:

[0651]

[0652]

[0653]

[0654] The following compounds have been synthesized according to Method H:

[0655]

[0656]

[0657] Example 66: 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyrrolidone Pyridine-3-carboxamide

[0658]

[0659] Step 1: Synthesis of 2-chloro-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide

[0660]

[0661] A mixture of HBTU (185 mg, 0.490 mmol), DIPEA (170 μL, 0.980 mmol), 2-chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid (100 mg, 0.440 mmol) and 3-methylsulfonylaniline (79.7 mg, 0.470 mmol) in chloroform (5 mL) was stirred at room temperature for 4 days (for convenience). The contents were treated with 5% Na2CO3 and extracted with CHCl3 (3×). The organic extracts were combined and the solvent was removed in vacuo to give a residue that was purified by automated normal phase chromatography (0%-100% EtOAc / heptane, 12 g silica gel cartridge) to give 2-chloro-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (86.2 mg, 0.229 mmol, 51.3% yield) as a yellow solid. MS, ES + m / z 379.0[M+H] + .

[0662] 1H-NMR (400MHz, DMSO-d6) δ11.19(s,1H),8.48(d,J=7.83Hz,1H),8.37(t,J=1.77Hz,1H),8.17(d, J=7.58Hz,1H),7.92(dt,J=7.71,1.83Hz,1H),7.72-7.76(m,1H),7.67-7.72(m,1H),3.25(s,3H).

[0663] Step 2: Synthesis of 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide

[0664]

[0665] A mixture of 2-chloro-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (40.0 mg, 0.110 mmol), 4-fluoro-2-methoxyphenol (15.1 μL, 0.130 mmol) and cesium carbonate (103 mg, 0.320 mmol) in MeCN (2 mL) was stirred at 80 °C for 1 h and then at room temperature overnight. The contents were diluted with EtOAc, washed with water (3x), brine (1x), dried over MgSO4, filtered and the solvent removed in vacuo to give a residue which was purified by automated normal phase chromatography (0%-100% EtOAc / heptane, 4 g silica gel cartridge) to give 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (46.5 mg, 0.0960 mmol, 90.9% yield) as a yellow solid. MS, ES + m / z 485.0[M+H] + .

[0666] 1 H-NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.42(s,1H),8.37(d,J=7.33Hz,1H),7.96(d,J=7.58Hz,1H),7.75(d,J=7.58Hz,1H),7.65-7 .73(m,2H),7.33(dd,J=8.72,5.94Hz,1H),7.12(dd,J=10.61,2.78Hz,1H),6.85(td,J=8.46,2.78Hz,1H),3.69(s,3H),3.23(s,3H).

[0667] Example 67: 4-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyrrolidone Pyridine-3-carboxamide

[0668] Method I

[0669]

[0670] Step 1: Synthesis of ethyl 4-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylate

[0671]

[0672] A mixture of 4-chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid ethyl ester (150mg, 0.668mmol), 4-fluoro-2-methoxyphenol (95.1μL, 0.834mmol) and cesium carbonate (653mg, 2.00mmol) in MeCN (3mL) was stirred at room temperature for 1h. The contents were treated with water and stirred at room temperature for 3 days (for convenience). The precipitate was collected by filtration, washed with water and dried under vacuum to give 4-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid ethyl ester (186mg, 0.518mmol, 77.5% yield) as an off-white solid. MS, ES + m / z 360.0[M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ9.03(s,1H),7.35(dd,J=8.84,5.81Hz,1H),7.23(dd,J=10.61,3 .03Hz,1H),6.88-6.95(m,2H),4.37(q,J=7.07Hz,2H),3.76(s,3H),1.33(t,J=7.07Hz,3H).

[0673] Step 2: Synthesis of 4-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid

[0674]

[0675] A mixture of ethyl 4-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylate (182 mg, 0.507 mmol) and lithium hydroxide monohydrate (23.4 mg, 0.558 mmol) in THF (2 mL) and water (0.1 mL) was stirred at room temperature for 7 days (for convenience). The solvent was removed with N2 flow, and the contents were diluted with water (15 mL). The pH was reduced to pH 5 by careful addition of 6N HCl. After stirring for 3 h, the precipitate was collected by filtration, washed with water and dried under vacuum to give 4-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid (102.6 mg, 0.3098 mmol, 61.1% yield) as a white solid. MS, ES + m / z 332.0[M+H] + .

[0676] 1 H-NMR(400MHz,DMSO-d6)δ13.83(br.s.,1H),9.00(s,1H),7.35(dd,J=8.72,5.68Hz,1H), 7.23 (dd, J=10.74, 2.65Hz, 1H), 6.92 (td, J=8.46, 3.03Hz, 1H), 6.86 (s, 1H), 3.76 (s, 3H).

[0677] Step 3: Synthesis of 4-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide

[0678]

[0679] A mixture of 4-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid (46.0 mg, 0.139 mmol), 3-methylsulfonylaniline (26.2 mg, 0.153 mmol), HBTU (57.9 mg, 0.153 mmol) and DIPEA (60.5 μL, 0.347 mmol) in chloroform (2 mL) was stirred at room temperature for 18 h. The solvent was removed under a stream of N2, and the residue was treated with water / MeOH (5:1). The mixture was sonicated briefly and then stirred at room temperature for 24 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 4-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (55.0 mg, 0.114 mmol, 81.7% yield) as a white solid. MS,ES +m / z 485.0[M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.93(s,1H),8.41(s,1H),7.95(d,J=7.33Hz,1H),7.65-7.73(m,2H),7.42(dd,J= 8.84, 5.81Hz, 1H), 7.22 (dd, J = 10.61, 2.78Hz, 1H), 6.96 (s, 1H), 6.92 (td, J = 8.46, 2.78Hz, 1H), 3.77 (s, 3H), 3.23 (s, 3H).

[0680] The following compounds have been synthesized according to Method I:

[0681]

[0682]

[0683]

[0684]

[0685] Example 73: 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[2-(dimethylamino)-4-pyridinyl]-6- (Trifluoromethyl)pyridine-3-carboxamide

[0686] Method J

[0687]

[0688] Step 1: Synthesis of 4-chloro-6-(trifluoromethyl)pyridine-3-carbaldehyde

[0689]

[0690] At -78 ° C, LiHMDS (149.66 mL, 149.66 mmol) was slowly added to a stirred solution of 4-chloro-2-(trifluoromethyl)pyridine (24.7 g, 136.06 mmol) in THF (2 mL). The solution was stirred at -78 ° C for 2 hours and then stirred at 0 ° C for 10 minutes. The solution was cooled back to -78 ° C, and then N, N-dimethylformamide (12.64 mL, 163.27 mmol) was added. The solution was allowed to return to room temperature overnight. Dilute hydrochloric acid (0.5N, 200 mL) was added. The solution was extracted with ethyl acetate (3 × 200 mL). The combined ethyl acetate solution was washed with brine (100 mL) and dried over sodium sulfate. The solution was filtered and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate / hexanes (0%-40%) to give 4-chloro-6-(trifluoromethyl)pyridine-3-carbaldehyde (5.7 g, 27.22 mmol, 20% yield).

[0691] Step 2: Synthesis of 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carbaldehyde

[0692]

[0693] To the stirring solution of 2-chloro-4-(trifluoromethoxy)phenol (2.79g, 13.12mmol), 4-chloro-6-(trifluoromethyl)pyridine-3-carboxaldehyde (2.5g, 11.93mmol) in acetonitrile (50mL) was added potassium carbonate (3.3g, 23.86mmol). The solution was heated at 80°C for 3 hours. The solution was cooled to room temperature. Ethyl acetate (50mL) was added. The solution was filtered and concentrated. The residue was purified by silica gel chromatography (eluted with ethyl acetate / heptane (0%-30%) to give 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxaldehyde (4.6g, 11.928mmol, 99.98% yield) as a colorless oil.

[0694] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.89 (s, 1H) 7.33-7.42 (m, 2H) 7.49-7.55 (m, 1H) 9.15 (s, 1H) 10.68-10.75 (m, 9H).

[0695] Step 3: Synthesis of 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylic acid

[0696]

[0697] Acetonitrile (50mL) is added to a stirred solution of sodium dihydrogen phosphate monohydrate (7.53g, 54.58mmol) and sodium chlorite (3.7g, 32.75mmol) in water (50mL). 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxaldehyde (4.21g, 10.92mmol) is added afterwards. The solution is stirred at room temperature for 3 hours. Sodium sulfite (aqueous, 10%, 0.5mL) is added. The solution is stirred at room temperature for 30min. The solution is concentrated. Hydrochloric acid (1N, 2mL) is added. The white precipitate is collected by filtration. It is washed with water and dried to give 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylic acid (4.2g, 10.4mmol, 95.4% yield) as a white solid.

[0698] 1 H NMR (400 MHz, chloroform-d) δ ppm 6.88 (s, 1H) 7.31 (d, J=1.52 Hz, 2H) 7.48-7.57 (m, 1H) 9.31 (s, 1H).

[0699] Step 4: Synthesis of 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[2-(dimethylamino)-4-pyridinyl]-6-(trifluoromethyl)pyridine-3-carboxamide

[0700]

[0701] At room temperature, oxalyl chloride (23.7 mg, 0.19 mmol) was added to a solution of 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylic acid (50 mg, 0.1200 mmol) stirred in DCM (2 mL). DMF (one drop) was added. The solution was stirred at room temperature for 1 hour. The solution was concentrated. The residue was dissolved in DCM (2 mL). Triethylamine (0.03 mL, 0.25 mmol) and N2, N2-dimethylpyridine-2,4-diamine (20.5 mg, 0.15 mmol) were added. The solution was stirred at room temperature for 1 hour. The solution was extracted once with hydrochloric acid (1 N, 2 mL) and concentrated. The residue was purified by preparative reverse phase HPLC to give 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[2-(dimethylamino)-4-pyridinyl]-6-(trifluoromethyl)pyridine-3-carboxamide (21 mg, 0.04 mmol, 32.4% yield) as a white solid.

[0702] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.33 (s, 6H) 6.91 (s, 1H) 7.37 (d, J=9.85 Hz, 1H) 7.48-7.60 (m, 3H) 8.03 (s, 1H) 9.18 (s, 1H) 10.48 (br. s., 1H).

[0703] The following compounds have been synthesized according to Method J:

[0704]

[0705]

[0706]

[0707]

[0708]

[0709] Example 83: 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(1-pyridin-1-ium-3-yl)-6-(trifluoromethoxy)phenoxy (fluoromethyl)pyridine-3-carboxamide

[0710] Method K

[0711]

[0712] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-pyridinyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Example LI-1971, 100 mg, 0.21 mmol) was added to a screw cap vial and dissolved in DCM (5 mL). m-CPBA (56 mg, 0.25 mmol) was added and the mixture was allowed to stir at room temperature for 15 minutes. The volatiles were evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC (high pH method) to provide the title compound (81 mg, 0.16 mmol, 78% yield) as a colorless glass. MS, ES + m / z 494[M+H] + .

[0713] The following compounds have been synthesized according to Method K:

[0714]

[0715]

[0716]

[0717]

[0718] Example 91: N-[3-(Methylsulfonylimino)phenyl]-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethoxy)phenyl Methyl)pyridine-3-carboxamide

[0719] Method L

[0720]

[0721] Step 1: Synthesis of methyl 4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylate

[0722]

[0723] 4-chloro-6-(trifluoromethyl)pyridine-3-methyl-formiate (1g, 4.2mmol) is added to the 20mL scintillation vial equipped with magnetic stirring bar, and is dissolved in acetonitrile (10mL).Add 4-(trifluoromethoxy)phenol (892mg, 5mmol) and cesium carbonate (2.72g, 8.34mmol), and the mixture is heated to 50 ℃ and continues 1 hour.After being cooled to room temperature, the mixture is diluted with water (100mL) and extracted with dichloromethane.The dichloromethane solution merged is dried over magnesium sulfate and concentrated, to provide the oil (1.2g, 3.15mmol, 75% yield) containing the product of expectation.

[0724] Step 2: Synthesis of 4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylic acid

[0725]

[0726] 4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylate (1.2 g, 3.15 mmol) was added to a round-bottomed flask equipped with a magnetic stirrer and dissolved in THF (9 mL) and water (1 mL). Excess sodium hydroxide was added and the mixture was allowed to stir at room temperature for 1 hour. The resulting mixture was diluted with water (200 mL) and made highly acidic by carefully adding 6N HCl. The resulting solution was extracted with dichloromethane and the combined organic extracts were dried over magnesium sulfate. Concentration under reduced pressure provided a clear oil (1.1 g, 3.0 mmol), which solidified when standing and was used without further purification. MS, ES + m / z 368[M+H] + .

[0727] Step 3: Synthesis of N-[3-(methylsulfonylimino)phenyl]-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide

[0728]

[0729] A screw cap vial was loaded with 4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylic acid (150 mg, 0.41 mmol), and DMF (3 mL) was added. Triethylamine (115 μL, 0.82 mmol) and HBTU (186 mg, 0.49 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. 3-(methylsulfonylimino)aniline (70 mg, 0.41 mol) was added, and stirring was continued for another 12 hours. The crude mixture was purified by preparative reverse phase HPLC (high pH method) to provide the desired product (97 mg, 0.19 mmol, 46% yield) as a beige solid. MS, ES + m / z520.0[M+H] + . 1 HNMR(400MHz,DMSO-d6)δppm 3.06(s,3H)4.25(s,1H)7.26(s,1H)7.44-7.50(m,2H)7.51-7.57(m,2H)7.60(t,J=7.96 Hz, 1H) 7.69 (d, J = 7.83Hz, 1H) 7.90 (d, J = 8.08Hz, 1H) 8.35 (t, J = 1.89Hz, 1H) 8.98 (s, 1H).

[0730] The following compounds have been synthesized according to Method L:

[0731]

[0732]

[0733] Example 93: 4-(4-Fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)- 1-(2-Yl)pyridine-3-carboxamide

[0734] Method M

[0735]

[0736] Step 1: Synthesis of 4-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid methyl ester

[0737]

[0738] 4-chloro-6-(trifluoromethyl)pyridine-3-methyl-formiate (1g, 4.2mmol) is loaded into round-bottomed flask and is dissolved in acetonitrile (10mL).Add cesium carbonate (2.7g, 8.3mmol) and 4-fluoro-2-methyl-phenol (632mg, 5.0mmol), and the mixture is heated to 50 ℃ and continues 1 hour under stirring.After being cooled to room temperature, the mixture is diluted with water (150mL) and extracted with dichloromethane.The dichloromethane extract merged is dried over magnesium sulfate and concentrated under reduced pressure, to give clarifying oil (1.13g, 3.42mmol, 82% yield), it is used without further purification.

