JPWO2020014246A5 - - Google Patents

Description

(Mutual reference of related applications)
This application claims the interests of US Provisional Application No. 62 / 695,571 filed July 9, 2018, which is incorporated herein by reference in its entirety.

Modern pharmacies have a variety of treatments for acute and chronic pain, including steroidal and non-steroidal anti-inflammatory drugs (NSAIDs), amine reuptake inhibitors and opioids (analgesics). All have their disadvantages, and extensive efforts have been made to develop new approaches to pain management, especially in light of the recent epidemic of opioid abuse (Skolnik, 2018) (Yekkirala et al., 2017). ). Voltage-gated sodium channels (Nav) ( _Catalyl 2012) are rational targets for pain management given that they play an important role in the neural conduction of sensory neurons (Riz et al., 2015).

There are a total of nine known subtypes of the major pore-forming alpha subunits. The Na _v 1.1, Na _v 1.2 and Na _v 1.3 subtypes are expressed primarily in the central nervous system (CNS), and Na _v 1.4 and Na _v 1.5 are abundant in skeletal muscle and myocardium. Exists in. Na _v 1.6 has been shown to be expressed in both the peripheral nervous system (PNS) and the CNS, whereas Na _v 1.7, Na _v 1.8 and Na _v 1.9 are It is usually considered to be limited to PNS (Yu and Catalyst, 2003). Non-selective sodium channel inhibitors are available as antiarrhythmic agents, anticonvulsants and local anesthetics, but none are suitable for the general treatment of chronic pain (Eijkelkamp, et al., 2012). The Nav family of channels is highly homologous and obtaining selective drug-like ligands is an important task ( _Bagal , et al, 2014). However, the identification of selective inhibitors of specific isoforms (Jukic, et al., 2014) or activators (Deuis, et al., 2017) is promising in many disorders.

Since both Na _v 1.7 and Na _v 1.8 isoforms are present in the nociceptors of PNS, they have received a great deal of attention as targets for pain treatment (Jukic, et al, 2014). Following extensive human genetic validation of this channel (Bennet and Woods, 2014) and the discovery of selective inhibitor classes (McCormac et al., 2013), active efforts towards Na _v 1.7 have been undertaken. It has been done (Vetter, et al., 2017). However, human clinical trials of some selective Na _v 1.7 inhibitors have been disappointing (Donnel et al., 2018; Zakrzewska et al., 2017), with Na _v 1.8 as an alternative target. It has been suggested that there is (Han et al., 2016).

The pore-forming α-subunit of the Na _v 1.8 sodium channel is encoded by the SCN10A gene and is expressed primarily in dorsal root ganglion (DRG) neurons as well as trigeminal and nodal ganglion neurons (although). , But not limited to these) (Akopian et al., 1996; Shelds et al., 2012). These neurons mediate most inward sodium currents in the depolarizing phase of action potentials, which are important for action potential transmission and repetitive firing (Akopian et al., 1999). Knockout and knockdown studies of the rodent _SCN10A gene have shown that Nav 1.8 is involved in inflammatory 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-diameter fiber neuropathy in humans, which is associated with Na _v 1.8 and nociceptive neuronal function. The sex is further enhanced (Faber et al., 2012).

Na _v 1.8 inhibitors have potential beyond pain treatment. Na _v 1.8 is expressed in the brain (Lu et al., 2015) and there is increasing evidence that it is involved in the etiology of multiple sclerosis (MS). In some reports, Na _v 1.8 was different in experimental autoimmune encephalomyelitis (EAE) mice (Black et al., 2000) and cerebellar Purkinje neurons (Damarjian et al., 2004) in MS patients. It has been shown to be expressed locally. Ectopic expression of Na _v 1.8 results in abnormal firing patterns in cerebellar Purkinje cells and impaired motor coordination despite no apparent signs of ataxia in the mouse model (Shelds et al). ., 2012).

Importantly, treatment with the Na _v 1.8 blocker N-methyl-6-amino-5- (2,3,5-trichlorophenyl) pyridin-2-carboxamide (PF01247324) is a mouse model of MS. It directs cerebellar disorders to recovery, thereby establishing potential new approaches to the treatment of MS (Shelds et al., 2015). Data on the physiological function of cortical neurons in an ex vivo cortical development model that disrupted transcription factor 4 (TCF4) demonstrate in vivo evidence that TCF4 normally suppresses the expression of the SCN10A gene in CNS. In an ex-vivo cell model of the genetic form of autism called Pitt-Hopkins syndrome (PTHS) defined by TCF4 haploinsufficiency and two independent rodent models (Sweatt, 2013), TCF4 deficiency results in action potential output. It gives rise to aberrant electrophysiological phenotypes characterized by a marked decrease in SCN10A (Na _v 1.8), which have been shown to be associated with increased expression of SCN10A (Na v 1.8) (Rannals et al., 2016). .. In addition, in these PTHS models, N- [6-amino-5- (2-chloro-5-methoxyphenyl) pyridin-2-yl] -1-methyl-1H-pyrazole-5-carboxamide (PF 4531083) and Na _v 1.8 inhibitors such as 5-4 (-chlorophenyl) -N- (3,5-dimethoxyphenyl) furan-2-carboxamide (A-803467) rapidly restore some of the excitatory phenotype. It has been shown that it can be made to. These results indicate that the ectopic expression of the sodium channel Na _v 1.8, which is normally restricted to the periphery, in the brain may cause some of the symptoms of PTHS, Na _v 1. It suggests that the 8 inhibitors have therapeutic value for PTHS patients.

Nav 1.8 channels are also expressed in back-related structures ( _Bucknill et al., 2002) and pulp (Renton et al., 2005), with burning pain (Shembalkar et al., 2001) and inflammatory. There is evidence that Nav 1.8 channels are also involved in intestinal disease ( _Beyak and Vanner, 2005).

Na _v 1.8 differs significantly from most other members of the voltage-gated ion channel family, which is tetrodotoxin, a classic sodium channel inhibitor that inhibits most other members of the family. It is "resistant" to inhibition by (Cestele and Catalyst, 2000). Na _v 1.8 inhibitors such as N-methyl-6-amino-5- (2,3,5-trichlorophenyl) pyridin-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-Molholinyl) -3-pyridinyl] methyl-3-pyridinecarboxamide (A-887826) (Zhang et al., 2010) and the like are known in the literature (see FIG. 1 (prior art)). .. Efficacy in various pain models was investigated, and efficacy was seen in both rodent models of inflammatory and neuropathic pain (Jarvis et al., 2007; Payne et al., 2015). These compounds and their similarities have various drawbacks, such as poor selectivity for other ion channels and poor pharmacokinetics.

［式中、
Ｘは、－ＣＨ－又は窒素であり；
Ｙは、炭素又は窒素であるが、Ｘ及びＹの少なくとも１つが窒素であることを条件とし；
Ｒ_１は、アリール若しくはヘテロアリールであり、前記アリール若しくはヘテロアリールは、非置換であるか、又はモノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、置換若しくは非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_１０シクロアルキル、ハロゲン、ヘテロアリール、シアノ、アミノ、ニトロ、アリールオキシル、アリール、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－若しくはトリハロアルコキシル、スルファニル、トリフルオロメチルスルファニル並びにアリールアルコキシルからなる群より選択される１つ若しくは複数の基で置換されており；
Ｒ_２は、アリール、ヘテロアリール及び複素環からなる群より選択され、前記アリール、ヘテロアリール及び複素環は、非置換であるか、又はモノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、置換若しくは非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_１０シクロアルキル、ハロゲン、ヘテロアリール、シアノ、アミノ、ニトロ、アリールオキシル、アリール、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－若しくはトリハロアルコキシル、アリールアルコキシル、オキソ、アルキルスルフィニル、アルキルスルホニル、アルキルイミノスルファノニル、アルキルスルホキシド、スルホンアミド、モルホリニル並びにオキサゾリルからなる群より選択される１つ若しくは複数の基で置換されており；
Ｒ_３は、Ｙが炭素の場合、水素、シアノ、ハロゲン、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルコキシル、置換又は非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_８シクロアルキル、－ＮＯ_２、－Ｎ^＋（＝Ｏ）－Ｏ^－からなる群より選択され、Ｙが窒素の場合は存在せず；
Ｒ_４は、水素、シアノ、ハロゲン、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルコキシル、置換若しくは非置換Ｃ_１－Ｃ_８アルキル並びにモルホリニルからなる群より選択されるが、Ｒ_３及びＲ_４が同時に水素ではないことを条件とし；又は
Ｒ_３及びＲ_４は、一緒になって、Ｒ_３及びＲ_４が結合している炭素原子を含むＣ_３－Ｃ_５炭素環を形成する］；
並びにその薬学的に許容される塩を提供する。 In some embodiments, the subject matter of the present disclosure is a compound of formula (I):

[During the ceremony,
X is -CH- or nitrogen;
Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;
R ₁ is an aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl. , C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C1 _- C ₈ alkoxyl, mono-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and arylalkoxyl. Substituted with one or more groups selected from the group consisting of;
_R2 is selected from the group consisting of aryls, heteroaryls and heterocycles, wherein the aryls, heteroaryls and heterocycles are unsubstituted or mono-, di- and trihalo-C1 _{- C4} alkyls. Substituent or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C1 _- C ₈ alkoxyl, mono-, di- or trihaloalkenyl. , Arylalkenyl, oxo, alkylsulfinyl, alkylsulfonyls, alkyliminosulfanonyls, alkylsulfoxides, sulfonamides, morpholinyls and oxazolyls substituted with one or more groups selected from the group;
When Y is carbon, R ₃ contains hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di- and trihalo-C ₁ -C ₄ alkyl, mono-, di- and trihalo-C ₁ -C. ₄ Alkoxy, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ , -N ⁺ (= O) -O ^- selected from the group, present when Y is nitrogen Not;
_R4 is hydrogen, cyano, halogen, C1 _- C8 alkoxyl, mono-, di- and trihalo-C _{1 -} C ₄ alkyl, mono-, di- and trihalo _{-C 1-4 alkoxyl} , substituted or non-substituted. Selected from the group consisting of substituted C1 _- C8 alkyl and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or R ₃ and R ₄ together _{, R 3 and} R. Form a C3 _{- C5} carbon ring containing the carbon atom to which ₄ is bonded];
It also provides a pharmaceutically acceptable salt thereof.

In a particular embodiment of the compound of formula (I):
X is -CH- or nitrogen;
Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;
R ₁ is selected from the group consisting of phenyl or pyridinyl, wherein the phenyl or pyridinyl is unsubstituted or substituted or unsubstituted C ₁ -C ₈ alkyl, halogen, -OR ₅ (in the formula, R). ₅ is C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ and-(CH ₂ ) _p -CF ₃ (in the formula, p is from 1, 2, 3, 4, 5, 6, 7 and 8). (Selected from the group consisting of) (which is an integer selected from the group consisting of) and substituted with one or more groups selected from the group consisting of -S- _CF3 ;
_R2 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazolyl, pyridin-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl. , Pyridyl, pyrimidinyl, pyridadinyl, pyridin- ₁ -oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl are unsubstituted, unsubstituted or substituted C1- C ₈ alkyl, halogen, cyano, oxo, -O-R ₅ (in the formula, R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ and -CHF ₂ ),-(CH ₂ ). ) _Q -OH (in the formula, q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8), -NR ₆ R ₇ (in the formula, R ₆ and R ₇ is selected from the group consisting of H and C ₁ -C ₄ alkyl), morpholinyl, oxazolyl, -C (= O) -R ₈ (in the formula, R ₈ is -NR ₆ R ₇ (in the formula). , R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl) and (selected from the group consisting of C ₁ -C ₄ alkyl), -S (= O) -R ₉ , -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the equation, each R ₉ is independent. Thus, C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), R. ₁₀ is H or C1 _{- C4} alkyl and _R11 is C1- _C4 alkyl) and is substituted with _one or more groups selected from the group, where Y is nitrogen and If R ₂ is phenyl or pyridyl, then R ₈ cannot be -NR ₆ R ₇ ;
R ₃ is hydrogen, cyano, halogen, -CF ₃ , C ₁ -C ₈ alkoxyl, -O-CH (F) ₂ , substituted or unsubstituted C ₁ -C ₈ alkyl, C _3- , when Y is carbon. Selected from the group consisting of _{C8 cycloalkyl, NO 2 and} not present when Y is nitrogen;
R ₄ is selected from the group consisting of hydrogen, cyano, halogen, C1-C ₈ alkoxyl, -CF ₃ , substituted or unsubstituted C _{1 -} C ₈ alkyl, and morpholinyl, with R ₃ and R ₄ simultaneously. Subject to non-hydrogen; or R ₃ and R ₄ together form a C ₃ -C ₅ carbon ring containing the carbon atom to which R ₃ and R ₄ are attached;
And its pharmaceutically acceptable salt.

［式中、
Ｘは、－ＣＨ－又は窒素であり；
Ｙは、炭素又は窒素であるが、Ｘ及びＹの少なくとも１つが窒素であることを条件とし；
Ｒ_２は、アリール、ヘテロアリール及び複素環からなる群より選択され、前記アリール、ヘテロアリール及び複素環は、非置換であるか、又はモノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、置換若しくは非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_１０シクロアルキル、ハロゲン、ヘテロアリール、シアノ、アミノ、ニトロ、アリールオキシル、アリール、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－若しくはトリハロアルコキシル、アリールアルコキシル、オキソ、アルキルスルフィニル、アルキルスルホニル、アルキルイミノスルファノニル、アルキルスルホキシド、スルホンアミド、モルホリニル並びにオキサゾリルからなる群より選択される１つ若しくは複数の基で置換されており；
Ｒ_３は、Ｙが炭素の場合、水素、シアノ、ハロゲン、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルコキシル、置換又は非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_８シクロアルキル、－ＮＯ_２からなる群より選択され、Ｙが窒素の場合は存在せず；
Ｒ_４は、水素、シアノ、ハロゲン、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルコキシル、置換若しくは非置換Ｃ_１－Ｃ_８アルキル並びにモルホリニルからなる群より選択されるが、Ｒ_３及びＲ_４が同時に水素ではないことを条件とし；又は
Ｒ_３及びＲ_４は、一緒になって、Ｒ_３及びＲ_４が結合している炭素原子を含むＣ_３－Ｃ_５炭素環を形成し；
ｎは、０、１、２、３、４及び５から選択される整数であり；
各Ｒ_２４は、独立して、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、置換又は非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_１０シクロアルキル、ハロゲン、ヘテロアリール、シアノ、アミノ、ニトロ、アリールオキシル、アリール、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－又はトリハロアルコキシル、スルファニル、トリフルオロメチルスルファニル並びにアリールアルコキシルからなる群より選択される］；
並びにその薬学的に許容される塩。 In a further specific embodiment of the compound of formula (I), the compound has the following structure:

[During the ceremony,
X is -CH- or nitrogen;
Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;
_R2 is selected from the group consisting of aryls, heteroaryls and heterocycles, wherein the aryls, heteroaryls and heterocycles are unsubstituted or mono-, di- and trihalo-C1 _{- C4} alkyls. Substituent or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C1 _- C ₈ alkoxyl, mono-, di- or trihaloalkenyl. , Arylalkenyl, oxo, alkylsulfinyl, alkylsulfonyls, alkyliminosulfanonyls, alkylsulfoxides, sulfonamides, morpholinyls and oxazolyls substituted with one or more groups selected from the group;
R ₃ is hydrogen, cyano, halogen, C1-C ₈ alkoxyl, mono-, di- and trihalo-C ₁ -C ₄ alkyl, mono-, di- and trihalo-C _{1 -} C when Y is carbon. Selected from the group consisting of ₄ alkoxyls, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ , not present when Y is nitrogen;
_R4 is hydrogen, cyano, halogen, C1 _- C8 alkoxyl, mono-, di- and trihalo-C _{1 -} C ₄ alkyl, mono-, di- and trihalo _{-C 1-4 alkoxyl} , substituted or non-substituted. Selected from the group consisting of substituted C1 _- C8 alkyl and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or R ₃ and R ₄ together _{, R 3 and} R. Form a C3 _{- C5} carbon ring containing the carbon atom to which ₄ is bonded;
n is an integer selected from 0, 1, 2, 3, 4 and 5;
Each R ₂₄ is independently mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, Selected from the group consisting of amino, nitro, aryloxyl, aryl, C1 _- C8 _alkoxyl , mono-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and arylalkoxyl];
And its pharmaceutically acceptable salt.

［式中、
ｍは、０、１、２、３及び４からなる群より選択される整数であり；
Ｒ_２５は、Ｈ、モルホリニル、オキサゾリル、ハロゲン、シアノ、－（ＣＨ_２）_ｑ－ＯＨ（式中、ｑは１、２、３、４、５、６、７及び８からなる群より選択される整数である）、－Ｃ（＝Ｏ）－Ｒ_８（式中、Ｒ_８は、－ＮＲ_６Ｒ_７及びＣ_１－Ｃ_４アルキルからなる群より選択され、Ｒ_６及びＲ_７は、Ｈ及びＣ_１－Ｃ_４アルキルからなる群より選択される）、－Ｓ（＝Ｏ）－Ｒ_９、－Ｓ（＝Ｏ）_２－Ｒ_９、－Ｓ（＝Ｏ）（＝ＮＲ_１０）－Ｒ_１１並びに－Ｎ＝Ｓ（＝Ｏ）－（Ｒ_１１）_２（式中、各Ｒ_９は、独立して、Ｃ_１－Ｃ_４アルキル、－ＣＦ_３又は－ＮＲ_６Ｒ_７（式中、Ｒ_６及びＲ_７は、Ｈ及びＣ_１－Ｃ_４アルキルからなる群より選択される）であり、Ｒ_１０はＨ又はＣ_１－Ｃ_４アルキルであり、Ｒ_１１はＣ_１－Ｃ_４アルキルである）からなる群より選択されるが、Ｙが窒素で、Ｒ_２がフェニル又はピリジルの場合、Ｒ_８を－ＮＲ_６Ｒ_７にすることはできないことを条件とする；
Ｒ_２６は、ハロゲン又はシアノであり；
各Ｒ_２７は、独立して、Ｈ、ハロゲン、Ｃ_１－Ｃ_８アルコキシル、シアノ及び－ＮＲ_６Ｒ_７からなる群より選択され；
各Ｒ_２８は、独立して、Ｈ又はＣ_１－Ｃ_４アルキルである］。 In certain embodiments of the compound of formula (I'), R ₂ is selected from the group consisting of:

[During the ceremony,
m is an integer selected from the group consisting of 0, 1, 2, 3 and 4;
R ₂₅ is selected from the group consisting of H, morpholinyl, oxazolyl, halogen, cyano,-(CH ₂ ) _q -OH (in the formula, q is 1, 2, 3, 4, 5, 6, 7 and 8). (Integer), -C (= O) -R ₈ (in the equation, R ₈ is selected from the group consisting of -NR ₆ R ₇ and C ₁ -C ₄ alkyl, R ₆ and R ₇ are H and (Selected from the group consisting of C ₁ -C ₄ alkyl), -S (= O) -R ₉ , -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ And -N = S (= O)-(R ₁₁ ) ₂ (in the formula, each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ ). And R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), R ₁₀ is H or C ₁ -C ₄ alkyl, and R ₁₁ is C ₁ -C ₄ alkyl). Selected from the group consisting of, provided that if Y is nitrogen and R ₂ is phenyl or pyridyl, then R ₈ cannot be -NR ₆ R ₇ ;
_R26 is a halogen or cyano;
Each R ₂₇ is independently selected from the group consisting of H, halogen, C ₁ -C ₈ alkoxyl, cyano and -NR ₆ R ₇ ;
Each R ₂₈ is independently an H or C1 _{- C4} alkyl].

In another aspect, the subject matter of the present disclosure is a method of modulating _Nav 1.8 sodium ion channels to a subject in need thereof in a regulatory effective amount of a compound of formula (I). Provide methods including administration of.

In another aspect, the subject of the present disclosure is a method of inhibiting Na _v 1.8, wherein a subject in need thereof is administered an inhibitory effective amount of a compound of formula (I) to said subject. Provide a method including that.

In yet another aspect, the subject matter of the present disclosure is a method of treating a condition, disease or disorder associated with increased activity or expression of _Nav 1.8, said to a subject in need thereof. Provided are methods comprising administering to a subject a therapeutically effective amount of a compound of formula (I).

In certain embodiments, the pathology, illness or disorder associated with increased activity or expression of Na _v 1.8 is selected from the group consisting of pain, respiratory illness, neuropathy and psychiatric disorders and combinations thereof.

Certain aspects of the subject matter of the present disclosure described above are described in whole or in part by the subject matter of the present disclosure, while other aspects are best described herein in the attachments below. It will become clear as the explanation progresses in connection with the embodiment of.

Since the subject matter of this disclosure has been described in general terms in this way, the attached figures will be referred to next, but these are not necessarily drawn to scale.
It is a figure which represents the preclinical and clinical Na _V 1.8 inhibitor (prior art) known in the art.

The subject matter of this disclosure will be described in more detail below. The subject matter of the present disclosure can be embodied in many different forms and should not be construed as confined to the embodiments described herein, the embodiments of which the present disclosure is applicable. It is provided to meet the requirements. In fact, many modifications and other embodiments of the subject matter of the present disclosure described herein will come to mind to those skilled in the art relating to the subject matter of the present disclosure that would benefit from the teachings presented in the aforementioned description. There will be. Accordingly, the subject matter of this disclosure is not limited to the particular embodiments disclosed, and amendments and other embodiments are intended to be included within the appended claims. I want you to understand.

(Pyridinecarboxamide compound for inhibiting Na _V 1.8)
The subject matter of the present disclosure provides sodium channel inhibitors and their use for treating pathological conditions, diseases or disorders associated with increased activity or expression of Na _v 1.8.

［式中、
Ｘは、－ＣＨ－又は窒素であり；
Ｙは、炭素又は窒素であるが、Ｘ及びＹの少なくとも１つが窒素であることを条件とし；
Ｒ_１は、アリール若しくはヘテロアリールであり、前記アリール若しくはヘテロアリールは、非置換であるか、又はモノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、置換若しくは非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_１０シクロアルキル、ハロゲン、ヘテロアリール、シアノ、アミノ、ニトロ、アリールオキシル、アリール、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－若しくはトリハロアルコキシル、スルファニル、トリフルオロメチルスルファニル並びにアリールアルコキシルからなる群より選択される１つ若しくは複数の基で置換されており；
Ｒ_２は、アリール、ヘテロアリール及び複素環からなる群より選択され、前記アリール、ヘテロアリール及び複素環は、非置換であるか、又はモノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、置換若しくは非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_１０シクロアルキル、ハロゲン、ヘテロアリール、シアノ、アミノ、ニトロ、アリールオキシル、アリール、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－若しくはトリハロアルコキシル、アリールアルコキシル、オキソ、アルキルスルフィニル、アルキルスルホニル、アルキルイミノスルファノニル、アルキルスルホキシド、スルホンアミド、モルホリニル並びにオキサゾリルからなる群より選択される１つ若しくは複数の基で置換されており；
Ｒ_３は、Ｙが炭素の場合、水素、シアノ、ハロゲン、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルコキシル、置換又は非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_８シクロアルキル、－ＮＯ_２からなる群より選択され、Ｙが窒素の場合は存在せず；
Ｒ_４は、水素、シアノ、ハロゲン、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルコキシル、置換若しくは非置換Ｃ_１－Ｃ_８アルキル並びにモルホリニルからなる群より選択されるが、Ｒ_３及びＲ_４が同時に水素ではないことを条件とし；又は
Ｒ_３及びＲ_４は、一緒になって、Ｒ_３及びＲ_４が結合している炭素原子を含むＣ_３－Ｃ_５炭素環を形成する］；
並びにその薬学的に許容される塩を提供する。 In some embodiments, the subject matter of the present disclosure is a compound of formula (I):

[During the ceremony,
X is -CH- or nitrogen;
Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;
R ₁ is an aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl. , C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C1 _- C ₈ alkoxyl, mono-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and arylalkoxyl. Substituted with one or more groups selected from the group consisting of;
_R2 is selected from the group consisting of aryls, heteroaryls and heterocycles, wherein the aryls, heteroaryls and heterocycles are unsubstituted or mono-, di- and trihalo-C1 _{- C4} alkyls. Substituent or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C1 _- C ₈ alkoxyl, mono-, di- or trihaloalkenyl. , Arylalkenyl, oxo, alkylsulfinyl, alkylsulfonyls, alkyliminosulfanonyls, alkylsulfoxides, sulfonamides, morpholinyls and oxazolyls substituted with one or more groups selected from the group;
R ₃ is hydrogen, cyano, halogen, C1-C ₈ alkoxyl, mono-, di- and trihalo-C ₁ -C ₄ alkyl, mono-, di- and trihalo-C _{1 -} C when Y is carbon. Selected from the group consisting of ₄ alkoxyls, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ , not present when Y is nitrogen;
_R4 is hydrogen, cyano, halogen, C1 _- C8 alkoxyl, mono-, di- and trihalo-C _{1 -} C ₄ alkyl, mono-, di- and trihalo _{-C 1-4 alkoxyl} , substituted or non-substituted. Selected from the group consisting of substituted C1 _- C8 alkyl and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or R ₃ and R ₄ together _{, R 3 and} R. Form a C3 _{- C5} carbon ring containing the carbon atom to which ₄ is bonded];
It also provides a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of formula (I):
X is -CH- or nitrogen;
Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;
R ₁ is phenyl or pyridinyl, and the phenyl or pyridinyl is unsubstituted, or substituted or unsubstituted C ₁ -C ₈ alkyl, halogen, -OR ₅ (in the formula, R ₅ is C). ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ and-(CH ₂ ) _p -CF ₃ (in the formula, p is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8). (Selected from the group consisting of) and -S-CF ₃ substituted with one or more groups selected from the group consisting of 3;
_R2 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazolyl, pyridin-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl. , Pyridyl, pyrimidinyl, pyridadinyl, pyridin- ₁ -oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl are unsubstituted, unsubstituted or substituted C1- C ₈ alkyl, halogen, cyano, oxo, -O-R ₅ (in the formula, R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ and -CHF ₂ ),-(CH ₂ ). ) _Q -OH (in the formula, q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8), -NR ₆ R ₇ (in the formula, R ₆ and R ₇ is selected from the group consisting of H and C ₁ -C ₄ alkyl), morpholinyl, oxazolyl, -C (= O) -R ₈ (in the formula, R ₈ is -NR ₆ R ₇ (in the formula). , R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl) and (selected from the group consisting of C ₁ -C ₄ alkyl), -S (= O) -R ₉ , -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the equation, each R ₉ is independent. Thus, C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), R. ₁₀ is H or C1 _{- C4} alkyl and _R11 is C1- _C4 alkyl) and is substituted with _one or more groups selected from the group, where Y is nitrogen and If R ₂ is phenyl or pyridyl, then R ₈ cannot be -NR ₆ R ₇ ;
R ₃ is hydrogen, cyano, halogen, -CF ₃ , C ₁ -C ₈ alkoxyl, -O-CH (F) ₂ , substituted or unsubstituted C ₁ -C ₈ alkyl, C _3- , when Y is carbon. Selected from the group consisting of C8 cycloalkyl, _{-NO 2 ,} not present when Y is nitrogen;
R ₄ is selected from the group consisting of hydrogen, cyano, halogen, C1-C ₈ alkoxyl, -CF ₃ , substituted or unsubstituted C _{1 -} C ₈ alkyl, and morpholinyl, with R ₃ and R ₄ simultaneously. Subject to non-hydrogen; or R ₃ and R ₄ together form a C ₃ -C ₅ carbon ring containing the carbon atom to which R ₃ and R ₄ are attached;
And its pharmaceutically acceptable salt.

［式中、
Ｘは、－ＣＨ－又は窒素であり；
Ｙは、炭素又は窒素であるが、Ｘ及びＹの少なくとも１つが窒素であることを条件とし；
Ｒ_２は、アリール、ヘテロアリール及び複素環からなる群より選択され、前記アリール、ヘテロアリール及び複素環は、非置換であるか、又はモノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、置換若しくは非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_１０シクロアルキル、ハロゲン、ヘテロアリール、シアノ、アミノ、ニトロ、アリールオキシル、アリール、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－若しくはトリハロアルコキシル、アリールアルコキシル、オキソ、アルキルスルフィニル、アルキルスルホニル、アルキルイミノスルファノニル、アルキルスルホキシド、スルホンアミド、モルホリニル並びにオキサゾリルからなる群より選択される１つ若しくは複数の基で置換されており；
Ｒ_３は、Ｙが炭素の場合、水素、シアノ、ハロゲン、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルコキシル、置換又は非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_８シクロアルキル、－ＮＯ_２からなる群より選択され、Ｙが窒素の場合は存在せず；
Ｒ_４は、水素、シアノ、ハロゲン、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルコキシル、置換若しくは非置換Ｃ_１－Ｃ_８アルキル並びにモルホリニルからなる群より選択されるが、Ｒ_３及びＲ_４が同時に水素ではないことを条件とし；又は
Ｒ_３及びＲ_４は、一緒になって、Ｒ_３及びＲ_４が結合している炭素原子を含むＣ_３－Ｃ_５炭素環を形成し；
ｎは、０、１、２、３、４及び５から選択される整数であり；
各Ｒ_２４は、独立して、モノ－、ジ－及びトリハロ－Ｃ_１－Ｃ_４アルキル、置換又は非置換Ｃ_１－Ｃ_８アルキル、Ｃ_３－Ｃ_１０シクロアルキル、ハロゲン、ヘテロアリール、シアノ、アミノ、ニトロ、アリールオキシル、アリール、Ｃ_１－Ｃ_８アルコキシル、モノ－、ジ－又はトリハロアルコキシル、スルファニル、トリフルオロメチルスルファニル並びにアリールアルコキシルからなる群より選択される］；
並びにその薬学的に許容される塩。 In certain embodiments of the compound of formula (I), the compound has the following structure:

[During the ceremony,
X is -CH- or nitrogen;
Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;
_R2 is selected from the group consisting of aryls, heteroaryls and heterocycles, wherein the aryls, heteroaryls and heterocycles are unsubstituted or mono-, di- and trihalo-C1 _{- C4} alkyls. Substituent or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C1 _- C ₈ alkoxyl, mono-, di- or trihaloalkenyl. , Arylalkenyl, Oxo, Alkylsulfinyl, Alksulfonyl, Alkyliminosulfanonyl, Alkylsulfoxide, Sulfonamide, Morphorinyl and Oxazolyl and is substituted with one or more groups selected from the group;
R ₃ is hydrogen, cyano, halogen, C1-C ₈ alkoxyl, mono-, di- and trihalo-C ₁ -C ₄ alkyl, mono-, di- and trihalo-C _{1 -} C when Y is carbon. Selected from the group consisting of ₄ alkoxyls, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ , not present when Y is nitrogen;
_R4 is hydrogen, cyano, halogen, C1 _- C8 alkoxyl, mono-, di- and trihalo-C _{1 -} C ₄ alkyl, mono-, di- and trihalo _{-C 1-4 alkoxyl} , substituted or non-substituted. Selected from the group consisting of substituted C1 _- C8 alkyl and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or R ₃ and R ₄ together _{, R 3 and} R. Form a C3 _{- C5} carbon ring containing the carbon atom to which ₄ is bonded;
n is an integer selected from 0, 1, 2, 3, 4 and 5;
Each R ₂₄ is independently mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, Selected from the group consisting of amino, nitro, aryloxyl, aryl, C1 _- C8 _alkoxyl , mono-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and arylalkoxyl];
And its pharmaceutically acceptable salt.

［式中、
ｍは、０、１、２、３及び４からなる群より選択される整数であり；
Ｒ_２５は、Ｈ、モルホリニル、オキサゾリル、ハロゲン、シアノ、－（ＣＨ_２）_ｑ－ＯＨ（式中、ｑは１、２、３、４、５、６、７及び８からなる群より選択される整数である）、－Ｃ（＝Ｏ）－Ｒ_８（式中、Ｒ_８は、－ＮＲ_６Ｒ_７及びＣ_１－Ｃ_４アルキルからなる群より選択され、Ｒ_６及びＲ_７は、Ｈ及びＣ_１－Ｃ_４アルキルからなる群より選択される）、－Ｓ（＝Ｏ）－Ｒ_９、－Ｓ（＝Ｏ）_２－Ｒ_９、－Ｓ（＝Ｏ）（＝ＮＲ_１０）－Ｒ_１１並びに－Ｎ＝Ｓ（＝Ｏ）－（Ｒ_１１）_２（式中、各Ｒ_９は、独立して、Ｃ_１－Ｃ_４アルキル、－ＣＦ_３又は－ＮＲ_６Ｒ_７（式中、Ｒ_６及びＲ_７は、Ｈ及びＣ_１－Ｃ_４アルキルからなる群より選択される）であり、Ｒ_１０はＨ又はＣ_１－Ｃ_４アルキルであり、Ｒ_１１はＣ_１－Ｃ_４アルキルである）からなる群より選択されるが、Ｙが窒素で、Ｒ_２がフェニル又はピリジルの場合、Ｒ_８を－ＮＲ_６Ｒ_７にすることはできないことを条件とする；
Ｒ_２６は、ハロゲン又はシアノであり；
各Ｒ_２７は、独立して、Ｈ、ハロゲン、Ｃ_１－Ｃ_８アルコキシル、シアノ及び－ＮＲ_６Ｒ_７からなる群より選択され；
各Ｒ_２８は、独立して、Ｈ又はＣ_１－Ｃ_４アルキルである］。 In a particular embodiment of the compound of formula (I'), R ₂ is selected from the group consisting of:

[During the ceremony,
m is an integer selected from the group consisting of 0, 1, 2, 3 and 4;
R ₂₅ is selected from the group consisting of H, morpholinyl, oxazolyl, halogen, cyano,-(CH ₂ ) _q -OH (in the formula, q is 1, 2, 3, 4, 5, 6, 7 and 8). (Integer), -C (= O) -R ₈ (in the equation, R ₈ is selected from the group consisting of -NR ₆ R ₇ and C ₁ -C ₄ alkyl, R ₆ and R ₇ are H and (Selected from the group consisting of C ₁ -C ₄ alkyl), -S (= O) -R ₉ , -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ And -N = S (= O)-(R ₁₁ ) ₂ (in the formula, each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ ). And R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), R ₁₀ is H or C ₁ -C ₄ alkyl, and R ₁₁ is C ₁ -C ₄ alkyl). Selected from the group consisting of, provided that if Y is nitrogen and R ₂ is phenyl or pyridyl, then R ₈ cannot be -NR ₆ R ₇ ;
_R26 is a halogen or cyano;
Each R ₂₇ is independently selected from the group consisting of H, halogen, C ₁ -C ₈ alkoxyl, cyano and -NR ₆ R ₇ ;
Each R ₂₈ is independently an H or C1 _{- C4} alkyl].

（Ｉ－Ｆ）
［式中、
Ｒ_２は、アリール及びヘテロアリールからなる群より選択され、前記アリール又はヘテロアリールは、任意選択で、シアノ、ヘテロシクロアルキル、－Ｓ（＝Ｏ）－Ｒ_９、－Ｓ（＝Ｏ）_２－Ｒ_９、－Ｓ（＝Ｏ）（＝ＮＲ_１０）－Ｒ_１１並びに－Ｎ＝Ｓ（＝Ｏ）－（Ｒ_１１）_２（式中、各Ｒ_９は、独立して、Ｃ_１－Ｃ_４アルキル、－ＣＦ_３又は－ＮＲ_６Ｒ_７（式中、Ｒ_６及びＲ_７は、Ｈ及びＣ_１－Ｃ_４アルキルからなる群より選択される）であり、Ｒ_１０はＨ又はＣ_１－Ｃ_４アルキルであり、Ｒ_１１はＣ_１－Ｃ_４アルキルである）からなる群より選択される置換基で置換されており；
Ｒ_１２は、ハロゲンであり；
Ｒ_１３は、Ｃ_１－Ｃ_４アルキルである］。 In some embodiments, the compound of formula (I) is a compound of formula (IF):

(IF)
[During the ceremony,
R ₂ is selected from the group consisting of aryl and heteroaryl, and the aryl or heteroaryl is optionally cyano, heterocycloalkyl, —S (= O) —R ₉ , —S (= O) ₂ −. R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the equation, each R ₉ is independently C ₁ -C ₄ Alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), where R ₁₀ is H or C ₁ -C. It is ₄ -alkyl and R ₁₁ is substituted with a substituent selected from the group consisting of C1 _{- C4} alkyl);
R ₁₂ is a halogen;
R ₁₃ is _a C1- _C4 alkyl].

In some embodiments of the compound of formula (IF), the aryl and heteroaryl are selected from the group consisting of phenyl, benzothiazolyl, pyridyl, pyridyl N-oxide and pyrimidinyl, each optionally cyano. , Heterocycloalkyl, -S (= O) -R ₉ , -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)- (R ₁₁ ) ₂ (In the equation, each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ and R ₁₀ is H or C ₁ -C ₄ alkyl. , R ₁₁ is substituted with a substituent selected from the group consisting of (C1 _{- C4} alkyl);
_R12 is fluorine;
R ₁₃ is methyl.

In certain embodiments of the compound of formula (IF), R ₂ is 1,3-benzothiazole-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-benzothiazole-2-yl, pyrimidin-4-yl , (Trifluorosulfonyl) phenyl, 3- (methylsulfonimideyl) phenyl, 2-methoxy-4-pyridyl, 3- (N, S-dimethylsulfonimideyl) phenyl, 2-methyl-4-pyridyl, 6- It is selected from the group consisting of methyl-3-pyridyl, pyridazine-4-yl and dimethyl (oxo) -λ ⁶ -sulfanilidene] amino] phenyl.

［式中、
Ｒ_１は、Ｃ_１－Ｃ_８アルキル、ハロゲン及びＣ_１－Ｃ_８アルコキシルのうちの１つ又は複数で置換されたフェニルであり、前記Ｃ_１－Ｃ_８アルコキシルは、任意選択で、１つ又は複数のハロゲンで置換されており；
Ｒ_１４は、Ｃ_１－Ｃ_４アルキルである］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IG):

[During the ceremony,
R ₁ is a phenyl substituted with _one or more of the C1-C8 alkyl, halogen and C1-C _{- 8} alkoxyl, wherein the C1 _{-C-8 alkoxyl is} optionally one or more. Substituted with multiple halogens;
R ₁₄ is _a C1- _C4 alkyl].

In some embodiments of the compound of formula (IG), the _R1 is 2,4-dichlorophenyl, 2,4-dimethylphenyl, 2-chloro-4-methoxyphenyl, 2-propylphenyl, 2- Phenyl-4-methylphenyl, 2-methoxy-4-chlorophenyl, 2-isopropoxyphenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2-chloro-4-methoxyphenyl, 3,4-difluorophenyl and It is selected from the group consisting of 2-chloro-4-fluorophenyl.

［式中、
Ｒ_１は、フェニル、ピリジル及び１，３－ベンゾチアゾール－４イルからなる群より選択され、前記フェニル及びピリジルは、非置換であっても、又はハロゲン、Ｃ_１－Ｃ_８アルキル、－Ｏ－Ｒ_５（式中、Ｒ_５は、Ｃ_１－Ｃ_８アルキル、－ＣＦ_３、－ＣＨＦ_２及び－（ＣＨ_２）_ｐ－ＣＦ_３（式中、ｐは、１、２、３、４、５、６、７及び８からなる群より選択される整数である）からなる群より選択される）、－Ｓ－ＣＦ_３、－ＮＲ_６Ｒ_７（式中、Ｒ_６及びＲ_７は、Ｈ及びＣ_１－Ｃ_４アルキルからなる群より選択される）の１つ又は複数で置換されていてもよく；
Ｒ_３及びＲ_４は、Ｈ又は－ＣＦ_３であるが、Ｒ_３がＨの場合、Ｒ_４は－ＣＦ_３であり、Ｒ_４がＨの場合、Ｒ_３は－ＣＦ_３であることを条件とし；
Ｒ_１４は、Ｃ_１－Ｃ_４アルキルであり；
Ｒ_１５は、Ｏ又はＮＲ_１０（式中、Ｒ_１０は、Ｈ又はＣ_１－Ｃ_４アルキルである）である］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IHI):

[During the ceremony,
R ₁ is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazole- _4yl , wherein the phenyl and pyridyl may be unsubstituted or halogen, C1 _- C8 alkyl, -O-. R ₅ (in the formula, R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ and-(CH ₂ ) _p -CF ₃ (in the formula, p is 1, 2, 3, 4, 5). , Which is an integer selected from the group consisting of 6, 7 and 8), -S-CF ₃ , -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are H and It may be substituted with one or more of (selected from the group consisting of C1 _{- C4} alkyl);
R ₃ and R ₄ are H or -CF ₃ , but if R ₃ is H, then R ₄ is -CF ₃ , and if R ₄ is H, then R ₃ is -CF ₃ . year;
R ₁₄ is _a C1- _C4 alkyl;
R ₁₅ is O or NR ₁₀ (in the formula, R ₁₀ is H or C1 _{- C4} alkyl)].

In some embodiments of the compound of formula (I-Hi), R ₁ is 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-Flurophenyl, 2-isopropylphenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 4- (2,2,2-trifluoroethoxy) phenyl, 4- (tri) Fluoromethylsulfanyl) Phenyl, 2-dimethylaminophenyl, 2-triflulomethylphenyl, 2,4-dimethoxyphenyl, 3,4,5-trifluorophenyl, 3,5-dichlorophenyl, 6-trifluoromethyl-3- It is selected from the group consisting of pyridyl, 1,3-benzothiazole-4-yl, 4-difluoromethoxyphenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methoxyphenyl and 2-chlorophenyl.

［式中、
Ｒ_１は、フェニル、ピリジル及び１，３－ベンゾチアゾール－４イルからなる群より選択され、前記フェニル又はピリジルは、非置換であっても、又はハロゲン、Ｃ_１－Ｃ_８アルキル、－Ｏ－Ｒ_５（式中、Ｒ_５は、Ｃ_１－Ｃ_８アルキル、－ＣＦ_３、－ＣＨＦ_２及び－（ＣＨ_２）_ｐ－ＣＦ_３（式中、ｐは、１、２、３、４、５、６、７及び８からなる群より選択される整数である）からなる群より選択される）、－Ｓ－ＣＦ_３、－ＮＲ_６Ｒ_７（式中、Ｒ_６及びＲ_７は、Ｈ及びＣ_１－Ｃ_４アルキルからなる群より選択される）の１つ又は複数で置換されていてもよく；
Ｒ_３及びＲ_４は、Ｈ又は－ＣＦ_３であるが、Ｒ_３がＨの場合、Ｒ_４は－ＣＦ_３であり、Ｒ_４がＨの場合、Ｒ_３は－ＣＦ_３であることを条件とする］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IH-ii):

[During the ceremony,
R ₁ is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazole- _4yl , wherein the phenyl or pyridyl may be unsubstituted or halogen, C1 _- C8 alkyl, -O-. R ₅ (in the formula, R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ and-(CH ₂ ) _p -CF ₃ (in the formula, p is 1, 2, 3, 4, 5). , Which is an integer selected from the group consisting of 6, 7 and 8), -S-CF ₃ , -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are H and It may be substituted with one or more of (selected from the group consisting of C1 _{- C4} alkyl);
R ₃ and R ₄ are H or -CF ₃ , but if R ₃ is H, then R ₄ is -CF ₃ , and if R ₄ is H, then R ₃ is -CF ₃ . Let].

In some embodiments of the compound of formula (IH-ii), R ₁ is selected from the group consisting of 2,4-dichlorophenyl, 4-difluoromethoxyphenyl and 2-chloro-4-methoxyphenyl.

［式中、
Ｒ_２は、フェニル、ピリダジニル及びピリジルからなる群より選択され、前記フェニルは、ハロゲン、－Ｓ（＝Ｏ）－Ｒ_９、－Ｓ（＝Ｏ）_２－Ｒ_９及び－Ｓ（＝Ｏ）（＝ＮＲ_１０）－Ｒ_１１（式中、各Ｒ_９は、独立して、Ｃ_１－Ｃ_４アルキル、－ＣＦ_３又は－ＮＲ_６Ｒ_７（式中、Ｒ_６及びＲ_７は、Ｈ及びＣ_１－Ｃ_４アルキルからなる群より選択される）であり、Ｒ_１０はＨ又はＣ_１－Ｃ_４アルキルであり、Ｒ_１１はＣ_１－Ｃ_４アルキルである）の１つ又は複数で置換されていてもよく；
Ｒ_１６は、ハロゲンであり；
Ｒ_１７は、Ｃ_１－Ｃ_４アルキルである］。 In some embodiments of the compound of formula (I0), the compound is a compound of formula (I-I):

[During the ceremony,
R ₂ is selected from the group consisting of phenyl, pyridadinyl and pyridyl, wherein the phenyl is halogen, —S (= O) —R ₉ , —S (= O) ₂ -R ₉ and —S (= O) ( = NR ₁₀ ) -R ₁₁ (In the formula, each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are H and C. (Selected from the group consisting of ₁ -C ₄ alkyl), where R ₁₀ is H or C ₁ -C ₄ alkyl and R ₁₁ is C ₁ -C ₄ alkyl). May be;
R ₁₆ is a halogen;
R ₁₇ is _a C1- _C4 alkyl].

In some embodiments of the compound of formula (I), R ₂ is 3-methylsulfinylphenyl, 2-fluoro-5-methylsulfonylphenyl, 3- (N, S-dimethylsulfonimideyl) phenyl, It is selected from the group consisting of pyridadinyl and pyridyl.

［式中、
Ｒ_２は、フェニル及びピリジルからなる群から選択され、前記フェニルは、ハロゲン、－Ｃ（＝Ｏ）－Ｒ_８（式中、Ｒ_８はＣ_１－Ｃ_４アルキルである）、－Ｓ（＝Ｏ）－Ｒ_９、－Ｓ（＝Ｏ）_２－Ｒ_９、－Ｓ（＝Ｏ）（＝ＮＲ_１０）－Ｒ_１１並びに－Ｎ＝Ｓ（＝Ｏ）－（Ｒ_１１）_２（式中、各Ｒ_９は、独立して、Ｃ_１－Ｃ_４アルキル、－ＣＦ_３又は－ＮＲ_６Ｒ_７であり、Ｒ_１０はＨ又はＣ_１－Ｃ_４アルキルであり、Ｒ_１１はＣ_１－Ｃ_４アルキルである）の１つ又は複数で置換されており；
Ｒ_１８は、ハロゲンである］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IJ):

[During the ceremony,
R ₂ is selected from the group consisting of phenyl and pyridyl, wherein the phenyl is halogen, -C (= O) -R ₈ (in the formula, R ₈ is C ₁ -C ₄ alkyl), -S (=). O) -R ₉ , -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (in the formula, Each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ , R ₁₀ is H or C ₁ -C ₄ alkyl, and R ₁₁ is C ₁ -C ₄ It is substituted with one or more of) (which is an alkyl);
R ₁₈ is a halogen].

In some embodiments of the compound of formula (IJ), _R2 is 3-methylsulfonylphenyl, 3-methylsulfinylphenyl, 3- (dimethylsulfamoyl) phenyl, 2-fluoro-5-methylsulfonyl. It is selected from the group consisting of phenyl, 3- (methylsulfonimideyl) phenyl, 3-carbamoylphenyl, 3 (N, S-dimethylsulfonimideyl) phenyl, 3-pyridyl and 4-pyridyl.

［式中、
Ｒ_１は、ハロゲン、Ｃ_１－Ｃ_８アルキル、－Ｏ－Ｒ_５（式中、Ｒ_５は、Ｃ_１－Ｃ_８アルキル、－ＣＦ_３、－ＣＨＦ_２及び－（ＣＨ_２）_ｐ－ＣＦ_３（式中、ｐは、１、２、３、４、５、６、７及び８からなる群より選択される整数である）からなる群より選択される）の１つ又は複数で置換されたフェニルである］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IK):

[During the ceremony,
R ₁ is halogen, C ₁ -C ₈ alkyl, -OR ₅ (in the formula, R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ and-(CH ₂ ) _p -CF ₃ Substituted with one or more of (in the formula, p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8). It is phenyl].

In some embodiments of the compound of formula (IK), R ₁ is 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl. , 2,4-Dimethoxyphenyl, 2,4-difluorophenyl and 3,4-difluorophenyl.

［式中、
Ｒ_２は、フェニル、ピリジル及びピリダジン－４－イルからなる群より選択され、前記フェニルは、－Ｓ（＝Ｏ）_２－Ｒ_９、－Ｓ（＝Ｏ）（＝ＮＲ_１０）－Ｒ_１１並びに－Ｎ＝Ｓ（＝Ｏ）－（Ｒ_１１）_２（式中、各Ｒ_９は、独立して、Ｃ_１－Ｃ_４アルキル又は－ＮＲ_６Ｒ_７（式中、Ｒ_６及びＲ_７はそれぞれＨであり、Ｒ_１０はＨ又はＣ_１－Ｃ_４アルキルであり、Ｒ_１１はＣ_１－Ｃ_４アルキルである）で置換されている］。特定の実施形態では、Ｒ_２は３－（Ｎ，Ｓ－ジメチルスルホンイミドイル）フェニルである。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IL):

[During the ceremony,
R ₂ is selected from the group consisting of phenyl, pyridyl and pyridazine-4-yl, wherein the phenyl is -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the formula, each R ₉ is independently C1 _{-C 4 alkyl} or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are respectively. H, R ₁₀ is H or C ₁ -C ₄ alkyl, and R ₁₁ is C ₁ -C ₄ alkyl)]. In certain embodiments, R ₂ is 3- (N). , S-dimethylsulfoneimideyl) Phenyl.

［式中、
Ｒ_２は、３－（Ｎ，Ｓ－ジメチルスルホンイミドイル）フェニル又はピリジジン－４－イルであり；
Ｒ_１６は、ハロゲンであり；
Ｒ_１９は、Ｃ_１－Ｃ_４アルキルである］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IMi):

[During the ceremony,
_R2 is 3- (N, S-dimethylsulfonimideyl) phenyl or pyrididin-4-yl;
R ₁₆ is a halogen;
R ₁₉ is _a C1- _C4 alkyl].

［式中、Ｒ_１は、４－トリフルオロメトキシフェニル、４－ジフルオロメトキシフェニル、２－クロロ－４－トリフルオロメトキシフェニル、２，４－ジメトキシフェニル及び２，４－ジフルオロフェニルからなる群より選択される］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IM-ii):

[In the formula, R ₁ is selected from the group consisting of 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl. Will be].

［式中、
Ｒ_１は、４－ジフルオロメトキシフェニル、２，４－ジメトキシフェニル及び２，４－ジフルオロフェニルからなる群より選択され；
Ｒ_２０は、Ｃ_１－Ｃ_４アルキルであり；
Ｒ_２１は、Ｈ又はＣ_１－Ｃ_４アルキルである］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IM-iii):

[During the ceremony,
_R1 is selected from the group consisting of 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl;
_R20 is _a C1- _C4 alkyl;
R ₂₁ is H or C1 _{- C4} alkyl].

［式中、Ｒ_１は、４－ジフルオロメトキシフェニル、４－トリフルオロメトキシフェニル、２－クロロ－４－トリフルオロメトキシフェニル、２，４－ジメトキシフェニル及び２，４－ジフルオロフェニルからなる群より選択される］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IM-iv):

[In the formula, R ₁ is selected from the group consisting of 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl. Will be].

［式中、
Ｒ_２は、３－（Ｎ，Ｓ－ジメチルスルホンイミドイル）フェニル、３－（メチルスルホンイミドイル）フェニル及びピリダジン－４－イルからなる群より選択され；
Ｒ_１６は、ハロゲンであり；
Ｒ_１９は、Ｃ_１－Ｃ_４アルキルである］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IN):

[During the ceremony,
_R2 is selected from the group consisting of 3- (N, S-dimethylsulfonimideyl) phenyl, 3- (methylsulfonimideyl) phenyl and pyridazine-4-yl;
R ₁₆ is a halogen;
R ₁₉ is _a C1- _C4 alkyl].

［式中、Ｒ_２は、フェニル、ピリジル及びピリダジン－４－イルからなる群より選択され、前記フェニルは、－Ｓ（＝Ｏ）_２－Ｒ_９、－Ｓ（＝Ｏ）（＝ＮＲ_１０）－Ｒ_１１並びに－Ｎ＝Ｓ（＝Ｏ）－（Ｒ_１１）_２（式中、各Ｒ_９は、独立して、Ｃ_１－Ｃ_４アルキル又は－ＮＲ_６Ｒ_７（式中、Ｒ_６及びＲ_７はそれぞれＨであり、Ｒ_１０はＨ又はＣ_１－Ｃ_４アルキルであり、Ｒ_１１はＣ_１－Ｃ_４アルキルである）で置換されている］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IO):

[In the formula, R ₂ is selected from the group consisting of phenyl, pyridyl and pyridazine-4-yl, and the phenyl is -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ). -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the formula, each R ₉ is independently C1 _{-C 4 alkyl} or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ is H, respectively, R ₁₀ is H or C ₁ -C ₄ alkyl, and R ₁₁ is C ₁ -C ₄ alkyl).

［式中、Ｒ_１は、４－フルオロ－２－メチルフェニル、４－フルオロ－２－メトキシフェニル、２，４－ジフルオロフェニル、４－ジフルオロメトキシフェニル、２，４－ジメトキシフェニル、２－クロロ－４－メトキシフェニル、３，４－ジフルロフェニル及び２－クロロ－４－フルオロフェニルからなる群より選択される］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IP):

[In the formula, R ₁ is 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl, 2,4-difluorophenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2-chloro- Selected from the group consisting of 4-methoxyphenyl, 3,4-diflulophenyl and 2-chloro-4-fluorophenyl].

［式中、
Ｒ_２は、フェニル、ピリジル、ピラゾリル、ピリミジニル、ピリダジニル、チアジアゾリル、ピラゾリル及び１，２，４－トリアゾリルからなる群より選択され、
フェニルは、非置換若しくは置換Ｃ_１－Ｃ_８アルキル、ハロゲン、シアノ、オキソ、－Ｏ－Ｒ_５（式中、Ｒ_５は、Ｃ_１－Ｃ_８アルキル、－ＣＦ_３及び－ＣＨＦ_２からなる群より選択される）、－（ＣＨ_２）_ｑ－ＯＨ（式中、ｑは、１、２、３、４、５、６、７及び８からなる群より選択される整数である）、－ＮＲ_６Ｒ_７（式中、Ｒ_６及びＲ_７は、Ｈ及びＣ_１－Ｃ_４アルキルからなる群より選択される）、モルホリニル、オキサゾリル、－Ｃ（＝Ｏ）－Ｒ_８（式中、Ｒ_８は、－ＮＲ_６Ｒ_７（式中、Ｒ_６及びＲ_７は、Ｈ及びＣ_１－Ｃ_４アルキルからなる群より選択される）及びＣ_１－Ｃ_４アルキルからなる群より選択される）、－Ｓ（＝Ｏ）－Ｒ_９、－Ｓ（＝Ｏ）_２－Ｒ_９、－Ｓ（＝Ｏ）（＝ＮＲ_１０）－Ｒ_１１並びに－Ｎ＝Ｓ（＝Ｏ）－（Ｒ_１１）_２（式中、各Ｒ_９は、独立して、Ｃ_１－Ｃ_４アルキル、－ＣＦ_３又は－ＮＲ_６Ｒ_７（式中、Ｒ_６及びＲ_７は、Ｈ及びＣ_１－Ｃ_４アルキルからなる群より選択される）であり、Ｒ_１０はＨ又はＣ_１－Ｃ_４アルキルであり、Ｒ_１１はＣ_１－Ｃ_４アルキルである）からなる群より選択される１つ若しくは複数の基で置換されており；
ピリジルは、非置換であるか、又はＣ_１－Ｃ_８アルキル、オキソ、Ｃ_１－Ｃ_８アルコキシル及びハロゲンで置換されており；
Ｒ_１８はハロゲンである］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IQ):

[During the ceremony,
_R2 is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyridadinyl, thiadiazolyl, pyrazolyl and 1,2,4-triazolyl.
The phenyl is a group consisting of unsubstituted or substituted C ₁ -C ₈ alkyl, halogen, cyano, oxo, -OR ₅ (in the formula, R ₅ is C ₁ -C ₈ alkyl, -CF ₃ and -CHF ₂ ). (Selected from),-(CH ₂ ) _q -OH (in the equation, q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8), -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), morpholinyl, oxazolyl, -C (= O) -R ₈ (in the formula, R ₈ ). Is -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkyl. -S (= O) -R ₉ , -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the formula, each R ₉ independently consists of C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ consist of H and C ₁ -C ₄ alkyl. R ₁₀ is H or C ₁ -C ₄ alkyl and R ₁₁ is C ₁ -C ₄ alkyl) and is substituted with one or more groups selected from the group). Has been;
Pyridil is unsubstituted or substituted with C1 _{-C8 alkyl, oxo, C1-C-8 alkoxyl and halogen} ;
R ₁₈ is a halogen].

［式中、
Ｒ_２は、３－（メチルスルホンイミドイル）フェニル又はピリダジン－４－イルであり；
Ｒ_２２及びＲ_２３は、それぞれＣ_１－Ｃ_４アルキルである］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IR):

[During the ceremony,
_R2 is 3- (methylsulfonimideyl) phenyl or pyridazine-4-yl;
R ₂₂ and R ₂₃ are C1 _{- C4} alkyl, respectively].

［式中、
Ｒ_２は、３－（メチルスルホンイミドイル）フェニル又はピリダジン－４－イルであり；
Ｒ_１６及びＲ_１８は、それぞれハロゲンである］。 In some embodiments of the compound of formula (I), the compound is a compound of formula (IS):

[During the ceremony,
_R2 is 3- (methylsulfonimideyl) phenyl or pyridazine-4-yl;
R ₁₆ and R ₁₈ are halogens, respectively].

In some embodiments of the compound of formula (I), the compound of formula (I) is
6-Chloro-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) Pyridine-3-carboxamide (Intermediate 3);
N- (1,3-Benzothiazole-6-yl) -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridin-3-carboxamide (1);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-morpholinophenyl) -5- (trifluoromethyl) pyridin-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) pyridin-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-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (6);
N- (6-cyano-3-pyridyl) -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide (7);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-methylsulfinylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (8);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-oxazole-5-ylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (9);
N- [3- (dimethylsulfamoyl) phenyl] -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridin-3-carboxamide (10);
N- (1,3-Benzothiazole-2-yl) -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridin-3-carboxamide (11);
2- (4-Fluoro-2-methoxy-phenoxy) -N-pyrimidine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (12);
2- (4-Fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) -N- [3- (trifluoromethylsulfonyl) phenyl] pyridin-3-carboxamide (13);
2- (4-Fluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (14);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (2-methoxy-4-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (15);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide (16);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (2-methyl-4-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (17);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (6-methyl-3-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (18);
2- (4-Fluoro-2-methoxy-phenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (19);
N- [3-[[dimethyl (oxo)]-λ ⁶ -sulfanilidene] amino] phenyl] -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide ( 20);
2- (2,4-dichlorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (21);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-morpholinophenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (22);
2- (2-Chloro-4-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (23);
N- (3-Methylsulfonylphenyl) -2- (2-propylphenoxy) -5- (trifluoromethyl) pyridin-3-carboxamide (24);
2- (2-Methoxy-4-methyl-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (25);
2- (4-Chloro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (26);
2- (2-isopropoxyphenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-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) pyridin-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) pyridin-3-carboxamide (35);
2- (2-Chloro-4-fluoro-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (36);
N- (3-Methylsulfonylphenyl) -2- [2-methyl-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (37);
N- (3-Methylsulfonylphenyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (38);
2- [4- (Difluoromethoxy) phenoxy] -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (39);
2- [3-Fluoro-4- (trifluoromethoxy) phenoxy] -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (40);
N- (3-Methylsulfonylphenyl) -2-phenoxy-5- (trifluoromethyl) pyridin-3-carboxamide (41);
2- (3-Fluorophenoxy) -N- (3-Methylsulfonylphenyl) -5- (trifluoromethyl) Pyridine-3-carboxamide (42);
2- (2,5-difluorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-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) pyridin-3-carboxamide (45);
2- (2-Isopropylphenoxy) -N- (3-Methylsulfonylphenyl) -5- (Trifluoromethyl) Pyridine-3-Carboxamide (46);
2- (3,4-difluorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (47);
2- (2,4-difluorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (48);
2- (3,5-difluorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (49);
N- (3-Methylsulfonylphenyl) -2- [4- (2,2,2-trifluoroethoxy) phenoxy] -5- (trifluoromethyl) pyridin-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) pyridin-3-carboxamide (52);
N- (3-Methylsulfonylphenyl) -5- (trifluoromethyl) -2- [2- (trifluoromethyl) phenoxy] pyridin-3-carboxamide (53);
2- (2,4-dimethoxyphenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (54);
N- (3-Methylsulfonylphenyl) -5- (trifluoromethyl) -2- (3,4,5-trifluorophenoxy) pyridin-3-carboxamide (55);
2- (3,5-dichlorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (56);
N- (3-Methylsulfonylphenyl) -5- (trifluoromethyl) -2-[[6- (trifluoromethyl) -3-pyridyl] oxy] Pyridine-3-carboxamide (57);
2- (1,3-Benzothiazole-4-yloxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (58);
2- [4- (Difluoromethoxy) phenoxy] -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (59);
2- (2-Chloro-4-fluoro-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (60);
2- (2-Chloro-4-methoxy-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (61);
2- (2-Chlorophenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (62);
2- (2,4-dichlorophenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (63);
2- [4- (Difluoromethoxy) phenoxy] -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (64);
2- (2-Chloro-4-methoxy-phenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (65);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (66);
4- (4-Fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (67);
4- (4-Fluoro-2-methoxy-phenoxy) -N- (3-methylsulfinylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (68);
4- (4-Fluoro-2-methoxy-phenoxy) -N- (2-fluoro-5-methylsulfonyl-phenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (69);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -4- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridin-3-carboxamide (70);
4- (4-Fluoro-2-methoxy-phenoxy) -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (71);
4- (4-Fluoro-2-methoxy-phenoxy) -N- (4-pyridyl) -6- (trifluoromethyl) pyridin-3-carboxamide (72);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [2- (dimethylamino) -4-pyridyl] -6- (trifluoromethyl) pyridin-3-carboxamide (73);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (74);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (3-methylsulfinylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (75);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (dimethylsulfamoyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (76);
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-pyridyl) -6- (trifluoromethyl) pyridin-3-carboxamide (78);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (4-pyridyl) -6- (trifluoromethyl) pyridin-3-carboxamide (79);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (80);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (N, S-dimethylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (82) ;
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (83);
4- (4-Fluoro-2-methoxy-phenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (84);
4- (4-Fluoro-2-methyl-phenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (85);
4- [4- (Difluoromethoxy) phenoxy] -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (86);
N- (1-oxide pyridine-1-ium-3-yl) -4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3-carboxamide (87);
4- (2,4-Dimethoxyphenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (88);
4- (2,4-Difluorophenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (89);
3- (4- (3,4-difluorophenoxy) -6- (trifluoromethyl) nicotinamide) pyridin 1-oxide (90);
N- [3- (Methylsulfonimideyl) phenyl] -4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridin-3-carboxamide (91);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridin-3-carboxamide (92);
4- (4-Fluoro-2-methyl-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (93);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -4- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridin-3-carboxamide (94);
4- (4-Fluoro-2-methyl-phenoxy) -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (95);
N-pyridazine-4-yl-4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridin-3-carboxamide (96);
4- [4- (Difluoromethoxy) phenoxy] -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (97);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (98);
4- (2,4-dimethoxyphenoxy) -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (99);
4- (2,4-difluorophenoxy) -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (100);
4- [4- (Difluoromethoxy) phenoxy] -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (101);
4- (2,4-dimethoxyphenoxy) -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (102);
4- (2,4-difluorophenoxy) -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (103);
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-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (109);
2- (4-Fluoro-2-methyl-phenoxy) -N- (2-oxo-1H-pyridin-4-yl) -5- (trifluoromethyl) pyridin-3-carboxamide (110);
5-bromo-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (111);
5-Cyclopropyl-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (112);
2- (4-Fluoro-2-methyl-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (113);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -2- (4-fluoro-2-methyl-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide (114);
2- (4-Fluoro-2-methyl-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (115);
2- (4-Fluoro-2-methyl-phenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (116);
2- (4-Fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (117);
2- (4-Fluoro-2-methoxy-phenoxy) -5,6-dimethyl-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (118);
5-Chloro-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (119);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6,7-dihydro-5H-cyclopentane [b] pyridin-3-carboxamide (120);
N- (3-Methylsulfinylphenyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (121);
N- (3-Sulfamoylphenyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (122);
N- [3- (Methylsulfonimideyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (123);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide (124);
N- (3-Ethylsulfonylphenyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (125);
N- (3-pyridyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (126);
N- (4-pyridyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (127);
N-pyridazine-4-yl-2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (128);
N- [3-[[dimethyl (oxo)]-λ ⁶ -sulfanilidene] amino] phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide (129) );
N- [3- (Methylsulfonimideyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide, enantiomer A (130);
N- [3- (Methylsulfonimideyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide, enantiomer B (131);
N- (1-oxide pyridine-1-ium-3-yl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide (132);
2- (4-Fluoro-2-methyl-phenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide (133);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide (134);
2- (2,4-difluorophenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide (135);
3- (2- (4- (Difluoromethoxy) phenoxy) -5- (trifluoromethyl) nicotinamide) pyridin 1-oxide (136);
3- (2- (2,4-dimethoxy) phenoxy) -5- (trifluoromethyl) nicotinamide) Pyridine 1-oxide (137);
3- (2- (2-Chloro-4-methoxyphenoxy) -5- (trifluoromethyl) nicotinamide) pyridin 1-oxide (138);
3- (2- (3,4-difluorophenoxy) -5- (trifluoromethyl) nicotinamide) pyridin 1-oxide (139);
2- (2-Chloro-4-fluoro-phenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide (140);
N- (1-oxide pyridine-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) pyridin-3-carboxamide (142);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (3-ethylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (143);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (N, S-dimethylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (144) ;
4-Pyridyl 2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxylate (145);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (3-cyanophenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (146);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (1-methylpyrazole-4-yl) -5- (trifluoromethyl) pyridin-3-carboxamide (147);
N- (3-carbamoylphenyl) -2- [2-chloro-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (148);
N- (3-Acetylphenyl) -2- [2-chloro-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (149);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (1-methyl-2-oxo-4-pyridyl) -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) pyridin-3-carboxamide (152);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (4-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (153);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (dimethylsulfamoyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (154);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (3,4-difluorophenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (155);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (6-methoxy-3-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (156);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N-pyrimidine-5-yl-5- (trifluoromethyl) pyridin-3-carboxamide (157);
N- (2-Chloro-4-pyridyl) -2- [2-chloro-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (158);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (6-fluoro-3-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (159);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (hydroxymethyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (160);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-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) pyridin-3-carboxamide (163);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (2-methyl-4-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (164);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (2-fluoro-4-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (165);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (thiadiazole-5-yl) -5- (trifluoromethyl) pyridin-3-carboxamide (166);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (2-methylpyrazole-3-yl) -5- (trifluoromethyl) pyridin-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-triazole-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide ( 169);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (1-methyl-1,2,4-triazole-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide ( 170);
2- (2,4-dimethoxyphenoxy) -N- [3- (N, S-dimethylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (171);
2- (2,4-dimethoxyphenoxy) -N- [3 (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (172);
2- (2,4-dimethoxyphenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (173);
2- (2,4-difluorophenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (174);
2- (2,4-difluorophenoxy) -N- [3- (N, S-dimethylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (175);
2- (2,4-difluorophenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (176);
5-Cyano-2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (177);
5-Fluoro-2- (4-fluoro-2-methoxy-phenoxy) -6-methoxy-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (178);
5- (Difluoromethoxy) -2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (179);
N- (3-Methylsulfonylphenyl) -5-nitro-2- [4- (trifluoromethoxy) phenoxy] pyridin-3-carboxamide (180); and 5-chloro-N- (3-methylsulfonylphenyl)- 2- [4- (Trifluoromethoxy) Phenoxy] Pyridine-3-Carboxamide (181)
Selected from the group consisting of.