[0739] Step 2: Synthesis of 4-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid

[0740]

[0741] 4-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-formic acid methyl ester (1.4g, 4.2mmol) is loaded into a round-bottomed flask and dissolved in THF (12mL) and water (2mL). Sodium hydroxide (960mg, 21mmol) is added, and the mixture is allowed to stir at room temperature for 1 hour. The crude mixture is diluted with water (200mL), and by adding 6N HCl, it is made highly acidic. The resulting turbid solution is extracted with dichloromethane, and the combined dichloromethane extracts are dried over magnesium sulfate and concentrated under reduced pressure to give a colorless solid (980mg, 3.1mmol, 74% yield), which is used without further purification.

[0742] Step 3: Synthesis of 4-(4-fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide

[0743]

[0744] 4-(4-Fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid (150mg, 0.48mmol) was loaded into a screw cap vial equipped with a magnetic stirrer and dissolved in DMF (3mL). Triethylamine (133μL, 0.95mmol) and HBTU (217mg, 0.57mmol) were added, and the mixture was stirred at room temperature for 10 minutes. 3-(Methylsulfonylimino)aniline (81mg, 0.48mmol) was added, and stirring was continued for another 12 hours. Purification by preparative reverse phase HPLC (high pH method) provided the title compound (129mg, 0.28mmol, 58% yield) as a beige solid. MS, ES + m / z 468.0[M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm 2.13 (s, 3H) 3.53 (s, 3H) 5.66-5.88 (m, 2H) 6.81-6.95 (m, 2H) 7.06-7.35 (m, 6H) 9.05 (s, 1H).

[0745] The following compounds have been synthesized according to Method M:

[0746]

[0747]

[0748]

[0749] The following compounds have been synthesized according to Method M:

[0750]

[0751]

[0752]

[0753] The following compounds have been synthesized according to Method M:

[0754]

[0755]

[0756]

[0757] The following compounds have been synthesized according to Method M:

[0758]

[0759]

[0760]

[0761] Example 109: 2-(4-Fluoro-2-methyl-phenoxy)-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridinyl Pyridine-3-carboxamide

[0762]

[0763] Step 1: Synthesis of 2-chloro-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide

[0764]

[0765] A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carbonyl chloride (250 mg, 1.02 mmol), 2-methoxypyridine-4-amine (127 mg, 1.02 mmol) and DIPEA (446 μL, 2.56 mmol) in chloroform (5 mL) was stirred at room temperature for 24 h. The contents were treated with 10% NaCO, extracted with CHCl (3×), and the solvent was removed in vacuo to give 2-chloro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (290 mg, 0.874 mmol, 85.3% yield) as a pink solid. The material was used without further purification. MS, ES + m / z 379.0[M+H] + .

[0766] Step 2: Synthesis of 2-(4-fluoro-2-methyl-phenoxy)-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide

[0767]

[0768] A mixture of 2-chloro-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (84.0 mg, 0.253 mmol), 4-fluoro-2-methyl-phenol (47.9 mg, 0.380 mmol) and cesium carbonate (248 mg, 0.760 mmol) in MeCN (3 mL) was stirred at 80 °C for 2 h. After cooling, the contents were diluted with EtOAc, washed with water (3×), brine (1×), dried over MgSO 4 , filtered and the solvent removed in vacuo to give a residue, which was triturated with 10% MeCN / water to give a precipitate, which was collected by filtration, washed with water and dried under vacuum to give 2-(4-fluoro-2-methyl-phenoxy)-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (50.0 mg, 0.119 mmol, 46.9% yield) as a beige solid. MS, ES + m / z 422.2[M+H] + .

[0769] 1 H-NMR (400MHz, DMSO-d6) δ10.99(s,1H),8.68(s,1H),8.57(s,1H),8.11(d,J= 5.81Hz,1H),7.18-7.30(m,4H),7.08-7.15(m,1H),3.85(s,3H),2.08(s,3H).

[0770] Example 110: 2-(4-Fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl) Pyridine-3-carboxamide

[0771]

[0772] A solution of 2-(4-fluoro-2-methyl-phenoxy)-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (50.0 mg, 0.119 mmol) in HBr (33% in HOAc) (538 μL, 2.97 mmol) was stirred at 80 °C for 18 h. After cooling, the contents were quenched by the slow addition of 5% Na2CO3. The aqueous layer was extracted with EtOAc, washed with 5% Na2CO3 (3×), brine (1×), dried over MgSO4, filtered and the solvent removed in vacuo to give 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (26.0 mg, 0.0638 mmol, 53.8% yield) as a tan solid. MS, ES + m / z 408.0[M+H] + .

[0773] 1 H-NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.64(dd,J=2.53,1.01Hz,1H),8.59(d,J=2.53Hz,1H),8.42-8.4 4(m,1H),7.98(dt,J=7.58,1.89Hz,1H),7.66-7.73(m,2H),7.08-7.16(m,3H),3.23(s,3H),2.07(s,6H).

[0774] Example 111: 5-Bromo-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxylate Amide

[0775]

[0776] Step 1: Synthesis of 5-bromo-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid methyl ester

[0777]

[0778] A mixture of 5-bromo-2-chloronicotinic acid methyl ester (100 mg, 0.399 mmol), 4-fluoro-2-methoxyphenol (47.8 μL, 0.419 mmol) and cesium carbonate (325 mg, 0.998 mmol) in MeCN (3 mL) was stirred at 50 ° C for 20 h. The contents were diluted with EtOAc, washed with 2% Na2CO3 (3×), brine (1×), dried over MgSO4, filtered and the solvent removed in vacuo to give 5-bromo-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid methyl ester (90.7 mg, 0.255 mmol, 63.8% yield) as a tan solid. The material was carried forward without further purification. MS, ES + m / z355.9 / 357.9[M+H] + .

[0779] 1 H-NMR (400MHz, DMSO-d6) δ8.40 (s, 2H), 7.18 (dd, J=8.84, 5.81Hz, 1H), 7.08 (dd, J=10.74,2.91Hz,1H),6.80(td,J=8.46,2.78Hz,1H),3.87(s,3H),3.69(s,3H).

[0780] Step 2: Synthesis of 5-bromo-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid

[0781]

[0782] A mixture of 5-bromo-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid methyl ester (65 mg, 0.183 mmol) and lithium hydroxide monohydrate (38.3 mg, 0.913 mmol) in THF (1 mL) and water (1 mL) was stirred at 50 °C for 2 h. After cooling, the pH was lowered to pH 5 by careful addition of 6N HCl. After cooling to 0 °C, the precipitate was collected by filtration, washed with cold water and dried under vacuum to give 5-bromo-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (39.3 mg, 0.115 mmol, 62.9% yield) as a white solid. MS, ES + m / z 341.9 / 343.9[M+H] + . 1 H-NMR(400MHz,DMSO-d6)δ13.56(br.s.,1H),8.33-8.37(m,2H),7.17(dd,J=8.72,5.9 4Hz, 1H), 7.07 (dd, J=10.86, 2.78Hz, 1H), 6.79 (td, J=8.46, 2.78Hz, 1H), 3.69 (s, 3H).

[0783] Step 3: Synthesis of 5-bromo-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0784]

[0785] A mixture of HBTU (42.7 mg, 0.113 mmol), DIPEA (39.2 μL, 0.225 mmol), 5-bromo-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (35 mg, 0.102 mmol) and 3-methylsulfonylanilide (18.4 mg, 0.107 mmol) in chloroform (3 mL) was stirred at room temperature for 18 h. The contents were treated with 5% NaCO and extracted with CHCl (3×). The solvent was removed in vacuo to give a residue which was purified by automated normal phase chromatography (0%-100% EtOAc / heptane, 4 g silica gel cartridge) to give 5-bromo-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (13.0 mg, 0.0262 mmol, 25.6% yield) as a white solid. MS,ES + m / z 494.9 / 496.9[M+H] + .

[0786] 1 H-NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.40-8.42(m,1H),8.34-8.36(m,2H),7.95-7.98(m,1H),7.64-7.71(m,2H),7 .29(dd,J=8.84,6.06Hz,1H),7.08(dd,J=10.74,2.91Hz,1H),6.82(td,J=8.59,3.03Hz,1H),3.70(s,3H),3.22(s,3H).

[0787] Example 112: 5-Cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine- 3-Formamide

[0788]

[0789] Step 1: Synthesis of 2-chloro-5-cyclopropyl-pyridine-3-carboxylic acid methyl ester

[0790]

[0791] To a solution of 5-bromo-2-chloronicotinate (200 mg, 0.799 mmol) in 1,4-dioxane (5 mL) was added cyclopropylboronic acid (206 mg, 2.40 mmol), tripotassium phosphate (508 mg, 2.40 mmol) and tetrakis(triphenylphosphine)palladium(0) (46.1 mg, 0.0399 mmol). The mixture was heated at 100 ° C in a microwave reactor for 30 min. The reaction was completed by LCMS. The reaction mixture was diluted with EtOAc, washed with water (1×), 5% NH4Cl (1×), water (1×), brine (1×), dried over MgSO4, filtered and the solvent removed in vacuo to give a yellow residue which was purified by automated normal phase chromatography (0%-100% EtOAc / heptane, 12 g silica gel cartridge) to give 2-chloro-5-cyclopropyl-pyridine-3-carboxylic acid methyl ester (73.0 mg, 0.345 mmol, 43.2% yield) as a colorless oil. MS, ES + m / z 212.0[M+H] + . 1 H-NMR(400MHz,DMSO-d6)δ8.41(d,J=2.53Hz,1H),7.86(d,J=2.53Hz,1H),3.8 7(s,3H),2.05(tt,J=8.46,5.05Hz,1H),1.02-1.09(m,2H),0.79-0.85(m,2H).

[0792] Step 2: Synthesis of 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid methyl ester

[0793]

[0794] A mixture of 2-chloro-5-cyclopropyl-pyridine-3-formic acid methyl esters (71mg, 0.336mmol), 4-fluoro-2-methoxyphenol (47.8μL, 0.419mmol) and cesium carbonate (327.91mg, 1.01mmol) in MeCN (2mL) was stirred at 80°C for 24h. After cooling, the solvent was removed under N2 flow. The residue was treated with water and stirred vigorously for 2h. The precipitate was collected by filtration, washed with water and dried under vacuum to give 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy) pyridine-3-formic acid methyl esters (20.0mg, 0.0630mmol, 18.8% yield) as a tan solid. The material was used without further purification. MS, ES + m / z 318.0[M+H] + .

[0795] Step 3: Synthesis of 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid

[0796]

[0797] A mixture of 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3-formic acid methyl ester (20.1mg, 0.0633mmol) and lithium hydroxide monohydrate (10.0mg, 0.238mmol) in THF (2mL) and methanol (0.2mL) was stirred at room temperature for 5 days (for convenience). The solvent was removed with N2 stream, and the content was diluted with water (3mL). The pH was reduced to pH 5 by careful addition of 6NHCl. After stirring for 3h, the precipitate was collected by filtration, washed with water and dried under vacuum to give 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3-formic acid (9.5mg, 0.031mmol, 49.4% yield) as an off-white solid. The material was used without further purification. MS, ES + m / z 304.0[M+H] + .

[0798] Step 4: Synthesis of 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0799]

[0800] A mixture of 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)picolinic acid (9.5 mg, 0.0313 mmol), HBTU (14.3 mg, 0.0376 mmol), 3-methylsulfonylanilide (5.9 mg, 0.0345 mmol) and DIPEA (16.4 μL, 0.0940 mmol) in chloroform (0.5 mL) was stirred at room temperature for 3 days (for convenience). The contents were diluted with EtOAc, washed with water (3x), brine (1x), dried over MgSO4, filtered and the solvent removed in vacuo to give a residue which was purified by automated normal phase chromatography (0%-100% EtOAc / heptane, 4 g silica gel cartridge) to give 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (2.6 mg, 0.0057 mmol, 18.2% yield) as a white solid. MS, ES + m / z 457.0[M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ10.73 (s, 1H), 8.40-8.43 (m, 1H), 8.02 (d, J = 2.53Hz, 1H), 7.97(dt,J=7.07,2.02Hz,1H),7.75(d,J=2.53Hz,1H),7.63-7.70(m,2H),7.27(dd, J=8.72,5.94Hz,1H),7.05(dd,J=10.74,2.91Hz,1H),6.81(td,J=8.46,3.03Hz,1H) ,3.70(s,3H),3.22(s,3H),1.93-2.01(m,1H),0.95-1.00(m,2H),0.72-0.77(m,2H).

[0801] Example 113: 2-(4-Fluoro-2-methyl-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyrrolidone Pyridine-3-carboxamide

[0802] Method N

[0803]

[0804] Step 1: Synthesis of 2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid

[0805]

[0806] A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (497 mg, 2.20 mmol), 4-fluoro-2-methyl-phenol (306 mg, 2.42 mmol) and cesium carbonate (1.79 g, 5.51 mmol) in MeCN (5 mL) was stirred at 80 ° C for 5 h, then stirred at room temperature for 4 days (for convenience). The solvent was removed under N2 flow and the residue was dissolved in water (10 mL). The pH was lowered to pH 5 by carefully adding 6N HCl. After stirring for 3 h, the precipitate was collected by filtration, washed with water and dried under vacuum to give 2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (407.5 mg, 1.293 mmol, 58.7% yield) as a beige solid. MS, ES + m / z 316.0[M+H] + .

[0807] Step 2: Synthesis of 2-(4-fluoro-2-methyl-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide

[0808]

[0809] A mixture of 2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (100 mg, 0.317 mmol), 3-methylsulfonylaniline (59.8 mg, 0.349 mmol), HBTU (132 mg, 0.349 mmol) and DIPEA (138 μL, 0.793 mmol) in chloroform (2 mL) was stirred at room temperature for 18 h. The solvent was removed under a stream of N2, and the residue was treated with water / MeOH (5:1). The mixture was sonicated briefly and then stirred at room temperature for 4 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 2-(4-fluoro-2-methyl-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (121.7 mg, 0.260 mmol, 81.9% yield) as a tan solid. MS, ES + m / z 469.0[M+H] + . 1H-NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.67-8.69(m,1H),8.57(d,J=2.53Hz,1H),8.40-8.42(m,1H),7.97(dt,J=7.58,1.89Hz,1H),7. 65-7.73(m,2H),7.27(dd,J=8.84,5.05Hz,1H),7.21(dd,J=9.35,3.03Hz,1H),7.12(td,J=8.78,3.16Hz,1H),3.23(s,3H),2.09(s,3H).