(Method for treating pathological conditions, diseases or disorders associated with increased activity or expression of B. NaV1.8)
In some embodiments, the subject matter of the present disclosure is a method of regulating _Nav 1.8 sodium ion channels, for a subject in need thereof, a regulatory effective amount for the subject, formula (I). Provided are methods comprising administering the compound of.

In another embodiment, the subject of the present disclosure is a method of inhibiting Na _v 1.8, wherein a subject in need thereof is administered a compound of formula (I) in an inhibitory effective amount for said subject. Provide methods that include doing.

As used herein, the term "inhibition" and its grammatical derivatives refer to the compounds of the present disclosure, eg, the compounds of the present disclosure of formula (I), to indicate the activity or expression of _Nav 1.8 in a subject. Refers to the ability to block, partially block, interfere, reduce or reduce. Thus, one of ordinary skill in the art will appreciate that the term "inhibiting" is a complete and / or partial reduction in channel function, eg, a reduction of at least 10%, in some embodiments at least 20%, 30%. , 50%, 75%, 95%, 98% and 100%.

In certain embodiments, the subject matter of the present disclosure provides a method of treating a condition, disease or disorder associated with increased activity or expression of _Nav 1.8. In a further specific embodiment, the pathology, disease or disorder associated with increased activity or expression of _Nav 1.8 is pain, especially inflammatory pain, visceral pain and neuropathic pain, neuropathy, especially multiple sclerosis. Selected from the group consisting of illness, autism, especially Pitt-Hopkins syndrome and psychiatric disorders and combinations thereof, the method is given to subjects in need thereof in a therapeutically effective amount of a compound of formula I or pharmaceutically effective thereof. Includes administration of acceptable salts.

In certain embodiments, the disease or condition is neuropathic pain, inflammatory pain, visceral pain, cancerous pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, birth pain, labor pain, Neuropathic bladder, ulcerative colitis, chronic pain, persistent pain, peripheral pain, central pain, chronic headache, migraine, headache due to sinusitis, tension headache, phantom limb pain, toothache, peripheral nerve damage Or it is selected from the group consisting of combinations thereof.

In other embodiments, the disease or condition is HIV-related pain, HIV treatment-induced neuropathy, trigeminal nerve pain, post-herpes zoster nerve pain, eudynia, heat hypersensitivity, tosarcoidosis, hypersensitive bowel syndrome. , Crohn's disease, pain associated with multiple sclerosis (MS), muscular atrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis , Paroxysmal dystonia, myasthenia syndrome, myotension, malignant hyperthermia cystic fibrosis, pseudoaldosteronism, erythromelalgia, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel Toxin-related disorders, familial erythromelalgia, primary erythromelalgia, familial erythromelalgia, cancer, epilepsy, partial and general tonic seizures, itchy leg syndrome, arrhythmia, fibromyalgia, stroke or It is selected from the group consisting of neuroprotection under ischemic conditions caused by nerve trauma, tachycardiac arrhythmia, atrial fibrillation and ventricular fibrillation.

In some embodiments, the disease or condition is Pitt-Hopkins Syndrome (PTHS).

The subject matter of the present disclosure is in the manufacture of agents for the treatment of a condition, disease or disorder associated with increased activity or expression of Na _v 1.8 to a subject suffering from such disorder. Also included is the use of compounds of formula (I).

Although the "subject" treated in many embodiments thereof by the methods of the present disclosure is preferably a human subject, the methods described herein may be included in the term "subject". It should be understood that it is effective for all intended vertebrate species. Therefore, a "subject" is a human subject for medical purposes such as treatment of an existing condition or disease or prophylactic treatment to prevent the onset of the condition or disease, or for medical, veterinary or developmental purposes. Can include animal subjects for. Suitable animal subjects include primates such as humans, monkeys, apes; cows such as cattle, bulls; sheep, such as sheep; goats, such as goats; pigs, such as pigs. Adult pigs, etc .; horses, such as horses, donkeys, zebras, etc .; cats including wild cats and domestic cats; dogs including dogs; rabbits including rabbits, wild rabbits, etc.; and mammals including rodents including mice, rats, etc. However, it is not limited to these. The animal may be a transgenic animal. In some embodiments, the subject is a human, including, but not limited to, fetal, neonatal, infant, juvenile and adult subjects. Further, the "subject" may include a patient who has or is suspected of having a condition or disease. As such, the terms "subject" and "patient" are used interchangeably herein. The term "subject" also refers to a collection of cells from an organism, tissue, cell or subject.

Generally, the "effective amount" of an activator or drug delivery device refers to the amount required to elicit the desired biological response. As will be appreciated by those of skill in the art, the effective amount of the agent or device may vary depending on factors such as the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue and the like.

The term "combination" is used in its broadest sense, with at least two drugs to the subject, more specifically a compound of formula (I) and at least one analgesic; and optionally one or more. Means to administer multiple analgesics. More specifically, the term "combination" refers to the simultaneous administration of two (or more) active agents, for example, for the treatment of a single medical condition. As used herein, the active agents may be administered in a single dosage form in combination, at the same time as separate dosage forms, or alternately or sequentially on the same or different days. It may be administered as a separate dosage form to be administered. In one embodiment of the subject of the present disclosure, the active agents are combined and administered in a single dosage form. In another embodiment, the active agent is administered in a separate dosage form (eg, varying the amount of one should not change the amount of the other). The single dosage form may contain an additional active agent for the treatment of the medical condition.

In addition, the compounds of formula (I) described herein are administered alone or in combination with an adjuvant that enhances the stability of the compound of formula (I), alone or in combination with one or more analgesics. , Can facilitate administration of pharmaceutical compositions containing them in certain embodiments, increase lysis or dispersion, enhance inhibitory activity, and provide adjuvant therapies and the like containing other active ingredients. Advantageously, such combination therapies require lower doses of conventional therapies, thus avoiding the toxic and harmful side effects that may occur when these drugs are used as monotherapy. ..

The timing of administration of the compound of formula (I) and at least one additional therapeutic agent can be varied as long as the beneficial effect of the combination of these agents is obtained. Thus, the expression "in combination with" refers to the administration of the compound of formula (I) and at least one additional therapeutic agent simultaneously, sequentially or in any combination thereof. Therefore, a subject to which a combination of a compound of formula (I) and at least one additional therapeutic agent is administered will have at least one compound of formula (I) and at least one as long as the effect of the combination of both agents is obtained in the subject. Additional therapeutic agents can be received simultaneously (ie, simultaneously) or at different times (ie, sequentially, in any order, on the same day or on different days).

When administered sequentially, the agents can be administered to each other within 1, 5, 10, 30, 60, 120, 180, 240 minutes or more. In other embodiments, the sequentially administered agents can be administered to each other within 1, 5, 10, 15, 20 or more days. When a compound of formula (I) and at least one additional therapeutic agent are administered simultaneously, they are subjects as separate pharmaceutical compositions each comprising either the compound of formula (I) or at least one additional therapeutic agent. Can be administered to a subject or can be administered to a subject as a single pharmaceutical composition comprising both agents.

When administered in combination, the effective concentration of each drug to elicit a particular biological response can be lower than the effective concentration when each drug is administered alone, thereby one or more. The dose of the drug can be reduced below the dose required when the drug is administered as a single agent. The effects of multiple agents can be additive or synergistic, but not necessarily. The drug may be administered multiple times.

In some embodiments, two or more agents can exert a synergistic effect when administered in combination. As used herein, the terms "synergistic", "synergistic", "synergistic" and their derivatives such as "synergistic" or "synergistic combination" or "synergistic composition", etc. Refers to a situation in which the bioactivity of a combination of a compound of formula (I) and at least one additional therapeutic agent is greater than the sum of the bioactivity of each agent when administered individually.

The synergistic effect can be expressed as a "synergy index (SI)", which is usually F.I. C. Kull et al. , Applied Microbiology 9, 538 (1961), which can be determined from the ratios determined as follows:
Q _a / Q _A + Q _b / Q _B = Synergy effect index (SI)
[During the ceremony,
QA is the concentration of component _A that acts alone and is the concentration that gave rise to the endpoint for component A;
Qa is the concentration of component _A in the mixture, which is the concentration that gave rise to the endpoint;
QB is the concentration of component _B that acts alone and gives rise to the endpoint for component B;
Q _b is the concentration of component B in the mixture, which is the concentration that gave rise to the endpoint.

In general, if the sum of Q _a / Q _A and Q _b / Q _B is greater than 1, it indicates an antagonistic effect. If the sum is equal to 1, it indicates an additive effect. If the total is less than 1, a synergistic effect is shown. The lower the SI, the greater the synergistic effect of the particular mixture. Thus, a "synergistic combination" has higher activity than expected based on the activity observed when the individual components are used alone. Further, the "synergistically effective amount" of one ingredient refers to, for example, the amount of ingredient required to elicit a synergistic effect in another therapeutic agent present in the composition.

More specifically, in some embodiments, the methods of the present disclosure will give the subject a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, one or more of the following compounds: Includes co-administration with one or more compounds selected from the group consisting of:
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as, but not limited to, aspirin, diclofenac, diflucinal, etdrac, fenbufen, phenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketrolac, meclofenamic acid, mephenamic acid. , Meloxycam, Nabumeton, Naproxen, Nimeslide, Nitroflurbiprofen, Orsalazine, Oxaprodin, Fenoprofen, Pyroxycam, Sulfasalazine, Thrindac, Tormethin and Zomepyrac;
Opioid analgesics, such as, but not limited to, morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, metadon, meperidine, fentanyl, cocaine, codeine, dihydrocodein, oxycodone, hydrocodone, propoxyphene, nalmephen, naloxone, Naloxone, naltrexone, buprenorfin, butorphanol, narbufin and pentazocine;
Barbituric acid agents such as, but not limited to, amobarbital, aprobarbital, butabarbital, mefobarbital, metalbital, methohexital, pentobarbital, phenobarbital, secobarbital, tarbutal, thiamilal and thiopental;
Benzodiazapines such as, but not limited to, chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam and triazolam;
Histamine H1 antagonists such as, but not limited to, diphenhydramine, _pyriramine , promethazine, chlorpheniramine and chlorcyclizine;
Sedatives such as, but not limited to, glutethimide, meprobamate, methaqualone and dichloralphenazone;
Skeletal muscle relaxants such as, but not limited to, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and orfrenazine;
NMDA receptor antagonists such as, but not limited to, dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextromethorphan ((+)-3-hydroxy-N-). Methylmorphinan), ketamine, memantine, pyrroloquinolinquinine, cis-4- (phosphonomethyl) -2-piperidincarboxylic acid, budipine, EN-3231 (MorphiDex®, a combination of morphine and dextromethorphan), topiramate , Neramexan or a Perdin hotel containing an NR2B antagonist, such as ifenprodil, traxoprodil and (-)-(R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1-piperidinyl]- 1-Hydroxyethyl-3,4-dihydro-2 (1H) -quinolinone;
Transient receptor potential ion channel antagonist;
α-adrenaline agonists such as, but not limited to, doxazosin, tamsulosin, clonidine, guanfacine, dexmetamidine, modafynyl and 4-amino-6,7-dimethoxy-2- (5-methanesulfonamide-1,2,3). , 4-Tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline;
Tricyclic antidepressants such as, but not limited to, desipramine, imipramine, amitriptyline and nortriptyline;
Anticonvulsants such as, but not limited to, carbamazepine (Tegretor®), lamotridin, topiramate, lacosamide (Vimpat®) and valproate;
Takikinin antagonists, especially NK-3, NK-2 or NK-1 antagonists, such as, but not limited to, (αR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9. , 10,11-Tetrahydro-9-Methyl-5- (4-Methylphenyl) -7H- [1,4] Diazosino [2,1-g] [1,7] -naphthylidine-6-13-dione (TAK) -637), 5-[[(2R, 3S) -2-[(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl ] -Methyl] -1,2-dihydro-3H-1,2,4-triazole-3-one (MK-869), aprepitant, lanepitant, dapitant and 3-[[2-methoxy-5- (trifluoromethoxy) ) Phenyl] -methylamino] -2-phenylpiperidin (2S, 3S);
Muscarinic antagonists such as, but not limited to, oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiberin and ipratropium;
Cyclooxygenase-2 selective (COX-2) inhibitors, such as, but not limited to, celecoxib, rofecoxib, parecoxib, valdecoxib, delacoxib, etoricoxib and lumiracoxib;
Coal tar analgesics, such as, but not limited to, paracetamol;
Neurorelaxers such as, but not limited to, droperidol, chlorpromazine, haloperidol, perfenazine, thioridazine, mesoridazine, trifluoperazine, flufenazine, clozapine, olanzapine, risperidone, zipracidone, quetiapine, sertindol, aripiprazole, sonepiprazole, Bronanserin, Iroperidone, Perospyrone, Lacloprid, Zotepine, Biphepurnox, Acenapine, Lulacidone, Amisulfride, Barapelidone, Palindol, Eprivanserin, Osanetanto, Limonavan, Mesoridazine, Miraxion® and Salisotan;
Vanilloid receptor agonists such as, but not limited to, resiniferatoxin or cibamide;
Vanilloid receptor antagonists such as, but not limited to, capsazepine, GRC-15300;
β-adrenaline agonists such as, but not limited to, propranolol;
Local anesthetics such as, but not limited to, mexiletine;
Corticosteroids such as, but not limited to, dexamethasone and prednisone;
5-HT receptor agonists or antagonists, in particular 5-HT1B / 1D agonists, such as, but not limited to, eletriptans, sumatriptan, naratriptan, solmitriptan or rizatriptan;
₅ -HT 2A receptor antagonists such as, but not limited to, R (+)-α- (2,3-dimethoxy-phenyl) -1- [2- (4-fluorophenylethyl)] -4-piperidin Methanol (MDL-100907), eprivanserin, ketanserin and pimavanserin;
Cholinergic (nicotinic) analgesics, such as, but not limited to, ispronicline (TC-1734), (E) -N-methyl-4- (3-pyridinyl) -3-buten-1-amine (RJR-2403). ), (R) -5- (2-azetidineylmethoxy) -2-chloropyridine (ABT-594) and nicotine;
α ₂ δ ligands, such as, but not limited to, gabapentin (Neurontin®), gabapentin GR (Gralice®), gabapentin enacalvir (Holizant®), pregabalin (Lyrica®), 3-Methyl gabapentin, (1 [α], 3 [α], 5 [α]) (3-amino-methyl-bicyclo [3.2.0] hepto-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-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one, C- [1- (1H-tetrazole-5-) Ilmethyl) -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;
Cannabinoid receptor ligands, such as, but not limited to, cannabidiol KHK-6188;
Metabotropic glutamate subtype 1 receptor antagonist;
Sertraline reuptake inhibitors such as, but not limited to, sertraline, sertraline metabolites demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluboxamine, paroxetine, citalopram, citalopram metabolites desmethylcitalopram, escitalopram, d. l-Fenofluoxetine, femoxetine, ifoxetine, citalopram, ritoxetine, dapoxetine, nephazodon, sertraline and trazodone;
Noradrenaline (norepinephrine) reuptake inhibitors, such as, but not limited to, maprothyrin, lofepramine, miltazepine, oxaprotyrin, fezolamin, tomoxetine, mianserin, buproprion, buproprion metabolites hydroxybuproprion, nomifencin and viloxazine (Registered Trademark). ), Especially selective noradrenaline reuptake inhibitors such as reboxetine, especially (S, S) -reboxetine;
Double serotonin-noradrenaline reuptake inhibitors such as, but not limited to, venlafaxine, venlafaxine metabolite O-desmethylbenlafaxine, clomipramine, clomipramine metabolites desmethylchromipramine, duloxetine (Cymbalta®). , Milnacipran and imipramine;
Rho-kinase inhibitor;
Inducible nitrogen monoxide synthase (iNOS) inhibitors, such as, but not limited to, S- [2-[(1-iminoethyl) amino] ethyl] -L-homocysteine, S- [2-[(l-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-[(l-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] -4-chlorobenzonitrile, (2S, 4R) ) -2-Amino-4-[[2-chloro-5- (trifluoromethyl) phenyl] thio] -5-thiazolibutanol, 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] thiophen-2-carboxamidine, NXN-462 and guanidinoethyl disulfide;
Acetylcholinesterase inhibitors, such as, but not limited to, donepezil;
Prostaglandin E ₂ subtype 4 antagonists, such as, but not limited to, N-[({2- [4- (2-ethyl-4,6-dimethyl-1H-imidazole [4,5-c] pyridine- 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;
Leukotriene B4 antagonists, such as, but not limited to, 1- (3-biphenyl- ₄ -ylmethyl-4-hydroxy-chroman-7-yl) -cyclopentanecarboxylic acid (CP-105696), 5- [2- ( 2-Carboxylic Acid) -3- [6- (4-Methoxyphenyl) -5E-hexenyl] oxyphenoxy] -valeric acid (ONO-4057) and DPC-11870;
5-lipoxygenase inhibitors such as, 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);
Sodium channel blockers such as, but not limited to, lidocaine, lidocaine + tetracaine cream (ZRS-201) and eslicarbazepine acetate;
₅ -HT3 antagonists such as, but not limited to, ondansetron;
N-methyl-D-aspartic acid receptor antagonist;
Voltage-gated calcium channel blockers (eg, N-type and T-type), such as, but not limited to, diconctide, Z-160, (R) -2- (4-cyclopropylphenyl) -N- (1- (5). -(2,2,2-trifluoroethoxy) pyridine-2-yl) ethyl) acetamide;
KCNQ opening drug (eg, KCNQ2 / 3 (K _v 7.2 / 3));
TPRV 1 receptor agonists such as, but not limited to, capsaicin (Neuroges®, Qutenza®); and pharmaceutically acceptable salts and solvates thereof;
Nicotinic receptor antagonists such as, but not limited to, varenicline;
Nerve growth factor antagonists such as, but not limited to, tanezumab;
Endopeptidase stimulants, such as, but not limited to, senrebotase;
Angiotensin II antagonists such as, but not limited to, EMA-401;
Tramadol®, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®);
PDE5 inhibitors, such as, 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-methylene) Dioxyphenyl) -pyrazino [2', 1': 6,1] -pyrido [3,4-b] indol-1,4-dione (IC-351 or tadalafil), 2- [2-ethoxy-5- (4-Ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazole [5,1-f] [1,2,4] triazine-4-one ( Valdenafil), 5- (5-Acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-di-hydro-7H-pyrazolo [4,3 -D] Pyrimidine-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) pyridine-3-yl] -3-ethyl-2- [2-methoxyethyl] ] -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl) amino] -2-[(2S) -2-( Hydroxymethyl) pyrrolidine-1-yl] -N- (pyrimidine-2-ylmethyl) pyrimidin-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;
Na _V 1.7 blockers, such as, but not limited to, XEN-402, XEN403, TV-4570, PF-0509771, CNV1014802, GDC-0276, RG7893 and WO 2011/140425; WO 2012/106499. No.; International Publication No. 2012/112743; International Publication No. 2012/125613, International Publication No. 2012/116440, International Publication No. 20110126240, US Patent No. 8,883,840 or 8,466,188 or What is disclosed in PCT / US2013 / 21535, the entire content of each application is incorporated by reference; as well as Na _V 1.7 blockers, eg, but not limited to 2-benzylspiro [3,4- Dihydropyrrolo [1,2-a] pyrazine-1,4'-piperidine] -1'-yl)-(4-isopropoxy-3-methyl-phenyl) methanone, 2,2,2-trifluoro-1- [1'-[3-Methyl-4- [2- (trifluoromethoxy) ethoxy] benzoyl] -2,4-dimethyl-spiro [3,4-dihydropyrrolo [1,2-a] pyrazine-1,4 ´-Piperidin] -6-yl] -etanone, [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-benzhydrylpiperazin-1-yl) -3- [2- (3,4-dimethylphenoxy) ) Ethoxy] Propane-2-ol, 4-butoxy-3-methoxy-phenyl)-[2-Methyl-6- (trifluoromethyl) spiro [3,4-dihydropyrrolo [1,2-a] piperazine-1 , 4'-piperidine] -1'-yl] methanone, [8-fluoro-2-methyl-6- (trifluoromethyl) spiro [3,4-dihydropyrrololo [1,2-a] pyrazine-1, 4'-Piperazine] -1'-Il]-(5-isopropoxy-6-methyl-2-pyridyl) 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'-piperidine] -1'-yl] methanone, 5- [2- Methyl-4- [2-methyl-6- (2,2,2-trifluoroacetyl) spiro [3,4- Dihydropyrrolo- [1,2-a] pyrazine-1,4'-piperidin] -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'-piperidin] -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' -Piperidine] -6-yl] Etanone, 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] Etanone, 2,2,2-trifluoro-1- [1'-(5-isopentyl) Oxypyridine-2-carbonyl) -2-methyl-L-spiro [3,4-dihydropyrrolo [1,2-a] pyrazine-1,4'-piperidin] -6-yl] etanone, (4-isopropoxy) -3-methoxy-phenyl)-[2-methyl-6- (trifluoromethyl) spiro [3,4-dihydropyrrolo [1,2-a] pyrazine-1,4'-piperidine] -1'-yl] Metanone, 2,2,2-trifluoro-1- [1'-(5-isopentyloxypyrazine-2-carbonyl) -2,4-dimethyl-spiro [3,4-dihydropyrroro [1,2-a] ] Pyrazine-1,4'-piperidin] -6-yl] Etanone, 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-etanone, 8-fluoro-2-methyl-6 -(Trifluoromethyl) spirolo [3,4-dihydropyrrolo [1,2-a] pyrazine-1,4'-piperidine] -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] ethano 1- [1'-[4-Methyl-3- (trifluoromethyl) benzoyl] -2-methyl-spiro [3,4-dihydropyrrolo [1,2-a] pyrazine-1,4'-piperidin ] -6-yl] -2,2-dimethyl-propane-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6- (trifluoromethyl) spiro [3,4- Dihydropyrro [1,2-a] pyrazine-1,4'-piperidin] -1'-yl] methanone, 2-methyl-6- (1-methylcyclopropanecarbonyl) spiro [3,4-dihydropyroro [1] , 2-a] -pyrazine-1,4'-piperidin] -1'-yl]-[4- (3,3,3-trifluoropropoxymethyl) phenyl] methanone, 4-bromo-N- (4-) Bromophenyl) -3-[(1-methyl-2-oxo-4-piperidyl) sulfamoyl] benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6- (1,1,2) , 2,2-Pentafluoroethyl) Spiro [34-dihydropyrro [1,2-a] pyrazine-1,4'-piperidin] -1'-yl] methanone.

In some embodiments, the method acetates a subject with or without a therapeutically effective amount of a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein, with or without a pharmaceutically acceptable carrier. It comprises administration in combination with a second therapeutic agent selected from the group consisting of aminophen, NSAIDs, opioid analgesics and combinations thereof.

In some embodiments, the method provides a subject with a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein with or without a pharmaceutically acceptable carrier. Includes administration in combination with additional therapeutic agents for the treatment of one or more pains. 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.

(C. Pharmaceutical composition and administration)
In another aspect, the present disclosure comprises a pharmaceutical composition comprising a compound of formula (I) alone or in combination with one or more additional therapeutic agents mixed with a pharmaceutically acceptable excipient. I will provide a. Those skilled in the art will recognize that the pharmaceutical composition comprises a pharmaceutically acceptable salt of the above-mentioned compound. Pharmaceutically acceptable salts are generally well known to those of skill in the art and are prepared with relatively non-toxic acids or bases, depending on the particular substituent moieties found in the compounds described herein. Contains salts of active compounds to be used. When the compounds of the present disclosure contain relatively acidic functional groups, the neutral form of such compounds is contacted with a sufficient amount of the desired base, either as is or in a suitable inert solvent. A base addition salt can be obtained by substituting one basic pair ion (base) of the ion complex with another by or by ion exchange. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts.

When the compounds of the present disclosure contain relatively basic functional groups, the neutral form of such compounds is contacted with a sufficient amount of the desired acid, either as is or in a suitable inert solvent. An acid addition salt can be obtained by replacing one acidic pair ion (acid) of the ion complex with another, either by this or by ion exchange. Examples of pharmaceutically acceptable acid addition salts are hydrochloric acid, hydrobromic acid, nitrate, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, iodide. Salts derived from inorganic acids such as hydrogenic acid or phosphoric acid, 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 other relatively non-toxic organic acid-derived salts. Also included are salts of amino acids such as arginate and salts of organic acids such as glucuronic acid or galacturonic acid (see, eg, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). .. Certain compounds of the present disclosure include both basic and acidic functional groups that allow the compound to be converted to either a base-added salt or an acid-added salt.

Accordingly, pharmaceutically acceptable salts suitable for use with the subject matter of the present disclosure include, but are not limited to, acetates, benzenesulfonates, benzoates, bicarbonates, hydrogen tartrates, bromides, etc. Calcium edetate, cansilate, carbonate, citrate, edetate, edicylate, estrate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylar alsanic acid Salt, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesyl Acids, mutinates, napsylates, nitrates, pamoates (embonates), pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearate, phosphite , Succinate, sulfate, tannate, tartrate or theocrate. Other pharmaceutically acceptable salts can be found, for example, in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).

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

Depending on the particular condition to be treated, such agents may be formulated in liquid or solid dosage form and administered systemically or topically. The agent can be delivered, for example, in a timed or sustained release form, as known to those of skill in the art. Techniques for formulation and administration can be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). Suitable routes are oral, buccal, inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or enteral; intramuscular, subcutaneous, intramedullary injection and intrathecal, direct brain Intravenous, intravenous, joint, intrathoracic, intrasynamic, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal or intraocular injection or parenteral delivery including other modes of delivery.

For injection, the agents of the present disclosure can be formulated and diluted with an aqueous solution such as a physiologically compatible buffer such as Hanks' solution, Ringer's solution or saline buffer. In such transmucosal administration, a penetrant suitable for the penetrating barrier is used in the formulation. Such penetrants are commonly known in the art.

It is within the scope of the present disclosure to formulate the compounds disclosed herein in dosages suitable for systemic administration for the practice of the present disclosure using pharmaceutically acceptable inert carriers. .. With proper selection of carriers and proper manufacturing practices, the compositions of the present disclosure, particularly those formulated as solutions, can be administered parenterally, such as by intravenous injection. The compound can be easily formulated into a dosage suitable for oral administration using a pharmaceutically acceptable carrier well known in the art. With such a carrier, the compounds of the present disclosure are formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by the subject to be treated (eg, patient). Can be transformed into.

For nasal or inhalation delivery, the agents of the present disclosure can be formulated by methods known to those of skill in the art, eg, solubilizing, diluting or dispersing agents such as saline; preservatives such as benzyl alcohol. Agents; absorption enhancers; and fluorocarbons and the like can be included, but are not limited thereto.

Suitable pharmaceutical compositions for use in the present disclosure include compositions in which the active ingredient is contained in an amount effective to achieve its intended purpose. Determination of an effective amount is well within the ability of one of ordinary skill in the art, especially in light of the detailed disclosure provided herein. In general, the compounds according to the present disclosure are effective over a wide dose range. For example, in the treatment of adults, doses of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg and 5 to 40 mg per day are examples of doses that can be used. The non-limiting dose is 10-30 mg per day. The exact dose is the route of administration, the form in which the compound is administered, the subject being treated, the weight of the subject being treated, the bioavailability of the compound (s), the compound (s). Depends on absorption, distribution, metabolism and excretion (ADME) / toxicity as well as the choice and experience of the attending physician.

In addition to the active ingredient, these pharmaceutical compositions are suitable pharmaceutically acceptable carriers, including excipients and auxiliaries that facilitate the processing of the active compound into pharmaceutically usable preparations. Can be contained. The preparation formulated for oral administration can be in the form of tablets, dragees, capsules or solutions.

Pharmaceutical preparations for oral use combine the active compound with a solid excipient, grind the resulting mixture optionally, add the appropriate auxiliaries as needed, and then treat the mixture of granules. It can be obtained by obtaining a tablet or a sugar-coated tablet core. Suitable excipients are, in particular, sugars such as lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacant gum, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium. Fillers such as (CMC) and / or polyvinylpyrrolidone (PVP: povidone) can be mentioned. If necessary, a disintegrant such as crosslinked polyvinylpyrrolidone, agar or a salt thereof such as alginic acid or sodium alginate can be added.

The dragee core has an appropriate coating. A concentrated sugar solution can be used for this purpose, which is optionally arabic gum, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solution and It may contain a suitable organic solvent or solvent mixture. Dyes or pigments can be added to the tablet or dragee coating to identify or characterize various combinations of doses of the active compound.

Pharmaceutical preparations that can be used orally include indentation capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-in capsule may contain the active ingredient mixed with a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin or liquid polyethylene glycol (PEG). In addition, stabilizers can be added.

(II. Definition)
Although specific terms are used herein, they are used only in a general and descriptive sense and are not intended to be limiting. 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. have.

The following terms relating to the compounds of formula (I) are believed to be well understood by those of skill in the art, but the following definitions are provided to facilitate explanation of the subject matter of the present disclosure. These definitions are intended to supplement and explain the definitions that will be apparent to those of skill in the art when considering this disclosure, and are not intended to be excluded.

As used herein, the terms substituted (with or without the term "optionally" preceded by) and substituents, as understood by those of skill in the art, are of all atoms. Refers to the ability to change one functional group on a molecule to another, provided that the valence is maintained. If multiple positions in any given structure can be substituted with multiple substituents selected from a particular group, the substituents may be the same or different at all positions. Also, the substituents can be further substituted (eg, one aryl substituent can have another substituent, such as another aryl group that is further substituted at one or more positions).

When substituents or linking groups are specified by conventional chemical formulas written from left to right, they equally include the chemically identical substituents obtained if the structure is written from right to left. Yes; for example, -CH ₂ O- is equivalent to -OCH _2- ; -C (= O) O- is equivalent to -OC (= O)-; -OC (= O) NR- is- Equivalent to NRC (= O) O-, etc.

When the term "independently selected" is used, the substituents mentioned (eg, R groups such as groups _R1 and _R2 or variables such as "m" and "n") are the same but different. May be. For example, both R ₁ and R ₂ may be substituted alkyl, R ₁ may be hydrogen, R ₂ may be substituted alkyl, and so on.

The terms "a", "an" or "a (n)" as used herein with respect to a group of substituents mean at least one. For example, if the compound is substituted with "an" alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl. Further, if the site is substituted with an R substituent, that group may be referred to as "R substitution". When the site is R-substituted, the site is substituted with at least one R-substituted group, and each R-substituted group is optionally different.

The designated "R" or group will have a structure generally recognized in the art as corresponding to the group having that name, unless otherwise specified herein. For illustrative purposes, certain representative "R" groups as described above are defined below.

Descriptions of the compounds of the present disclosure are limited by the principles of chemical bonding known to those of skill in the art. Thus, if a group can be substituted with one or more of several substituents, such substituents are based on the principle of chemical bonding and are not inherently unstable compounds and / or aqueous, medium. Selected to give compounds that will be known to those of skill in the art to be likely to be unstable under ambient conditions such as sex and some known physiological conditions. For example, heterocycloalkyls or heteroaryls bind to the rest of the molecule via the heteroatoms of the ring according to the principles of chemical bonding known to those of skill in the art, thereby avoiding essentially unstable compounds. do.