[0810] The following compounds have been synthesized according to Method N:

[0811]

[0812]

[0813]

[0814] Example 117: 2-(4-Fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3- Formamide

[0815]

[0816] Step 1: Synthesis of 2-chloro-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0817]

[0818] A mixture of HBTU (243 mg, 0.641 mmol), DIPEA (223 μL, 1.28 mmol), 2-chloro-6-methylnicotinic acid (100 mg, 0.583 mmol) and 3-methylsulfonylaniline (105 mg, 0.613 mmol) in chloroform (5 mL) was stirred at room temperature for 48 h. The contents were treated with 5% NaCO and extracted with CHCl (3×). The solvent was removed in vacuo to give 2-chloro-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (175 mg, 0.539 mmol, 92.5% yield) as a residue, which was used without further purification. MS, ES + m / z 325.0[M+H] + .

[0819] Step 2: Synthesis of 2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0820]

[0821] A mixture of crude 2-chloro-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (70.0 mg, 0.216 mmol), 4-fluoro-2-methoxyphenol (30.7 μL, 0.269 mmol) and cesium carbonate (211 mg, 0.647 mmol) in MeCN (2 mL) was stirred at 60 ° C for 24 h. After cooling, the contents were treated with water and stirred at room temperature overnight. The precipitate was collected by filtration, washed with water and dried under vacuum to give 2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (29.0 mg, 0.0674 mmol, 31.3% yield) as a beige solid. MS, ES + m / z 431.0[M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.41(s,1H),8.04(d,J=7.58Hz,1H),7.96(d,J=7.07Hz,1H),7.62-7.69(m,2H), 7.33(dd,J=8.72,5.94Hz,1H),7.05-7.13(m,2H),6.83(td,J=8.46,3.03Hz,1H),3.71(s,3H),3.22(s,3H),2.30(s,3H).

[0822] Example 118: 2-(4-Fluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfonylphenyl)pyrrolidone Pyridine-3-carboxamide

[0823]

[0824] Step 1: Synthesis of 2-chloro-5,6-dimethyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0825]

[0826] To a mixture of 2-chloro-5,6-dimethyl-pyridine-3-carboxylic acid (100 mg, 0.539 mmol), 3-methylsulfonylaniline (96.9 mg, 0.566 mmol) and HBTU (225 mg, 0.593 mmol) in chloroform (4 mL) was added DIPEA (206.5 μL, 1.19 mmol). The resulting mixture was stirred at room temperature for 6 days (for convenience). The solvent was removed under a N2 stream, and the residue was treated with water / MeOH (4: 1). The mixture was sonicated briefly and then stirred at room temperature for 18 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 2-chloro-5,6-dimethyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (137 mg, 0.404 mmol, 75.1% yield) as a beige solid. MS, ES + m / z 339.0[M+H] + . 1 H-NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.37(s,1H),7.94(d,J=7.33Hz,1 H),7.88(s,1H),7.64-7.72(m,2H),3.23(s,3H),2.48(s,3H),2.31(s,3H).

[0827] Step 2: Synthesis of 2-(4-fluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0828]

[0829] A mixture of 2-chloro-5,6-dimethyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (50.0 mg, 0.148 mmol), 4-fluoro-2-methoxyphenol (17.7 μL, 0.155 mmol) and cesium carbonate (106 mg, 0.327 mmol) in MeCN (4 mL) was stirred at 80 ° C for 10 h. The solvent was removed under a stream of N2, and the residue was treated with water / MeOH (2: 1). The mixture was sonicated briefly and then stirred at room temperature for 18 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 2-(4-fluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (21.0 mg, 0.0472 mmol, 32.0% yield) as a reddish brown solid. MS, ES + m / z 445.0[M+H] + .

[0830] 1 H-NMR (400MHz, DMSO-d6) δ10.58(s,1H),8.40(s,1H),7.97(d,J=7.07Hz,1H),7.92(s,1H),7.62-7.70(m,2H),7.30(dd,J=8.84,6.06 Hz,1H),7.07(dd,J=10.74,2.91Hz,1H),6.82(td,J=8.59,3.03Hz,1H),3.71(s,3H),3.22(s,3H),2.25(br.s.,3H),2.24(br.s.,3H).

[0831] Example 119: 5-Chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxylate Amide

[0832]

[0833] Step 1: Synthesis of 2,5-dichloro-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0834]

[0835] A mixture of HBTU (217 mg, 0.571 mmol), DIPEA (200 μL, 1.15 mmol), 2,5-dichloropyridine-3-carboxylic acid (100 mg, 0.521 mmol) and 3-methylsulfonylaniline (93.6 mg, 0.547 mmol) in chloroform (5 mL) was stirred at room temperature for 22 h. The contents were treated with 5% Na2CO3 and extracted with CHCl3 (3×). The solvent was removed in vacuo to give 2,5-dichloro-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (150 mg, 0.435 mmol, 83.4% yield) as a semisolid, which was used without further purification. MS, ES + m / z 344.8[M+H] + .

[0836] Step 2: Synthesis of 5-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0837]

[0838] A mixture of crude 2,5-dichloro-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (59.3 mg, 0.172 mmol), 4-fluoro-2-methoxyphenol (27.4 μL, 0.241 mmol) and cesium carbonate (168 mg, 0.517 mmol) in MeCN (3 mL) was stirred at 80 ° C for 3 h. After cooling, water was added and a precipitate began to form. After stirring for 1 h, the material was collected by filtration, washed with water and dried under vacuum to give 5-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (21 mg, 0.047 mmol, 27.1% yield) as a beige solid. MS, ES + m / z 451.0[M+H] + .

[0839] 1 H-NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.41(s,1H),8.25-8.31(m,2H),7.97(d,J=7.58Hz,1H),7.64-7. 72(m,2H),7.26-7.32(m,1H),7.08(d,J=10.86Hz,1H),6.83(t,J=8.08Hz,1H),3.70(s,3H),3.22(s,3H).

[0840] Example 120: 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6,7-dihydro-5H- Cyclopenta[b]pyridine-3-carboxamide

[0841]

[0842] Step 1: Synthesis of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid

[0843]

[0844] A solution of 2-chloro-6,7-dihydro-5H-cyclopenta [b] pyridine-3-carbonitrile (173 mg, 0.969 mmol) in 2 mL of concentrated sulfuric acid / water (1: 1) was stirred at 100 ° C for 9 h. After cooling, the contents were added to ice water in portions with stirring. After stirring for 1 h, the precipitate was collected by filtration, washed with cold water and dried under vacuum to give 2-chloro-6,7-dihydro-5H-cyclopenta [b] pyridine-3-carboxylic acid (117 mg, 0.592 mmol, 61.1% yield) as a tan solid. MS, ES + m / z 198.0[M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ13.53 (br.s., 1H), 8.02 (s, 1H), 2.93 (q, J=7.24 Hz, 4H), 2.10 (quintet, J=7.24 Hz, 2H).

[0845] Step 2: Synthesis of 2-chloro-N-(3-methylsulfonylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide

[0846]

[0847] To a mixture of 2-chloro-6,7-dihydro-5H-cyclopenta [b] pyridine-3-carboxylic acid (114 mg, 0.577 mmol), 3-methylsulfonylaniline (104 mg, 0.607 mmol) and HBTU (241 mg, 0.637 mmol) in chloroform (4 mL) was added DIPEA (221 μL, 1.27 mmol). The resulting mixture was stirred at room temperature for 5 days (for convenience). The solvent was removed under N2 flow, and the residue was treated with water / MeOH (3: 1). The mixture was sonicated briefly and then stirred at room temperature for 1 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 2-chloro-N-(3-methylsulfonylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (147.6 mg, 0.421 mmol, 72.9% yield) as a brown solid which was used without further purification. MS, ES + m / z 351.1[M+H] + .

[0848] Step 3: Synthesis of 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide

[0849]

[0850] A mixture of 2-chloro-N-(3-methylsulfonylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (50.0 mg, 0.143 mmol), 4-fluoro-2-methoxyphenol (17.1 μL, 0.150 mmol) and cesium carbonate (102 mg, 0.313 mmol) in MeCN (3 mL) was stirred at 80 ° C for 10 h. The solvent was removed under a N2 stream, and the residue was treated with water / MeOH (2: 1). The mixture was sonicated briefly and then stirred at room temperature for 24 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (24 mg, 0.053 mmol, 36.9% yield) as a brown solid. MS, ES + m / z 457.1[M+H] + . 1 H-NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.42(br.s.,1H),7.96(s,2H),7.63-7.69(m,2H),7.28-7.33(m,1H),7.05-7.10 (m,1H),6.79-6.86(m,1H),3.72(s,3H),3.22(s,3H),2.89(t,J=7.20Hz,2H),2.75(t,J=7.71Hz,2H),2.01-2.11(m,2H).

[0851] Example 121: N-(3-methylsulfinylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)phenyl 1-(2-Yl)pyridine-3-carboxamide

[0852] Method O

[0853]

[0854] Step 1: Synthesis of 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxylic acid

[0855]

[0856] A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (510 mg, 2.26 mmol), 4-(trifluoromethoxy)phenol (322 μL, 2.49 mmol) and cesium carbonate (1.84 g, 5.65 mmol) in MeCN (5 mL) was stirred at 80 ° C for 5 h, then stirred at room temperature for 4 days (for convenience). The solvent was removed under N2 flow, and the residue was treated with water / MeOH (5: 1). The mixture was sonicated briefly and then stirred at room temperature for 18 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxylic acid (604 mg, 1.65 mmol, 72.8% yield) as an off-white solid. MS, ES + m / z 368.0[M+H] + .

[0857] Step 2: Synthesis of N-(3-methylsulfinylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide

[0858]

[0859] A mixture of 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxylic acid (35.0 mg, 0.0953 mmol), 3-methylsulfinylaniline (16.3 mg, 0.105 mmol), HBTU (39.8 mg, 0.105 mmol) and DIPEA (41.5 μL, 0.238 mmol) in chloroform (2 mL) was stirred at room temperature for 3 days (for convenience). The solvent was removed under a stream of N2, and the residue was treated with water / MeOH (3:1). The mixture was sonicated briefly and then stirred at room temperature for 24 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give N-(3-methylsulfinylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (39.0 mg, 0.0773 mmol, 81.1% yield) as a beige solid. MS, ES + m / z 505.0[M+H] + .

[0860] 1H-NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.72(d,J=1.52Hz,1H),8.56(d,J=2.53Hz,1H),8. 14(s,1H),7.83(d,J=7.58Hz,1H),7.58(t,J=7.83Hz,1H),7.40-7.52(m,5H),2.75(s,3H).

[0861] The following compounds have been synthesized according to Method O:

[0862]

[0863]

[0864]

[0865]

[0866]

[0867] Example 130: N-[3-(Methylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)phenyl Methyl)pyridine-3-carboxamide, enantiomer A

[0868]

[0869] Racemic N-[3-(methylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (Example LI-1859) was resolved by chiral chromatography using a Chiralpak IG column with a mobile phase consisting of a 5%-40% methanol gradient in CO2 (modified with 0.05% DEA) to provide the first eluting enantiomer, R T =1.46min. MS, ES + m / z,520.8(M+H) + . 1 H NMR(400MHz, DMSO-d6)δppm3.07(s,3H)4.27(s,1H)7.39-7.54(m,4H)7.62(t,J=7.83Hz,1H)7.70(dt,J=7.96,1.20Hz,1H)7.90 -8.02(m,1H)8.38(t,J=1.89Hz,1H)8.57(d,J=2.53Hz,1H)8.72(d,J=1.52Hz,1H)11.01(s,1H).

[0870] Example 131: N-[3-(Methylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)phenyl Methyl)pyridine-3-carboxamide, enantiomer B

[0871]

[0872] Racemic N-[3-(methylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (Example LI-1859) was resolved by chiral chromatography using a Chiralpak IG column with a mobile phase consisting of a 5%-40% methanol gradient in CO2 (modified with 0.05% DEA) to provide the first eluting enantiomer, R T =1.98min. MS, ES + m / z,520.8(M+H) + . 1 H NMR(400MHz, DMSO-d6)δppm3.07(s,3H)4.27(s,1H)7.39-7.54(m,4H)7.62(t,J=7.83Hz,1H)7.70(dt,J=7.96,1.20Hz,1H)7.90 -8.02(m,1H)8.38(t,J=1.89Hz,1H)8.57(d,J=2.53Hz,1H)8.72(d,J=1.52Hz,1H)11.01(s,1H).

[0873] Example 132: N-(1-pyridin-1-ium-3-yl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)phenoxy 1-(2-Yl)pyridine-3-carboxamide

[0874] Method P

[0875]

[0876] Step 1: Synthesis of 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxylic acid (Intermediate ABC)

[0877]

[0878] A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (510 mg, 2.26 mmol), 4-(trifluoromethoxy)phenol (322 μL, 2.49 mmol) and cesium carbonate (1.84 g, 5.65 mmol) in MeCN (5 mL) was stirred at 80 ° C for 5 h, then stirred at room temperature for 4 days (for convenience). The solvent was removed under N2 flow, and the residue was treated with water / MeOH (5: 1). The mixture was sonicated briefly and then stirred at room temperature for 18 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxylic acid (604 mg, 1.65 mmol, 72.8% yield) as an off-white solid. MS, ES + m / z 368.0[M+H] + .

[0879] Step 2: Synthesis of N-(3-pyridyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide

[0880]

[0881] 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxylic acid (250mg, 0.68mmol) is added to a screw cap vial equipped with a magnetic stirrer and dissolved in dichloromethane (2.5mL). Add oxalyl chloride (72μL, 0.82mmol), then add a drop of DMF, and allow the mixture to stir for 1 hour. 3-aminopyridine (96mg, 1.0mmol) and trimethylamine (190μL, 1.36mmol) are added dropwise as a solution in DCM (2.5mL). Volatiles are evaporated under reduced pressure, and the residue is purified by preparative reverse phase HPLC (high pH method) to give N-(3-pyridyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide as a colorless glass. (266mg, 0.6mmol, 88% yield). MS, ES + m / z 368.0[M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 7.40-7.53(m,5H)8.18(ddd,J=8.34,2.53,1.52Hz,1H)8.36(dd,J=4.55,1.52Hz,1H) 8.55-8.60(m,1H)8.73(dd,J=2.53,1.01Hz,1H)8.87(d,J=2.02Hz,1H)10.88(s,1H).