Unless otherwise explicitly defined, "substituents" as used herein include functional groups selected from one or more of the following sites as defined herein:

As used herein, the term "hydrocarbon" refers to any chemical group containing hydrogen and carbon. Hydrocarbons may or may not be substituted. As is known to those skilled in the art, all valences must be met when making a substitution. Hydrocarbons can be unsaturated, saturated, branched, unbranched, cyclic, polycyclic or heterocyclic. Exemplary hydrocarbons are further defined herein, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl and the like. Be done.

The term "alkyl" is a linear (ie, unbranched) or branched, acyclic or cyclic hydrocarbon group by itself or as part of another substituent, unless otherwise noted. Or a combination thereof, which may be fully saturated, monovalent or multivalent unsaturated, may contain divalent and polyvalent groups, and may contain a specified number of carbons. It has an atom (ie, C _1-10 means 1-10 carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 carbons). In certain embodiments, the term "alkyl" is used as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and Linear (ie, "straight"), branched or cyclic, saturated or at least partially unsaturated, and in some cases completely unsaturated (ie, alkenyl) within C _1-20 containing 20 carbons. And alkynyl), a hydrocarbon radical obtained by removing one hydrogen atom from the hydrocarbon moiety containing 1 to 20 carbon atoms.

Typical saturated hydrocarbon groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, and the like. Examples include, but are not limited to, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undesyl, dodecyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl and their homologues and isomers.

"Branch" refers to an alkyl group in which a lower alkyl group such as methyl, ethyl or propyl is attached to a linear alkyl chain. A "lower alkyl" is an alkyl group having 1 to about 8 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7 or ₈ carbon atoms (ie, C1 _- C8 alkyl). ). "Higher alkyl" refers to an alkyl group having about 10 to about 20 carbon atoms, eg, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. .. In certain embodiments, "alkyl" specifically refers to C1 _- C8 _linear alkyl. _In other embodiments, "alkyl" specifically refers to a C1 _- C8 branched chain alkyl.

Alkyl groups can optionally be substituted with one or more alkyl group substituents (referred to as "substituted alkyl"), which may be the same or different. The term "alkyl group substituent" includes alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo and cycloalkyl. However, it is not limited to these. Along the alkyl chain, optionally one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (nitrogen substituents are hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"). Or aryl) can be inserted.

Thus, as used herein, the term "substituted alkyl" includes an alkyl group as defined herein, wherein one or more atoms or functional groups of the alkyl group are, for example, alkyl, substituted alkyl. , Halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano and substituted with another atom or functional group including mercapto.

The term "heteroalkyl", by itself or in combination with another term, is a stable linear or branched chain with 1-20 carbon atoms or heteroatoms or 3-10 carbons unless otherwise noted. A cyclic hydrocarbon group having an atom or a heteroatom or a combination thereof, and at least one heteroatom (nitrogen) selected from the group consisting of at least one carbon atom and O, N, P, Si and S. , Phosphorus and sulfur atoms may be optionally oxidized, and nitrogen heteroatoms may be optionally quaternized). Heteroatoms (s) O, N, P and S and Si may be located at any internal position of the heteroalkyl group or at positions where the alkyl group is attached to the rest of the molecule. For example, -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N (CH ₃ ) -CH ₃ , -CH ₂ -S- CH ₂ -CH ₃ , -CH ₂ -CH ₂ -S (O) -CH ₃ , -CH ₂ -CH ₂ -S (O) ₂ -CH ₃ , -CH = CH-O-CH ₃ , -Si ( CH ₃ ) ₃ , -CH ₂ -CH = N-OCH ₃ , -CH = CH-N (CH ₃ ) -CH ₃ , O-CH ₃ , -O-CH ₂ -CH ₃ and -CN. However, it is not limited to these. For example, there are cases where a maximum of two or three heteroatoms are continuous, such as -CH ₂ -NH-OCH ₃ and -CH ₂ -O-Si (CH ₃ ) ₃ .

As mentioned above, the heteroalkyl groups used herein include -C (O) NR', -NR'R', -OR', -SR, -S (O) R and / or -S. (O ₂ ) Includes groups such as R'attached to the rest of the molecule via a heteroatom. When described as "heteroalkyl" followed by a specific heteroalkyl group such as -NR'R, the terms heteroalkyl and -NR'R' should not be redundant or mutually exclusive. Will be understood. Rather, specific heteroalkyl groups have been described for added clarity. Therefore, the term "heteroalkyl" should not be construed herein to exclude certain heteroalkyl groups such as -NR'R'.

"Cyclic" and "cycloalkyl" are non-aromatic monocycles having about 3 to about 10 carbon atoms, such as 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Refers to a cyclic or polycyclic ring system. The cycloalkyl group may optionally be partially unsaturated. Further, the cycloalkyl group may be optionally substituted with an alkyl group substituent, oxo and / or alkylene as defined herein. Along the cyclic alkyl chain, optionally one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (nitrogen substituents are hydrogen, unsubstituted alkyl, substituted alkyl, aryl or substituted aryl). ) Can be inserted, which gives a heterocyclic group. Typical monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, cycloheptyl and the like. Examples of the polycyclic cycloalkyl ring include adamantyl, octahydronaphthyl, decalin, camphor, camphor and noradamantyl, and fused ring systems such as dihydronaphthalene and tetrahydronaphthalene.

As used herein, the term "cycloalkylalkyl" is a cycloalkyl group as defined herein and is a parent molecule site via an alkylene site also defined above, such as a C _1-20 alkylene site. Refers to a cycloalkyl group attached to. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

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. The heteroatoms may be the same or different, including one or more heteroatoms, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P) and silicon (Si). ), Which is selected from the group consisting of) and can optionally contain one or more double bonds.

The cycloheteroalkyl ring can optionally be fused to or otherwise attached to another cycloheteroalkyl ring and / or a non-aromatic hydrocarbon ring. Heterocycles include those having 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, in which case the nitrogen and sulfur heteroatoms may be optionally oxidized. Often, the nitrogen heteroatom may be quaternized at will. In certain embodiments, the term heterocyclic is a heteroatom in which at least one ring atom is selected from O, S and N (nitrogen and sulfur heteroatoms may be optionally oxidized). A non-aromatic 5, 6 or 7-membered ring or polycyclic group, but not limited to, a fused 6-membered ring having 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen. (I) Each 5-membered ring has 0-2 double bonds, each 6-membered ring has 0-2 double bonds, each containing 7 members. The ring has 0 to 3 double bonds, and (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized and (iii) the nitrogen heteroatoms may be optionally quaternized. Well, (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, pyrazoridinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinucridinyl, morpholinyl, thiomorpholinyl, thiadiadinanyl, tetrahydrofuranyl and the like.

The terms "cycloalkyl" and "heterocycloalkyl", alone or in combination with other terms, represent cyclic versions of "alkyl" and "heteroalkyl", respectively, unless otherwise noted. Further, in the case of heterocycloalkyl, the heteroatom can occupy the position where the heterocycle attaches to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl and the like. Examples of heterocycloalkyls are 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran. Examples thereof include, but are not limited to, -3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl and the like. The terms "cycloalkylene" and "heterocycloalkylene" refer to cycloalkyl and heterocycloalkyl divalent derivatives, respectively.

Unsaturated hydrocarbons have one or more double or triple bonds. Examples of unsaturated alkyl groups are vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (l, 4-pentadienyl), ethynyl, 1- and 3 -Includes, but is not limited to, propynyl, 3-butynyl and higher homologues and isomers. Alkyl groups limited to hydrocarbon groups are called "homoalkyl".

More specifically, as used herein, the term "alkenyl" is a single hydrogen molecule from a linear or branched hydrocarbon moiety within C _2-20 with at least one carbon-carbon double bond. Refers to the monovalent group obtained by removing. Examples of the alkenyl group include ethenyl (ie, vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, arenyl and butazienyl.

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

As used herein, the term "alkynyl" is a monovalent group derived from a linear or branched C _2-20 hydrocarbon containing at least one carbon-carbon triple bond and having a specified number of carbon atoms. Point to. Examples of "alkynyl" include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl and heptynyl groups.

The term "alkylene" is used by itself or as part of another substituent from 1 to about 20 carbon atoms such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ,. Refers to a linear or branched divalent aliphatic hydrocarbon group derived from an alkyl group having 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The alkylene group can be linear, branched or cyclic. Further, the alkylene group may be optionally unsaturated and / or may be substituted with one or more "alkyl group substituents". Along the alkylene group, one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl") can be optionally inserted and the nitrogen substituents. Is alkyl as described above. Exemplary alkylene groups include methylene (-CH _2- ); ethylene (-CH ₂ -CH _2- ); propylene (-(CH ₂ ) _3- ); cyclohexylene (-C ₆ H ₁₀ -);- CH = CH-CH = CH-; -CH = CH-CH _2- ; -CH ₂ CH ₂ CH ₂ CH _2- , -CH ₂ CH = CHCH _2- , -CH ₂ CsCCH _2- , -CH ₂ CH ₂ CH (CH ₂ CH ₂ CH ₃ ) CH ₂ -,-(CH ₂ ) _q -N (R)-(CH ₂ ) _r- (In the formula, q and r are independently 0 to about 20. Integers up to, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. R is hydrogen or lower alkyl); methylenedioxyl (-O-CH ₂ -O-); and ethylenedioxyl (-O- (CH ₂ ) ₂ -O-). The alkylene group can have about 2 to about 3 carbon atoms and can have an additional 6 to 20 carbon atoms. In general, an alkyl (or alkylene) group has 1 to 24 carbon atoms and a group with 10 or less carbon atoms is some embodiment of the present disclosure. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having no more than eight carbon atoms.

The term "heteroalkylene" is a divalent group derived from a heteroalkyl, either by itself or as part of another substituent, -CH ₂ -CH ₂ -S-CH ₂ -CH _2- and. It means a group exemplified by, but not limited to, -CH ₂ -S-CH ₂ -CH ₂ -NH-CH _2- . In the case of a heteroalkylene group, the heteroatom may occupy one or both of the chain ends (eg, alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, etc.). Furthermore, in the case of alkylene and heteroalkylene linking groups, the orientation of the linking group is not suggested by the orientation in which the formula for the linking group is written. For example, the formula —C (O) OR ′ − represents both −C (O) OR ′ − and −R ′ OC (O) −.

The term "aryl" refers to an aromatic hydrocarbon substituent that can be a single ring or multiple rings that are fused or covalently bonded to each other (such as 1 to 3 rings), unless otherwise noted. means. The term "heteroaryl" is selected from N, O and S (nitrogen and sulfur atoms are optionally oxidized and nitrogen atoms (s) are optionally quaternized) 1-4. Refers to an aryl group (or ring) containing a heteroatom (in the case of multiple rings, each in a separate ring). Heteroaryl groups can be attached to the rest of the molecule via carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolill, 2-pyrrolill, 3-pyrrolill, 3-pyrazolyl, 2-imidazolyl, 4 -Imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isooxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2 -Frills, 3-frills, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, prynyl, 2-benzimidazolyl, 5-indrill, Examples thereof include 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents for each of the above 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.

For brevity, the term "aryl", when used in combination with other terms (eg, aryloxy, aryltioxy, arylalkyl), refers to an aryl ring and a heteroaryl ring as defined above. Includes both. Thus, the terms "arylalkyl" and "heteroarylalkyl" mean that an aryl group or a heteroaryl group comprises a group attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, frillmethyl, etc.). Then, a group in which a carbon atom (for example, a methylene group) is bonded to an alkyl group substituted with an oxygen atom (for example, phenoxymethyl, 2-pyridyloxymethyl, 3- (l-naphthyloxy) propyl, etc.) )including. However, as used herein, the term "haloaryl" is meant to include only aryl substituted with one or more halogens.

When a heteroalkyl, heterocycloalkyl or heteroaryl comprises a certain number of members (eg, "3-7 members"), the term "member" refers to a carbon or heteroatom.

で一般に表される構造は、環構造を指し、例えば、限定されないが、炭素数３、炭素数４、炭素数５、炭素数６、炭素数７等の、飽和環構造、部分飽和環構造及び不飽和環構造を含む脂肪族並びに／又は芳香族の環式化合物であって、置換基Ｒ基（式中、Ｒ基は存在していても、存在していなくてもよく、存在する場合、１つ又は複数のＲ基はそれぞれ、環構造の１個又は複数個の利用可能な炭素原子上で置換され得る）を含む環構造である。Ｒ基の有無及びＲ基の数は、変数「ｎ」の値によって決まり、ｎは、一般的に０～置換可能な環上の炭素原子の数までの値を持つ整数である。各Ｒ基は、複数ある場合、別のＲ基上ではなく、環構造の利用可能な炭素上に置換される。例えば、ｎが０～２である上記構造は、

等を含むが、これらに限定されない化合物基を含むであろう。 In addition, when used herein, the formula

The structure generally represented by the above refers to a ring structure, for example, but not limited to, a saturated ring structure having 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, etc., a partially saturated ring structure, and a partially saturated ring structure. When an aliphatic and / or aromatic cyclic compound containing an unsaturated ring structure and a substituent R group (in the formula, the R group may or may not be present is present) is present. Each of the one or more R groups is a ring structure comprising one or more available carbon atoms of the ring structure). The presence or absence of R groups and the number of R groups are determined by the value of the variable "n", where n is generally an integer having a value ranging from 0 to the number of substitutable carbon atoms on the ring. Each R group, if present in plural, is substituted on the available carbon of the ring structure rather than on another R group. For example, the above structure in which n is 0 to 2 is

Etc., but will include, but are not limited to, compound groups.

A dashed line representing a bond in a cyclic structure indicates that the bond may or may not be present within the ring. That is, the broken line representing the bond in the cyclic 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.

は、ある部位のその分子の残りの部分への結合点を示す。

Indicates the binding point of a site to the rest of the molecule.

If the designated atom of an aromatic or heterocyclic aromatic ring is defined as "non-existent," the designated atom is replaced by a direct bond.

Each of the above terms (eg, "alkyl", "heteroalkyl", "cycloalkyl" and "heterocycloalkyl", "aryl", "heteroaryl", "phosphonate" and "sulfonate" and their divalent derivatives). Means to include both substituted and unsubstituted forms of the indicated group. The optional substituents for each type of group are shown below.

Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl monovalent and divalent derivative groups (alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl, often referred to. Substituents for (including groups) are -OR', = O, = NR', = N-OR', -NR'R'', -SR', -halogen, -SiR'R''R'''. , -OC (O) R', -C (O) R', -CO ₂ R', -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) ₂ R', -S (O) ₂ NR'R', -NRSO ₂ R', -CN, CF ₃ , Fluorinated C _1-4 Alkyne and- Only a number from NO ₂ to 0 to (2 m'+ l) (m'is the total number of carbon atoms in such a group) is selected, but can be one or more of various groups, not limited to these. .. R', R', R', and R', respectively are independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, respectively. , Substituent or unsubstituted aryl (eg, aryl substituted with 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy group or arylalkyl group. As used herein, the "alkoxy" group is an alkyl attached to the rest of the molecule via divalent oxygen. For example, when the compound of the present disclosure contains a plurality of R groups, each R group is independently selected, and each R ′, R ″, R ″ ″ and R ″ ″ group also contains these groups. The same applies when there are multiple. When R ′ and R ′ ′ are bonded to the same nitrogen atom, they can be bonded to the nitrogen atom to form a 4, 5, 6 or 7-membered ring. For example, -NR'R'means to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above description of substituents, those skilled in the art will appreciate the term "alkyl" as haloalkyl (eg, -CF ₃ and -CH ₂ CF ₃ ) and acyls (eg, -C (O) CH ₃ , -C). It will be understood that it means to include a group containing a carbon atom bonded to a group other than a hydrogen group such as (O) CF ₃ , -C (O) CH ₂ , OCH ₃ , etc.).

Similar to the substituents described for alkyl groups above, there are various exemplary substituents on aryl and heteroaryl groups (and their divalent derivatives), such as halogen, -OR', -NR'R'. ´, -SR ′, －SiR ′ R ′ ´R ′ ´, −OC (O) R ′, −C (O) R ′, −CO ₂ R ′, −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" R "") = NR "", -NR-C (NR "R") = NR "", -S (O) R ", -S (O) ) ₂ R', -S (O) ₂ NR'R', -NRSO ₂ R', -CN and -NO ₂ , -R', -N ₃ , -CH (Ph) ₂ , fluoro (C _1- ) ₄ ) From 0 to the total number of vacant valences of the aromatic ring system, selected from 0 to the total number of vacant valences of the alkyloso and fluoro (C _1-4 ) alkyl, where R ′, R ″, R ″ and R are selected. ´´´´ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl. And can be selected from substituted or unsubstituted heteroaryl. For example, when the compound of the present disclosure contains a plurality of R groups, each R group is independently selected, and each R ′, R ″, R ″ ″ and R ″ ″ group also contains these groups. The same applies when there are multiple.

Two of the substituents on the adjacent atoms of the aryl ring or the heteroaryl ring may optionally form a ring of formula-TC (O)-(CRR') _q -U-. , In the equation, T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of 0 to 3. Alternatively, two of the substituents on the adjacent atoms of the aryl ring or the heteroaryl ring may optionally be substituted with substituents of the formula —A— (CH ₂ ) _r —B—. In the formula, A and B are independently -CRR'-, -O-, -NR-, -S-, -S (O)-, -S (O) _2- , -S (O) ₂ . It is NR'-or a single bond, and r is an integer of 1 to 4.

One of the single bonds of the new ring thus formed may optionally be replaced with a double bond. Alternatively, two of the substituents on the adjacent atoms of the aryl ring or the heteroaryl ring are optionally of the formula-(CRR') _s -X'-(C "" R "") _d- . It may be substituted with a substituent, and in the formula, s and d are independently integers of 0 to 3, and X'is -O-, -NR'-, -S-, -S (. O)-, -S (O) ₂ -or-S (O) ₂ NR'-. Substituents R, R ′, R ″ and R ″ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or non-substituted. It can be selected from substituted aryls and substituted or unsubstituted heteroaryls.

As used herein, the term "acyl" refers to an organic acid group in which the carboxyl group -OH is substituted with another substituent and has the general formula RC (= O) -in the formula. R is an alkyl, alkenyl, alkynyl, aryl, carboxyl group, heterocyclic group or aromatic heterocyclic group as defined herein). Thus, the term "acyl" specifically includes arylacyl groups such as 2- (furan-2-yl) acetyl)-and 2-phenylacetyl groups. Specific examples of the acyl group include acetyl and benzoyl. Acyl groups may also include amides, -RC (= O) NR', esters, -RC (= O) OR', ketones, -RC (= O) R'and aldehydes, -RC (= O) H. Intended.

The terms "alkoxy" or "alkoxy" are used interchangeably herein and are saturated (ie, alkyl-O-) groups or unsaturated (ie, alkenyl) groups attached to the parent molecule site via an oxygen atom. -O- and alkynyl-O-) groups, where the terms "alkyl", "alkenyl" and "alkynyl" are as described above, eg, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-. Linear, branched or cyclic saturated or unsaturated oxohydrocarbon chains within C _1-20 , including butoxyl, sec-butoxyl, tert-butoxyl and n-pentoxyl, neopentoxyl, n-hexoxyl and the like. Can include.

As used herein, the term "alkoxyalkyl" refers to an alkyl-O-alkyl ether, such as a methoxyethyl group or an ethoxymethyl group.

"Aryloxyl" refers to an aryl-O-group, where the aryl group is as described above and the aryl group comprises a substituted aryl. As used herein, the term "aryloxyl" can refer to phenyloxyl or hexyloxyl and phenyloxyl or hexyloxyl substituted with alkyl, substituted alkyl, halo or alkoxyl.

"Aralkyl" refers to an aryl-alkyl-group, where aryl and alkyl are as described above, and aryl and alkyl include substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl and naphthylmethyl.

"Aralkyloxyl" refers to an Aralkyl-O-group, where the Aralkyl group is as described above. An exemplary aralkyloxyl group is benzyloxyl, i.e. C ₆ H5- _{CH2 -} O-. The aralkyloxyl group can be optionally substituted.

"Alkoxycarbonyl" refers to an alkyl-OC (= O) -group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl and tert-butyloxycarbonyl.

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

"Aralkoxycarbonyl" refers to an aralkyl-OC (= O) -group. An exemplary ararcoxycarbonyl group is benzyloxycarbonyl.

"Carbamoyl" refers to the amide group of formula-C (= O) NH ₂ . "Alkylcarbamoyl" refers to the R'RN-C (= O) -group, where one of R and R'is hydrogen and the other of R and R'is alkyl and as described above. / Or a substituted alkyl. The term "dialkylcarbamoyl" refers to the R'RN-C (= O) -group, where each of R and R'is independently an alkyl and / or a substituted alkyl as described above.

As used herein, the term "carbonyldioxyl" refers to a carbonate group of formula-OC (= O) -OR.

The term "acyloxyl" refers to an acyl-O-group, where acyl is as described above.

The term "amino" refers to _two -NH groups and also refers to nitrogen-containing groups as known in the art, obtained from ammonia by substituting one or more hydrogen radicals with organic groups. For example, the terms "acylamino" and "alkylamino" refer to a particular N-substituted organic group having an acyl substituent and an alkyl substituent, respectively.

As used herein, "aminoalkyl" refers to an amino group covalently attached to an alkylene linker. More specifically, as used herein, the terms alkylamino, dialkylamino and trialkylamino are one, two or three above, respectively, attached to the parent molecule site via a nitrogen atom. Refers to an alkyl group as defined. The term alkylamino refers to a group having a structure-NHR', where R'is an alkyl group as defined above; while the term dialkylamino refers to a group having a structure-NR'R'. Here, R ′ and R ″ are independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having a structure-NR'R''R', where R', R''and R''' are independently from the group consisting of alkyl groups. Be selected. Further, R ′, R ″ and / or R ″ ″ may be arbitrarily selected as − (CH ₂ ) _k − (k is an integer of 2 to 6). Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino and propylamino.

The amino group is -NR'R', where R'and R'' are generally hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cyclo. It is selected from alkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

The terms alkyl thioether and thioalkoxy refer to saturated (ie, alkyl-S-) or unsaturated (ie, alkenyl-S- and alkynyl-S-) groups attached to the parent molecule site via a sulfur atom. .. Examples of the thioalkoxyl moiety include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio and the like.

"Acylamino" refers to an acyl-NH-group, where acyl is as described above. "Aloylamino" refers to an aloyl-NH-group, where aloyl is as described above.

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

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

The term "cyano" refers to the -C≡N group.

As used herein, the terms "halo", "halide" or "halogen" refer to fluoro, chloro, bromo and iodo groups. Further, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C _1-4 ) alkyl" means including, but not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. ..

The term "hydroxyl" refers to the -OH group.

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

The term "mercapto" refers to the -SH group.

As used herein, the term "oxo" means an oxygen atom that double bonds to a carbon atom or another element (including nitrogen in the pyridine ring) to form a pyridine N-oxide.

The term "nitro" refers to _two -NOs and can also be expressed as -N ⁺ (= O) ^-O- .

The term "thio" refers to a compound described above herein in which a carbon atom or oxygen atom is replaced with a sulfur atom.

The term "sulfate" refers to _four -SOs.

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

More specifically, the term "sulfide" refers to a compound having a group of formula-SR.

The term "sulfone" refers to a compound having a sulfonyl group -S (O ₂ ) R'.

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

The term "ureido" refers to the urea group of formula-NH-CO-NH ₂ .

The "S (= O) (= NR ₁₀ ) -R ₁₁ " group is, for example, described in Frings et al. , Sulfoximines from Medicinal Chemist's Persective: Physicochemical and in vitro Parameters Relevant for Drug Discovery 2

Throughout the specification and claims, a given chemical formula or name is a racemic mixture in which such isomers and mixtures are present, as are all tautomers, homologues and optical and stereoisomers. Shall be included.

Certain compounds of the present disclosure may have an asymmetric carbon atom or sulfur atom (optical or chiral center) or double bond (enantiomer, racemic, diastereomeric, remutable, geometric isomer, absolute). Each isomer is included in the scope of the present disclosure as (R)-or (S)-from a stereochemical point of view, or D- or L- in the case of amino acids). .. The compounds of the present disclosure do not include those known in the art to be too unstable to be synthesized and / or isolated. The present disclosure is meant to include racemic, scalemic and optically pure forms of the compound. The optically active (R)-and (S)-or D- and L-isomers can be prepared using chiral synthons or chiral reagents or can be partitioned using conventional techniques. Where the compounds described herein contain olephenic bonds or other geometric asymmetric centers, the compounds are intended to contain both E and Z geometric isomers, unless otherwise stated.

Unless otherwise stated, the structure illustrated herein is also meant to include all stereochemical forms of the structure, i.e. the R and S arrangements of each asymmetric center. Thus, mixtures of enantiomers and diastereomers as well as single stereochemical isomers of the compounds of the invention are within the scope of the present disclosure.

It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomers and all tautomers of such 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 easily convert from one isomer to another. Point to.

Unless otherwise stated, the structures illustrated herein are also meant to contain different compounds only in the presence of one or more isotope enriched atoms. For example, a compound having the present structure in which hydrogen is replaced with deuterium or tritium, or a compound having the present structure in which carbon is replaced with ¹³ C or ¹⁴ C concentrated carbon is within the scope of the present disclosure.

The compounds of the present disclosure may also contain non-naturally occurring proportions of atomic isotopes in one or more atoms constituting such compounds. For example, the compound may be radiolabeled with a radioisotope such as deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

The compounds of the present disclosure may be present as salts. The present disclosure includes such salts. Examples of applicable salt forms are hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (eg, (eg, +)-Salts of amino acids such as succinate, benzoate and glutamate), (-)-tartrate or mixtures thereof, including rasemimixes). 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, the neutral form of such compounds is contacted with a sufficient amount of the desired acid, either as is or in a suitable inert solvent. The acid addition salt can be obtained by this or by ion exchange. Examples of acceptable acid addition salts are hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid or Salts derived from inorganic acids such as phosphoric acid, 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- Examples thereof include salts derived from organic acids such as trill sulfonic acid, citric acid, tartaric acid and methane sulfonic acid. Also included are salts of amino acids such as arginate and salts of organic acids such as glucuronic acid or galacturonic acid. Certain compounds of the present disclosure include both basic and acidic functional groups that allow the compound to be converted to either a base-added salt or an acid-added salt.

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

The particular compound of the present disclosure can also be present in a solvated form, including a hydrated form, as well as a non-solvated form. In general, the solvated form is equivalent to the non-solvated form and is included within the scope of the present disclosure. The particular compounds of the present disclosure may be present in multiple crystalline or amorphous forms. In general, all physical forms are equivalent to the intended use of this disclosure and are intended to be within the scope of this disclosure.

In addition to the salt form, the present disclosure provides compounds in the prodrug form. The prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. In addition, the prodrug can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, the prodrug can be slowly converted to the compounds of the present disclosure by placing it in a transdermal patch reservoir with the appropriate enzyme or chemical reagent.

The term "protecting group" refers to a chemical site that protects some or all of the reactive sites of a compound and prevents such sites from engaging in a chemical reaction until the protective group is removed, eg, T. .. W. Greene, P.M. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd ed. Refers to the sites listed and described in John Wiley & Sons (1999). When different protecting groups are used, it may be advantageous for each (different) protecting group to be removable by different means. Protecting groups cleaved under completely different reaction conditions allow for distinct removal of such protecting groups. For example, protecting groups can be removed by acid, base and hydrocracking. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid-reactive and the protection of carboxy-reactive and hydroxy-reactive sites using them is Cbz groups and bases that can be removed by hydrocracking. It can be done in the presence of an amino group protected by a reactive Fmoc group. Protection of carboxylic acid and hydroxy reactive sites with non-limiting base reactive groups such as methyl, ethyl and acetyl is stable but hydrolyzed to acid reactive groups such as tert-butyl carbamate or both acids and bases. It can be done in the presence of a carbamate-protected amine that can be removed by decomposition.

Carboxylic acid and hydroxyreactive sites can also be protected with hydrolyzable and demovable protecting groups such as benzyl groups, and amine groups hydrogen-bondable to acids can be protected with basic reactive groups such as Fmoc. .. The carboxylic acid reactive moiety can be protected with an oxidatively demovable protecting group such as 2,4-dimethoxybenzyl, and the coexisting amino groups can be protected with a fluoride-reactive silylcarbamate.

Allyl blocking groups are useful in the presence of acid and base protecting groups, because the former is stable and can be later removed by a metal or π acid catalyst. For example, the allyl-protected carboxylic acid can be deprotected by a palladium (O) -catalyzed reaction in the presence of an acid-reactive t-butyl carbamate or a base-reactive acetate amine protecting group. Yet another form of protecting group is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, the functional group is protected and cannot react. Once released from the resin, the functional group becomes reactive.

が挙げられるが、これらに限定されない。 Typical blocking / protecting groups include the following sites:

However, it is not limited to these.

Following long-standing practice in patent law, the terms "one (a) (an)" and "the" mean "one or more" as used in this application, including the claims. do. Thus, for example, reference to a "subject" includes a plurality of subjects unless the contextual opposite (eg, the plurality of subjects) is obvious.

Throughout the specification and claims, the terms "comprises" and "comprising" are used in a non-exclusive sense unless the context implies otherwise. Will be done. Similarly, the term "include" and its grammatical variants are intended to be non-limiting and other similarities that may be substituted or added to the items in the list by enumerating the items in the list. Items are not excluded.

Quantities, sizes, dimensions, ratios, shapes, formulations, parameters, used in the specification and claims, unless otherwise indicated, for the purposes of the specification and the accompanying claims. All numbers representing percentages, quantities, properties and other numbers are modified by the term "about" in all cases, even if the word "about" does not explicitly appear with the value, quantity or range. Please understand that there is. Therefore, unless the opposite is explicitly stated, the numerical parameters described in the specification and the accompanying claims are not strict and need not be strict, but are to be obtained by the subject matter of the present disclosure. Depending on the desired characteristics, tolerances, conversion factors, rounding, measurement errors, etc. and other factors known to those of skill in the art may be approximated and / or larger as necessary. It may be small. For example, the term "about", when referring to a value, is ± 100% in some embodiments, ± 50% in some embodiments, ± 20% in some embodiments, from the specified amount. ± 10% in some embodiments, ± 5% in some embodiments, ± 1% in some embodiments, ± 0.5% in some embodiments, ± 0 in some embodiments. It can be meant to include a .1% variability, as such variability is valid for performing the disclosed method and utilizing the disclosed composition.

Further, the term "about" should be understood to refer to all such numbers, including all numbers within the range, when used in connection with one or more numbers or numerical ranges. Correct the range by expanding the upper and lower limits of the numerical value of. The enumeration of numerical ranges by endpoints includes all numerical values contained within the range, eg, whole integers containing the fractions (eg, enumeration of 1-5 is similar to 1, 2, 3, 4 and 5). Fractions thereof, such as 1.5, 2.25, 3.75, 4.1, etc.) and any range within that range are included.

The following examples are included to provide one of ordinary skill in the art with guidance for practicing representative embodiments of the subject matter of the present disclosure. In light of the present disclosure and the general skill in the art, those skilled in the art intend that the following examples are merely exemplary and will not deviate from the scope of the subject matter of this disclosure. Understand that changes, modifications and modifications can be made to. Subsequent description of the synthesis and specific examples will be construed as merely exemplary and does not limit the production of the compounds of the present disclosure in any other way.

(Synthesis procedure)
Exemplary compounds were prepared via several common synthetic routes described in the Examples below. Any of the compounds disclosed in the present invention can be prepared according to one or more of these synthetic routes or specific examples or via modifications thereof available to those of skill in the art.

ＭｅＣＮ（５ｍＬ）中の２－クロロ－５－（トリフルオロメチル）ピリジン－３－カルボン酸（５００ｍｇ、２．２２ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（２７８μＬ、２．４４ｍｍｏｌ）及び炭酸セシウム（１８０６ｍｇ、５．５４ｍｍｏｌ）の混合液を、８０℃で１８時間撹拌した。冷却後、内容物を２０ｍＬの水で希釈し、２ＮのＨＣｌを慎重に加えてｐＨ５に酸性化した後、２時間撹拌した。沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、２－（４－フルオロ－２－メトキシ－フェノキシ）－５－（トリフルオロメチル）ピリジン－３－カルボン酸をベージュ色の固体として得た（６９５ｍｇ、２．１０ｍｍｏｌ、収率９４．６％）。ＭＳ， ＥＳ＋ ｍ／ｚ ３３２．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １３．７４ （ｂｒ． ｓ．， １ Ｈ）， ８．６７ （ｂｒ． ｓ．， １ Ｈ）， ８．５０ （ｓ， １ Ｈ）， ７．２２ （ｄｄ， Ｊ＝８．９７， ５．６８ Ｈｚ， １ Ｈ）， ７．１０ （ｄｄ， Ｊ＝１１．１２， ２．７８ Ｈｚ， １ Ｈ）， ６．７９ － ６．８６ （ｍ， １ Ｈ）， ３．７０ （ｓ， ３ Ｈ）． (Intermediate 1; 2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid)
[Method A]

2-Chloro-5- (trifluoromethyl) pyridine-3-carboxylic acid (500 mg, 2.22 mmol), 4-fluoro-2-methoxyphenol (278 μL, 2.44 mmol) and cesium carbonate (2,44 mmol) in MeCN (5 mL). A mixture of 1806 mg (5.54 mmol) was stirred at 80 ° C. for 18 hours. After cooling, the contents were diluted with 20 mL of water, carefully added 2N HCl to acidify to pH 5, and then stirred for 2 hours. The precipitate is collected by filtration, washed with water, vacuum dried and 2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid as a beige solid. Obtained (695 mg, 2.10 mmol, yield 94.6%). MS, ES + m / z 332.0 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 13.74 (br. S., 1 H), 8.67 (br. S., 1 H), 8.50 (s, 1 H), 7. 22 (dd, J = 8.97, 5.68 Hz, 1 H), 7.10 (dd, J = 11.12, 2.78 Hz, 1 H), 6.79-6.86 (m, 1 H), 3.70 (s, 3 H).