[0882] Step 3: Synthesis of N-(1-oxypyridin-1-ium-3-yl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide

[0883]

[0884] N-(3-pyridyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (100 mg, 0.23 mmol) was added to a screw cap vial equipped with a magnetic stirrer and dissolved in DCM (5 mL). mCPBA (61 mg, 0.27 mmol) was added and the mixture was allowed to stir at room temperature for 15 minutes. The volatiles were evaporated under reduced pressure and the resulting residue was purified by preparative reverse phase HPLC (high pH method) to provide the title compound (69 mg, 0.15 mmol, 67% yield) as a colorless glass. MS, ES + m / z 460.0[M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm7.38-7.60 (m, 6H) 8.05 (ddd, J = 6.32, 1.77, 1.01Hz, 1H) 8.59 (d, J = 2.53Hz, 1H) 8.71-8.84 (m, 2H) 11.04 (s, 1H).

[0885] The following compounds have been synthesized according to Method P:

[0886]

[0887]

[0888]

[0889]

[0890]

[0891] Example 141: N-(1-oxypyridin-1-ium-4-yl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)phenoxy 1-(2-Yl)pyridine-3-carboxamide

[0892]

[0893] N-(4-pyridyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (Example 129, 100 mg, 0.23 mmol) was added to a screw cap vial equipped with a magnetic stirrer and dissolved in DCM (5 mL). m-CPBA (61 mg, 0.27 mmol) was added and the mixture was allowed to stir at room temperature for 15 minutes. The volatiles were evaporated under reduced pressure and the resulting residue was purified by preparative reverse phase HPLC (high pH method) to provide the desired product as a colorless glass. (55 mg, 0.12 mmol, 53% yield). MS, ES + m / z 460.0[M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm 7.38-7.55 (m, 4H) 7.69-7.80 (m, 2H) 8.15-8.26 (m, 2H) 8.58 (d, J = 2.53Hz, 1H) 8.73 (d, J = 1.26Hz, 1H) 11.16 (s, 1H).

[0894] Example 142: 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethoxy)phenoxy Methyl)pyridine-3-carboxamide

[0895] Method Q

[0896]

[0897] Step 1: Synthesis of 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxylic acid

[0898]

[0899] A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (150 mg, 0.665 mmol), 2-chloro-4-(trifluoromethoxy)phenol (141 mg, 0.665 mmol) and cesium carbonate (433 mg, 1.33 mmol) in MeCN (2 mL) was stirred at 80 ° C for 68 h. After cooling, the contents were diluted with 20 mL of water and acidified to pH 6 via careful addition of 2N HCl. The precipitate was collected by filtration, washed with water and dried under vacuum to give 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxylic acid (149.5 mg, 0.372 mmol, 56.0% yield) as a beige solid. MS, ES +m / z401.9[M+H] + .

[0900] Step 2: Synthesis of 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide

[0901]

[0902] A mixture of 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxylic acid (33.4 mg, 0.0832 mmol), 3-methylsulfonylaniline (15.7 mg, 0.0915 mmol), HBTU (34.7 mg, 0.0915 mmol) and DIPEA (36.2 μL, 0.208 mmol) in chloroform (2 mL) was stirred at room temperature for 20 h. The solvent was removed under a stream of N2, and the residue was treated with water / MeOH (4:1). The mixture was sonicated briefly and then stirred at room temperature overnight. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (34.8 mg, 0.0627 mmol, 75.4% yield) as a beige solid. MS, ES + m / z 554.9[M+H] + . 1 H-NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.74(br.s.,1H),8.64(d,J=2.27Hz,1H),8.40(s,1H),7 .99(d,J=7.58Hz,1H),7.81(d,J=2.53Hz,1H),7.65-7.74(m,3H),7.52-7.57(m,1H),3.23(s,3H).

[0903] The following compounds have been synthesized according to Method Q:

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914] Example 171: 2-(2,4-dimethoxyphenoxy)-N-[3-(N,S-dimethylsulfonylimino)phenyl]-5- (Trifluoromethyl)pyridine-3-carboxamide

[0915] Method R

[0916]

[0917] Step 1: Synthesis of 2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid

[0918]

[0919] 2-Chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (1.5 g, 6.7 mmol) was loaded into a round-bottom flask equipped with a magnetic stirrer, and acetonitrile (15 mL) was added. Cesium carbonate (4.3 g, 13.3 mmol) and 2,4-dimethoxyphenol (1.1 g, 7.3 mmol) were added, and the mixture was heated to reflux for 12 hours. The volatiles were evaporated under reduced pressure, and the residue was dissolved in water. The pH was adjusted to about 3 by careful addition of 2N HCl, and the resulting precipitate was collected by filtration, rinsed with water and blotted to provide the desired product as a solid. (1.75 g, 5.1 mmol, 76% yield). MS, ES + m / z344.0[M+H] + .

[0920] Step 2: Synthesis of 2-(2,4-dimethoxyphenoxy)-N-[3-(N,S-dimethylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide

[0921]

[0922] 2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (150mg, 0.44mmol) is added to a screw cap vial and dissolved in DMF (3mL). Triethylamine (122μL, 0.87mmol) and HBTU (200mg, 0.52mmol) are added, and the mixture is stirred at room temperature for 10 minutes. 3-(N,S-dimethylsulfonylimino)aniline (81mg, 0.44mmol) is added, and stirring is continued for another 12 hours. Purification by preparative reverse phase HPLC (high pH method) provides the title compound as a beige solid. (111mg, 0.22mmol, 50% yield). MS, ES + m / z 510.4[M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 2.49(s,3H)3.12(s,3H)3.66-3.71(m,3H)3.79(s,3H)6.57(dd,J=8.84,2.78Hz,1H)6.72(d,J=2.78Hz,1H)7.20(d,J=8.84Hz,1H) 7.56-7.61(m,1H)7.62-7.69(m,1H)7.96(d,J=8.08Hz,1H)8.32(s,1H)8.50(d,J=2.27Hz,1H)8.65(d,J=1.52Hz,1H)10.93(s,1H).

[0923] The following compounds have been synthesized according to Method R:

[0924]

[0925]

[0926]

[0927] Example 174: 2-(2,4-difluorophenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl) Pyridine-3-carboxamide

[0928] Method S

[0929]

[0930] Step 1: 2-(2,4-difluorophenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid

[0931]

[0932] 2-Chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (1.5 g, 6.7 mmol) was added to a round-bottom flask equipped with a magnetic stirrer, and acetonitrile (15 mL) was added. Cesium carbonate (4.3 g, 13.3 mmol) and 2,4-difluorophenol (952 mg, 7.3 mmol) were added, and the mixture was heated to reflux for 12 hours. The solvent was removed under reduced pressure, and the resulting residue was dissolved in water. The pH was adjusted to about 3 by adding 2N HCl, and the resulting precipitate was collected by filtration, rinsed with water and blotted to provide the desired product (1.9 g, 2.1 mmol, 91% yield) as a white solid. MS, ES + m / z320[M+H] + .

[0933] Step 2: Synthesis of 2-(2,4-difluorophenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide

[0934]

[0935] 2-(2,4-difluorophenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (150mg, 0.44mmol) is added to a screw cap vial and dissolved in DMF (3mL). Triethylamine (122μL, 0.87mmol) and HBTU (200mg, 0.52mmol) are added, and the mixture is stirred at room temperature for 10 minutes. 3-(N,S-dimethylsulfonylimino)aniline (75mg, 0.44mmol) is added, and stirring is continued for another 12 hours. The title compound is provided as a beige solid by purification by preparative reverse phase HPLC (high pH method). (97mg, 0.21mmol, 47% yield). MS, ES + m / z 472.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 3.07(s,3H)7.46-7.59(m,2H)7.59-7.66(m,1H)7.67-7.74(m,1H)7.96(d,J=8.08Hz, 1H) 8.39 (t, J = 1.77Hz, 1H) 8.61 (d, J = 2.53Hz, 1H) 8.72 (d, J = 1.52Hz, 1H) 11.03 (s, 1H).

[0936] The following compounds have been synthesized according to Method S:

[0937]

[0938]

[0939]

[0940] Example 177: 5-Cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl) Pyridine-3-carboxamide

[0941]

[0942] Step 1: Synthesis of 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-pyridine-3-carboxylic acid ethyl ester

[0943]

[0944] A mixture of 2-chloro-5-cyano-6-methyl-pyridine-3-carboxylic acid ethyl ester (150mg, 0.668mmol), 4-fluoro-2-methoxyphenol (95.1μL, 0.835mmol) and cesium carbonate (653mg, 2.00mmol) in MeCN (5mL) was stirred at 60°C for 1h. After cooling, the contents were treated with water and stirred at room temperature overnight. The precipitate was collected by filtration, washed with water and dried under vacuum to give 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-pyridine-3-carboxylic acid ethyl ester (135mg, 0.409mmol, 61.2% yield) as a green-grey solid. MS, ES + m / z 331.0[M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ8.64(s,1H),7.20(dd,J=8.97,5.94Hz,1H),7.11(dd,J=10.48,2.65Hz,1H),6 .82(td,J=8.46,2.78Hz,1H),4.33(q,J=7.07Hz,2H),3.70(s,3H),2.46(s,3H),1.32(t,J=7.07Hz,3H).

[0945] Step 2: Synthesis of 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-pyridine-3-carboxylic acid

[0946]

[0947] A mixture of 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-pyridine-3-carboxylic acid ethyl ester (135 mg, 0.409 mmol) and lithium hydroxide monohydrate (18.9 mg, 0.450 mmol) in THF (2 mL) and water (0.1 mL) was stirred at room temperature for 2 h. The solvent was removed under a N2 stream, and the residue was dissolved in water. The pH was lowered to pH 5 by careful addition of 6N HCl, and the product was extracted with CHCl3 (4×) and the solvent was removed in vacuo to give a residue, which was purified by automatic normal phase chromatography (0%-100% EtOAc / heptane, 4 g silica gel cartridge) to give 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-pyridine-3-carboxylic acid (77.2 mg, 0.255 mmol, 62.5% yield) as a yellow solid. MS, ES + m / z 303.0[M+H] + . 1 H-NMR(400MHz,DMSO-d6)δ13.55(br.s.,1H),8.57(s,1H),7.19(dd,J=8.84,6.06Hz,1H), 7.11(dd,J=10.74,2.91Hz,1H), 6.82(td,J=8.53,2.91Hz,1H), 3.70(s,3H),2.44(s,3H).

[0948] Step 3: Synthesis of 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0949]

[0950] A mixture of 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-pyridine-3-carboxylic acid (75.0 mg, 0.248 mmol), 3-methylsulfonylanilide (46.7 mg, 0.273 mmol), HBTU (113 mg, 0.298 mmol) and DIPEA (130 μL, 0.744 mmol) in chloroform (3 mL) was stirred at room temperature for 19 h. The contents were diluted with EtOAc, washed with water (3x), brine (1x), dried over MgSO4, filtered and the solvent removed in vacuo to give a residue which was purified by automated normal phase chromatography (0%-100% EtOAc / heptane, 4 g silica gel cartridge) to give 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (49.0 mg, 0.108 mmol, 43.4% yield) as a light yellow solid. MS, ES + m / z 456.0[M+H] + . 1 H-NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.57(s,1H),8.39(s,1H),7.94-7.99(m,1H),7.64-7.72(m,2H),7.31(d d,J=8.84,5.81Hz,1H),7.11(dd,J=10.74,2.91Hz,1H),6.84(td,J=8.53,2.91Hz,1H),3.71(s,3H),3.22(s,3H).

[0951] Example 178: 5-Fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-N-(3-methylsulfonylphenyl) Pyridine-3-carboxamide

[0952]

[0953] Step 1: Synthesis of 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-pyridine-3-carboxylic acid methyl ester

[0954]

[0955] A mixture of 2-chloro-5-fluoro-6-methoxy-pyridine-3-formic acid methyl ester (200 mg, 0.911 mmol), 4-fluoro-2-methoxyphenol (114 μL, 1.00 mmol) and cesium carbonate (742 mg, 2.28 mmol) in MeCN (8 mL) was stirred at 80 ° C for 3 h, then allowed to cool to room temperature with stirring. Water (30 mL) and methanol (5 mL) were added, and the resulting mixture was sonicated briefly, then stirred for 4 h. The precipitate was collected by filtration, washed with water and dried under vacuum to give 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-pyridine-3-formic acid methyl ester (237 mg, 0.727 mmol, 79.9% yield) as a beige solid. MS, ES + m / z 326.0[M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ8.12(d,J=10.11Hz,1H),7.18(dd,J=8.72,5.94Hz,1H),7.09(dd, J=10.74,2.91Hz,1H),6.81(td,J=8.46,2.78Hz,1H),3.83(s,3H),3.72(s,3H),3.57(s,3H).

[0956] Step 2: Synthesis of 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-pyridine-3-carboxylic acid

[0957]

[0958] A mixture of 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-pyridine-3-formic acid methyl ester (231 mg, 0.710 mmol) and lithium hydroxide monohydrate (32.8 mg, 0.781 mmol) in THF (3 mL) and water (0.1 mL) was stirred at room temperature for 48 h. The solvent was removed with N2 flow, and the contents were diluted with water (15 mL). The contents were filtered, and the pH of the filtrate was reduced to pH 4 by carefully adding 2N HCl. After stirring for 1 h, the precipitate was collected by filtration, washed with water and dried under vacuum to give 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-pyridine-3-formic acid (201 mg, 0.646 mmol, 90.9% yield) as a white solid. MS, ES + m / z 312.0[M+H] + .

[0959] 1H-NMR (400MHz, DMSO-d6) δ13.05(br.s.,1H),8.08(d,J=10.11Hz,1H),7.17(dd,J=8.84,6.06Hz ,1H),7.08(dd,J=10.74,2.91Hz,1H),6.80(td,J=8.53,2.91Hz,1H),3.72(s,3H),3.56(s,3H).

[0960] Step 3: Synthesis of 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0961]

[0962] A mixture of 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-pyridine-3-carboxylic acid (40 mg, 0.129 mmol), 3-methylsulfonylaniline (24.2 mg, 0.141 mmol), HBTU (53.6 mg, 0.141 mmol) and DIPEA (56.0 μL, 0.321 mmol) in chloroform (2 mL) was stirred at room temperature for 22 h. The reaction was only ~25% complete according to LCMS. Stirring continued at 50 ° C for 54 h. The solvent was removed under N2 flow, and the residue was treated with water / MeOH (3: 1). The mixture was sonicated briefly and then stirred at room temperature for 24 h. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (45.8 mg, 0.0986 mmol, 76.7% yield) as a white solid. MS, ES + m / z 465.1[M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.38(s,1H),8.14(d,J=9.85Hz,1H),7.99(d,J=7.07Hz,1H),7.63-7.70(m,2H), 7.39-7.44(m,1H),7.11(dd,J=10.74,2.65Hz,1H),6.85(td,J=8.59,2.78Hz,1H),3.75(s,3H),3.64(s,3H),3.22(s,3H).