クロロホルム（１０ｍＬ）中の２－クロロ－５－（トリフルオロメチル）ピリジン－３－カルボン酸（５０８ｍｇ、２．２５ｍｍｏｌ）、３－メチルスルホニルアニリン（４２４ｍｇ、２．４８ｍｍｏｌ）、ＨＢＴＵ（８５４ｍｇ、２．２５ｍｍｏｌ）及びＤＩＰＥＡ（９８１μＬ、５．６３ｍｍｏｌ）の混合液を、室温で４０時間撹拌した。 ６３ ｍｍｏｌ）をクロロホルム（１０ ｍＬ）に入れて、室温で４０時間撹拌した。溶媒をＮ_２気流下で除去し、残留物を水／ＭｅＯＨ（５：１）で処理した。この混合液を短時間超音波処理した後、室温で２４時間撹拌した。得られた沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、２－（ベンゾトリアゾール－１－イルオキシ）－Ｎ－（３－メチルスルホニルフェニル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミドをベージュ色の固体として得た（６６５ｍｇ、１．３９ｍｍｏｌ、収率６１．９％）。ＭＳ， ＥＳ＋ ｍ／ｚ ４４８．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １１．３７ （ｓ， １ Ｈ）， ８．８８ （ｄ， Ｊ＝２．２７ Ｈｚ， １ Ｈ）， ８．７２ （ｄ， Ｊ＝１．０１ Ｈｚ， １ Ｈ）， ８．４３ （ｓ， １ Ｈ）， ８．２０ （ｄ， Ｊ＝８．５９ Ｈｚ， １ Ｈ）， ８．０３ － ８．０７ （ｍ， １ Ｈ）， ７．８３ （ｄ， Ｊ＝８．５９ Ｈｚ， １ Ｈ）， ７．６７ － ７．７７ （ｍ， ３ Ｈ）， ７．５４ － ７．５８ （ｍ， １ Ｈ）， ３．２５ （ｓ， ３ Ｈ）． (Intermediate 2; 2- (benzotriazole-1-yloxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide)
[Method B]

2-Chloro-5- (trifluoromethyl) pyridine-3-carboxylic acid (508 mg, 2.25 mmol) in chloroform (10 mL), 3-methylsulfonylaniline (424 mg, 2.48 mmol), HBTU (854 mg, 2. A mixture of 25 mmol) and DIPEA (981 μL, 5.63 mmol) was stirred at room temperature for 40 hours. 63 mmol) was placed in chloroform (10 mL) and stirred at room temperature for 40 hours. The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (5: 1). The mixture was sonicated for a short time and then stirred at room temperature for 24 hours. The resulting precipitate was collected by filtration, washed with water, vacuum dried and 2- (benzotriazole-1-yloxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-. 3-Carboxamide was obtained as a beige solid (665 mg, 1.39 mmol, 61.9% yield). MS, ES + m / z 448.0 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1 H), 8.88 (d, J = 2.27 Hz, 1 H), 8.72 (d, J = 1.01) Hz, 1H), 8.43 (s, 1H), 8.20 (d, J = 8.59 Hz, 1H), 8.03-8.07 (m, 1H), 7.83 (D, J = 8.59 Hz, 1 H), 7.67-7.77 (m, 3 H), 7.54-7.58 (m, 1 H), 3.25 (s, 3 H) ).

(Intermediate 3: 6-chloro-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide)

クロロホルム（５ｍＬ）中の２，６－ジクロロピリジン－３－カルボニルクロリド（２００ｍｇ、０．９５０ｍｍｏｌ）、３－メチルスルホニルアニリン（１７９ｍｇ、１．０５ｍｍｏｌ）及びＤＩＰＥＡ（４１４μＬ、２．３８ｍｍｏｌ）の混合液を、室温で２４時間撹拌した。内容物を１０％Ｎａ_２ＣＯ_３で処理し、ＣＨＣｌ_３（３ｘ）で抽出し、溶媒を真空除去して、２，６－ジクロロ－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミドを黄色の泡沫として得て（３７８ｍｇ、１．１０ｍｍｏｌ、収率１１５％）、これをさらに精製することなく使用した。ＭＳ， ＥＳ＋ ｍ／ｚ ３４４．９ ［Ｍ＋Ｈ］＋． Step 1: Synthesis of 2,6-dichloro-N- (3-methylsulfonylphenyl) pyridine-3-carboxamide [Method C]

A mixture of 2,6-dichloropyridin-3-carbonylchloride (200 mg, 0.950 mmol), 3-methylsulfonylaniline (179 mg, 1.05 mmol) and DIPEA (414 μL, 2.38 mmol) in chloroform (5 mL). , Stirred at room temperature for 24 hours. The contents were treated with 10% Na ₂ CO ₃ and extracted with CHCl ₃ (3x), the solvent was evacuated to give 2,6-dichloro-N- (3-methylsulfonylphenyl) pyridine-3-carboxamide. Obtained as yellow foam (378 mg, 1.10 mmol, 115% yield), which was used without further purification. MS, ES + m / z 344.9 [M + H] +.

ＭｅＣＮ（２ｍＬ）中のクルード２，６－ジクロロ－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（２７６ｍｇ、０．８００ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（９１．１μＬ、０．８００ｍｍｏｌ）及び炭酸セシウム（２７３ｍｇ、０．８４０ｍｍｏｌ）の混合液を、室温で２３時間撹拌した。内容物を２０ｍＬの水で希釈し、室温で２時間撹拌した。得られた沈殿物を濾過して回収し、水で洗浄し、真空乾燥させ、６－クロロ－２－（４－フルオロ－２－メトキシ－フェノキシ）－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（２４２ｍｇ、０．５３６ｍｍｏｌ、収率６７．０％）を白色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４５１．１ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．８２ （ｓ， １ Ｈ）， ８．４１ （ｓ， １ Ｈ）， ８．１９ （ｄ， Ｊ＝７．８３ Ｈｚ， １ Ｈ）， ７．９６ （ｄ， Ｊ＝７．５８ Ｈｚ， １ Ｈ）， ７．６３ － ７．７１ （ｍ， ２ Ｈ）， ７．３２ － ７．３９ （ｍ， ２ Ｈ）， ７．１２ （ｄｄ， Ｊ＝１０．７４， ２．９１ Ｈｚ， １ Ｈ）， ６．８６ （ｔｄ， Ｊ＝８．４６， ２．７８ Ｈｚ， １ Ｈ）， ３．７３ （ｓ， ３ Ｈ）， ３．２２ （ｓ， ３ Ｈ） Step 2: Synthesis of 6-chloro-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide [Method D]

Crude 2,6-dichloro-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (276 mg, 0.800 mmol) in MeCN (2 mL), 4-fluoro-2-methoxyphenol (91.1 μL, 0. A mixture of 800 mmol) and cesium carbonate (273 mg, 0.840 mmol) was stirred at room temperature for 23 hours. The contents were diluted with 20 mL of water and stirred at room temperature for 2 hours. The resulting precipitate was filtered and collected, washed with water, vacuum dried and 6-chloro-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridine-. 3-Carboxamide (242 mg, 0.536 mmol, 67.0% yield) was obtained as a white solid. MS, ES + m / z 451.1 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1 H), 8.41 (s, 1 H), 8.19 (d, J = 7.83 Hz, 1 H), 7 .96 (d, J = 7.58 Hz, 1H), 7.63-771 (m, 2H), 7.32-7.39 (m, 2H), 7.12 (dd, 2H) J = 10.74, 2.91 Hz, 1 H), 6.86 (td, J = 8.46, 2.78 Hz, 1 H), 3.73 (s, 3 H), 3.22 ( s, 3 H)

クロロホルム（５ｍＬ）中の２－クロロ－５－（トリフルオロメチル）ピリジン－３－カルボニルクロリド（２５０ｍｇ、１．０２ｍｍｏｌ）、３－メチルスルホニルアニリン（１９３ｍｇ、１．１３ｍｍｏｌ）及びＤＩＰＥＡ（４４６μＬ、２．５６ｍｍｏｌ）の混合液を室温で２４時間撹拌した。内容物を１０％Ｎａ_２ＣＯ_３で処理し、ＣＨＣｌ_３（３ｘ）で抽出し、溶媒を真空除去して黄色の泡沫を得て、これをＭｅＯＨ／２％Ｎａ_２ＣＯ_３（１：１０）でトリチュレートした。濾過により固体を回収し、水で洗浄し、真空乾燥させ、２－クロロ－Ｎ－（３－メチルスルホニルフェニル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（１７５ｍｇ、０．４６２ｍｍｏｌ、収率４５．１％）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３７９．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １１．１７ （ｓ， １ Ｈ）， ９．０４ （ｓ， １ Ｈ）， ８．７２ （ｄ， Ｊ＝２．２７ Ｈｚ， １ Ｈ）， ８．３５ （ｓ， １ Ｈ）， ７．９４ （ｄ， Ｊ＝７．８３ Ｈｚ， １ Ｈ）， ７．６７ － ７．７６ （ｍ， ２ Ｈ）， ３．２５ （ｓ， ３ Ｈ）． (Intermediate 4; 2-Chloro-N- (3-Methylsulfonylphenyl) -5- (trifluoromethyl) Pyridine-3-carboxamide)
[Method E]

2-Chloro-5- (trifluoromethyl) pyridine-3-carbonyl chloride (250 mg, 1.02 mmol), 3-methylsulfonylaniline (193 mg, 1.13 mmol) and DIPEA (446 μL, 2. The mixture (56 mmol) was stirred at room temperature for 24 hours. The contents were treated with 10% Na ₂ CO ₃ and extracted with CHCl ₃ (3x), the solvent was evacuated to give a yellow foam, which was MeOH / 2% Na ₂ CO ₃ (1:10). Triturated with. The solid is collected by filtration, washed with water, vacuum dried and collected in 2-chloro-N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (175 mg, 0.462 mmol). A rate of 45.1%) was obtained as a beige solid. MS, ES + m / z 379.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1 H), 9.04 (s, 1 H), 8.72 (d, J = 2.27 Hz, 1 H), 8 .35 (s, 1H), 7.94 (d, J = 7.83 Hz, 1H), 7.67-7.76 (m, 2H), 3.25 (s, 3H).

クロロホルム（２ｍＬ）中の２－（４－フルオロ－２－メトキシ－フェノキシ）－５－（トリフルオロメチル）ピリジン－３－カルボン酸（中間体１）（３０．０ｍｇ、０．０９０ｍｍｏｌ）、１，３－ベンゾチアゾール－６－アミン（１５．０ｍｇ、０．１００ｍｍｏｌ）、ＨＢＴＵ（３７．８ｍｇ、０．１００ｍｍｏｌ）及びＤＩＰＥＡ（２９．３ｍｇ、３９．４μＬ、０．２３０ｍｍｏｌ）の混合液を、室温で２０時間撹拌した。溶媒をＮ_２気流下で除去し、残留物を水／ＭｅＯＨ（３：１）で処理した。この混合液を短時間超音波処理した後、室温で３時間撹拌した。得られた沈殿物を濾過によって回収し、水で洗浄し、真空乾燥させ、Ｎ－（１，３－ベンゾチアゾール－６－イル）－２－（４－フルオロ－２－メトキシ－フェノキシ）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（３５．４ｍｇ、０．０７６４ｍｍｏｌ、８４．３％収率）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４６４．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．８８ （ｓ， １ Ｈ）， ９．３２ （ｓ， １ Ｈ）， ８．７０ （ｄ， Ｊ＝２．０２ Ｈｚ， １ Ｈ）， ８．６６ － ８．６８ （ｍ， １ Ｈ）， ８．５３ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ）， ８．０９ （ｄ， Ｊ＝８．８４ Ｈｚ， １ Ｈ）， ７．７５ （ｄｄ， Ｊ＝８．８４， ２．０２ Ｈｚ， １ Ｈ）， ７．３５ （ｄｄ， Ｊ＝８．８４， ５．８１ Ｈｚ， １ Ｈ）， ７．１１ （ｄｄ， Ｊ＝１０．７４， ２．９１ Ｈｚ， １ Ｈ）， ６．８５ （ｔｄ， Ｊ＝８．５３， ２．９１ Ｈｚ， １ Ｈ）， ３．７２ （ｓ， ３ Ｈ）． (Example 1; N- (1,3-benzothiazole-6-yl) -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide)
[Method F]

2- (4-Fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridin-3-carboxylic acid (intermediate 1) (30.0 mg, 0.090 mmol) in chloroform (2 mL), 1, A mixture of 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) at room temperature. It was stirred for 20 hours. The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (3: 1). The mixture was sonicated for a short time and then stirred at room temperature for 3 hours. The resulting precipitate was collected by filtration, washed with water, vacuum dried and N- (1,3-benzothiazole-6-yl) -2- (4-fluoro-2-methoxy-phenoxy) -5. -(Trifluoromethyl) pyridine-3-carboxamide (35.4 mg, 0.0764 mmol, 84.3% yield) was obtained as a beige solid. MS, ES + m / z 464.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1 H), 9.32 (s, 1 H), 8.70 (d, J = 2.02 Hz, 1 H), 8 .66-8.68 (m, 1H), 8.53 (d, J = 2.53 Hz, 1H), 8.09 (d, J = 8.84 Hz, 1H), 7.75 (Dd, J = 8.84, 2.02 Hz, 1 H), 7.35 (dd, J = 8.84, 5.81 Hz, 1 H), 7.11 (dd, J = 10.74) , 2.91 Hz, 1 H), 6.85 (td, J = 8.53, 2.91 Hz, 1 H), 3.72 (s, 3 H).

The following compounds were synthesized according to Method F.

ＭｅＣＮ（３ｍＬ）中の２－（ベンゾトリアゾール－１－イルオキシ）－Ｎ－（３－メチルスルホニルフェニル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（中間体２）（５０．０ｍｇ、０．１００ｍｍｏｌ）、２，４－ジクロロフェノール（２０．５ｍｇ、０．１３０ｍｍｏｌ）及び炭酸セシウム（１０２ｍｇ、０．３１０ｍｍｏｌ）の混合液を、５０℃で１時間撹拌した。Ｎ_２気流下で溶媒を除去し、残留物を水／ＭｅＯＨ（４：１）で処理した。この混合液を短時間超音波処理した後、室温で２４時間撹拌した。得られた沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、２－（２，４－ジクロロフェノキシ）－Ｎ－（３－メチルスルホニルフェニル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（４３．６ｍｇ、０．０８６３ｍｍｏｌ、収率８２．４％）をオフホワイト色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ５０５．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １１．０７ （ｓ， １ Ｈ）， ８．７１ － ８．７３ （ｍ， １ Ｈ）， ８．６３ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ）， ８．３９ － ８．４２ （ｍ， １ Ｈ）， ７．９７ － ８．０１ （ｍ， １ Ｈ）， ７．８２ － ７．８４ （ｍ， １ Ｈ）， ７．６６ － ７．７４ （ｍ， ２ Ｈ）， ７．５３ － ７．６０ （ｍ， ２ Ｈ）， ３．２４ （ｓ， ３ Ｈ）． Example 21: 2- (2,4-dichlorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide)
[Method G]

2- (benzotriazole-1-yloxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (intermediate 2) (50.0 mg, 0) in MeCN (3 mL) A mixture of 100 mmol), 2,4-dichlorophenol (20.5 mg, 0.130 mmol) and cesium carbonate (102 mg, 0.310 mmol) was stirred at 50 ° C. for 1 hour. The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (4: 1). The mixture was sonicated for a short time and then stirred at room temperature for 24 hours. The resulting precipitate was collected by filtration, washed with water, vacuum dried and 2- (2,4-dichlorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-. 3-Carboxamide (43.6 mg, 0.0863 mmol, 82.4% yield) was obtained as an off-white solid. MS, ES + m / z 505.0 [M + H] +.
1 H-NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H), 8.71-8.73 (m, 1 H), 8.63 (d, J = 2.53 Hz, 1) H), 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).

The following compounds were synthesized according to Method G.

The following compounds were synthesized according to Method G.

ＭｅＣＮ（２ｍＬ）中の２－クロロ－Ｎ－（３－メチルスルホニルフェニル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（中間体４）（５９ｍｇ、０．１６０ｍｍｏｌ）、２，６－ジメチルフェノール（２０．９ｍｇ、０．１７０ｍｍｏｌ）及び炭酸セシウム（１５２ｍｇ、０．４７０ｍｍｏｌ）の混合液を、室温で１８時間撹拌した。内容物をＥｔＯＡｃで希釈し、水（３ｘ）、ブライン（１ｘ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、溶媒を真空除去して残留物を得、これを自動順相クロマトグラフィー（０－１００％ＥｔＯＡｃ／ヘプタン、４ｇシリカゲルカートリッジ）で精製し、２－（２，６－ジメチルフェノキシ）－Ｎ－（３－メチルスルホニルフェニル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（３２．６ｍｇ、０．０７０２ｍｍｏｌ、４５．１％収率）を白色泡沫として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４６５．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １１．０８ （ｓ， １ Ｈ）， ８．６４ （ｄｄ， Ｊ＝２．５３， １．０１ Ｈｚ， １ Ｈ）， ８．５９ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ）， ８．４２ － ８．４４ （ｍ， １ Ｈ）， ７．９８ （ｄｔ， Ｊ＝７．５８， １．８９ Ｈｚ， １ Ｈ）， ７．６６ － ７．７３ （ｍ， ２ Ｈ）， ７．０８ － ７．１６ （ｍ， ３ Ｈ）， ３．２３ （ｓ， ３ Ｈ）， ２．０７ （ｓ， ６ Ｈ）． Example 33: 2- (2,6-dimethylphenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide)
[Method H]

2-Chloro-N- (3-Methylsulfonylphenyl) -5- (trifluoromethyl) Pyridine-3-carboxamide (Intermediate 4) (59 mg, 0.160 mmol), 2,6-dimethyl in MeCN (2 mL) A mixture of phenol (20.9 mg, 0.170 mmol) and cesium carbonate (152 mg, 0.470 mmol) was stirred at room temperature for 18 hours. The contents are diluted with EtOAc, washed with water (3x), brine (1x), dried on silica gel ₄ , filtered, the solvent vacuum removed to give a residue, which is subjected to automatic normal phase chromatography (0). Purified with -100% EtOAc / Heptane, 4 g silica gel cartridge) and 2- (2,6-dimethylphenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (32). 0.6 mg, 0.0702 mmol, 45.1% yield) was obtained as white foam. MS, ES + m / z 465.0 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1 H), 8.64 (dd, J = 2.53, 1.01 Hz, 1 H), 8.59 (d, J) = 2.53 Hz, 1 H), 8.42-8.44 (m, 1 H), 7.98 (dt, J = 7.58, 1.89 Hz, 1 H), 7.66-7 .73 (m, 2H), 7.08-7.16 (m, 3H), 3.23 (s, 3H), 2.07 (s, 6H).

The following compounds were synthesized according to Method H.

The following compounds were synthesized according to Method H.

The following compounds were synthesized according to Method H.

(Example 66: 2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridine-3-carboxamide)

クロロホルム（５ｍＬ）中のＨＢＴＵ（１８５ｍｇ、０．４９０ｍｍｏｌ）、ＤＩＰＥＡ（１７０μＬ、０．９８０ｍｍｏｌ）、２－クロロ－６－（トリフルオロメチル）ピリジン－３－カルボン酸（１００ｍｇ、０．４４０ｍｍｏｌ）及び３－メチルスルホニルアニリン（７９．７ｍｇ、０．４７０ｍｍｏｌ）の混合液を、室温で４日間（便宜上）撹拌した。内容物を５％Ｎａ_２ＣＯ_３で処理し、ＣＨＣｌ_３で抽出した（３ｘ）。有機抽出液を合わせ、溶媒を真空除去して残留物を得、これを自動順相クロマトグラフィー（０－１００％ＥｔＯＡｃ／ヘプタン、１２ｇシリカゲルカートリッジ）で精製し、２－クロロ－Ｎ－（３－メチルスルホニルフェニル）－６－（トリフルオロメチル）ピリジン－３－カルボキサミド（８６．２ｍｇ、０．２２９ｍｍｏｌ、収率５１．３％）を黄色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３７９．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １１．１９ （ｓ， １ Ｈ）， ８．４８ （ｄ， Ｊ＝７．８３ Ｈｚ， １ Ｈ）， ８．３７ （ｔ， Ｊ＝１．７７ Ｈｚ， １ Ｈ）， ８．１７ （ｄ， Ｊ＝７．５８ Ｈｚ， １ Ｈ）， ７．９２ （ｄｔ， Ｊ＝７．７１， １．８３ Ｈｚ， １ Ｈ）， ７．７２ － ７．７６ （ｍ， １ Ｈ）， ７．６７ － ７．７２ （ｍ， １ Ｈ）， ３．２５ （ｓ， ３ Ｈ）． Step 1: Synthesis of 2-chloro-N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridine-3-carboxamide

HBTU (185 mg, 0.490 mmol) in chloroform (5 mL), DIPEA (170 μL, 0.980 mmol), 2-chloro-6- (trifluoromethyl) pyridine-3-carboxylic acid (100 mg, 0.440 mmol) and 3 A mixture of -methylsulfonylaniline (79.7 mg, 0.470 mmol) was stirred at room temperature for 4 days (for convenience). The contents were treated with 5% Na ₂ CO ₃ and extracted with CHCl ₃ (3x). The organic extracts were combined and the solvent was vacuum removed to give a residue, which was purified by automatic normal phase chromatography (0-100% EtOAc / heptane, 12 g silica gel cartridge) and 2-chloro-N- (3-chloro-N- (3-). Methylsulfonylphenyl) -6- (trifluoromethyl) pyridine-3-carboxamide (86.2 mg, 0.229 mmol, yield 51.3%) was obtained as a yellow solid. MS, ES + m / z 379.0 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1 H), 8.48 (d, J = 7.83 Hz, 1 H), 8.37 (t, J = 1.77) Hz, 1H), 8.17 (d, J = 7.58 Hz, 1H), 7.92 (dt, J = 7.71, 1.83 Hz, 1H), 7.72-7. 76 (m, 1H), 7.67-772 (m, 1H), 3.25 (s, 3H).

ＭｅＣＮ（２ｍＬ）中の２－クロロ－Ｎ－（３－メチルスルホニルフェニル）－６－（トリフルオロメチル）ピリジン－３－カルボキサミド（４０．０ｍｇ、０．１１０ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（１５．１μＬ、０．１３０ｍｍｏｌ）及び炭酸セシウム（１０３ｍｇ、０．３２０ｍｍｏｌ）の混合液を８０℃で１時間、その後、室温で一晩撹拌した。内容物をＥｔＯＡｃで希釈し、水（３ｘ）、ブライン（１ｘ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、溶媒を真空除去して残留物を得、これを自動順相クロマトグラフィー（０－１００％ＥｔＯＡｃ／ヘプタン、４ｇシリカゲルカートリッジ）で精製し、２－（４－フルオロ－２－メトキシ－フェノキシ）－Ｎ－（３－メチルスルホニルフェニル）－６－（トリフルオロメチル）ピリジン－３－カルボキサミド（４６．５ｍｇ、０．０９６０ｍｍｏｌ、９０．９％収率）を黄色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４８５．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １１．０２ （ｓ， １ Ｈ）， ８．４２ （ｓ， １ Ｈ）， ８．３７ （ｄ， Ｊ＝７．３３ Ｈｚ， １ Ｈ）， ７．９６ （ｄ， Ｊ＝７．５８ Ｈｚ， １ Ｈ）， ７．７５ （ｄ， Ｊ＝７．５８ Ｈｚ， １ Ｈ）， ７．６５ － ７．７３ （ｍ， ２ Ｈ）， ７．３３ （ｄｄ， Ｊ＝８．７２， ５．９４ Ｈｚ， １ Ｈ）， ７．１２ （ｄｄ， Ｊ＝１０．６１， ２．７８ Ｈｚ， １ Ｈ）， ６．８５ （ｔｄ， Ｊ＝８．４６， ２．７８ Ｈｚ， １ Ｈ）， ３．６９ （ｓ， ３ Ｈ）， ３．２３ （ｓ， ３ Ｈ）． Step 2: Synthesis of 2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide

2-Chloro-N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (40.0 mg, 0.110 mmol) in MeCN (2 mL), 4-fluoro-2-methoxyphenol A mixture of (15.1 μL, 0.130 mmol) and cesium carbonate (103 mg, 0.320 mmol) was stirred at 80 ° C. for 1 hour and then at room temperature overnight. The contents are diluted with EtOAc, washed with water (3x), brine (1x), dried on silica ₄ , filtered, the solvent vacuum removed to give a residue, which is subjected to automatic normal phase chromatography (0). Purified with -100% EtOAc / Heptane, 4 g silica gel cartridge) and 2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridine-3- Carboxamide (46.5 mg, 0.0960 mmol, 90.9% yield) was obtained as a yellow solid. MS, ES + m / z 485.0 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1 H), 8.42 (s, 1 H), 8.37 (d, J = 7.33 Hz, 1 H), 7 .96 (d, J = 7.58 Hz, 1 H), 7.75 (d, J = 7.58 Hz, 1 H), 7.65-7.73 (m, 2 H), 7.33 (Dd, J = 8.72, 5.94 Hz, 1 H), 7.12 (dd, J = 10.61, 2.78 Hz, 1 H), 6.85 (td, J = 8.46) , 2.78 Hz, 1 H), 3.69 (s, 3 H), 3.23 (s, 3 H).

(Example 67: 4- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridine-3-carboxamide)

ＭｅＣＮ（３ｍＬ）中の４－クロロ－６－（トリフルオロメチル）ピリジン－３－カルボキシル酸エチル（１５０ｍｇ、０．６６８ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（９５．１μＬ、０．８３４ｍｍｏｌ）及び炭酸セシウム（６５３ｍｇ、２．００ｍｍｏｌ）の混合液を室温で１時間撹拌した。内容物を水で処理し、室温で３日間撹拌した（便宜上）。沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、４－（４－フルオロ－２－メトキシ－フェノキシ）－６－（トリフルオロメチル）ピリジン－３－カルボン酸エチル（１８６ｍｇ、０．５１８ｍｍｏｌ、７７．５％収率）をオフホワイトの固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３６０．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ９．０３ （ｓ， １ Ｈ）， ７．３５ （ｄｄ， Ｊ＝８．８４， ５．８１ Ｈｚ， １ Ｈ）， ７．２３ （ｄｄ， Ｊ＝１０．６１， ３．０３ Ｈｚ， １ Ｈ）， ６．８８ － ６．９５ （ｍ， ２ Ｈ）， ４．３７ （ｑ， Ｊ＝７．０７ Ｈｚ， ２ Ｈ）， ３．７６ （ｓ， ３ Ｈ）， １．３３ （ｔ， Ｊ＝７．０７ Ｈｚ， ３ Ｈ）． Step 1: Synthesis of ethyl 4- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridine-3-carboxylate

Ethyl 4-chloro-6- (trifluoromethyl) pyridine-3-carboxylate (150 mg, 0.668 mmol) in MeCN (3 mL), 4-fluoro-2-methoxyphenol (95.1 μL, 0.834 mmol) and A mixture of cesium carbonate (653 mg, 2.00 mmol) was stirred at room temperature for 1 hour. 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, vacuum dried and ethyl 4- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridine-3-carboxylate (186 mg, 0. 518 mmol, 77.5% yield) was obtained as an off-white solid. MS, ES + m / z 360.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1 H), 7.35 (dd, J = 8.84, 5.81 Hz, 1 H), 7.23 (dd, J) = 10.61, 3.03 Hz, 1 H), 6.88-6.95 (m, 2 H), 4.37 (q, J = 7.07 Hz, 2 H), 3.76 (s) , 3 H), 1.33 (t, J = 7.07 Hz, 3 H).

ＴＨＦ（２ｍＬ）及び水（０．１ｍＬ）中の４－（４－フルオロ－２－メトキシ－フェノキシ）－６－（トリフルオロメチル）ピリジン－３－カルボン酸エチル（１８２ｍｇ、０．５０７ｍｍｏｌ）及び水酸化リチウム一水和物（２３．４ｍｇ、０．５５８ｍｍｏｌ）の混合液を、室温で７日間（便宜上）撹拌した。溶媒をＮ_２気流下で除去し、内容物を水（１５ｍＬ）で希釈した。６ＮのＨＣｌを慎重に加えて、ｐＨをｐＨ５に下げた。３時間撹拌した後、沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、４－（４－フルオロ－２－メトキシ－フェノキシ）－６－（トリフルオロメチル）ピリジン－３－カルボン酸（１０２．６ｍｇ、０．３０９８ｍｍｏｌ、６１．１％収率）を白色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３３２．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １３．８３ （ｂｒ． ｓ．， １ Ｈ）， ９．００ （ｓ， １ Ｈ）， ７．３５ （ｄｄ， Ｊ＝８．７２， ５．６８ Ｈｚ， １ Ｈ）， ７．２３ （ｄｄ， Ｊ＝１０．７４， ２．６５ Ｈｚ， １ Ｈ）， ６．９２ （ｔｄ， Ｊ＝８．４６， ３．０３ Ｈｚ， １ Ｈ）， ６．８６ （ｓ， １ Ｈ）， ３．７６ （ｓ， ３ Ｈ）． Step 2: Synthesis of 4- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridine-3-carboxylic acid

Ethyl 4- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridine-3-carboxylate in THF (2 mL) and water (0.1 mL) (182 mg, 0.507 mmol) and water. A mixture of lithium oxide monohydrate (23.4 mg, 0.558 mmol) was stirred at room temperature for 7 days (for convenience). The solvent was removed under _N2 airflow and the contents were diluted with water (15 mL). 6N HCl was carefully added to reduce the pH to pH 5. After stirring for 3 hours, the precipitate is collected by filtration, washed with water, vacuum dried and 4- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridine-3-carboxylic acid. (102.6 mg, 0.3098 mmol, 61.1% yield) was obtained as a white solid. MS, ES + m / z 332.0 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 13.83 (br. S., 1 H), 9.00 (s, 1 H), 7.35 (dd, J = 8.72, 5.68) Hz, 1H), 7.23 (dd, J = 10.74, 2.65 Hz, 1H), 6.92 (td, J = 8.46, 3.03 Hz, 1H), 6. 86 (s, 1H), 3.76 (s, 3H).

クロロホルム（２ｍＬ）中の４－（４－フルオロ－２－メトキシ－フェノキシ）－６－（トリフルオロメチル）ピリジン－３－カルボン酸（４６．０ｍｇ、０．１３９ｍｍｏｌ）、３－メチルスルホニルアニリン（２６．２ｍｇ、０．１５３ｍｍｏｌ）、ＨＢＴＵ（５７．９ｍｇ、０．１５３ｍｍｏｌ）及びＤＩＰＥＡ（６０．５μＬ、０．３４７ｍｍｏｌ）の混合液を、室温で１８時間撹拌した。溶媒をＮ_２気流下で除去し、残留物を水／ＭｅＯＨ（５：１）で処理した。この混合液を短時間超音波処理した後、室温で２４時間撹拌した。得られた沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、４－（４－フルオロ－２－メトキシ－フェノキシ）－Ｎ－（３－メチルスルホニルフェニル）－６－（トリフルオロメチル）ピリジン－３－カルボキサミド（５５．０ｍｇ、０．１１４ｍｍｏｌ、収率８１．７％）を白色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４８５．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １１．０８ （ｓ， １ Ｈ）， ８．９３ （ｓ， １ Ｈ）， ８．４１ （ｓ， １ Ｈ）， ７．９５ （ｄ， Ｊ＝７．３３ Ｈｚ， １ Ｈ）， ７．６５ － ７．７３ （ｍ， ２ Ｈ）， ７．４２ （ｄｄ， Ｊ＝８．８４， ５．８１ Ｈｚ， １ Ｈ）， ７．２２ （ｄｄ， Ｊ＝１０．６１， ２．７８ Ｈｚ， １ Ｈ）， ６．９６ （ｓ， １ Ｈ）， ６．９２ （ｔｄ， Ｊ＝８．４６， ２．７８ Ｈｚ， １ Ｈ）， ３．７７ （ｓ， ３ Ｈ）， ３．２３ （ｓ， ３ Ｈ）． Step 3: Synthesis of 4- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide

4- (4-Fluor-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridin-3-carboxylic acid (46.0 mg, 0.139 mmol) in chloroform (2 mL), 3-methylsulfonylaniline (26) A mixture of .2 mg, 0.153 mmol), HBTU (57.9 mg, 0.153 mmol) and DIPEA (60.5 μL, 0.347 mmol) was stirred at room temperature for 18 hours. The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (5: 1). The mixture was sonicated for a short time and then stirred at room temperature for 24 hours. The resulting precipitate was collected by filtration, washed with water, vacuum dried and 4- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl). ) Pyridine-3-carboxamide (55.0 mg, 0.114 mmol, yield 81.7%) was obtained as a white solid. MS, ES + m / z 485.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1 H), 8.93 (s, 1 H), 8.41 (s, 1 H), 7.95 (d, J = 7.33 Hz, 1 H), 7.65-773 (m, 2 H), 7.42 (dd, J = 8.84, 5.81 Hz, 1 H), 7.22 (dd, dd, J = 10.61, 2.78 Hz, 1 H), 6.96 (s, 1 H), 6.92 (td, J = 8.46, 2.78 Hz, 1 H), 3.77 ( s, 3H), 3.23 (s, 3H).