[0963] Example 179: 5-(Difluoromethoxy)-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylbenzene 1-(2-Yl)pyridine-3-carboxamide

[0964]

[0965] Step 1: Synthesis of 3-bromo-2-chloro-5-(difluoromethoxy)pyridine

[0966]

[0967] The round-bottomed flask equipped with a magnetic stirring bar is loaded with 5-bromo-6-chloro-pyridine-3-alcohol (1.0g, 4.8mmol), and then acetonitrile (20mL) and water (20mL) are added. Solid potassium hydroxide (5.4g, 96mmol) is added, and the mixture is cooled in a dry ice / acetone bath. When the mixture starts freezing, 1-[[bromo (difluoro) methyl]-ethoxy-phosphoryl] oxyethane (2.6g, 9.6mmol) is added, and the mixture is allowed to heat to room temperature. The crude mixture is distributed between water and ether, and the ether layer is collected, dried and concentrated, to provide the colorless oil containing the product desired, which is used without further purification.

[0968] Step 2: Synthesis of 3-bromo-2-chloro-5-(difluoromethoxy)pyridine

[0969]

[0970] The crude product (1.2g, 4.6mmol) from step 1 is added to a round-bottom flask equipped with a magnetic stirrer, and is dissolved in acetonitrile (20mL).Add 4-fluoro-2-methoxy-phenol (726mg, 5.11mmol) and cesium carbonate (1.7g, 5.1mmol), and the mixture is heated to 60 ° C for 24 hours.After cooling to room temperature, the crude mixture is diluted with water and extracted with dichloromethane.The combined organic layer is dried, concentrated and purified by silica gel chromatography (0%-35% EtOAc in heptane), to provide the desired product as a colorless oil, which solidifies (1.1g, 3.1mmol) when standing. MS, ES + m / z 364.0 / 365.0[M+H] + .

[0971] Step 3: Synthesis of 5-(difluoromethoxy)-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide

[0972]

[0973] 3-bromo-5-(difluoromethoxy)-2-(4-fluoro-2-methoxy-phenoxy)pyridine (250mg, 0.69mmol), DPEpHos (27.7mg, 0.05mmol), palladium acetate (II) (3.85mg, 0.02mmol), 3-methylsulfonylanilide (235mg, 1.37mmol) and cesium hydroxide (1.2g, 6.9mmol) were added to a microwave vial equipped with a magnetic stirrer. The vial was sealed, evacuated and backfilled with nitrogen three times, and then toluene (4mL) and chloroform (0.17mL) were added. The resulting mixture was heated to 80°C for 18 hours, and after cooling to room temperature, diluted with dichloromethane and filtered through a diatomaceous earth plug. The clear filtrate was concentrated and purified by preparative reverse phase HPLC (high pH method) to provide the desired product (166mg, 50.1% yield) as a colorless solid. MS, ES + m / z 483.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 3.18-3.26(m,3H)3.68-3.72(m,3H)6.83(td,J=8.53,2.91Hz,1H)7.06-7.11(m,1H)7.32(dd,J=8.72,5.94Hz, 1H)7.64-7.73(m,2H)7.93-8.02(m,1H)8.07(d,J=3.03Hz,1H)8.16(d,J=2.78Hz,1H)8.41(s,1H)10.90(s,1H).

[0974] Example 180: N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethoxy)phenoxy]pyridine-3- Formamide

[0975]

[0976] Step 1: Synthesis of 2-chloro-N-(3-methylsulfonylphenyl)-5-nitro-pyridine-3-carboxamide

[0977]

[0978] Oxalyl chloride (6.35mL, 74.06mmol) is added to the stirring solution of 2-chloro-5-nitro-pyridine-3-carboxylic acid (10g, 49.37mmol) in dichloromethane (200mL). DMF (g, 2.47mmol) (three drops) is added. The solution is stirred at room temperature for 5 hours until bubbles are not seen from the solution. 3-methylsulfonylaniline (10.14g, 59.24mmol) is added. N, N-diisopropylethylamine (17.72mL, 98.74mmol) is added dropwise to the solution. The solution is stirred at room temperature for 1 hour. DCM (200mL) is added, and the solution is extracted with hydrochloric acid solution (1N, 2×100mL), brine (100mL), and then dried over sodium sulfate. The solution is filtered and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate / heptane (30%-100% gradient) to give 2-chloro-N-(3-methylsulfonylphenyl)-5-nitro-pyridine-3-carboxamide (11.28 g, 22.195 mmol, 44.957% yield) as a purple solid. MS, ES + m / z 356.0[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ ppm 3.02-3.11 (m, 3H) 7.60-7.82 (m, 3H) 7.94-8.05 (m, 1H) 8.61 (d, J=2.78 Hz, 1H) 9.22-9.31 (m, 1H).

[0979] Step 2: Synthesis of N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide

[0980]

[0981] To a stirred solution of 2-chloro-N-(3-methylsulfonylphenyl)-5-nitro-pyridine-3-carboxamide (11.18 g, 22 mmol) in acetonitrile (100 mL) was added 4-(trifluoromethoxy)phenol (5.88 g, 33 mmol) and potassium carbonate (6.08 g, 44 mmol). The solution was stirred overnight at 60 ° C. The solution was cooled to room temperature and filtered to remove solids. Water (300 mL) was added. The slightly colored solid was separated by filtration and dried to give N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (10.43 g, 20.969 mmol, 95.32% yield) as a slightly colored solid. A small sample of 100 mg was purified by ISCO eluting with ethyl acetate / heptane (0%-60%) to give N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (10.43 g, 20.97 mmol, 95.32% yield) as a white solid. MS, ES + m / z 498.0[M+H] + 1H NMR (400 MHz, CHLOROFORM-d) dppm 3.12 (s, 3H) 7.26-7.38 (m, 3H) 7.43 (d, J = 8.84 Hz, 2H) 7.61-7.70 (m, 1H) 7.79 (dd, J = 7.83, 1.26 Hz, 1H) 8.10-8.21 (m, 2H) 9.12 (d, J = 2.78 Hz, 1H) 9.48 (d, J = 2.78 Hz, 1H) 9.68 (s, 1H).

[0982] Example 181: 5-Chloro-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate Amide

[0983]

[0984] Step 1: Synthesis of 5-amino-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide

[0985]

[0986] To a stirred solution of N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (10.33 g, 20.77 mmol) in THF (50 mL) and ethanol (100 mL) was added palladium on carbon 10% (g, 20.77 mmol). The solution was bubbled with nitrogen for 5 minutes. The solution was loaded with a hydrogen balloon and stirred for two days. The solution was filtered and concentrated. The residue was purified by ISCO (eluted with methanol / DCM (0%-8%)) to give 5-amino-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (4.64 g, 9.9268 mmol, 47.799% yield) as a white solid. MS, ES + m / z 468.0[M+H] + . 1H NMR(400MHz,DMSO-d6)d ppm3.15-3.26(m,3H)5.44(s,2H)7.12-7.21(m,2H)7.30-7.41(m,3H)7.60-7.71(m,3H)7.92(d,J=7.58Hz,1H)8.38(s,1H)10.76(s,1H).

[0987] Step 2: Synthesis of 5-chloro-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide

[0988]

[0989] To a stirred solution of 5-amino-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (200 mg, 0.4300 mmol) in water (3 mL) was added hydrochloric acid (2 mL). The solution was cooled to an ice-water bath. Sodium nitrite (32.48 mg, 0.4700 mmol) dissolved in water (0.2 mL) was added. After stirring at 0 ° C for 15 min, copper (II) chloride (172.59 mg, 1.28 mmol) dissolved in water (1 mL) was added. The solution was stirred at room temperature overnight. The solution was extracted with ethyl acetate (2×3 mL). The combined organic solution was washed with water (2 mL), brine (2 mL) and dried over sodium sulfate. The solution was filtered and concentrated. The residue was purified by ISCO eluting with ethyl acetate / heptane (0%-50%) to give 5-chloro-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (43 mg, 0.0883 mmol, 20.642% yield) as a white solid. MS, ES + m / z 487.0[M+H]+ . 1H NMR (400MHz, chloroform-d)d ppm 3.11(s,3H)7.24-7.32(m,2H)7.39(d,J=8.34Hz,2H)7.58-7.68(m,1H)7.74-7.83(m,1H)8.10(d ,J=8.08Hz,1H)8.17(t,J=1.89Hz,1H)8.23(d,J=2.53Hz,1H)8.70(d,J=2.53Hz,1H)9.79(s,1H).

[0990] Determination method

[0991] The picolinamide derivatives exemplified above inhibit Na v 1.8 Channel capabilities are determined using one or more of the methods described below.

[0992] Stable expression of Na v 1.8β1 / β2 HEK cell line

[0993] Construct stably expressing human Na with β1 / β2 subunits v 1.8(hNa v 1.8) HEK293 cell line for ion channels. This cell line is suitable for IC in fluorescence-based and electrophysiological assays. 50 It is also suitable for mechanism of action pharmacology studies in electrophysiological assays. v 1.8 cells were grown as adherent monolayers in DMEM / high glucose medium, 10% fetal bovine serum, sodium pyruvate (2 mM), Hepes (10 mM) and the selection agents G418 (400 mg / L) and puromycin (0.5 mg / L) at 37°C, 10% CO2.

[0994] Na v 1.8 Fluorescence inhibition assay

[0995] Compounds were made into 10-mM stock solutions or supplied as 10-mM stock solutions using DMSO as a vehicle. Concentration response curves were generated using a Matrix multichannel pipette. Compound source plates were prepared by diluting 10mM compound stock solutions in DMSO in a 96-well v-bottom plate to produce a 500 μM (100×) solution. Compounds were then serially diluted in 100% DMSO to produce a 5-point, 4-fold dilution scheme dose response curve. 2 μL of the 100× dose response curve was then added to the pre-incubation plate and the stimulation assay plate. 100 μL of pre-incubation buffer and 200 μL of stimulation buffer were then added to the plate, resulting in a final assay test concentration range of 5 μM to 0.02 μM, with a final DMSO concentration of 1%.

[0996] On the day of the assay, the plates were washed with 2K EBSS buffer (135 mM NaCl, 2 mM KCl, 5 mM glucose, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, pH 7.4) to remove the cell culture medium. The Na-sensitive fluorescent dye AsanteNatrium Green-2 (ANG-2) was incubated for 60 min to allow equilibrium and then washed with 2K EBSS. The plates were transferred to a fluorescent plate reader (FLIPR TM , Molecular Devices), using an excitation wavelength of 490 nm and an emission wavelength of 565 nm for fluorescence measurement. Compounds were pre-incubated at the final test concentration for 5 min in the presence of ouabain (30 μM) to inhibit Na + By Na + / K + After the preincubation period, hNa was stimulated with 10 μM of the pyrethroid deltamethrin. v 1.8 channels to prevent channel inactivation. The assay was run for 15 min, with vehicle and 30 μM tetracaine used as negative and positive controls, respectively. The peak fluorescence change relative to the negative and positive control wells was calculated and fitted with a logistic equation to determine the IC 50 .

[0997] PatchXpress Na v 1.8 Inhibition assay

[0998] HEK-Na v 1.8β1 / β2 cells were recorded in whole-cell patch clamp using the PatchXpress automated patch clamp platform (Molecular Devices). Cell suspensions were obtained by trypsinization of adherent monolayers followed by gentle shaking for a minimum of 30 min. Compounds were prepared from 10 mM DMSO stocks.

[0999]

[1000] use Solution 1 Nav1.8 channel variants were evaluated, where cells were initially voltage clamped at a holding potential of -100 mV to keep Nav1.8 in a closed resting state. After the current amplitude became stable, a series of 5-second adjustment steps to an incrementally depolarizing voltage (-100 mV to 0 mV) were used to determine the midpoint voltage of steady-state inactivation for each cell. The holding potential was then reset to a voltage that produced ~50% inactivation (V 半 -automatically set via PatchXpress script) so that closed and inactivated channel inhibition can be assessed. Protocol 1 was run at 0.1 Hz until the current amplitude stabilized (automatically determined by the PatchXpress script). The effect of the test reagents on the Nav current amplitude was monitored using a custom PatchXpress stability script that determines the timing of compound addition and washout.

[1001] DataXpress 2.0 (Molecular Devices) was used to process and analyze data. Microsoft Excel was used to calculate the percentage inhibition so that the compound block was normalized relative to the mean value of the control current and the removal current according to the following formula: % inhibition = (((control + removal) / 2)-drug) / ((control + removal) / 2)*100. The normalized concentration-response relationship was fitted using XLfit software (IDBS) 4-parameter logistic model or sigmoidal dose-response model.

[1002] HkDJ v 1.8 Automated patch clamp - IonFlux HT Determination

[1003] The IonFlux HT automated whole-cell patch clamp instrument (Fluxion Biosciences, Inc., Almeda, CA USA) was used to record inward sodium currents.

[1004] Cells: HEK-293 cells were cultured with human Na v 1.8 cDNA (X-type voltage-gated sodium channel alpha subunit, accession number NM_006514) and human beta subunit 1 (accession number NM_001037) were stably transfected. The cells were harvested with trypsin and kept in serum-free medium at room temperature before recording. Before application to the instrument, the cells were washed and resuspended in extracellular solution.

[1005] Test concentrations: Stock solutions were prepared in DMSO at 300× the final assay concentration and stored at -80°C until the day of assay. On the day of assay, aliquots of the stock solutions were thawed and diluted into the external solution to make the final assay concentrations. A final concentration of 0.33% DMSO was maintained for each concentration of assay compound and control.

[1006] Recording conditions: Intracellular solution (mM): 100 CsF, 45 CsCl, 5 NaCl, 10 HEPES, 5 EGTA (pH 7.3, titrated with 1 M CsOH).

[1007] Extracellular solution (mM): 150 NaCl, 4 BaCl, 1 MgCl2, 1.8 CaCl2, 10 HEPES, 5 glucose (pH 7.4, titrated with 10 M NaOH).