The following compounds were synthesized according to Method I.

(Example 73: 4- [2-chloro-4- (trifluoromethoxy) phenoxy] -N- [2- (dimethylamino) -4-pyridyl] -6- (trifluoromethyl) pyridine-3-carboxamide)
[Method J]

ＴＨＦ（２ｍＬ）中の４－クロロ－２－（トリフルオロメチル）ピリジン（２４．７ｇ、１３６．０６ｍｍｏｌ）の－７８℃の撹拌溶液に、ＬｉＨＭＤＳ（１４９．６６ｍＬ、１４９．６６ｍｍｏｌ）をゆっくりと加えた。この溶液を－７８℃で２時間撹拌した後、０℃で１０分間撹拌した。溶液を再び－７８℃に冷却した後、Ｎ，Ｎ－ジメチルホルムアミド（１２．６４ｍＬ、１６３．２７ｍｍｏｌ）を加えた。この溶液を一晩かけて室温に戻した。希塩酸（０．５Ｎ、２００ｍＬ）を加えた。この溶液を酢酸エチル（３×２００ｍＬ）で抽出した。合わせた酢酸エチル溶液をブライン（１００ｍＬ）で洗浄し、硫酸ナトリウムで乾燥させた。この溶液をろ濾過、濃縮した。残留物をシリカゲルクロマトグラフィーで精製、酢酸エチル／ヘキサン（０－４０％）で溶出し、４－クロロ－６－（トリフルオロメチル）ピリジン－３－カルバルデヒド（５．７ｇ、２７．２２ｍｍｏｌ、２０％収率）を得た。 Step 1: Synthesis of 4-chloro-6- (trifluoromethyl) pyridine-3-carbaldehyde

LiHMDS (149.66 mL, 149.66 mmol) is slowly added to a stirred solution of 4-chloro-2- (trifluoromethyl) pyridine (24.7 g, 136.06 mmol) in THF (2 mL) at −78 ° C. rice field. The solution was stirred at −78 ° C. for 2 hours and then at 0 ° C. for 10 minutes. After cooling the solution to −78 ° C. again, N, N-dimethylformamide (12.64 mL, 163.27 mmol) was added. The solution was allowed to warm to room temperature overnight. Dilute hydrochloric acid (0.5N, 200 mL) was added. This solution was extracted with ethyl acetate (3 x 200 mL). The combined ethyl acetate solution was washed with brine (100 mL) and dried over sodium sulfate. This solution was filtered and concentrated. The residue was purified by silica gel chromatography, eluted with ethyl acetate / hexane (0-40%) and 4-chloro-6- (trifluoromethyl) pyridin-3-carbaldehyde (5.7 g, 27.22 mmol, 20). % Yield) was obtained.

アセトニトリル（５０ｍＬ）中の２－クロロ－４－（トリフルオロメトキシ）フェノール（２．７９ｇ、１３．１２ｍｍｏｌ）、４－クロロ－６－（トリフルオロメチル）ピリジン－３－カルバルデヒド（２．５ｇ、１１．９３ｍｍｏｌ）の撹拌溶液に、炭酸カリウム（３．３ｇ、２３．８６ｍｍｏｌ）を加えた。この溶液を８０℃で３時間加熱した。この溶液を室温まで冷却した。酢酸エチル（５０ｍＬ）を加えた。溶液を濾過し、濃縮した。残留物を酢酸エチル／ヘプタン（０－３０％）で溶出するシリカゲルクロマトグラフィーで精製し、４－［２－クロロ－４－（トリフルオロメトキシ）フェノキシ］－６－（トリフルオロメチル）ピリジン－３－カルバルデヒド（４．６ｇ、１１．９２８ｍｍｏｌ、収率９９．９８％）を無色油として得た。
１Ｈ ＮＭＲ （４００ ＭＨｚ， クロロホルム－ｄ） δ ｐｐｍ ６．８９ （ｓ， １ Ｈ） ７．３３ － ７．４２ （ｍ， ２ Ｈ） ７．４９ － ７．５５ （ｍ， １ Ｈ） ９．１５ （ｓ， １ Ｈ） １０．６８ － １０．７５ （ｍ， ９ Ｈ） Step 2: Synthesis of 4- [2-chloro-4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridin-3-carbaldehyde

2-Chloro-4- (trifluoromethoxy) phenol (2.79 g, 13.12 mmol) in acetonitrile (50 mL), 4-chloro-6- (trifluoromethyl) pyridin-3-carbaldehyde (2.5 g, Potassium carbonate (3.3 g, 23.86 mmol) was added to the stirred solution of 11.93 mmol). The solution was heated at 80 ° C. for 3 hours. The solution was cooled to room temperature. Ethyl acetate (50 mL) was added. The solution was filtered and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate / heptane (0-30%) and 4- [2-chloro-4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3. -Calvaludehide (4.6 g, 11.928 mmol, yield 99.98%) was obtained as a colorless oil.
1H 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)

水（５０ｍＬ）中のリン酸一ナトリウム一水和物（７．５３ｇ、５４．５８ｍｍｏｌ）及び亜塩素酸ナトリウム（３．７ｇ、３２．７５ｍｍｏｌ）の撹拌溶液に、アセトニトリル（５０ｍＬ）を加えた。その後、４－［２－クロロ－４－（トリフルオロメトキシ）フェノキシ］－６－（トリフルオロメチル）ピリジン－３－カルバルデヒド（４．２１ｇ、１０．９２ｍｍｏｌ）を加えた。この溶液を室温で３時間撹拌した。亜硫酸ナトリウム（水溶液、１０％、０，５ｍＬ）を加えた。この溶液を室温で３０分間撹拌した。この溶液を濃縮した。塩酸（１Ｎ、２ｍＬ）を加えた。白い沈殿物を濾過して回収した。これを水で洗浄し、乾燥させ、４－［２－クロロ－４－（トリフルオロメトキシ）フェノキシ］－６－（トリフルオロメチル）ピリジン－３－カルボン酸（４．２ｇ、１０．４ｍｍｏｌ、収率９５．４％）の白色固体を得た。
１Ｈ ＮＭＲ （４００ ＭＨｚ， クロロホルム－ｄ） δ ｐｐｍ ６．８８ （ｓ， １ Ｈ） ７．３１ （ｄ， Ｊ＝１．５２ Ｈｚ， ２ Ｈ） ７．４８ － ７．５７ （ｍ， １ Ｈ） ９．３１ （ｓ， １ Ｈ） Step 3: Synthesis of 4- [2-chloro-4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3-carboxylic acid

Acetonitrile (50 mL) was added to a stirred solution of monosodium phosphate monohydrate (7.53 g, 54.58 mmol) and sodium chlorite (3.7 g, 32.75 mmol) in water (50 mL). Then, 4- [2-chloro-4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridin-3-carbaldehyde (4.21 g, 10.92 mmol) was added. The solution was stirred at room temperature for 3 hours. Sodium sulfite (aqueous solution, 10%, 0.5 mL) was added. The solution was stirred at room temperature for 30 minutes. This solution was concentrated. Hydrochloric acid (1N, 2 mL) was added. The white precipitate was filtered and recovered. This was washed with water and dried to obtain 4- [2-chloro-4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3-carboxylic acid (4.2 g, 10.4 mmol, yield). A white solid having a rate of 95.4%) was obtained.
1H NMR (400 MHz, chloroform-d) δ ppm 6.88 (s, 1 H) 7.31 (d, J = 1.52 Hz, 2 H) 7.48-7.57 (m, 1 H) 9.31 (s, 1 H)

室温でＤＣＭ（２ｍＬ）中の４－［２－クロロ－４－（トリフルオロメトキシ）フェノキシ］－６－（トリフルオロメチル）ピリジン－３－カルボン酸（５０ｍｇ、０．１２００ｍｍｏｌ）の撹拌溶液に、塩化オキサリル（２３．７ｍｇ、０．１９ｍｍｏｌ）を加えた。ＤＭＦ（１滴）を加えた。この溶液を室温で１時間撹拌した。この溶液を濃縮した。残留物をＤＣＭ（２ｍＬ）に溶解し、トリエチルアミン（０．０３ｍＬ、０．２５ｍｍｏｌ）及びＮ２，Ｎ２－ジメチルピリジン－２，４－ジアミン（２０．５ｍｇ、０．１５ｍｍｏｌ）を加えた。この溶液を室温で１時間撹拌した。溶液を塩酸（１Ｎ、２ｍＬ）で１回抽出し、濃縮した。残留物を分取逆相ＨＰＬＣで精製し、４－［２－クロロ－４－（トリフルオロメトキシ）フェノキシ］－Ｎ－［２－（ジメチルアミノ）－４－ピリジル］－６－（トリフルオロメチル）ピリジン－３－カルボキサミド（２１ｍｇ、０．０４ｍｍｏｌ、収率３２．４％）を白色固体として得た。
１Ｈ ＮＭＲ （４００ ＭＨｚ， クロロホルム－ｄ） δ ｐｐｍ ３．３３ （ｓ， ６ Ｈ） ６．９１ （ｓ， １ Ｈ） ７．３７ （ｄ， Ｊ＝９．８５ Ｈｚ， １ Ｈ） ７．４８ － ７．６０ （ｍ， ３ Ｈ） ８．０３ （ｓ， １ Ｈ） ９．１８ （ｓ， １ Ｈ） １０．４８ （ｂｒ． ｓ．， １ Ｈ） Step 4: Synthesis of 4- [2-chloro-4- (trifluoromethoxy) phenoxy] -N- [2- (dimethylamino) -4-pyridyl] -6- (trifluoromethyl) pyridine-3-carboxamide

In a stirred solution of 4- [2-chloro-4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3-carboxylic acid (50 mg, 0.1200 mmol) in DCM (2 mL) at room temperature. Oxalyl chloride (23.7 mg, 0.19 mmol) was added. DMF (1 drop) was added. The solution was stirred at room temperature for 1 hour. This solution was concentrated. The residue was dissolved in DCM (2 mL) and triethylamine (0.03 mL, 0.25 mmol) and N2, N2-dimethylpyridin-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 (1N, 2 mL) and concentrated. The residue was purified by preparative reverse phase HPLC and 4- [2-chloro-4- (trifluoromethoxy) phenoxy] -N- [2- (dimethylamino) -4-pyridyl] -6- (trifluoromethyl). ) Pyridine-3-carboxamide (21 mg, 0.04 mmol, yield 32.4%) was obtained as a white solid.
1H NMR (400 MHz, chloroform-d) δ ppm 3.33 (s, 6 H) 6.91 (s, 1 H) 7.37 (d, J = 9.85 Hz, 1 H) 7.48- 7.60 (m, 3H) 8.03 (s, 1H) 9.18 (s, 1H) 10.48 (br. S., 1H)

The following compounds were synthesized according to Method J.

４－［２－クロロ－４－（トリフルオロメトキシ）フェノキシ］－Ｎ－（３－ピリジル）－６－（トリフルオロメチル）ピリジン－３－カルボキサミド（実施例ＬＩ－１９７１、１００ｍｇ、０．２１ｍｍｏｌ）をスクリューキャップバイアルに加え、ＤＣＭ（５ ｍＬ）に溶解させた。ｍ－ＣＰＢＡ（５６ｍｇ、０．２５ｍｍｏｌ）を加え、混合液を室温で１５分間撹拌した。揮発性物質を減圧下で蒸発させ、残留物を分取逆相ＨＰＬＣ（高ｐＨ法）で精製し、表題化合物を無色ガラスとして得た（８１ｍｇ、０．１６ｍｍｏｌ、７８％収率）。ＭＳ， ＥＳ＋ ｍ／ｚ ４９４ ［Ｍ＋Ｈ］＋． (Example 83: 4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3- Carboxamide)
[Method K]

4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (3-pyridyl) -6- (trifluoromethyl) pyridin-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 stirred at room temperature for 15 minutes. The volatile material was evaporated under reduced pressure and the residue was purified by preparative reverse phase HPLC (high pH method) to give the title compound as colorless glass (81 mg, 0.16 mmol, 78% yield). MS, ES + m / z 494 [M + H] +.

The following compounds were synthesized according to Method K.

(Example 91: N- [3- (methylsulfonimideyl) phenyl] -4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3-carboxamide)
[Method L]

４－クロロ－６－（トリフルオロメチル）ピリジン－３－カルボン酸メチル（１ｇ、４．２ｍｍｏｌ）を磁気撹拌子を備えた２０ｍＬシンチレーションバイアルに加え、アセトニトリル（１０ｍＬ）に溶解させた。４－（トリフルオロメトキシ）フェノール（８９２ｍｇ、５ｍｍｏｌ）及び炭酸セシウム（２．７２ｇ、８．３４ｍｍｏｌ）を加え、混合液を５０℃で１時間加熱した。室温まで冷却した後、混合液を水（１００ｍＬ）で希釈し、ジクロロメタンで抽出した。合わせたジクロロメタン溶液を硫酸マグネシウムで乾燥させ、濃縮し、目的の生成物を含む油（１．２ｇ、３．１５ｍｍｏｌ、収率７５％）を得た。 Step 1: Synthesis of 4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3-carboxylate methyl

Methyl 4-chloro-6- (trifluoromethyl) pyridine-3-carboxylate (1 g, 4.2 mmol) was added to a 20 mL scintillation vial equipped with a magnetic stir bar and dissolved in acetonitrile (10 mL). 4- (Trifluoromethoxy) phenol (892 mg, 5 mmol) and cesium carbonate (2.72 g, 8.34 mmol) were added, and the mixture was heated at 50 ° C. for 1 hour. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with dichloromethane. The combined dichloromethane solution was dried over magnesium sulfate and concentrated to give an oil containing the desired product (1.2 g, 3.15 mmol, 75% yield).

磁気撹拌子を備えた丸底フラスコに４－［４－（トリフルオロメトキシ）フェノキシ］－６－（トリフルオロメチル）ピリジン－３－カルボキシレート（１．２ｇ、３．１５ｍｍｏｌ）を加え、ＴＨＦ（９ｍＬ）及び水（１ｍＬ）に溶解させた。過剰な水酸化ナトリウムを加え、混合液を室温で１時間撹拌させた。得られた混合液を水（２００ｍＬ）で希釈し、６ＮのＨＣｌを慎重に加えて強酸性にした。得られた溶液をジクロロメタンで抽出し、合わせた有機抽出液を硫酸マグネシウムで乾燥させた。減圧下で濃縮すると、透明オイル（１．１ｇ、３．０ｍｍｏｌ）が得られ、これは放置すると固化し、さらに精製することなく使用した。ＭＳ， ＥＳ＋ ｍ／ｚ ３６８ ［Ｍ＋Ｈ］＋． Step 2: Synthesis of 4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3-carboxylic acid

To a round bottom flask equipped with a magnetic stirrer, 4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3-carboxylate (1.2 g, 3.15 mmol) was added to THF (3,15 mmol). It was dissolved in 9 mL) and water (1 mL). Excess sodium hydroxide was added and the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (200 mL) and carefully added 6N HCl to make it strongly acidic. The resulting solution was extracted with dichloromethane and the combined organic extracts were dried over magnesium sulfate. Concentration under reduced pressure gave a clear oil (1.1 g, 3.0 mmol), which solidified on standing and used without further purification. MS, ES + m / z 368 [M + H] +.

スクリューキャップバイアルに４－［４－（トリフルオロメトキシ）フェノキシ］－６－（トリフルオロメチル）ピリジン－３－カルボン酸（１５０ｍｇ、０．４１ｍｍｏｌ）を入れ、ＤＭＦ（３ｍＬ）を加えた。トリエチルアミン（１１５μＬ、０．８２ｍｍｏｌ）及びＨＢＴＵ（１８６ｍｇ、０．４９ｍｍｏｌ）を加え、混合液を室温で１０分間撹拌した。３－（メチルスルホンイミドイル）アニリン（７０ｍｇ、０．４１ｍｏｌ）を加え、さらに１２時間撹拌を続けた。クルード混合液を分取逆相ＨＰＬＣ（高ｐＨ法）で精製すると、目的の生成物（９７ｍｇ、０．１９ｍｍｏｌ、４６％収率）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ５２０．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ３．０６ （ｓ， ３ Ｈ） ４．２５ （ｓ， １ Ｈ） ７．２６ （ｓ， １ Ｈ） ７．４４ － ７．５０ （ｍ， ２ Ｈ） ７．５１ － ７．５７ （ｍ， ２ Ｈ） ７．６０ （ｔ， Ｊ＝７．９６ Ｈｚ， １ Ｈ） ７．６９ （ｄ， Ｊ＝７．８３ Ｈｚ， １ Ｈ） ７．９０ （ｄ， Ｊ＝８．０８ Ｈｚ， １ Ｈ） ８．３５ （ｔ， Ｊ＝１．８９ Ｈｚ， １ Ｈ） ８．９８ （ｓ， １ Ｈ） Step 3: Synthesis of N- [3- (methylsulfonimideyl) phenyl] -4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3-carboxamide

4- [4- (Trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3-carboxylic acid (150 mg, 0.41 mmol) was placed in a screw cap vial, 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- (Methylsulfonimideyl) 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 give the desired product (97 mg, 0.19 mmol, 46% yield) as a beige solid. MS, ES + m / z 520.0 [M + H] +. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.06 (s, 3H) 4.25 (s, 1H) 7.26 (s, 1H) 7.44-7.50 (m, 2) H) 7.51-7.57 (m, 2 H) 7.60 (t, J = 7.96 Hz, 1 H) 7.69 (d, J = 7.83 Hz, 1 H) 7.90 (D, J = 8.08 Hz, 1 H) 8.35 (t, J = 1.89 Hz, 1 H) 8.98 (s, 1 H)

The following compounds were synthesized according to Method L.

(Example 93: 4- (4-fluoro-2-methyl-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridine-3-carboxamide)
[Method M]

４－クロロ－６－（トリフルオロメチル）ピリジン－３－カルボン酸メチル（１ｇ、４．２ｍｍｏｌ）を丸底フラスコに入れ、アセトニトリル（１０ｍＬ）に溶解させた。炭酸セシウム（２．７ｇ、８．３ｍｍｏｌ）及び４－フルオロ－２－メチル－フェノール（６３２ｍｇ、５．０ｍｍｏｌ）を加え、混合液を１時間撹拌しながら５０℃に加熱した。室温まで冷却した後、混合液を水（１５０ｍＬ）で希釈し、ジクロロメタンで抽出した。合わせたジクロロメタン抽出液を硫酸マグネシウムで乾燥させ、減圧下で濃縮し、透明油（１．１３ｇ、３．４２ｍｍｏｌ、８２％の収率）を得て、これをさらに精製することなく使用した。 Step 1: Synthesis of 4- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridine-3-carboxylate methyl

Methyl 4-chloro-6- (trifluoromethyl) pyridine-3-carboxylate (1 g, 4.2 mmol) was placed in a round bottom flask and dissolved in acetonitrile (10 mL). Cesium carbonate (2.7 g, 8.3 mmol) and 4-fluoro-2-methyl-phenol (632 mg, 5.0 mmol) were added, and the mixture was heated to 50 ° C. with stirring for 1 hour. After cooling to room temperature, the mixture was diluted with water (150 mL) and extracted with dichloromethane. The combined dichloromethane extract was dried over magnesium sulphate and concentrated under reduced pressure to give a clear oil (1.13 g, 3.42 mmol, 82% yield), which was used without further purification.

４－（４－フルオロ－２－メチル－フェノキシ）－６－（トリフルオロメチル）ピリジン－３－カルボン酸メチル（１．４ｇ、４．２ｍｍｏｌ）を丸底フラスコに入れ、ＴＨＦ（１２ｍＬ）及び水（２ｍＬ）に溶解した。水酸化ナトリウム（９６０ｍｇ、２１ｍｍｏｌ）を加え、混合液を室温で１時間撹拌した。クルード混合液を水（２００ｍＬ）で希釈し、６ＮのＨＣｌを加えて強酸性にした。得られた濁った溶液をジクロロメタンで抽出し、合わせたジクロロメタン抽出液を硫酸マグネシウムで乾燥させ、減圧下で濃縮して無色の固体（９８０ｍｇ、３．１ｍｍｏｌ、７４％収率）を得て、これをさらに精製することなく使用した。 Step 2: Synthesis of 4- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridine-3-carboxylic acid

Methyl 4- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridine-3-carboxylate (1.4 g, 4.2 mmol) is placed in a round bottom flask with THF (12 mL) and water. Dissolved in (2 mL). Sodium hydroxide (960 mg, 21 mmol) was added and the mixture was stirred at room temperature for 1 hour. The crude mixture was diluted with water (200 mL) and added with 6N HCl to make it strongly acidic. The resulting turbid solution was extracted with dichloromethane, the combined dichloromethane extract was dried over magnesium sulfate and concentrated under reduced pressure to give a colorless solid (980 mg, 3.1 mmol, 74% yield). Was used without further purification.

４－（４－フルオロ－２－メチル－フェノキシ）－６－（トリフルオロメチル）ピリジン－３－カルボン酸（１５０ｍｇ、０．４８ｍｍｏｌ）を、磁気撹拌子を備えたスクリュートップバイアルに入れ、ＤＭＦ（３ｍＬ）に溶解した。トリエチルアミン（１３３μＬ、０．９５ｍｍｏｌ）及びＨＢＴＵ（２１７ｍｇ、０．５７ｍｍｏｌ）を加え、混合液を室温で１０分間撹拌した。３－（メチルスルホンイミドイル）アニリン（８１ｍｇ、０．４８ｍｍｏｌ）を加え、さらに１２時間撹拌を続けた。分取逆相ＨＰＬＣ（高ｐＨ法）により精製し、表題化合物（１２９ｍｇ、０．２８ｍｍｏｌ、５８％収率）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４６８．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ
６） δ ｐｐｍ ２．１３ （ｓ， ３ Ｈ） ３．５３ （ｓ， ３ Ｈ） ５．６６ － ５．８８ （ｍ， ２ Ｈ） ６．８１ － ６．９５ （ｍ， ２ Ｈ） ７．０６ － ７．３５ （ｍ， ６ Ｈ） ９．０５ （ｓ， １ Ｈ）． Step 3: Synthesis of 4- (4-fluoro-2-methyl-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridine-3-carboxamide

4- (4-Fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridine-3-carboxylic acid (150 mg, 0.48 mmol) was placed in a screw top vial equipped with a magnetic stir bar and DMF ( 3 mL) was dissolved. Triethylamine (133 μL, 0.95 mmol) and HBTU (217 mg, 0.57 mmol) were added and the mixture was stirred at room temperature for 10 minutes. 3- (Methylsulfonimideyl) aniline (81 mg, 0.48 mmol) was added, and stirring was continued for another 12 hours. Purification by preparative reverse phase HPLC (high pH method) gave the title compound (129 mg, 0.28 mmol, 58% yield) as a beige solid. MS, ES + m / z 468.0 [M + H] +. 1H NMR (400 MHz, DMSO-d
6) δ ppm 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).

The following compounds were synthesized according to Method M.

The following compounds were synthesized according to Method M.

The following compounds were synthesized according to Method M.

The following compounds were synthesized according to Method M.

(Example 109: 2- (4-fluoro-2-methyl-phenoxy) -N- (2-methoxy-4-pyridyl) -5- (trifluoromethyl) pyridine-3-carboxamide)

クロロホルム（５ｍＬ）中の２－クロロ－５－（トリフルオロメチル）ピリジン－３－カルボニルクロリド（２５０ｍｇ、１．０２ｍｍｏｌ）、２－メトキシピリジン－４－アミン（１２７ｍｇ、１．０２ｍｍｏｌ）及びＤＩＰＥＡ（４４６μＬ、２．５６ｍｍｏｌ）の混合液を、室温で２４時間撹拌した。内容物を１０％Ｎａ_２ＣＯ_３で処理し、ＣＨＣｌ_３（３ｘ）で抽出し、溶媒を真空除去し、２－クロロ－Ｎ－（２－メトキシ－４－ピリジル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（２９０ｍｇ、０．８７４ｍｍｏｌ、収率８５．３％）をピンク色の固体として得た。この物質をさらに精製することなく使用した。ＭＳ， ＥＳ＋ ｍ／ｚ ３７９．０ ［Ｍ＋Ｈ］＋． Step 1: Synthesis of 2-chloro-N- (2-methoxy-4-pyridyl) -5- (trifluoromethyl) pyridine-3-carboxamide

2-Chloro-5- (trifluoromethyl) pyridine-3-carbonyl chloride (250 mg, 1.02 mmol), 2-methoxypyridin-4-amine (127 mg, 1.02 mmol) and DIPEA (446 μL) in chloroform (5 mL). , 2.56 mmol) was stirred at room temperature for 24 hours. The contents were treated with 10% Na ₂ CO ₃ and extracted with CHCl ₃ (3x), the solvent was vacuum removed and 2-chloro-N- (2-methoxy-4-pyridyl) -5- (trifluoromethyl) ) Pyridine-3-carboxamide (290 mg, 0.874 mmol, yield 85.3%) was obtained as a pink solid. This material was used without further purification. MS, ES + m / z 379.0 [M + H] +.

ＭｅＣＮ（３ｍＬ）中の２－クロロ－Ｎ－（２－メトキシ－４－ピリジル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（８４．０ｍｇ、０．２５３ｍｍｏｌ）、４－フルオロ－２－メチル－フェノール（４７．９ｍｇ、０．３８０ｍｍｏｌ）及び炭酸セシウム（２４８ｍｇ、０．７６０ｍｍｏｌ）の混合液を８０℃で２時間撹拌した。冷却後、内容物をＥｔＯＡｃで希釈し、水（３ｘ）、ブライン（１ｘ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、溶媒を真空除去して残留物を得、これを１０％ＭｅＣＮ／水でトリチュレートして沈殿物を得、これを濾過して回収し、水で洗浄し、真空乾燥させ、２－（４－フルオロ－２－メチル－フェノキシ）－Ｎ－（２－メトキシ－４－ピリジル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（５０． ０ｍｇ、０．１１９ｍｍｏｌ、４６．９％収率）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４２２．２ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．９９ （ｓ， １ Ｈ）， ８．６８ （ｓ， １ Ｈ）， ８．５７ （ｓ， １ Ｈ）， ８．１１ （ｄ， Ｊ＝５．８１ Ｈｚ， １ Ｈ）， ７．１８ － ７．３０ （ｍ， ４ Ｈ）， ７．０８ － ７．１５ （ｍ， １ Ｈ）， ３．８５ （ｓ， ３ Ｈ）， ２．０８ （ｓ， ３ Ｈ）． Step 2: Synthesis of 2- (4-fluoro-2-methyl-phenoxy) -N- (2-methoxy-4-pyridyl) -5- (trifluoromethyl) pyridine-3-carboxamide

2-Chloro-N- (2-methoxy-4-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (84.0 mg, 0.253 mmol) in MeCN (3 mL), 4-fluoro-2- A mixture of methyl-phenol (47.9 mg, 0.380 mmol) and cesium carbonate (248 mg, 0.760 mmol) was stirred at 80 ° C. for 2 hours. After cooling, the contents are diluted with EtOAc, washed with water (3x), brine (1x), dried with _regsvr4 , filtered and the solvent vacuum removed to give a residue, which is 10% MeCN /. Triturate with water to obtain a precipitate, which is filtered and collected, washed with water, vacuum dried and 2- (4-fluoro-2-methyl-phenoxy) -N- (2-methoxy-4-). Pyridyl) -5- (trifluoromethyl) pyridine-3-carboxamide (50.0 mg, 0.119 mmol, 46.9% yield) was obtained as a beige solid. MS, ES + m / z 422.2 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.11 (d, J = 5.81 Hz, 1 H), 7.18-7.30 (m, 4 H), 7.08-7.15 (m, 1 H), 3.85 (s, 3 H), 2.08 (S, 3H).

ＨＢｒ（ＨＯＡｃ中３３％）（５３８μＬ、２．９７ｍｍｏｌ）中の２－（４－フルオロ－２－メチル－フェノキシ）－Ｎ－（２－メトキシ－４－ピリジル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（５０．０ｍｇ、０．１１９ｍｍｏｌ）の溶液を、８０℃で１８時間撹拌した。冷却後、５％Ｎａ_２ＣＯ_３にゆっくりと加えて内容物をクエンチした。水層をＥｔＯＡｃで抽出し、５％Ｎａ_２ＣＯ_３（３ｘ）、ブライン（１ｘ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、溶媒を真空で除去して、２－（４－フルオロ－２－メチル－フェノキシ）－Ｎ－（２－オキソ－１Ｈ－ピリジン－４－イル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（２６．０ｍｇ、０．０６３８ｍｍｏｌ、収率５３．８％）を褐色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４０８．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １１．０８ （ｓ， １ Ｈ）， ８．６４ （ｄｄ， Ｊ＝２．５３， １．０１ Ｈｚ， １ Ｈ）， ８．５９ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ）， ８．４２ － ８．４４ （ｍ， １ Ｈ）， ７．９８ （ｄｔ， Ｊ＝７．５８， １．８９ Ｈｚ， １ Ｈ）， ７．６６ － ７．７３ （ｍ， ２ Ｈ）， ７．０８ － ７．１６ （ｍ， ３ Ｈ）， ３．２３ （ｓ， ３ Ｈ）， ２．０７ （ｓ， ６ Ｈ）． (Example 110: 2- (4-fluoro-2-methyl-phenoxy) -N- (2-oxo-1H-pyridin-4-yl) -5- (trifluoromethyl) pyridine-3-carboxamide)

2- (4-Fluor-2-methyl-phenoxy) -N- (2-methoxy-4-pyridyl) -5- (trifluoromethyl) pyridine in HBr (33% in HOAc) (538 μL, 2.97 mmol) A solution of -3-carboxamide (50.0 mg, 0.119 mmol) was stirred at 80 ° C. for 18 hours. After cooling, the contents were quenched by slowly adding to 5% Na ₂ CO ₃ . The aqueous layer is extracted with EtOAc, washed with 5% Na ₂ CO ₃ (3x), brine (1x), dried with י ₄ , filtered, the solvent removed in vacuo and 2- (4-fluoro-). 2-Methyl-phenoxy) -N- (2-oxo-1H-Pyridine-4-yl) -5- (Trifluoromethyl) Pyridine-3-Carboxamide (26.0 mg, 0.0638 mmol, yield 53.8%) ) Was obtained as a brown solid. MS, ES + m / z 408.0 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1 H), 8.64 (dd, J = 2.53, 1.01 Hz, 1 H), 8.59 (d, J) = 2.53 Hz, 1 H), 8.42-8.44 (m, 1 H), 7.98 (dt, J = 7.58, 1.89 Hz, 1 H), 7.66-7 .73 (m, 2H), 7.08-7.16 (m, 3H), 3.23 (s, 3H), 2.07 (s, 6H).

(Example 111: 5-bromo-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide)

ＭｅＣＮ（３ｍＬ）中の５－ブロモ－２－クロロニコチン酸メチル（１００ｍｇ、０．３９９ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（４７．８μＬ、０．４１９ｍｍｏｌ）及び炭酸セシウム（３２５ｍｇ、０．９９８ｍｍｏｌ）の混合液を５０℃で２０時間撹拌した。内容物をＥｔＯＡｃで希釈し、２％Ｎａ_２ＣＯ_３（３ｘ）、ブライン（１ｘ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、溶媒を真空除去して、５－ブロモ－２－（４－フルオロ－２－メトキシ－フェノキシ）ピリジン－３－カルボン酸メチル（９０．７ｍｇ、０．２５５ｍｍｏｌ、収率６３．８％）を褐色の固体として得た。この物質をさらに精製することなく進めた。ＭＳ， ＥＳ＋ ｍ／ｚ ３５５．９／３５７．９ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ８．４０ （ｓ， ２ Ｈ）， ７．１８ （ｄｄ， Ｊ＝８．８４， ５．８１ Ｈｚ， １ Ｈ）， ７．０８ （ｄｄ， Ｊ＝１０．７４， ２．９１ Ｈｚ， １ Ｈ）， ６．８０ （ｔｄ， Ｊ＝８．４６， ２．７８ Ｈｚ， １ Ｈ）， ３．８７ （ｓ， ３ Ｈ）， ３．６９ （ｓ， ３ Ｈ）． Step 1: Synthesis of methyl 5-bromo-2- (4-fluoro-2-methoxy-phenoxy) pyridin-3-carboxylate

Methyl 5-bromo-2-chloronicotinate (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 hours. The contents were diluted with EtOAc, washed with 2% Na ₂ CO ₃ (3x), brine (1x), dried with _regsvr4 , filtered, the solvent evacuated and 5-bromo-2- (4). Methyl (90.7 mg, 0.255 mmol, 63.8% yield) pyridine-3-carboxylate (90.7 mg, 0.255 mmol, yield 63.8%) was obtained as a brown solid. This material proceeded without further purification. MS, ES + m / z 355.9 / 357.9 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 8.40 (s, 2H), 7.18 (dd, J = 8.84, 5.81 Hz, 1H), 7.08 (dd, J) = 10.74, 2.91 Hz, 1 H), 6.80 (td, J = 8.46, 2.78 Hz, 1 H), 3.87 (s, 3 H), 3.69 (s) , 3 H).

ＴＨＦ（１ｍＬ）及び水（１ｍＬ）中の５－ブロモ－２－（４－フルオロ－２－メトキシ－フェノキシ）ピリジン－３－カルボン酸メチル（６５ｍｇ、０．１８３ｍｍｏｌ）及び水酸化リチウム一水和物（３８．３ｍｇ、０．９１３ｍｍｏｌ）の混合液を５０℃で２時間撹拌した。冷却後、６ＮのＨＣｌを慎重に加えてｐＨをｐＨ５に下げた。０℃に冷却した後、沈殿物を濾過で集め、冷水で洗浄し、真空乾燥させ、５－ブロモ－２－（４－フルオロ－２－メトキシ－フェノキシ）ピリジン－３－カルボン酸（３９．３ｍｇ、０．１１５ｍｍｏｌ、収率６２．９％）を白色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３４１．９／３４３．９ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １３．５６ （ｂｒ． ｓ．， １ Ｈ）， ８．３３ － ８．３７ （ｍ， ２ Ｈ）， ７．１７ （ｄｄ， Ｊ＝８．７２， ５．９４ Ｈｚ， １ Ｈ）， ７．０７ （ｄｄ， Ｊ＝１０．８６， ２．７８ Ｈｚ， １ Ｈ）， ６．７９ （ｔｄ， Ｊ＝８．４６， ２．７８ Ｈｚ， １ Ｈ）， ３．６９ （ｓ， ３ Ｈ）． Step 2: Synthesis of 5-bromo-2- (4-fluoro-2-methoxy-phenoxy) pyridin-3-carboxylic acid

Methyl 5-bromo-2- (4-fluoro-2-methoxy-phenoxy) pyridine-3-carboxylate (65 mg, 0.183 mmol) and lithium hydroxide monohydrate in THF (1 mL) and water (1 mL) The mixed solution (38.3 mg, 0.913 mmol) was stirred at 50 ° C. for 2 hours. After cooling, 6N HCl was carefully added to lower the pH to pH 5. After cooling to 0 ° C., the precipitate is collected by filtration, washed with cold water, vacuum dried and 5-bromo-2- (4-fluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid (39.3 mg). , 0.115 mmol, yield 62.9%) as a white solid. MS, ES + m / z 341.9 / 343.9 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 13.56 (br. S., 1 H), 8.33-8.37 (m, 2 H), 7.17 (dd, J = 8.72) , 5.94 Hz, 1 H), 7.07 (dd, J = 10.86, 2.78 Hz, 1 H), 6.79 (td, J = 8.46, 2.78 Hz, 1 H) ), 3.69 (s, 3H).

クロロホルム（３ｍＬ）中のＨＢＴＵ（４２．７ｍｇ、０．１１３ｍｍｏｌ）、ＤＩＰＥＡ（３９．２μＬ、０．２２５ｍｍｏｌ）、５－ブロモ－２－（４－フルオロ－２－メトキシ－フェノキシ）ピリジン－３－カルボン酸（３５ｍｇ、０．１０２ｍｍｏｌ）及び３－メチルスルホニルアニリン（１８． ４ｍｇ、０．１０７ｍｍｏｌ）の混合液を、室温で１８時間撹拌した。内容物を５％Ｎａ_２ＣＯ_３で処理し、ＣＨＣｌ_３（３ｘ）で抽出した。溶媒を真空除去して残留物を得、これを自動順相クロマトグラフィー（０－１００％ＥｔＯＡｃ／ヘプタン、４ｇシリカゲルカートリッジ）で精製し、５－ブロモ－２－（４－フルオロ－２－メトキシ－フェノキシ）－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（１３．０ｍｇ、０．０２６２ ｍｍｏｌ、２５．６％収率）を白色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４９４．９／４９６．９ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．９１ （ｓ， １ Ｈ）， ８．４０ － ８．４２ （ｍ， １ Ｈ）， ８．３４ － ８．３６ （ｍ， ２ Ｈ）， ７．９５ － ７．９８ （ｍ， １ Ｈ）， ７．６４ － ７．７１ （ｍ， ２ Ｈ）， ７．２９ （ｄｄ， Ｊ＝８．８４， ６．０６ Ｈｚ， １ Ｈ）， ７．０８ （ｄｄ， Ｊ＝１０．７４， ２．９１ Ｈｚ， １ Ｈ）， ６．８２ （ｔｄ， Ｊ＝８．５９， ３．０３ Ｈｚ， １ Ｈ）， ３．７０ （ｓ， ３ Ｈ）， ３．２２ （ｓ， ３ Ｈ）． Step 3: Synthesis of 5-bromo-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide

HBTU (42.7 mg, 0.113 mmol) in chloroform (3 mL), DIPEA (39.2 μL, 0.225 mmol), 5-bromo-2- (4-fluoro-2-methoxy-phenoxy) pyridin-3-carboxylic acid A mixture of acid (35 mg, 0.102 mmol) and 3-methylsulfonylaniline (18.4 mg, 0.107 mmol) was stirred at room temperature for 18 hours. The contents were treated with 5% Na ₂ CO ₃ and extracted with CHCl ₃ (3x). The solvent was removed by vacuum to give a residue, which was purified by automatic normal phase chromatography (0-100% EtOAc / heptane, 4 g silica gel cartridge) and 5-bromo-2- (4-fluoro-2-methoxy-). Phenoxy) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide (13.0 mg, 0.0262 mmol, 25.6% yield) was obtained as a white solid. MS, ES + m / z 494.9 / 496.9 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 10.91 (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, 6.06 Hz, 1H), 7 .08 (dd, J = 10.74, 2.91 Hz, 1 H), 6.82 (td, J = 8.59, 3.03 Hz, 1 H), 3.70 (s, 3 H) , 3.22 (s, 3H).

(Example 112: 5-Cyclopropyl-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide)

１，４－ジオキサン（５ｍＬ）中の５－ブロモ－２－クロロニコチン酸メチル（２００ｍｇ、０．７９９ｍｍｏｌ）の溶液に、シクロプロピルボロン酸（２０６ｍｇ、２．４０ｍｍｏｌ）、リン酸三カリウム（５０８ｍｇ、２．４０ｍｍｏｌ）及びテトラキス（トリフェニルホスフィン）パラジウム（０）（４６．１ｍｇ、０．０３９９ｍｍｏｌ）を加えた。この混合液を、マイクロ波反応器で１００℃で３０分間加熱した。ＬＣＭＳにより反応を完了した。反応混合液をＥｔＯＡｃで希釈し、水（１ｘ）、５％ＮＨ_４Ｃｌ（１ｘ）、水（１ｘ）、ブライン（１ｘ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、溶媒を真空除去して黄色の残留物を得、これを自動順相クロマトグラフィー（０－１００％ＥｔＯＡｃ／ヘプタン、１２ｇシリカゲルカートリッジ）で精製して、２－クロロ－５－シクロプロピル－ピリジン－３－カルボン酸メチル（７３．０ｍｇ、０．３４５ｍｍｏｌ、収率４３．２％）を無色の油として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ２１２．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ８．４１ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ）， ７．８６ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ）， ３．８７ （ｓ， ３ Ｈ）， ２．０５ （ｔｔ， Ｊ＝８．４６， ５．０５ Ｈｚ， １ Ｈ）， １．０２ － １．０９ （ｍ， ２ Ｈ）， ０．７９ － ０．８５ （ｍ， ２ Ｈ）． Step 1: Synthesis of Methyl 2-Chloro-5-Cyclopropyl-Pyridine-3-carboxylate

In a solution of methyl 5-bromo-2-chloronicotinate (200 mg, 0.799 mmol) in 1,4-dioxane (5 mL), cyclopropylboronic acid (206 mg, 2.40 mmol), tripotassium phosphate (508 mg, 508 mg,). 2.40 mmol) and tetrakis (triphenylphosphine) palladium (0) (46.1 mg, 0.0399 mmol) were added. The mixture was heated in a microwave reactor at 100 ° C. for 30 minutes. The reaction was completed by LCMS. The reaction mixture is diluted with EtOAc, washed with water (1x), 5% NH ₄ Cl (1x), water (1x), brine (1x), dried with ו ₄ , filtered and the solvent vacuum removed. Yellow residue was obtained and purified by automatic normal phase chromatography (0-100% EtOAc / heptane, 12 g silica gel cartridge) to methyl 2-chloro-5-cyclopropyl-pyridine-3-carboxylate (0-100% EtOAc / Heptane, 12 g silica gel cartridge). 73.0 mg, 0.345 mmol, yield 43.2%) was obtained as a colorless oil. MS, ES + m / z 212.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 2.53 Hz, 1 H), 7.86 (d, J = 2.53 Hz, 1 H), 3.87 ( s, 3H), 2.05 (tt, J = 8.46, 5.05 Hz, 1H), 1.02-1.09 (m, 2H), 0.79-0.85 (m) , 2 H).

ＭｅＣＮ（２ｍＬ）中の２－クロロ－５－シクロプロピル－ピリジン－３－カルボン酸メチル（７１ ｍｇ、０．３３６ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（４７．８μＬ、０．４１９ｍｍｏｌ）及び炭酸セシウム（３２７．９１ｍｇ、１．０１ｍｍｏｌ）の混合液を８０℃で２４時間撹拌した。冷却後、Ｎ_２気流下で溶媒を除去した。残留物を水で処理し、２時間激しく撹拌した。沈殿物を濾過で集め、水で洗浄し、真空乾燥させ、５－シクロプロピル－２－（４－フルオロ－２－メトキシ－フェノキシ）ピリジン－３－カルボン酸メチル（２０．０ｍｇ、０．０６３０ｍｍｏｌ、収率１８．８％）を褐色の固体として得た。この物質をさらに精製することなく使用した。ＭＳ， ＥＳ＋ ｍ／ｚ ３１８．０ ［Ｍ＋Ｈ］＋． Step 2: Synthesis of methyl 5-cyclopropyl-2- (4-fluoro-2-methoxy-phenoxy) pyridin-3-carboxylate

Methyl 2-chloro-5-cyclopropyl-pyridine-3-carboxylate (71 mg, 0.336 mmol), 4-fluoro-2-methoxyphenol (47.8 μL, 0.419 mmol) and carbonate in MeCN (2 mL). A mixture of cesium (327.91 mg, 1.01 mmol) was stirred at 80 ° C. for 24 hours. After cooling, the solvent was removed under _N2 airflow. The residue was treated with water and stirred vigorously for 2 hours. The precipitate is collected by filtration, washed with water, vacuum dried and methyl 5-cyclopropyl-2- (4-fluoro-2-methoxy-phenoxy) pyridine-3-carboxylate (20.0 mg, 0.0630 mmol,). Yield 18.8%) was obtained as a brown solid. This material was used without further purification. MS, ES + m / z 318.0 [M + H] +.

ＴＨＦ（２ｍＬ）及びメタノール（０．２ｍＬ）中の５－シクロプロピル－２－（４－フルオロ－２－メトキシ－フェノキシ）ピリジン－３－カルボン酸メチル（２０．１ ｍｇ、０．０６３３ｍｍｏｌ）及び水酸化リチウム一水和物（１０．０ｍｇ、０．２３８ｍｍｏｌ）の混合液を、室温で５日間（便宜上）撹拌した。溶媒をＮ_２気流下で除去し、内容物を水（３ｍＬ）で希釈した。６ＮのＨＣｌを慎重に加えてｐＨを５に下げた。３時間撹拌した後、沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、５－シクロプロピル－２－（４－フルオロ－２－メトキシ－フェノキシ）ピリジン－３－カルボン酸（９．５ｍｇ、０．０３１ｍｍｏｌ、４９．４％収率）をオフホワイトの固体として得た。この物質をさらに精製することなく使用した。ＭＳ， ＥＳ＋ ｍ／ｚ ３０４．０ ［Ｍ＋Ｈ］＋． Step 3: Synthesis of 5-cyclopropyl-2- (4-fluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid

Methyl 5-cyclopropyl-2- (4-fluoro-2-methoxy-phenoxy) pyridine-3-carboxylate (20.1 mg, 0.0633 mmol) in THF (2 mL) and methanol (0.2 mL) and water. A mixture of lithium oxide monohydrate (10.0 mg, 0.238 mmol) was stirred at room temperature for 5 days (for convenience). The solvent was removed under _N2 airflow and the contents were diluted with water (3 mL). The pH was lowered to 5 by careful addition of 6N HCl. After stirring for 3 hours, the precipitate is collected by filtration, washed with water, vacuum dried and subjected to 5-cyclopropyl-2- (4-fluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid (9. 5 mg, 0.031 mmol, 49.4% yield) was obtained as an off-white solid. This material was used without further purification. MS, ES + m / z 304.0 [M + H] +.

クロロホルム（０．５ｍＬ）中の５－シクロプロピル－２－（４－フルオロ－２－メトキシ－フェノキシ）ピリジン－３－カルボン酸（９．５ｍｇ、０．０３１３ｍｍｏｌ）、ＨＢＴＵ（１４．３ｍｇ、０．０３７６ｍｍｏｌ）、３－メチルスルホニルアニリン（５．９ｍｇ、０．０３４５ｍｍｏｌ）及びＤＩＰＥＡ（１６．４μＬ、０．０９４０ｍｍｏｌ）の混合液を、室温で３日間（便宜上）撹拌した。内容物をＥｔＯＡｃで希釈し、水（３ｘ）、ブライン（１ｘ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、溶媒を真空除去して残留物を得、これを自動順相クロマトグラフィー（０－１００％ＥｔＯＡｃ／ヘプタン、４ｇシリカゲルカートリッジ）で精製し、５－シクロプロピル－２－（４－フルオロ－２－メトキシ－フェノキシ）－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（２．６ｍｇ、０．００５７ｍｍｏｌ、１８．２％収率）を白色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４５７．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．７３ （ｓ， １ Ｈ）， ８．４０ － ８．４３ （ｍ， １ Ｈ）， ８．０２ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ）， ７．９７ （ｄｔ， Ｊ＝７．０７， ２．０２ Ｈｚ， １ Ｈ）， ７．７５ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ）， ７．６３ － ７．７０ （ｍ， ２ Ｈ）， ７．２７ （ｄｄ， Ｊ＝８．７２， ５．９４ Ｈｚ， １ Ｈ）， ７．０５ （ｄｄ， Ｊ＝１０．７４， ２．９１ Ｈｚ， １ Ｈ）， ６．８１ （ｔｄ， Ｊ＝８．４６， ３．０３ Ｈｚ， １ Ｈ）， ３．７０ （ｓ， ３ Ｈ）， ３．２２ （ｓ， ３ Ｈ）， １．９３ － ２．０１ （ｍ， １ Ｈ）， ０．９５ － １．００ （ｍ， ２ Ｈ）， ０．７２ － ０．７７ （ｍ， ２ Ｈ）． Step 4: Synthesis of 5-cyclopropyl-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide

5-Cyclopropyl-2- (4-fluoro-2-methoxy-phenoxy) pyridine-3-carboxylic acid (9.5 mg, 0.0313 mmol) in chloroform (0.5 mL), HBTU (14.3 mg, 0. A mixture of 0376 mmol), 3-methylsulfonylaniline (5.9 mg, 0.0345 mmol) and DIPEA (16.4 μL, 0.0940 mmol) was stirred at room temperature for 3 days (for convenience). The contents are diluted with EtOAc, washed with water (3x), brine (1x), dried on silica ₄ , filtered, the solvent vacuum removed to give a residue, which is subjected to automatic normal phase chromatography (0). Purified with -100% EtOAc / heptane, 4 g silica gel cartridge) and 5-cyclopropyl-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridine-3-carboxamide (2). 0.6 mg, 0.0057 mmol, 18.2% yield) was obtained as a white solid. MS, ES + m / z 457.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1 H), 8.40-8.43 (m, 1 H), 8.02 (d, J = 2.53 Hz, 1) H), 7.97 (dt, J = 7.07, 2.02 Hz, 1 H), 7.75 (d, J = 2.53 Hz, 1 H), 7.63-7.70 (m). , 2 H), 7.27 (dd, J = 8.72, 5.94 Hz, 1 H), 7.05 (dd, J = 10.74, 2.91 Hz, 1 H), 6.81 (Td, J = 8.46, 3.03 Hz, 1 H), 3.70 (s, 3 H), 3.22 (s, 3 H), 1.93-2.01 (m, 1 H) ), 0.95-1.00 (m, 2H), 0.72-0.77 (m, 2H).

(Example 113: 2- (4-fluoro-2-methyl-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide)
[Method N]

ＭｅＣＮ（５ｍＬ）中の２－クロロ－５－（トリフルオロメチル）ピリジン－３－カルボン酸（４９７ｍｇ、２．２０ｍｍｏｌ）、４－フルオロ－２－メチル－フェノール（３０６ｍｇ、２．４２ｍｍｏｌ）及び炭酸セシウム（１．７９ｇ、５．５１ｍｍｏｌ）の混合液を、８０℃で５時間撹拌した後、室温で４日間（便宜上）撹拌した。溶媒をＮ_２気流下で除去し、残留物を水（１０ｍＬ）に溶解した。６ＮのＨＣｌを慎重に加えてｐＨを５に下げた。３時間撹拌した後、沈殿物を濾過で集め、水で洗浄し、真空乾燥させ、２－（４－フルオロ－２－メチル－フェノキシ）－５－（トリフルオロメチル）ピリジン－３－カルボン酸（４０７．５ｍｇ、１．２９３ｍｍｏｌ、収率５８．７％）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３１６．０ ［Ｍ＋Ｈ］＋． Step 1: Synthesis of 2- (4-fluoro-2-methyl-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid

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 in MeCN (5 mL). The mixed solution (1.79 g, 5.51 mmol) was stirred at 80 ° C. for 5 hours and then at room temperature for 4 days (for convenience). The solvent was removed under _N2 airflow and the residue was dissolved in water (10 mL). The pH was lowered to 5 by careful addition of 6N HCl. After stirring for 3 hours, the precipitate is collected by filtration, washed with water, vacuum dried and 2- (4-fluoro-2-methyl-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid ( 407.5 mg, 1.293 mmol, yield 58.7%) was obtained as a beige solid. MS, ES + m / z 316.0 [M + H] +.

クロロホルム（２ｍＬ）中の２－（４－フルオロ－２－メチル－フェノキシ）－５－（トリフルオロメチル）ピリジン－３－カルボン酸（１００ｍｇ、０．３１７ｍｍｏｌ）、３－メチルスルホニルアニリン（５９．８ｍｇ、０．３４９ｍｍｏｌ）、ＨＢＴＵ（１３２ｍｇ、０．３４９ ｍｍｏｌ）及びＤＩＰＥＡ（１３８μＬ、０．７９３ｍｍｏｌ）の混合液を、室温で１８時間撹拌した。Ｎ_２気流下で溶媒を除去し、残留物を水／ＭｅＯＨ（５：１）で処理した。この混合液を短時間超音波処理した後、室温で４時間撹拌した。得られた沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、２－（４－フルオロ－２－メチル－フェノキシ）－Ｎ－（３－メチルスルホニルフェニル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（１２１．７ｍｇ、０．２６０ｍｍｏｌ、収率８１．９％）を褐色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４６９．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １１．０５ （ｓ， １ Ｈ）， ８．６７ － ８．６９ （ｍ， １ Ｈ）， ８．５７ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ）， ８．４０ － ８．４２ （ｍ， １ Ｈ）， ７．９７ （ｄｔ， Ｊ＝７．５８， １．８９ Ｈｚ， １ Ｈ）， ７．６５ － ７．７３ （ｍ， ２ Ｈ）， ７．２７ （ｄｄ， Ｊ＝８．８４， ５．０５ Ｈｚ， １ Ｈ）， ７．２１ （ｄｄ， Ｊ＝９．３５， ３．０３ Ｈｚ， １ Ｈ）， ７．１２ （ｔｄ， Ｊ＝８．７８， ３．１６ Ｈｚ， １ Ｈ）， ３．２３ （ｓ， ３ Ｈ）， ２．０９ （ｓ， ３ Ｈ）． Step 2: Synthesis of 2- (4-fluoro-2-methyl-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide

2- (4-Fluor-2-methyl-phenoxy) -5- (trifluoromethyl) pyridin-3-carboxylic acid (100 mg, 0.317 mmol) in chloroform (2 mL), 3-methylsulfonylaniline (59.8 mg) , 0.349 mmol), HBTU (132 mg, 0.349 mmol) and DIPEA (138 μL, 0.793 mmol) were stirred at room temperature for 18 hours. The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (5: 1). The mixture was sonicated for a short time and then stirred at room temperature for 4 hours. The resulting precipitate is collected by filtration, washed with water, vacuum dried and 2- (4-fluoro-2-methyl-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl). ) Pyridine-3-carboxamide (121.7 mg, 0.260 mmol, yield 81.9%) was obtained as a brown solid. MS, ES + m / z 469.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1 H), 8.67-8.69 (m, 1 H), 8.57 (d, J = 2.53 Hz, 1) H), 8.40-8.42 (m, 1H), 7.97 (dt, J = 7.58, 1.89 Hz, 1H), 7.65-773 (m, 2H) ), 7.27 (dd, J = 8.84, 5.05 Hz, 1H), 7.21 (dd, J = 9.35, 3.03 Hz, 1H), 7.12 (td, J = 8.78, 3.16 Hz, 1 H), 3.23 (s, 3 H), 2.09 (s, 3 H).

The following compounds were synthesized according to Method M.

(Example 117: 2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridine-3-carboxamide)

クロロホルム（５ｍＬ）中のＨＢＴＵ（２４３ｍｇ、０．６４１ｍｍｏｌ）、ＤＩＰＥＡ（２２３μＬ、１．２８ｍｍｏｌ）、２－クロロ－６－メチルニコチン酸（１００ｍｇ、０．５８３ｍｍｏｌ）及び３－メチルスルホニルアニリン（１０５ｍｇ、０．６１３ｍｍｏｌ）の混合液を室温で４８時間撹拌した。内容物を５％Ｎａ_２ＣＯ_３で処理し、ＣＨＣｌ_３（３ｘ）で抽出した。溶媒を真空除去し、２－クロロ－６－メチル－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（１７５ｍｇ、０．５３９ｍｍｏｌ、収率９２．５％）を残留物として得て、これをさらに精製することなく使用した。ＭＳ， ＥＳ＋ ｍ／ｚ ３２５．０ ［Ｍ＋Ｈ］＋． Step 1: Synthesis of 2-chloro-6-methyl-N- (3-methylsulfonylphenyl) pyridine-3-carboxamide

HBTU (243 mg, 0.641 mmol) in chloroform (5 mL), DIPEA (223 μL, 1.28 mmol), 2-chloro-6-methylnicotinic acid (100 mg, 0.583 mmol) and 3-methylsulfonylaniline (105 mg, 0). The mixture of .613 mmol) was stirred at room temperature for 48 hours. The contents were treated with 5% Na ₂ CO ₃ and extracted with CHCl ₃ (3x). The solvent was evacuated to give 2-chloro-6-methyl-N- (3-methylsulfonylphenyl) pyridine-3-carboxamide (175 mg, 0.539 mmol, 92.5% yield) as a residue. Was used without further purification. MS, ES + m / z 325.0 [M + H] +.

ＭｅＣＮ（２ｍＬ）中のクルード２－クロロ－６－メチル－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（７０．０ｍｇ、０．２１６ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（３０．７μＬ、０．２６９ｍｍｏｌ）及び炭酸セシウム（２１１ｍｇ、０．６４７ｍｍｏｌ）の混合液を６０℃で２４時間撹拌した。冷却後、内容物を水で処理し、室温で一晩撹拌した。沈殿物を濾過で集め、水で洗浄し、真空乾燥させ、２－（４－フルオロ－２－メトキシ－フェノキシ）－６－メチル－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（２９．０ｍｇ、０．０６７４ｍｍｏｌ、収率３１．３％）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４３１．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．６３ （ｓ， １ Ｈ）， ８．４１ （ｓ， １ Ｈ）， ８．０４ （ｄ， Ｊ＝７．５８ Ｈｚ， １ Ｈ）， ７．９６ （ｄ， Ｊ＝７．０７ Ｈｚ， １ Ｈ）， ７．６２ － ７．６９ （ｍ， ２ Ｈ）， ７．３３ （ｄｄ， Ｊ＝８．７２， ５．９４ Ｈｚ， １ Ｈ）， ７．０５ － ７．１３ （ｍ， ２ Ｈ）， ６．８３ （ｔｄ， Ｊ＝８．４６， ３．０３ Ｈｚ， １ Ｈ）， ３．７１ （ｓ， ３ Ｈ）， ３．２２ （ｓ， ３ Ｈ）， ２．３０ （ｓ， ３ Ｈ）． Step 2: Synthesis of 2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridine-3-carboxamide

Crude 2-chloro-6-methyl-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (70.0 mg, 0.216 mmol) in MeCN (2 mL), 4-fluoro-2-methoxyphenol (30. A mixture of 7 μL (0.269 mmol) and cesium carbonate (211 mg, 0.647 mmol) was stirred at 60 ° C. for 24 hours. After cooling, the contents were treated with water and stirred at room temperature overnight. The precipitate is collected by filtration, washed with water, vacuum dried and 2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridine-3-carboxamide (29). 0.0 mg, 0.0674 mmol, yield 31.3%) was obtained as a beige solid. MS, ES + m / z 431.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1 H), 8.41 (s, 1 H), 8.04 (d, J = 7.58 Hz, 1 H), 7 .96 (d, J = 7.07 Hz, 1 H), 7.62-7.69 (m, 2 H), 7.33 (dd, J = 8.72, 5.94 Hz, 1 H) , 7.05-7.13 (m, 2H), 6.83 (td, J = 8.46, 3.03 Hz, 1H), 3.71 (s, 3H), 3.22 ( s, 3H), 2.30 (s, 3H).

(Example 118: 2- (4-fluoro-2-methoxy-phenoxy) -5,6-dimethyl-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide)

クロロホルム（４ｍＬ）中の２－クロロ－５，６－ジメチル－ピリジン－３－カルボン酸（１００ｍｇ、０．５３９ｍｍｏｌ）、３－メチルスルホニルアニリン（９６．９ｍｇ、０．５６６ｍｍｏｌ）及びＨＢＴＵ（２２５ｍｇ、０．５９３ｍｍｏｌ）の混合液に、ＤＩＰＥＡ（２０６．５μＬ、１．１９ｍｍｏｌ）を加えた。得られた混合液を室温で６日間撹拌した（便宜上）。溶媒をＮ_２気流下で除去し、残留物を水／ＭｅＯＨ（４：１）で処理した。この混合液を短時間超音波処理した後、室温で１８時間撹拌した。得られた沈殿物を濾過によって回収し、水で洗浄し、真空乾燥させ、２－クロロ－５，６－ジメチル－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（１３７ｍｇ、０．４０４ｍｍｏｌ、収率７５．１％）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３３９．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．９６ （ｓ， １ Ｈ）， ８．３７ （ｓ， １ Ｈ）， ７．９４ （ｄ， Ｊ＝７．３３ Ｈｚ， １ Ｈ）， ７．８８ （ｓ， １ Ｈ）， ７．６４ － ７．７２ （ｍ， ２ Ｈ）， ３．２３ （ｓ， ３ Ｈ）， ２．４８ （ｓ， ３ Ｈ）， ２．３１ （ｓ， ３ Ｈ）． Step 1: Synthesis of 2-chloro-5,6-dimethyl-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide

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) in chloroform (4 mL) DIPEA (206.5 μL, 1.19 mmol) was added to the mixed solution of .593 mmol). The resulting mixture was stirred at room temperature for 6 days (for convenience). The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (4: 1). The mixture was sonicated for a short time and then stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration, washed with water, vacuum dried and 2-chloro-5,6-dimethyl-N- (3-methylsulfonylphenyl) pyridine-3-carboxamide (137 mg, 0.404 mmol). , Yield 75.1%) was obtained as a beige solid. MS, ES + m / z 339.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1 H), 8.37 (s, 1 H), 7.94 (d, J = 7.33 Hz, 1 H), 7 .88 (s, 1H), 7.64-7.72 (m, 2H), 3.23 (s, 3H), 2.48 (s, 3H), 2.31 (s, 3) H).

ＭｅＣＮ（４ｍＬ）中の２－クロロ－５，６－ジメチル－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（５０．０ｍｇ、０．１４８ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（１７．７μＬ、０．１５５ｍｍｏｌ）及び炭酸セシウム（１０６ｍｇ、０．３２７ｍｍｏｌ）の混合液を８０℃で１０時間撹拌した。Ｎ_２気流下で溶媒を除去し、残留物を水／ＭｅＯＨ（２：１）で処理した。この混合液を短時間超音波処理した後、室温で１８時間撹拌した。得られた沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、２－（４－フルオロ－２－メトキシ－フェノキシ）－５，６－ジメチル－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（２１．０ｍｇ、０．４７２ｍｍｏｌ、収率３２．０％）を赤褐色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４４５．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．５８ （ｓ， １ Ｈ）， ８．４０ （ｓ， １ Ｈ）， ７．９７ （ｄ， Ｊ＝７．０７ Ｈｚ， １ Ｈ）， ７．９２ （ｓ， １ Ｈ）， ７．６２ － ７．７０ （ｍ， ２ Ｈ）， ７．３０ （ｄｄ， Ｊ＝８．８４， ６．０６ Ｈｚ， １ Ｈ）， ７．０７ （ｄｄ， Ｊ＝１０．７４， ２．９１ Ｈｚ， １ Ｈ）， ６．８２ （ｔｄ， Ｊ＝８．５９， ３．０３ Ｈｚ， １ Ｈ）， ３．７１ （ｓ， ３ Ｈ）， ３．２２ （ｓ， ３ Ｈ）， ２．２５ （ｂｒ． ｓ．， ３ Ｈ）， ２．２４ （ｂｒ． ｓ．， ３ Ｈ）． Step 2: Synthesis of 2- (4-fluoro-2-methoxy-phenoxy) -5,6-dimethyl-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide

2-Chloro-5,6-dimethyl-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (50.0 mg, 0.148 mmol) in MeCN (4 mL), 4-fluoro-2-methoxyphenol (17) A mixture of 0.7 μL (0.155 mmol) and cesium carbonate (106 mg, 0.327 mmol) was stirred at 80 ° C. for 10 hours. The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (2: 1). The mixture was sonicated for a short time and then stirred at room temperature for 18 hours. The resulting precipitate is collected by filtration, washed with water, vacuum dried and 2- (4-fluoro-2-methoxy-phenoxy) -5,6-dimethyl-N- (3-methylsulfonylphenyl) pyridine. -3-Carboxamide (21.0 mg, 0.472 mmol, yield 32.0%) was obtained as a reddish brown solid. MS, ES + m / z 445.0 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1 H), 8.40 (s, 1 H), 7.97 (d, J = 7.07 Hz, 1 H), 7 .92 (s, 1H), 7.62-7.70 (m, 2H), 7.30 (dd, J = 8.84, 6.06 Hz, 1H), 7.07 (dd, 1H) J = 10.74, 2.91 Hz, 1 H), 6.82 (td, J = 8.59, 3.03 Hz, 1 H), 3.71 (s, 3 H), 3.22 ( s, 3H), 2.25 (br. S., 3H), 2.24 (br. S., 3H).

(Example 119: 5-chloro-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide)

クロロホルム（５ｍＬ）中のＨＢＴＵ（２１７ｍｇ、０．５７１ｍｍｏｌ）、ＤＩＰＥＡ（２００μＬ、１．１５ｍｍｏｌ）、２，５－ジクロロピリジン－３－カルボン酸（１００ｍｇ、０．５２１ｍｍｏｌ）及び３－メチルスルホニルアニリン（９３．６ｍｇ、０．５４７ｍｍｏｌ）の混合液を室温で２２時間撹拌した。内容物を５％Ｎａ_２ＣＯ_３で処理し、ＣＨＣｌ_３（３ｘ）で抽出した。溶媒を真空除去し、２，５－ジクロロ－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（１５０ｍｇ、０．４３５ｍｍｏｌ、収率８３．４％）を半固形物として得て、これをさらに精製することなく使用した。ＭＳ， ＥＳ＋ ｍ／ｚ ３４４．８ ［Ｍ＋Ｈ］＋． Step 1: Synthesis of 2,5-dichloro-N- (3-methylsulfonylphenyl) pyridine-3-carboxamide

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 mg) in chloroform (5 mL). A mixture of .6 mg, 0.547 mmol) was stirred at room temperature for 22 hours. The contents were treated with 5% Na ₂ CO ₃ and extracted with CHCl ₃ (3x). 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 semi-solid, which was obtained. Used without further purification. MS, ES + m / z 344.8 [M + H] +.