[1008] When the sodium channel is held at a depolarized membrane potential, the channel opens and inactivates, and remains inactivated until the membrane potential is stepped back to a hyperpolarized membrane potential, at which time the inactivated channel returns to the closed state. Compounds that show more inhibition in pulse 2 compared to pulse 1 are state-dependent inhibitors. An example is tetracaine, which is a much more potent inhibitor in the inactivated state than in the tonic or open state.

[1009] The cells were held at -120 mV for 50 ms, then stepped to -10 mV for 2 s to completely inactivate the sodium channels (pulse 1), and stepped back to -120 mV for 10 ms (to fully recover from inactivation, however, channels with inhibitors bound to them may not recover from inactivation), then stepped to -10 mV for 50 ms (pulse 2). The scan interval was 20 s (0.05 Hz). Each concentration of compound was applied for two minutes. The assay was performed at room temperature.

[1010] Reference compound: Tetracaine was used as a positive control and was tested simultaneously with the test compounds.

[1011] Data Analysis: Only current amplitudes exceeding 3 nA during the control phase were analyzed. The amplitude of the sodium current was calculated by measuring the difference between the peak inward current (i.e., the current peak) when stepping to -10 mV and the residual current at the end of the step. The sodium current was evaluated under vehicle control conditions and then at the end of each two (2) minute compound application. Individual cell capture results were normalized to the vehicle control amplitude and the mean ± SEM calculated for each compound concentration. These values ​​were then plotted and the estimated IC was calculated. 50 Curve fitting.

[1012] The estimated IC values ​​of the picolinamide compounds exemplified above are 50The values ​​are listed in Table 1.

[1013]

[1014]

[1015]

[1016] The present invention also provides the following items: 1. A compound of formula (I):

[1017]

[1018] in:

[1019] X is -CH- or nitrogen;

[1020] Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;

[1021] R1 is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is unsubstituted or substituted by one or more groups selected from the group consisting of a monohalogenated C1-C4 hydrocarbon group, a dihalogenated C1-C4 hydrocarbon group and a trihalogenated C1-C4 hydrocarbon group, a substituted or unsubstituted C1-C8 hydrocarbon group, a C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, sulfanyl, trifluoromethylsulfanyl and arylalkoxy;

[1022] R2 is selected from the group consisting of aryl, heteroaryl and heterocyclic, wherein the aryl, heteroaryl and heterocyclic are unsubstituted or substituted by one or more groups selected from the group consisting of monohalogenated C1-C4 hydrocarbon groups, dihalogenated C1-C4 hydrocarbon groups and trihalogenated C1-C4 hydrocarbon groups, substituted or unsubstituted C1-C8 hydrocarbon groups, C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, arylalkoxy, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;

[1023] R3, when Y is carbon, is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalo, dihalo and trihalo C1-C4 alkoxy, monohalo, dihalo and trihalo C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy, C3-C8 cycloalkyl, -NO2, and is absent when Y is nitrogen;

[1024] R4 is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy and morpholinyl, with the proviso that R3 and R4 are not hydrogen at the same time; or

[1025] R3 and R4 together form a C3-C5 carbocyclic ring including the carbon atoms to which R3 and R4 are attached;

[1026] and pharmaceutically acceptable salts thereof.

[1027] 2. The compound according to item 1, wherein:

[1028] X is -CH- or nitrogen;

[1029] Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;

[1030] R1 is phenyl or pyridyl, wherein the phenyl or pyridyl is unsubstituted or substituted by one or more groups selected from the group consisting of: substituted or unsubstituted C1-C8 hydrocarbon group; halogen; -O-R5, wherein R5 is selected from C1-C8 hydrocarbon group, -CF3, -CHF2 and -(CH2) p -CF3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; and -S-CF3;

[1031] R2 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl are unsubstituted or substituted with one or more groups selected from the group consisting of unsubstituted or substituted C1-C8 hydrocarbon group; halogen; cyano; oxo; -O-R5, wherein R5 is selected from the group consisting of C1-C8 hydrocarbon group, -CF3 and -CHF2; -(CH2) q -OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; morpholinyl; oxazolyl; -C(=O)-R8, wherein R8 is selected from the group consisting of -NR6R7 and C1-C4 hydrocarbon groups, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group, provided that when Y is nitrogen and R2 is phenyl or pyridyl, R8 cannot be -NR6R7;

[1032] R3, when Y is carbon, is selected from the group consisting of hydrogen, cyano, halogen, -CF3, C1-C8 alkoxy, -O-CH(F)2, substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, -N + (=O)-O - , and is absent when Y is nitrogen;

[1033] R4 is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, -CF3, substituted or unsubstituted C1-C8 alkyl and morpholinyl, provided that R3 and R4 are not hydrogen at the same time; or

[1034] R3 and R4 together form a C3-C5 carbocyclic ring including the carbon atoms to which R3 and R4 are attached;

[1035] and pharmaceutically acceptable salts thereof.

[1036] 3. The compound according to item 1, wherein the compound has the following structure:

[1037]

[1038] in:

[1039] X is -CH- or nitrogen;

[1040] Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;

[1041] R2 is selected from the group consisting of aryl, heteroaryl and heterocyclic, wherein the aryl, heteroaryl and heterocyclic are unsubstituted or substituted by one or more groups selected from the group consisting of monohalogenated C1-C4 hydrocarbon groups, dihalogenated C1-C4 hydrocarbon groups and trihalogenated C1-C4 hydrocarbon groups, substituted or unsubstituted C1-C8 hydrocarbon groups, C3-C 10Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, arylalkoxy, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;

[1042] R3, when Y is carbon, is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalo, dihalo and trihalo C1-C4 alkoxy, monohalo, dihalo and trihalo C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy, C3-C8 cycloalkyl, -NO2, and is absent when Y is nitrogen;

[1043] R4 is selected from the group consisting of hydrogen, cyano, halogen, C1-C8 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, monohalogenated C1-C4 alkoxy, dihalogenated C1-C4 alkoxy and trihalogenated C1-C4 alkoxy, substituted or unsubstituted C1-C8 alkoxy and morpholinyl, with the proviso that R3 and R4 are not hydrogen at the same time; or

[1044] R3 and R4 together form a C3-C5 carbocyclic ring including the carbon atoms to which R3 and R4 are attached;

[1045] n is an integer selected from 0, 1, 2, 3, 4 and 5;

[1046] Each R 24 independently selected from the group consisting of monohalogenated C1-C4 hydrocarbon groups, dihalogenated C1-C4 hydrocarbon groups and trihalogenated C1-C4 hydrocarbon groups, substituted or unsubstituted C1-C8 hydrocarbon groups, C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxy, aryl, C1-C8 alkoxy, monohaloalkoxy, dihaloalkoxy or trihaloalkoxy, sulfanyl, trifluoromethylsulfanyl and arylalkoxy;

[1047] and pharmaceutically acceptable salts thereof.

[1048] 5. The compound according to item 4, wherein R2 is selected from the group consisting of:

[1049]

[1050] in:

[1051] m is an integer selected from the group consisting of 0, 1, 2, 3 and 4;

[1052] R 25Selected from the group consisting of: H; morpholinyl; oxazolyl; halogen; cyano; -(CH2) q -OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -C(=O)-R8, wherein R8 is selected from the group consisting of -NR6R7 and C1-C4 hydrocarbon groups, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group, provided that when Y is nitrogen and R2 is phenyl or pyridyl, R8 cannot be -NR6R7;

[1053] R 26 is a halogen or a cyano group;

[1054] Each R 27 are independently selected from the group consisting of: H, halogen, C1-C8 alkoxy, cyano, and -NR6R7; and

[1055] Each R 28 are independently H or a C1-C4 hydrocarbon group.

[1056] 5. The compound according to item 1, wherein the compound of formula (I) is a compound of formula (IF):

[1057]

[1058] in:

[1059] R2 is selected from the group consisting of aryl and heteroaryl, wherein the aryl or heteroaryl is optionally substituted by a substituent group selected from the group consisting of cyano, heterocycloalkyl, -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group;

[1060] R 12 is a halogen; and

[1061] R 13 It is a C1-C4 hydrocarbon group.

[1062] 6. The compound according to item 5, wherein the aryl group and the heteroaryl group are selected from the group consisting of phenyl, benzothiazolyl, pyridyl, pyridyl N-oxide and pyrimidinyl, each of which is optionally substituted by a substituent group selected from the group consisting of cyano, heterocyclic hydrocarbon, -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group;

[1063] R 12 is fluorine; and

[1064] R 13 It's methyl.

[1065] 7. The compound according to item 6, wherein R2 is selected from the group consisting of 1,3-benzothiazol-6-yl, 3-morpholinophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-pyridyl, 4-pyridyl, 6-cyano-3-pyridyl, 3-methylsulfinylphenyl, 3-oxazol-5-ylphenyl, 3-dimethylsulfamoylphenyl, 1,3-benzothiazol-2-yl, pyrimidin-4-yl, (trifluorosulfonyl)phenyl, 3-(methylsulfonylimino)phenyl, 2-methoxy-4-pyridyl, 3-(N,S-dimethylsulfonylimino)phenyl, 2-methyl-4-pyridyl, 6-methyl-3-pyridyl, pyridazin-4-yl and dimethyl(oxo)-λ 6 -sulfanyl]amino]phenyl.

[1066] 8. The compound according to item 1, wherein the compound is a compound of formula (IG):

[1067]

[1068] in:

[1069] R1 is phenyl substituted by one or more of C1-C8 hydrocarbyl, halogen and C1-C8 hydrocarbyloxy, and wherein the C1-C8 hydrocarbyloxy is optionally substituted by one or more halogen; and

[1070] R 14It is a C1-C4 hydrocarbon group.

[1071] 9. The compound according to item 8, wherein R1 is selected from the group consisting of 2,4-dichlorophenyl, 2,4-dimethylphenyl, 2-chloro-4-methoxyphenyl, 2-propylphenyl, 2-methoxy-4-methylphenyl, 2-methoxy-4-chlorophenyl, 2-isopropoxyphenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2-chloro-4-methoxyphenyl, 3,4-difluorophenyl and 2-chloro-4-fluorophenyl.

[1072] 10. The compound according to item 1, wherein the compound is a compound of formula (IHi):

[1073]

[1074] in:

[1075] R1 is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazol-4-yl, wherein the phenyl and pyridyl can be unsubstituted or substituted by one or more of the following: halogen; C1-C8 hydrocarbon group; -O-R5, wherein R5 is selected from the group consisting of C1-C8 hydrocarbon group, -CF3, -CHF2 and -(CH2) p -CF3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -S-CF3; -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups;

[1076] R3 and R4 are H or -CF3, provided that if R3 is H, then R4 is -CF3, and if R4 is H, then R3 is -CF3;

[1077] R 14 is a C1-C4 hydrocarbon group; and

[1078] R 15 Is O or NR 10 , where R 10 It is H or C1-C4 hydrocarbon group.

[1079] 11. The compound according to item 10, wherein R1 is selected from the group consisting of phenyl, 4-fluorophenyl, 4-fluoro-2-methoxyphenyl, 2-chloro-4-fluorophenyl, 2-methyl-4-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, difluoromethoxyphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3-fluorophenyl, 2,5-difluorophenyl, 4-methylphenyl, 3-chloro-5-fluorophenyl, 2-isopropylphenyl, 3,4-difluorophenyl, 2,4 phenyl, 2-trifluorophenyl, 3,5-difluorophenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(trifluoromethylsulfanyl)phenyl, 2-dimethylaminophenyl, 2-trifluoromethylphenyl, 2,4-dimethoxyphenyl, 3,4,5-trifluorophenyl, 3,5-dichlorophenyl, 6-trifluoromethyl-3-pyridyl, 1,3-benzothiazol-4-yl, 4-difluoromethoxyphenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methoxyphenyl and 2-chlorophenyl.

[1080] 12. The compound according to item 1, wherein the compound is a compound of formula (IH-ii):

[1081]

[1082] in:

[1083] R1 is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazol-4-yl, wherein the phenyl and pyridyl can be unsubstituted or substituted by one or more of the following: halogen; C1-C8 hydrocarbon group; -O-R5, wherein R5 is selected from the group consisting of C1-C8 hydrocarbon group, -CF3, -CHF2 and -(CH2) p -CF3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -S-CF3; -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; and

[1084] R3 and R4 are H or -CF3, provided that if R3 is H then R4 is -CF3, and if R4 is H then R3 is -CF3.

[1085] 13. The compound according to item 12, wherein R1 is selected from the group consisting of 2,4-dichlorophenyl, 4-difluoromethoxyphenyl and 2-chloro-4-methoxyphenyl.

[1086] 14. The compound according to item 1, wherein the compound is a compound of formula (II):

[1087]

[1088] in:

[1089] R2 is selected from the group consisting of phenyl, pyridazinyl and pyridinyl, wherein the phenyl can be substituted by one or more of the following: halogen, -S(=O)-R9, -S(=O)2-R9 and -S(=O)(=NR 10 )-R 11 , wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group;

[1090] R 16 is a halogen; and

[1091] R 17 It is a C1-C4 hydrocarbon group.

[1092] 15. The compound according to item 14, wherein R2 is selected from the group consisting of 3-methylsulfinylphenyl, 2-fluoro-5-methylsulfonylphenyl, 3-(N,S-dimethylsulfonylimino)phenyl, pyridazinyl and pyridinyl.

[1093] 16. The compound according to item 1, wherein the compound is a compound of formula (IJ):

[1094]

[1095] in:

[1096] R2 is selected from the group consisting of phenyl and pyridyl, wherein the phenyl is substituted by one or more of the following: halogen; -C(=O)-R8, wherein R8 is selected from the group consisting of -NR6R7 and C1-C4 hydrocarbon, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon; -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group; and

[1097] R 18 It's a halogen.

[1098] 17. The compound according to item 16, wherein R2 is selected from the group consisting of 3-methylsulfonylphenyl, 3-methylsulfinylphenyl, 3-(dimethylsulfamoyl)phenyl, 2-fluoro-5-methylsulfonylphenyl, 3-(methylsulfonylimino)phenyl, 3-carbamoylphenyl, 3-(N,S-dimethylsulfonylimino)phenyl, 3-pyridyl and 4-pyridyl.

[1099] 18. The compound according to item 1, wherein the compound is a compound of formula (IK):

[1100]

[1101] in:

[1102] R1 is phenyl substituted by one or more of the following: halogen; C1-C8 hydrocarbon group; -O-R5, wherein R5 is selected from C1-C8 hydrocarbon group, -CF3, -CHF2 and -(CH2) p -CF3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8.

[1103] 19. The compound according to item 18, wherein R1 is selected from the group consisting of 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,4-difluorophenyl and 3,4-difluorophenyl.

[1104] 20. The compound according to item 1, wherein the compound is a compound of formula (IL):

[1105]

[1106] wherein R2 is selected from the group consisting of phenyl, pyridyl and pyridazin-4-yl, wherein the phenyl is substituted by: -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently a C1-C4 hydrocarbon group or -NR6R7, wherein R6 and R7 are each H, R 10 is H or a C1-C4 hydrocarbon group, and R 11 It is a C1-C4 hydrocarbon group.

[1107] 21. The compound according to item 1, wherein the compound is a compound of formula (IMi):

[1108]

[1109] in:

[1110] R2 is 3-(N,S-dimethylsulfonylimino)phenyl or pyridazin-4-yl;

[1111] R 16 is a halogen; and

[1112] R 19 It is a C1-C4 hydrocarbon group.

[1113] 22. The compound according to item 1, wherein the compound is a compound of formula (IM-ii):

[1114]

[1115] wherein R1 is selected from the group consisting of 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl.

[1116] 23. The compound according to item 1, wherein the compound is a compound of formula (IM-iii):

[1117]

[1118] in:

[1119] R1 is selected from the group consisting of 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl;

[1120] R 20 is a C1-C4 hydrocarbon group; and

[1121] R 21 It is H or C1-C4 hydrocarbon group.

[1122] 24. The compound according to item 1, wherein the compound is a compound of formula (IM-iv):

[1123]

[1124] wherein R1 is selected from the group consisting of 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl.

[1125] 25. The compound according to item 1, wherein the compound is a compound of formula (IN):

[1126]

[1127] in:

[1128] R2 is selected from the group consisting of 3-(N,S-dimethylsulfonylimino)phenyl, 3-(methylsulfonylimino)phenyl and pyridazin-4-yl;

[1129] R 16 is a halogen; and

[1130] R 19 It is a C1-C4 hydrocarbon group.

[1131] 26. The compound according to item 1, wherein the compound is a compound of formula (IO):

[1132]

[1133] wherein R2 is selected from the group consisting of phenyl, pyridyl and pyridazin-4-yl, wherein the phenyl is substituted by: -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently a C1-C4 hydrocarbon group or -NR6R7, wherein R6 and R7 are each H, R 10 is H or a C1-C4 hydrocarbon group, and R 11 It is a C1-C4 hydrocarbon group.

[1134] 27. The compound according to item 1, wherein the compound is a compound of formula (IP):

[1135]

[1136] wherein R1 is selected from the group consisting of 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl, 2,4-difluorophenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2-chloro-4-methoxyphenyl, 3,4-difluorophenyl and 2-chloro-4-fluorophenyl.

[1137] 28. The compound according to item 1, wherein the compound is a compound of formula (IQ):

[1138]

[1139] in:

[1140] R2 is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiadiazolyl, pyrazolyl and 1,2,4-triazolyl;

[1141] in:

[1142] The phenyl group is substituted by one or more groups selected from the group consisting of: unsubstituted or substituted C1-C8 hydrocarbon group; halogen; cyano; oxo; -O-R5, wherein R5 is selected from the group consisting of C1-C8 hydrocarbon group, -CF3 and -CHF2; -(CH2) q -OH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; morpholinyl; oxazolyl; -C(=O)-R8, wherein R8 is selected from the group consisting of -NR6R7 and C1-C4 hydrocarbon groups, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2, wherein each R9 is independently C1-C4 hydrocarbon group, -CF3 or -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon group, R 10 is H or a C1-C4 hydrocarbon group, and R 11 is a C1-C4 hydrocarbon group;

[1143] Pyridyl is unsubstituted or substituted by C1-C8 alkyl, oxo, C1-C8 alkoxy and halogen; and

[1144] R 18 It's a halogen.

[1145] 29. The compound according to item 1, wherein the compound is a compound of formula (IR):

[1146]

[1147] in:

[1148] R2 is 3-(methylsulfonylimino)phenyl or pyridazin-4-yl; and

[1149] R 22 and R 23 Each is a C1-C4 hydrocarbon group.

[1150] 30. The compound according to item 1, wherein the compound is a compound of formula (IS):

[1151]

[1152] in:

[1153] R2 is 3-(methylsulfonylimino)phenyl or pyridazin-4-yl; and

[1154] R16 and R 18 Each is a halogen.

[1155] 31. The compound according to item 1, wherein the compound of formula (I) is selected from the group consisting of:

[1156] 6-Chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (Intermediate 3);

[1157] N-(1,3-Benzothiazol-6-yl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (1);

[1158] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-morpholinophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (2);

[1159] N-(3-cyanophenyl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (3);

[1160] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (4);

[1161] N-(4-cyanophenyl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (5);

[1162] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (6);

[1163] N-(6-cyano-3-pyridinyl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (7);

[1164] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfinylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (8);

[1165] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-oxazol-5-ylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (9);

[1166] N-[3-(Dimethylsulfamoyl)phenyl]-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (10);

[1167] N-(1,3-Benzothiazol-2-yl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (11);

[1168] 2-(4-Fluoro-2-methoxy-phenoxy)-N-pyrimidin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (12);

[1169] 2-(4-Fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)-N-[3-(trifluoromethylsulfonyl)phenyl]pyridine-3-carboxamide (13);

[1170] 2-(4-Fluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (14);

[1171] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (15);

[1172] N-[3-(N,S-dimethylsulfonylimino)phenyl]-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (16);

[1173] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(2-methyl-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (17);

[1174] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(6-methyl-3-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (18);

[1175] 2-(4-Fluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (19);

[1176] N-[3-[[dimethyl(oxy)-λ 6 -sulfanyl]amino]phenyl]-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (20);

[1177] 2-(2,4-Dichlorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (21);

[1178] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-morpholinophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (22);

[1179] 2-(2-Chloro-4-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (23);

[1180] N-(3-methylsulfonylphenyl)-2-(2-propylphenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (24);

[1181] 2-(2-Methoxy-4-methyl-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (25);

[1182] 2-(4-Chloro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (26);

[1183] 2-(2-Isopropoxyphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (27);

[1184] 2-(4-(difluoromethoxy)phenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (28);

[1185] 2-(2,4-dimethoxyphenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (29);

[1186] 2-(2-Chloro-4-methoxyphenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (30);

[1187] 2-(3,4-difluorophenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (31);

[1188] 2-(2-Chloro-4-fluorophenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (32);

[1189] 2-(2,6-Dimethylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (33);

[1190] 2-(4-Fluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (34);

[1191] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (35);

[1192] 2-(2-Chloro-4-fluoro-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (36);

[1193] N-(3-Methylsulfonylphenyl)-2-[2-methyl-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (37);

[1194] N-(3-Methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (38);

[1195] 2-[4-(Difluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (39);

[1196] 2-[3-Fluoro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (40);

[1197] N-(3-Methylsulfonylphenyl)-2-phenoxy-5-(trifluoromethyl)pyridine-3-carboxamide (41);

[1198] 2-(3-Fluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (42);

[1199] 2-(2,5-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (43);

[1200] 2-(4-Methylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (44);

[1201] 2-(3-Chloro-5-fluoro-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (45);

[1202] 2-(2-Isopropylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (46);

[1203] 2-(3,4-Difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (47);

[1204] 2-(2,4-Difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (48);

[1205] 2-(3,5-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (49);

[1206] N-(3-Methylsulfonylphenyl)-2-[4-(2,2,2-trifluoroethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (50);

[1207] N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-[4-(trifluoromethylsulfanyl)phenoxy]pyridine-3-carboxamide (51);

[1208] 2-[2-(Dimethylamino)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (52);

[1209] N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-[2-(trifluoromethyl)phenoxy]pyridine-3-carboxamide (53);

[1210] 2-(2,4-Dimethoxyphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (54);

[1211] N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-(3,4,5-trifluorophenoxy)pyridine-3-carboxamide (55);

[1212] 2-(3,5-Dichlorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (56);

[1213] N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-[[6-(trifluoromethyl)-3-pyridinyl]oxy]pyridine-3-carboxamide (57);

[1214] 2-(1,3-Benzothiazol-4-yloxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (58);

[1215] 2-[4-(Difluoromethoxy)phenoxy]-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (59);

[1216] 2-(2-Chloro-4-fluoro-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (60);

[1217] 2-(2-Chloro-4-methoxy-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (61);

[1218] 2-(2-Chlorophenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (62);

[1219] 2-(2,4-Dichlorophenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (63);

[1220] 2-[4-(Difluoromethoxy)phenoxy]-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (64);

[1221] 2-(2-Chloro-4-methoxy-phenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (65);

[1222] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (66);

[1223] 4-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (67);

[1224] 4-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfinylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (68);

[1225] 4-(4-Fluoro-2-methoxy-phenoxy)-N-(2-fluoro-5-methylsulfonyl-phenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (69);

[1226] N-[3-(N,S-dimethylsulfonylimino)phenyl]-4-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxamide (70);

[1227] 4-(4-Fluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (71);

[1228] 4-(4-Fluoro-2-methoxy-phenoxy)-N-(4-pyridinyl)-6-(trifluoromethyl)pyridine-3-carboxamide (72);

[1229] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[2-(dimethylamino)-4-pyridinyl]-6-(trifluoromethyl)pyridine-3-carboxamide (73);

[1230] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (74);

[1231] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfinylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (75);

[1232] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethylsulfamoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (76);

[1233] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro-5-methylsulfonyl-phenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (77);

[1234] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-pyridinyl)-6-(trifluoromethyl)pyridine-3-carboxamide (78);

[1235] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(4-pyridinyl)-6-(trifluoromethyl)pyridine-3-carboxamide (79);

[1236] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (80);

[1237] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(N,S-dimethylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (82);

[1238] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (83);

[1239] 4-(4-Fluoro-2-methoxy-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (84);

[1240] 4-(4-Fluoro-2-methyl-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (85);

[1241] 4-[4-(Difluoromethoxy)phenoxy]-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (86);

[1242] N-(1-Oxopyridin-1-ium-3-yl)-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (87);

[1243] 4-(2,4-Dimethoxyphenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (88);

[1244] 4-(2,4-Difluorophenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (89);

[1245] 3-(2-(3,4-difluorophenoxy)-5-(trifluoromethyl)nicotinylamino)pyridine-1-oxide (90);

[1246] N-[3-(Methylsulfonylimino)phenyl]-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (91);

[1247] N-[3-(N,S-dimethylsulfonylimino)phenyl]-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (92);

[1248] 4-(4-Fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (93);

[1249] N-[3-(N,S-dimethylsulfonylimino)phenyl]-4-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxamide (94);

[1250] 4-(4-Fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (95);

[1251] N-pyridazin-4-yl-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (96);

[1252] 4-[4-(Difluoromethoxy)phenoxy]-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (97);

[1253] 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (98);

[1254] 4-(2,4-Dimethoxyphenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (99);

[1255] 4-(2,4-Difluorophenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (100);

[1256] 4-[4-(Difluoromethoxy)phenoxy]-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (101);

[1257] 4-(2,4-Dimethoxyphenoxy)-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (102);

[1258] 4-(2,4-Difluorophenoxy)-N-[3-(methylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (103);

[1259] 2-(4-(difluoromethoxy)phenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (104);

[1260] N-(Pyridin-3-yl)-4-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)nicotinamide (105)

[1261] 4-(2-Chloro-4-(trifluoromethoxy)phenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl)nicotinamide (106);

[1262] 4-(2,4-dimethoxyphenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl)nicotinamide (107);

[1263] 4-(2,4-difluorophenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl)nicotinamide (108);

[1264] 2-(4-Fluoro-2-methyl-phenoxy)-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (109);

[1265] 2-(4-Fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (110);

[1266] 5-Bromo-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (111);

[1267] 5-Cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (112);

[1268] 2-(4-Fluoro-2-methyl-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (113);

[1269] N-[3-(N,S-dimethylsulfonylimino)phenyl]-2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (114);

[1270] 2-(4-Fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (115);

[1271] 2-(4-Fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (116);

[1272] 2-(4-Fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (117);

[1273] 2-(4-Fluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (118);

[1274] 5-Chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (119);

[1275] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (120);

[1276] N-(3-Methylsulfinylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (121);

[1277] N-(3-sulfamoylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (122);

[1278] N-[3-(Methylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (123);

[1279] N-[3-(N,S-dimethylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (124);

[1280] N-(3-ethylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (125);

[1281] N-(3-pyridinyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (126);

[1282] N-(4-pyridinyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (127);

[1283] N-pyridazin-4-yl-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (128);

[1284] N-[3-[[dimethyl(oxy)-λ 6 -sulfanyl]amino]phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (129);

[1285] N-[3-(Methylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide, Enantiomer A (130);

[1286] N-[3-(Methylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide, enantiomer B (131);

[1287] N-(1-Oxopyridin-1-ium-3-yl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (132);

[1288] 2-(4-Fluoro-2-methyl-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (133);

[1289] 2-(4-Fluoro-2-methoxy-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (134);

[1290] 2-(2,4-Difluorophenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (135);

[1291] 3-(2-(4-(difluoromethoxy)phenoxy)-5-(trifluoromethyl)nicotinoylamino)pyridine 1-oxide (136);

[1292] 3-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)nicotinylamino)pyridine 1-oxide (137);

[1293] 3-(2-(2-chloro-4-methoxyphenoxy)-5-(trifluoromethyl)nicotinylamino)pyridine 1-oxide (138);

[1294] 3-(2-(3,4-difluorophenoxy)-5-(trifluoromethyl)nicotinylamino)pyridine 1-oxide (139);

[1295] 2-(2-Chloro-4-fluoro-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (140);

[1296] N-(1-Oxidopyridin-1-ium-4-yl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (141);

[1297] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (142);

[1298] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-ethylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (143);

[1299] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(N,S-dimethylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (144);

[1300] 4-Pyridinyl 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)picolinate (145);

[1301] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-cyanophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (146);

[1302] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (147);

[1303] N-(3-Carbamoylphenyl)-2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (148);

[1304] N-(3-Acetylphenyl)-2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (149);

[1305] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methyl-2-oxo-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (150);

[1306] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethylcarbamoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (151);

[1307] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(4-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (152);

[1308] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(4-methylsulfinylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (153);

[1309] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethylsulfamoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (154);

[1310] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3,4-difluorophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (155);

[1311] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(6-methoxy-3-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (156);

[1312] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-pyrimidin-5-yl-5-(trifluoromethyl)pyridine-3-carboxamide (157);

[1313] N-(2-chloro-4-pyridinyl)-2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (158);

[1314] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(6-fluoro-3-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (159);

[1315] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(hydroxymethyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (160);

[1316] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (161);

[1317] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro-5-methylsulfonyl-phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (162);

[1318] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-fluorophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (163);

[1319] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (164);

[1320] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (165);

[1321] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (166);

[1322] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methylpyrazol-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (167);

[1323] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-5-methylsulfonyl-phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (168);

[1324] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (169);

[1325] 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methyl-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (170);

[1326] 2-(2,4-Dimethoxyphenoxy)-N-[3-(N,S-dimethylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (171);

[1327] 2-(2,4-Dimethoxyphenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (172);

[1328] 2-(2,4-Dimethoxyphenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (173);

[1329] 2-(2,4-Difluorophenoxy)-N-[3-(methylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (174);

[1330] 2-(2,4-Difluorophenoxy)-N-[3-(N,S-dimethylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (175);

[1331] 2-(2,4-Difluorophenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (176);

[1332] 5-Cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (177);

[1333] 5-Fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (178);

[1334] 5-(Difluoromethoxy)-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (179);

[1335] N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (180); and

[1336] 5-Chloro-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (181).

[1337] 32. A method for regulating Na v 1.8 A method for regulating sodium ion channels, the method comprising administering an effective amount of a compound described in any one of items 1-31 to a subject in need thereof.

[1338] 33. A method for inhibiting Na v 1.8 The method comprises administering an inhibitory effective amount of a compound according to any one of items 1-31 to a subject in need thereof.

[1339] 34. A method for treating and / or reducing and increasing Na v 1.8 A method for treating and / or reducing the symptoms of a condition, disease or disorder associated with the activity or expression of a drug, the method comprising administering to a subject in need of corresponding treatment a therapeutically effective amount of a compound as described in any one of items 1-29 to treat and / or reduce the symptoms of the condition, disease or disorder.

[1340] 35. The method according to item 34, wherein the Na v 1.8 The condition, disease or disorder associated with activity or expression is selected from the group consisting of pain, respiratory disease, neurological disorder and psychiatric disease and combinations thereof.

[1341] 36. The method according to claim 35, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, post-surgical pain, labor pain, labor pain, neurogenic bladder disorder, ulcerative colitis, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury and combinations thereof.

[1342] 37. The method of claim 35, wherein the disease or condition is selected from the group consisting of: HIV-treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenic syndrome, myotonia , malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related disorders, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, partial and generalized tonic seizures, restless legs syndrome, cardiac arrhythmias, fibromyalgia, neuroprotection in ischemic conditions caused by stroke or neurotrauma, tachyarrhythmias, atrial fibrillation, ventricular fibrillation, and Pitt Hopkins syndrome (PTHS).

[1343] 38. The method according to item 34 further comprises administering one or more additional therapeutic agents to the subject.

[1344] 39. The method of claim 38, wherein the one or more additional therapeutic agents are selected from the group consisting of acetaminophen, one or more NSAIDs, opioid analgesics, and combinations thereof.

[1345] 40. The compound of formula (I) is used in the manufacture of a drug for treating a patient with increased Na v 1.8 Use in a medicament for treating a condition, disease or disorder associated with the activity or expression of such disorder in a subject.

[1346] References

[1347] All publications, patent applications, patents, and other references mentioned in the specification are indicative of the level of those skilled in the art to which the subject matter disclosed herein belongs. All publications, patent applications, patents, and other references are incorporated herein by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. It will be understood that although many patent applications, patents, and other references are referred to herein, such references do not constitute an admission that any of these documents form part of the common general knowledge in the art.

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[1402] Although the foregoing subject matter has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

1. A compound of formula (IH-ii) or a pharmaceutically acceptable salt thereof: in: R1 is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazol-4-yl, wherein the phenyl and pyridyl can be unsubstituted or substituted by one or more of the following: halogen; C1-C8 hydrocarbon group; -O-R5, wherein R5 is selected from the group consisting of C1-C8 hydrocarbon group, -CF3, -CHF2 and -(CH2) p -CF3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; -S-CF3; -NR6R7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 hydrocarbon groups; and R3 and R4 are H or -CF3, provided that if R3 is H then R4 is -CF3, and if R4 is H then R3 is -CF3. 2 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of 2,4-dichlorophenyl, 4-difluoromethoxyphenyl and 2-chloro-4-methoxyphenyl.

3. A compound of formula (II) or a pharmaceutically acceptable salt thereof: in: R2 is selected from the group consisting of 3-methylsulfinylphenyl, 2-fluoro-5-methylsulfonylphenyl, 3-(N,S-dimethylsulfonylimino)phenyl, pyridazinyl and pyridinyl; R 16 is a halogen; and R 17 It is a C1-C4 hydrocarbon group.

4. A compound of formula (IK) or a pharmaceutically acceptable salt thereof: in: R1 is phenyl substituted by one or more of the following: halogen; C1-C8 hydrocarbon group; -O-R5, wherein R5 is selected from C1-C8 hydrocarbon group, -CF3, -CHF2 and -(CH2) p -CF3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,4-difluorophenyl and 3,4-difluorophenyl.

6. A compound of formula (IMi) or a pharmaceutically acceptable salt thereof: in: R2 is 3-(N,S-dimethylsulfonylimino)phenyl or pyridazin-4-yl; R 16 is a halogen; and R 19 It is a C1-C4 hydrocarbon group.

7. A compound of formula (IM-ii) or a pharmaceutically acceptable salt thereof: wherein R1 is selected from the group consisting of 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl.

8. A compound of formula (IM-iii) or a pharmaceutically acceptable salt thereof: in: R1 is selected from the group consisting of 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl; R 20 is a C1-C4 hydrocarbon group; and R 21 It is H or C1-C4 hydrocarbon group.

9. A compound of formula (IM-iv) or a pharmaceutically acceptable salt thereof: wherein R1 is selected from the group consisting of 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl.

10. A compound of formula (IP) or a pharmaceutically acceptable salt thereof: wherein R1 is selected from the group consisting of 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl, 2,4-difluorophenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2-chloro-4-methoxyphenyl, 3,4-difluorophenyl and 2-chloro-4-fluorophenyl.

11. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 6-Chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (Intermediate 3); N-(1,3-Benzothiazol-6-yl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (1); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-morpholinophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (2); N-(3-cyanophenyl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (3); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (4); N-(4-cyanophenyl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (5); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (6); N-(6-cyano-3-pyridinyl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (7); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfinylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (8); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-oxazol-5-ylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (9); N-(1,3-Benzothiazol-2-yl)-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (11); 2-(4-Fluoro-2-methoxy-phenoxy)-N-pyrimidin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (12); 2-(4-Fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)-N-[3-(trifluoromethylsulfonyl)phenyl]pyridine-3-carboxamide (13); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (15); N-[3-(N,S-dimethylsulfonylimino)phenyl]-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (16); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(2-methyl-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (17); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(6-methyl-3-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (18); 2-(4-Fluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (19); N-[3-[[dimethyl(oxy)-λ 6 -sulfanyl]amino]phenyl]-2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (20); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-morpholinophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (22); 2-(2-Chloro-4-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (23); N-(3-methylsulfonylphenyl)-2-(2-propylphenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (24); 2-(2-Methoxy-4-methyl-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (25); 2-(4-Chloro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (26); 2-(2-Isopropoxyphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (27); 2-(4-(difluoromethoxy)phenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (28); 2-(2,4-dimethoxyphenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (29); 2-(2-Chloro-4-methoxyphenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (30); 2-(3,4-difluorophenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (31); 2-(2-Chloro-4-fluorophenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl)nicotinamide (32); 2-(2,6-Dimethylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (33); 2-(4-Fluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (34); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (35); 2-(2-Chloro-4-fluoro-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (36); N-(3-Methylsulfonylphenyl)-2-[2-methyl-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (37); N-(3-Methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (38); 2-[4-(Difluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (39); 2-[3-Fluoro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (40); N-(3-Methylsulfonylphenyl)-2-phenoxy-5-(trifluoromethyl)pyridine-3-carboxamide (41); 2-(3-Fluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (42); 2-(2,5-Difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (43); 2-(4-Methylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (44); 2-(3-Chloro-5-fluoro-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (45); 2-(2-Isopropylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (46); 2-(3,4-Difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (47); 2-(2,4-Difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (48); 2-(3,5-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (49); N-(3-Methylsulfonylphenyl)-2-[4-(2,2,2-trifluoroethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (50); N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-[4-(trifluoromethylsulfanyl)phenoxy]pyridine-3-carboxamide (51); 2-[2-(Dimethylamino)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (52); N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-[2-(trifluoromethyl)phenoxy]pyridine-3-carboxamide (53); 2-(2,4-Dimethoxyphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (54); N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-(3,4,5-trifluorophenoxy)pyridine-3-carboxamide (55); 2-(3,5-Dichlorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (56); N-(3-Methylsulfonylphenyl)-5-(trifluoromethyl)-2-[[6-(trifluoromethyl)-3-pyridinyl]oxy]pyridine-3-carboxamide (57); 2-(1,3-Benzothiazol-4-yloxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (58); 2-(2,4-Dichlorophenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (63); 2-[4-(Difluoromethoxy)phenoxy]-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (64); 2-(2-Chloro-4-methoxy-phenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (65); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (66); 4-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (67); 4-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfinylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (68); 4-(4-Fluoro-2-methoxy-phenoxy)-N-(2-fluoro-5-methylsulfonyl-phenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (69); N-[3-(N,S-dimethylsulfonylimino)phenyl]-4-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxamide (70); 4-(4-Fluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (71); 4-(4-Fluoro-2-methoxy-phenoxy)-N-(4-pyridinyl)-6-(trifluoromethyl)pyridine-3-carboxamide (72); 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[2-(dimethylamino)-4-pyridinyl]-6-(trifluoromethyl)pyridine-3-carboxamide (73); 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (74); 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfinylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (75); 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro-5-methylsulfonyl-phenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (77); 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-pyridinyl)-6-(trifluoromethyl)pyridine-3-carboxamide (78); 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(4-pyridinyl)-6-(trifluoromethyl)pyridine-3-carboxamide (79); 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(N,S-dimethylsulfonylimino)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (82); 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (83); 4-(4-Fluoro-2-methoxy-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (84); 4-(4-Fluoro-2-methyl-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (85); 4-[4-(Difluoromethoxy)phenoxy]-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (86); N-(1-Oxopyridin-1-ium-3-yl)-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (87); 4-(2,4-Dimethoxyphenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (88); 4-(2,4-Difluorophenoxy)-N-(1-oxypyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (89); 3-(4-(3,4-difluorophenoxy)-6-(trifluoromethyl)nicotinylamino)pyridine-1-oxide (90); N-[3-(N,S-dimethylsulfonylimino)phenyl]-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (92); N-[3-(N,S-dimethylsulfonylimino)phenyl]-4-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxamide (94); 4-(4-Fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (95); N-pyridazin-4-yl-4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (96); 4-[4-(Difluoromethoxy)phenoxy]-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (97); 4-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (98); 4-(2,4-Dimethoxyphenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (99); 4-(2,4-Difluorophenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridine-3-carboxamide (100); 4-(4-(difluoromethoxy)phenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl)nicotinamide (104); N-(Pyridin-3-yl)-4-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)nicotinamide (105) 4-(2-Chloro-4-(trifluoromethoxy)phenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl)nicotinamide (106); 4-(2,4-dimethoxyphenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl)nicotinamide (107); 4-(2,4-difluorophenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl)nicotinamide (108); 2-(4-Fluoro-2-methyl-phenoxy)-N-(2-methoxy-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (109); 2-(4-Fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (110); 5-Bromo-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (111); 5-Cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (112); 2-(4-Fluoro-2-methyl-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (113); N-[3-(N,S-dimethylsulfonylimino)phenyl]-2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (114); 2-(4-Fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (116); 2-(4-Fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (117); 2-(4-Fluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (118); 5-Chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (119); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (120); N-(3-Methylsulfinylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (121); N-[3-(N,S-dimethylsulfonylimino)phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (124); N-(3-Ethylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (125); N-(3-pyridinyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (126); N-(4-pyridinyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (127); N-pyridazin-4-yl-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (128); N-[3-[[dimethyl(oxy)-λ 6 -sulfanyl]amino]phenyl]-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (129); N-(1-Oxopyridin-1-ium-3-yl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (132); 2-(4-Fluoro-2-methyl-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (133); 2-(4-Fluoro-2-methoxy-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (134); 2-(2,4-Difluorophenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (135); 3-(2-(4-(difluoromethoxy)phenoxy)-5-(trifluoromethyl)nicotinoylamino)pyridine 1-oxide (136); 3-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)nicotinylamino)pyridine 1-oxide (137); 3-(2-(2-chloro-4-methoxyphenoxy)-5-(trifluoromethyl)nicotinylamino)pyridine 1-oxide (138); 3-(2-(3,4-difluorophenoxy)-5-(trifluoromethyl)nicotinylamino)pyridine 1-oxide (139); 2-(2-Chloro-4-fluoro-phenoxy)-N-(1-oxypyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (140); N-(1-Oxidopyridin-1-ium-4-yl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (141); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (142); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-ethylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (143); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(N,S-dimethylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (144); 4-Pyridinyl 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)picolinate (145); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-cyanophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (146); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (147); N-(3-Carbamoylphenyl)-2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (148); N-(3-Acetylphenyl)-2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (149); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methyl-2-oxo-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (150); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethylcarbamoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (151); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(4-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (152); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(4-methylsulfinylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (153); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3,4-difluorophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (155); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(6-methoxy-3-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (156); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-pyrimidin-5-yl-5-(trifluoromethyl)pyridine-3-carboxamide (157); N-(2-chloro-4-pyridinyl)-2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (158); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(6-fluoro-3-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (159); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(hydroxymethyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (160); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (161); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro-5-methylsulfonyl-phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (162); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(3-fluorophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (163); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (164); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro-4-pyridinyl)-5-(trifluoromethyl)pyridine-3-carboxamide (165); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (166); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methylpyrazol-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (167); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-5-methylsulfonyl-phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (168); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (169); 2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methyl-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (170); 2-(2,4-Dimethoxyphenoxy)-N-[3-(N,S-dimethylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (171); 2-(2,4-Dimethoxyphenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (173); 2-(2,4-Difluorophenoxy)-N-[3-(N,S-dimethylsulfonylimino)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (175); 2-(2,4-Difluorophenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)pyridine-3-carboxamide (176); 5-Cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (177); 5-Fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (178); 5-(Difluoromethoxy)-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (179); N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (180); and 5-Chloro-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (181).

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