ＭｅＣＮ（３ｍＬ）中のクルード２，５－ジクロロ－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（５９．３ｍｇ、０．１７２ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（２７．４μＬ、０．２４１ｍｍｏｌ）及び炭酸セシウム（１６８ｍｇ、０．５１７ｍｍｏｌ）の混合液を８０℃で３時間撹拌した。冷却後、水を加えたところ、沈殿物ができ始めた。１時間撹拌した後、この物質を濾過で集め、水で洗浄し、真空乾燥させ、５－クロロ－２－（４－フルオロ－２－メトキシ－フェノキシ）－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（２１ｍｇ、０．０４７ｍｍｏｌ、収率２７．１％）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４５１．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．９１ （ｓ， １ Ｈ）， ８．４１ （ｓ， １ Ｈ）， ８．２５ － ８．３１ （ｍ， ２ Ｈ）， ７．９７ （ｄ， Ｊ＝７．５８ Ｈｚ， １ Ｈ）， ７．６４ － ７．７２ （ｍ， ２ Ｈ）， ７．２６ － ７．３２ （ｍ， １ Ｈ）， ７．０８ （ｄ， Ｊ＝１０．８６ Ｈｚ， １ Ｈ）， ６．８３ （ｔ， Ｊ＝８．０８ Ｈｚ， １ Ｈ）， ３．７０ （ｓ， ３ Ｈ）， ３．２２ （ｓ， ３ Ｈ）． Step 2: Synthesis of 5-chloro-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide

Crude 2,5-dichloro-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (59.3 mg, 0.172 mmol) in MeCN (3 mL), 4-fluoro-2-methoxyphenol (27.4 μL,) A mixture of 0.241 mmol) and cesium carbonate (168 mg, 0.517 mmol) was stirred at 80 ° C. for 3 hours. After cooling, water was added and a precipitate began to form. After stirring for 1 hour, the material is collected by filtration, washed with water, vacuum dried and 5-chloro-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridine. -3-Carboxamide (21 mg, 0.047 mmol, yield 27.1%) was obtained as a beige solid. MS, ES + m / z 451.0 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1 H), 8.41 (s, 1 H), 8.25-8.31 (m, 2 H), 7.97 ( d, J = 7.58 Hz, 1 H), 7.64-7.72 (m, 2 H), 7.26-7.32 (m, 1 H), 7.08 (d, J = 10) .86 Hz, 1 H), 6.83 (t, J = 8.08 Hz, 1 H), 3.70 (s, 3 H), 3.22 (s, 3 H).

(Example 120: 2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6,7-dihydro-5H-cyclopentane [b] pyridin-3-carboxamide)

２ｍＬの濃硫酸／水（１：１）中の２－クロロ－６，７－ジヒドロ－５Ｈ－シクロペンタ［ｂ］ピリジン－３－カルボニトリル（１７３ｍｇ、０．９６９ｍｍｏｌ）の溶液を１００℃で９時間撹拌した。冷却後、撹拌しながら氷水に内容物を少しずつ加えた。１時間撹拌した後、沈殿物を濾過して回収し、冷水で洗浄し、真空乾燥させ、２－クロロ－６，７－ジヒドロ－５Ｈ－シクロペンタ［ｂ］ピリジン－３－カルボン酸（１１７ｍｇ、０．５９２ｍｍｏｌ、収率６１．１％）を褐色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ １９８．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １３．５３ （ｂｒ． ｓ．， １ Ｈ）， ８．０２ （ｓ， １ Ｈ）， ２．９３ （ｑ， Ｊ＝７．２４ Ｈｚ， ４ Ｈ）， ２．１０ （ｑｕｉｎ， Ｊ＝７．２４ Ｈｚ， ２ Ｈ）． Step 1: Synthesis of 2-chloro-6,7-dihydro-5H-cyclopentane [b] pyridine-3-carboxylic acid

A solution of 2-chloro-6,7-dihydro-5H-cyclopentane [b] pyridin-3-carbonitrile (173 mg, 0.969 mmol) in 2 mL of concentrated sulfuric acid / water (1: 1) at 100 ° C. for 9 hours. Stirred. After cooling, the contents were added little by little to ice water with stirring. After stirring for 1 hour, the precipitate is filtered and collected, washed with cold water, vacuum dried and 2-chloro-6,7-dihydro-5H-cyclopenta [b] pyridine-3-carboxylic acid (117 mg, 0). .592 mmol, yield 61.1%) was obtained as a brown solid. MS, ES + m / z 198.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 13.53 (br. S., 1 H), 8.02 (s, 1 H), 2.93 (q, J = 7.24 Hz, 4 H) ), 2.10 (quin, J = 7.24 Hz, 2 H).

クロロホルム（４ｍＬ）中の２－クロロ－６，７－ジヒドロ－５Ｈ－シクロペンタ［ｂ］ピリジン－３－カルボン酸（１１４ｍｇ、０．５７７ｍｍｏｌ）、３－メチルスルホニルアニリン（１０４ｍｇ、０．６０７ｍｍｏｌ）及びＨＢＴＵ（２４１ｍｇ、０．６３７ｍｍｏｌ）の混合液に、ＤＩＰＥＡ（２２１μＬ、１．２７ｍｍｏｌ）を加えた。得られた混合液を室温で５日間撹拌した（便宜上）。溶媒をＮ_２気流下で除去し、残留物を水／ＭｅＯＨ（３：１）で処理した。この混合液を短時間超音波処理した後、室温で１時間撹拌した。得られた沈殿物を濾過によって回収し、水で洗浄し、真空乾燥させ、２－クロロ－Ｎ－（３－メチルスルホニルフェニル）－６，７－ジヒドロ－５Ｈ－シクロペンタ［ｂ］ピリジン－３－カルボキサミド（１４７．６ｍｇ、０．４２１ｍｍｏｌ、収率７２．９％）を茶色の固体として得て、これをさらに精製することなく使用した。ＭＳ， ＥＳ＋ ｍ／ｚ ３５１．１ ［Ｍ＋Ｈ］＋． Step 2: Synthesis of 2-chloro-N- (3-methylsulfonylphenyl) -6,7-dihydro-5H-cyclopentane [b] pyridin-3-carboxamide

2-Chloro-6,7-dihydro-5H-cyclopentane [b] pyridin-3-carboxylic acid (114 mg, 0.577 mmol), 3-methylsulfonylaniline (104 mg, 0.607 mmol) and HBTU in chloroform (4 mL) DIPEA (221 μL, 1.27 mmol) was added to the mixed solution (241 mg, 0.637 mmol). The resulting mixture was stirred at room temperature for 5 days (for convenience). The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (3: 1). The mixture was sonicated for a short time and then stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration, washed with water, vacuum dried and 2-chloro-N- (3-methylsulfonylphenyl) -6,7-dihydro-5H-cyclopenta [b] pyridine-3-. Carboxamide (147.6 mg, 0.421 mmol, 72.9% yield) was obtained as a brown solid and used without further purification. MS, ES + m / z 351.1 [M + H] +.

ＭｅＣＮ（３ ｍＬ）中の２－クロロ－Ｎ－（３－メチルスルホニルフェニル）－６，７－ジヒドロ－５Ｈ－シクロペンタ［ｂ］ピリジン－３－カルボキサミド（５０．０ｍｇ、０．１４３ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（１７．１μＬ、０．１５０ｍｍｏｌ）及び炭酸セシウム（１０２ｍｇ、０．３１３ｍｍｏｌ）の混合液を８０℃で１０時間撹拌した。Ｎ_２気流下で溶媒を除去し、残留物を水／ＭｅＯＨ（２：１）で処理した。この混合液を短時間超音波処理した後、室温で２４時間撹拌した。得られた沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、２－（４－フルオロ－２－メトキシ－フェノキシ）－Ｎ－（３－メチルスルホニルフェニル）－６，７－ジヒドロ－５Ｈ－シクロペンタ［ｂ］ピリジン－３－カルボキサミド（２４ｍｇ、０．０５３ｍｍｏｌ、収率３６．９％）を茶色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４５７．１ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．６３ （ｓ， １ Ｈ）， ８．４２ （ｂｒ． ｓ．， １ Ｈ）， ７．９６ （ｓ， ２ Ｈ）， ７．６３ － ７．６９ （ｍ， ２ Ｈ）， ７．２８ － ７．３３ （ｍ， １ Ｈ）， ７．０５ － ７．１０ （ｍ， １ Ｈ）， ６．７９ － ６．８６ （ｍ， １ Ｈ）， ３．７２ （ｓ， ３ Ｈ）， ３．２２ （ｓ， ３ Ｈ）， ２．８９ （ｔ， Ｊ＝７．２０ Ｈｚ， ２ Ｈ）， ２．７５ （ｔ， Ｊ＝７．７１ Ｈｚ， ２ Ｈ）， ２．０１ － ２．１１ （ｍ， ２ Ｈ）． Step 3: Synthesis of 2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6,7-dihydro-5H-cyclopentane [b] pyridin-3-carboxamide

2-Chloro-N- (3-methylsulfonylphenyl) -6,7-dihydro-5H-cyclopenta [b] pyridin-3-carboxamide (50.0 mg, 0.143 mmol) in MeCN (3 mL), 4- A mixture of fluoro-2-methoxyphenol (17.1 μL, 0.150 mmol) and cesium carbonate (102 mg, 0.313 mmol) was stirred at 80 ° C. for 10 hours. The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (2: 1). The mixture was sonicated for a short time and then stirred at room temperature for 24 hours. The resulting precipitate was collected by filtration, washed with water, vacuum dried and 2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6,7-dihydro-. 5H-Cyclopenta [b] pyridine-3-carboxamide (24 mg, 0.053 mmol, yield 36.9%) was obtained as a brown solid. MS, ES + m / z 457.1 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1 H), 8.42 (br. S., 1 H), 7.96 (s, 2 H), 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 = 7.20 Hz, 2H), 2.75 (t, J = 7.71 Hz) , 2 H), 2.01-2.11 (m, 2 H).

(Example 121: N- (3-methylsulfinylphenyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide)
[Method O]

ＭｅＣＮ（５ｍＬ）中の２－クロロ－５－（トリフルオロメチル）ピリジン－３－カルボン酸（５１０ｍｇ、２．２６ｍｍｏｌ）、４－（トリフルオロメトキシ）フェノール（３２２μＬ、２．４９ｍｍｏｌ）及び炭酸セシウム（１．８４ｇ、５．６５ｍｍｏｌ）の混合液を８０℃で５時間撹拌した後、室温で４日間（便宜上）撹拌した。溶媒をＮ_２気流下で除去し、残留物を水／ＭｅＯＨ（５：１）で処理した。この混合液を短時間超音波処理した後、室温で１８時間撹拌した。得られた沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、２－［４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボン酸（６０４ｍｇ、１．６５ｍｍｏｌ、収率７２．８％）をオフホワイトの固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３６８．０ ［Ｍ＋Ｈ］＋． Step 1: Synthesis of 2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxylic acid

2-Chloro-5- (trifluoromethyl) pyridine-3-carboxylic acid (510 mg, 2.26 mmol), 4- (trifluoromethoxy) phenol (322 μL, 2.49 mmol) and cesium carbonate (2.49 mmol) in MeCN (5 mL). A mixed solution of 1.84 g (5.65 mmol) was stirred at 80 ° C. for 5 hours, and then stirred at room temperature for 4 days (for convenience). The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (5: 1). The mixture was sonicated for a short time and then stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration, washed with water, vacuum dried and 2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxylic acid (604 mg, 1). .65 mmol, yield 72.8%) was obtained as an off-white solid. MS, ES + m / z 368.0 [M + H] +.

クロロホルム（２ｍＬ）中の２－［４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボン酸（３５．０ｍｇ、０．０９５３ｍｍｏｌ）、３－メチルスルフィニルアニリン（１６．３ ｍｇ、０．１０５ｍｍｏｌ）、ＨＢＴＵ（３９．８ｍｇ、０．１０５ｍｍｏｌ）及びＤＩＰＥＡ（４１．５μＬ、０．２３８ｍｍｏｌ）の混合液を、室温で３日間（便宜上）撹拌した。溶媒をＮ_２気流下で除去し、残留物を水／ＭｅＯＨ（３：１）で処理した。この混合液を短時間超音波処理した後、室温で２４時間撹拌した。得られた沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、Ｎ－（３－メチルスルフィニルフェニル）－２－［４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（３９．０ｍｇ、０．０７７３ｍｍｏｌ、収率８１．１％）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ５０５．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．９５ （ｓ， １ Ｈ）， ８．７２ （ｄ， Ｊ＝１．５２ Ｈｚ， １ Ｈ）， ８．５６ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ）， ８．１４ （ｓ， １ Ｈ）， ７．８３ （ｄ， Ｊ＝７．５８ Ｈｚ， １ Ｈ）， ７．５８ （ｔ， Ｊ＝７．８３ Ｈｚ， １ Ｈ）， ７．４０ － ７．５２ （ｍ， ５ Ｈ）， ２．７５ （ｓ， ３ Ｈ）． Step 2: Synthesis of N- (3-methylsulfinylphenyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide

2- [4- (Trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxylic acid (35.0 mg, 0.0953 mmol) in chloroform (2 mL), 3-methylsulfinylaniline (16. A mixture of 3 mg, 0.105 mmol), HBTU (39.8 mg, 0.105 mmol) and DIPEA (41.5 μL, 0.238 mmol) was stirred at room temperature for 3 days (for convenience). The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (3: 1). The mixture was sonicated for a short time and then stirred at room temperature for 24 hours. The resulting precipitate was collected by filtration, washed with water, vacuum dried and N- (3-methylsulfinylphenyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl). Pyridine-3-carboxamide (39.0 mg, 0.0773 mmol, yield 81.1%) was obtained as a beige solid. MS, ES + m / z 505.0 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1 H), 8.72 (d, J = 1.52 Hz, 1 H), 8.56 (d, J = 2.53) Hz, 1H), 8.14 (s, 1H), 7.83 (d, J = 7.58 Hz, 1H), 7.58 (t, J = 7.83 Hz, 1H), 7.40-7.52 (m, 5H), 2.75 (s, 3H).

The following compounds were synthesized according to Method O.

ラセミ体のＮ－［３－（メチルスルホニミドイル）フェニル］－２－［４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（実施例ＬＩ－１８５９）を、ＣＯ_２中のメタノール（０．０５％ＤＥＡで修飾）の５－４０％グラジエントからなる移動相でのＣｈｉｒａｌｐａｋ ＩＧカラムを使用したキラルクロマトグラフィーにより分離し、Ｒ_Ｔ＝１．４６分で最初に溶出するエナンチオマーを得た。ＭＳ， ＥＳ＋ ｍ／ｚ， ５２０．８ （Ｍ＋Ｈ）＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ３．０７ （ｓ， ３ Ｈ） ４．２７ （ｓ， １ Ｈ） ７．３９ － ７．５４ （ｍ， ４ Ｈ） ７．６２ （ｔ， Ｊ＝７．８３ Ｈｚ， １ Ｈ） ７．７０ （ｄｔ， Ｊ＝７．９６， １．２０ Ｈｚ， １ Ｈ） ７．９０ －８．０２ （ｍ， １ Ｈ） ８．３８ （ｔ， Ｊ＝１．８９ Ｈｚ， １ Ｈ） ８．５７ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ） ８．７２ （ｄ， Ｊ＝１．５２ Ｈｚ， １ Ｈ） １１．０１ （ｓ， １ Ｈ） (Example 130: N- [3- (methylsulfonimideyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide, enantiomer A)

Racemic N- [3- (methylsulfonimidyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide (Example LI-1859) Separated by chiral chromatography using a Chiralpak IG column in a mobile phase consisting of a 5-40% gradient of methanol (modified with 0.05% DEA) in CO ₂ , first at _RT = 1.46 minutes. An elution enantiomer was obtained. MS, ES + m / z, 520.8 (M + H) +. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.07 (s, 3H) 4.27 (s, 1H) 7.39-7.54 (m, 4H) 7.62 (t, J) = 7.83 Hz, 1 H) 7.70 (dt, J = 7.96, 1.20 Hz, 1 H) 7.90-8.02 (m, 1 H) 8.38 (t, J = 1.89 Hz, 1 H) 8.57 (d, J = 2.53 Hz, 1 H) 8.72 (d, J = 1.52 Hz, 1 H) 11.01 (s, 1 H)

ラセミ体のＮ－［３－（メチルスルホニミドイル）フェニル］－２－［４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（実施例ＬＩ－１８５９）を、ＣＯ_２中のメタノール（０．０５％ＤＥＡで修飾）の５－４０％グラジエントからなる移動相でのＣｈｉｒａｌｐａｋ ＩＧカラムを使用したキラルクロマトグラフィーにより分離し、Ｒ_Ｔ＝１．９８分で最初に溶出するエナンチオマーを得た。ＭＳ， ＥＳ＋ ｍ／ｚ， ５２０．８ （Ｍ＋Ｈ）＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ３．０７ （ｓ， ３ Ｈ） ４．２７ （ｓ， １ Ｈ） ７．３９ － ７．５４ （ｍ， ４ Ｈ） ７．６２ （ｔ， Ｊ＝７．８３ Ｈｚ， １ Ｈ） ７．７０ （ｄｔ， Ｊ＝７．９６， １．２０ Ｈｚ， １ Ｈ） ７．９０ －８．０２ （ｍ， １ Ｈ） ８．３８ （ｔ， Ｊ＝１．８９ Ｈｚ， １ Ｈ） ８．５７ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ） ８．７２ （ｄ， Ｊ＝１．５２ Ｈｚ， １ Ｈ） １１．０１ （ｓ， １ Ｈ）． (Example 131: N- [3- (methylsulfonimideyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide, enantiomer B)

Racemic N- [3- (methylsulfonimidyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide (Example LI-1859) Separated by chiral chromatography using a Chiralpak IG column in a mobile phase consisting of a 5-40% gradient of methanol (modified with 0.05% DEA) in CO ₂ , first at _RT = 1.98 minutes. An elution enantiomer was obtained. MS, ES + m / z, 520.8 (M + H) +. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.07 (s, 3H) 4.27 (s, 1H) 7.39-7.54 (m, 4H) 7.62 (t, J) = 7.83 Hz, 1 H) 7.70 (dt, J = 7.96, 1.20 Hz, 1 H) 7.90-8.02 (m, 1 H) 8.38 (t, J = 1.89 Hz, 1 H) 8.57 (d, J = 2.53 Hz, 1 H) 8.72 (d, J = 1.52 Hz, 1 H) 11.01 (s, 1 H).

(Example 132: N- (1-oxide pyridine-1-ium-3-yl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide)
[Method P]

ＭｅＣＮ（５ｍＬ）中の２－クロロ－５－（トリフルオロメチル）ピリジン－３－カルボン酸（５１０ｍｇ、２．２６ｍｍｏｌ）、４－（トリフルオロメトキシ）フェノール（３２２μＬ、２．４９ｍｍｏｌ）及び炭酸セシウム（１．８４ｇ、５．６５ｍｍｏｌ）の混合液を８０℃で５時間撹拌した後、室温で４日間（便宜上）撹拌した。溶媒をＮ_２気流下で除去し、残留物を水／ＭｅＯＨ（５：１）で処理した。この混合液を短時間超音波処理した後、室温で１８時間撹拌した。得られた沈殿物を濾過で回収し、水で洗浄し、真空乾燥させ、２－［４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボン酸（６０４ｍｇ、１．６５ｍｍｏｌ、収率７２．８％）をオフホワイトの固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３６８．０ ［Ｍ＋Ｈ］＋． Step 1: Synthesis of 2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxylic acid (intermediate ABC)

2-Chloro-5- (trifluoromethyl) pyridine-3-carboxylic acid (510 mg, 2.26 mmol), 4- (trifluoromethoxy) phenol (322 μL, 2.49 mmol) and cesium carbonate (2.49 mmol) in MeCN (5 mL). A mixed solution of 1.84 g (5.65 mmol) was stirred at 80 ° C. for 5 hours, and then stirred at room temperature for 4 days (for convenience). The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (5: 1). The mixture was sonicated for a short time and then stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration, washed with water, vacuum dried and 2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxylic acid (604 mg, 1). .65 mmol, yield 72.8%) was obtained as an off-white solid. MS, ES + m / z 368.0 [M + H] +.

２－［４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボン酸（２５０ｍｇ、０．６８ｍｍｏｌ）を、磁気撹拌子を備えたスクリューキャップバイアルに加え、ジクロロメタン（２．５ｍＬ）に溶解させた。塩化オキサリル（７２μＬ、０．８２ｍｍｏｌ）を加え、続いてＤＭＦを１滴加え、混合液を１時間撹拌した。３－アミノピリジン（９６ｍｇ、１．０ｍｍｏｌ）及びトリメチルアミン（１９０μＬ、１．３６ｍｍｏｌ）をＤＣＭ（２．５ｍＬ）中の溶液として滴加した。減圧下で揮発性物質を蒸発させ、残留物を分取逆相ＨＰＬＣ（高ｐＨ法）で精製し、Ｎ－（３－ピリジル）－２－［４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボキサミドを無色ガラスとして得た（２６６ｍｇ、０．６ｍｍｏｌ、収率８８％）。ＭＳ， ＥＳ＋ ｍ／ｚ ３６８．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ７．４０ － ７．５３ （ｍ， ５ Ｈ） ８．１８ （ｄｄｄ， Ｊ＝８．３４， ２．５３， １．５２ Ｈｚ， １ Ｈ） ８．３６ （ｄｄ， Ｊ＝４．５５， １．５２ Ｈｚ， １ Ｈ） ８．５５ － ８．６０ （ｍ， １Ｈ） ８．７３ （ｄｄ， Ｊ＝２．５３， １．０１ Ｈｚ， １ Ｈ） ８．８７ （ｄ， Ｊ＝２．０２ Ｈｚ， １ Ｈ） １０．８８ （ｓ， １ Ｈ） Step 2: Synthesis of N- (3-pyridyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide

2- [4- (Trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxylic acid (250 mg, 0.68 mmol) was added to a screw cap vial equipped with a magnetic stir bar and dichloromethane (2). .5 mL) was dissolved. Oxalyl chloride (72 μL, 0.82 mmol) was added, followed by 1 drop of DMF, and the mixture was stirred for 1 hour. 3-Aminopyridine (96 mg, 1.0 mmol) and trimethylamine (190 μL, 1.36 mmol) were added dropwise as a solution in DCM (2.5 mL). The volatile material is evaporated under reduced pressure, the residue is purified by preparative reverse phase HPLC (high pH method), and N- (3-pyridyl) -2- [4- (trifluoromethoxy) phenoxy] -5. (Trifluoromethyl) pyridine-3-carboxamide was obtained as colorless glass (266 mg, 0.6 mmol, 88% yield). MS, ES + m / z 368.0 [M + H] +. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.40-7.53 (m, 5 H) 8.18 (ddd, J = 8.34, 2.53, 1.52 Hz, 1 H) 8 .36 (dd, J = 4.55, 1.52 Hz, 1H) 8.55-8.60 (m, 1H) 8.73 (dd, J = 2.53, 1.01 Hz, 1H) ) 8.87 (d, J = 2.02 Hz, 1 H) 10.88 (s, 1 H)

Ｎ－（３－ピリジル）－２－［４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（１００ｍｇ、０．２３ｍｍｏｌ）を磁気撹拌子を備えたスクリューキャップバイアルに加え、ＤＣＭ（５ｍＬ）に溶解させた。ｍＣＰＢＡ（６１ｍｇ、０．２７ｍｍｏｌ）を加え、混合液を室温で１５分間撹拌した。揮発性物質を減圧下で蒸発させ、得られた残留物を分取逆相ＨＰＬＣ（高ｐＨ法）で精製し、表題化合物を無色ガラスとして得た（６９ｍｇ、０．１５ｍｍｏｌ、６７％収率）。ＭＳ， ＥＳ＋ ｍ／ｚ ４６０．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ７．３８ － ７．６０ （ｍ， ６ Ｈ） ８．０５ （ｄｄｄ， Ｊ＝６．３２， １．７７， １．０１ Ｈｚ， １ Ｈ） ８．５９ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ） ８．７１ － ８．８４ （ｍ， ２ Ｈ）
１１．０４ （ｓ， １ Ｈ）． Step 3: Synthesis of N- (1-oxide pyridine-1-ium-3-yl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide

N- (3-pyridyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (100 mg, 0.23 mmol) in a screw cap vial equipped with a magnetic stirrer. In addition, it was dissolved in DCM (5 mL). mCPBA (61 mg, 0.27 mmol) was added and the mixture was stirred at room temperature for 15 minutes. The volatile material was evaporated under reduced pressure and the resulting residue was purified by preparative reverse phase HPLC (high pH method) to give the title compound as colorless glass (69 mg, 0.15 mmol, 67% yield). .. MS, ES + m / z 460.0 [M + H] +. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.38-7.60 (m, 6 H) 8.05 (ddd, J = 6.32, 1.77, 1.01 Hz, 1 H) 8 .59 (d, J = 2.53 Hz, 1 H) 8.71-8.84 (m, 2 H)
11.04 (s, 1H).

The following compounds were synthesized according to Method P.

Ｎ－（４－ピリジル）－２－［４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（実施例１２９、１００ｍｇ、０．２３ｍｍｏｌ）を磁気撹拌子を備えたスクリュートップバイアルに加え、ＤＣＭ（５ｍＬ）に溶解させた。ｍ－ＣＰＢＡ（６１ｍｇ、０．２７ｍｍｏｌ）を加え、混合液を室温で１５分間撹拌させた。揮発性物質を減圧下で蒸発させ、得られた残留物を分取逆相ＨＰＬＣ（高ｐＨ法）で精製し、目的の生成物を無色ガラスとして得た。（５５ｍｇ、０．１２ｍｍｏｌ、５３％収率）。ＭＳ， ＥＳ＋ ｍ／ｚ ４６０．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ７．３８ － ７．５５ （ｍ， ４ Ｈ） ７．６９ － ７．８０ （ｍ， ２ Ｈ） ８．１５ － ８．２６ （ｍ， ２ Ｈ） ８．５８ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ） ８．７３ （ｄ， Ｊ＝１．２６ Ｈｚ， １
Ｈ） １１．１６ （ｓ， １ Ｈ）． (Example 141: N- (1-oxide pyridine-1-ium-4-yl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide)

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

Example 142: 2- [2-chloro-4- (trifluoromethoxy) phenoxy] -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide)
[Method Q]

ＭｅＣＮ（２ｍＬ）中の２－クロロ－５－（トリフルオロメチル）ピリジン－３－カルボン酸（１５０ｍｇ、０．６６５ｍｍｏｌ）、２－クロロ－４－（トリフルオロメトキシ）フェノール（１４１ｍｇ、０．６６５ｍｍｏｌ）及び炭酸セシウム（４３３ｍｇ、１．３３ｍｍｏｌ）の混合液を８０℃で６８時間撹拌した。冷却後、内容物を２０ｍＬの水で希釈し、２ＮのＨＣｌを慎重に加えてｐＨ６に酸性化した。沈殿物を濾過して集め、水で洗浄し、真空乾燥させ、２－［２－クロロ－４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボン酸（１４９．５ｍｇ、０．３７２ｍｍｏｌ、収率５６．０％）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４０１．９ ［Ｍ＋Ｈ］＋． Step 1: Synthesis of 2- [2-chloro-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxylic acid

2-Chloro-5- (trifluoromethyl) pyridine-3-carboxylic acid (150 mg, 0.665 mmol), 2-chloro-4- (trifluoromethoxy) phenol (141 mg, 0.665 mmol) in MeCN (2 mL) And a mixed solution of cesium carbonate (433 mg, 1.33 mmol) was stirred at 80 ° C. for 68 hours. After cooling, the contents were diluted with 20 mL of water and acidified to pH 6 with careful addition of 2N HCl. The precipitate is filtered, collected, washed with water, vacuum dried and 2- [2-chloro-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxylic acid (149. 5 mg, 0.372 mmol, yield 56.0%) was obtained as a beige solid. MS, ES + m / z 401.9 [M + H] +.

クロロホルム（２ｍＬ）中の２－［２－クロロ－４－（トリフルオロメトキシ）フェノキシ］－５－（トリフルオロメチル）ピリジン－３－カルボン酸（３３．４ｍｇ、０．０８３２ｍｍｏｌ）、３－メチルスルホニルアニリン（１５．７ｍｇ、０．０９１５ｍｍｏｌ）、ＨＢＴＵ（３４．７ｍｇ、０．０９１５ｍｍｏｌ）及びＤＩＰＥＡ（３６．２μＬ、０．２０８ｍｍｏｌ）の混合液を室温で２０時間撹拌した。Ｎ_２気流下で溶媒を除去し、残留物を水／ＭｅＯＨ（４：１）と反応させた。この混合液を短時間超音波処理した後、室温で一晩撹拌した。得られた沈殿物を濾過して集め、水で洗浄し、真空乾燥させ、２－［２－クロロ－４－（トリフルオロメトキシ）フェノキシ］－Ｎ－（３－メチルスルホニルフェニル）－５－（トリフルオロメチル）ピリジン－３－カルボキサミド（３４．８ｍｇ、０．０６２７ｍｍｏｌ、収率７５．４％）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ５５４．９ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １１．０７ （ｓ， １ Ｈ）， ８．７４ （ｂｒ． ｓ．， １ Ｈ）， ８．６４ （ｄ， Ｊ＝２．２７ Ｈｚ， １ Ｈ）， ８．４０ （ｓ， １ Ｈ）， ７．９９ （ｄ， Ｊ＝７．５８ Ｈｚ， １ Ｈ）， ７．８１ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ）， ７．６５ － ７．７４ （ｍ， ３ Ｈ）， ７．５２ － ７．５７ （ｍ， １ Ｈ）， ３．２３ （ｓ， ３ Ｈ）． Step 2: Synthesis of 2- [2-chloro-4- (trifluoromethoxy) phenoxy] -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide

2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxylic acid (33.4 mg, 0.0832 mmol) in chloroform (2 mL), 3-methylsulfonyl A mixture of aniline (15.7 mg, 0.0915 mmol), HBTU (34.7 mg, 0.0915 mmol) and DIPEA (36.2 μL, 0.208 mmol) was stirred at room temperature for 20 hours. The solvent was removed under _N2 airflow and the residue was reacted with water / MeOH (4: 1). The mixture was sonicated for a short time and then stirred overnight at room temperature. The resulting precipitate is filtered, collected, washed with water, vacuum dried and 2- [2-chloro-4- (trifluoromethoxy) phenoxy] -N- (3-methylsulfonylphenyl) -5-( Trifluoromethyl) pyridine-3-carboxamide (34.8 mg, 0.0627 mmol, 75.4% yield) was obtained as a beige solid. MS, ES + m / z 554.9 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H), 8.74 (br. S., 1 H), 8.64 (d, J = 2.27 Hz, 1 H) ), 8.40 (s, 1H), 7.99 (d, J = 7.58 Hz, 1H), 7.81 (d, J = 2.53 Hz, 1H), 7.65- 7.74 (m, 3H), 7.52-7.57 (m, 1H), 3.23 (s, 3H).

The following compounds were synthesized according to Method Q.

(Example 171: 2- (2,4-dimethoxyphenoxy) -N- [3- (N, S-dimethylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridine-3-carboxamide)
[Method R]

磁気撹拌子を備えた丸底フラスコに２－クロロ－５－（トリフルオロメチル）ピリジン－３－カルボン酸（１．５ｇ、６．７ｍｍｏｌ）を入れ、アセトニトリル（１５ｍＬ）を加えた。炭酸セシウム（４．３ｇ、１３．３ｍｍｏｌ）及び２，４－ジメトキシフェノール（１．１ｇ、７．３ｍｍｏｌ）を加え、混合液を１２時間還流させた。揮発性物質を減圧下で蒸発させ、残留物を水に溶解させた。２ＮのＨＣＬを慎重に加えてｐＨを約３に調整し、得られた沈殿物を濾過で回収し、水で洗浄し、乾燥するまで吸引し、目的の生成物を固体として得た。（１．７５ｇ、５．１ｍｍｏｌ、７６％収率）。ＭＳ， ＥＳ＋ ｍ／ｚ ３４４．０ ［Ｍ＋Ｈ］＋． Step 1: Synthesis of 2- (2,4-dimethoxyphenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid

2-Chloro-5- (trifluoromethyl) pyridine-3-carboxylic acid (1.5 g, 6.7 mmol) was placed in a round bottom flask equipped with a magnetic stir bar, 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 refluxed for 12 hours. The volatiles were evaporated under reduced pressure and the residue was dissolved in water. 2N HCl was carefully added to adjust the pH to about 3, and the resulting precipitate was collected by filtration, washed with water and aspirated to dryness to give the desired product as a solid. (1.75 g, 5.1 mmol, 76% yield). MS, ES + m / z 344.0 [M + H] +.

２－（２，４－ジメトキシフェノキシ）－５－（トリフルオロメチル）ピリジン－３－カルボン酸（１５０ｍｇ、０．４４ｍｍｏｌ）をスクリューキャップバイアルに加え、ＤＭＦ（３ｍＬ）に溶解させた。トリエチルアミン（１２２μＬ、０．８７ｍｍｏｌ）及びＨＢＴＵ（２００ｍｇ、０．５２ｍｍｏｌ）を加え、混合液を室温で１０分間撹拌した。３－（Ｎ、Ｓ－ジメチルスルホンイミドイル）アニリン（８１ｍｇ、０．４４ｍｍｏｌ）を加え、さらに１２時間撹拌を続けた。分取逆相ＨＰＬＣ（高ｐＨ法）で精製し、表題化合物をベージュ色の固体として得た。（１１１ｍｇ、０．２２ｍｍｏｌ、５０％収率）。ＭＳ， ＥＳ＋ ｍ／ｚ ５１０．４ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ２．４９ （ｓ， ３ Ｈ） ３．１２ （ｓ， ３ Ｈ） ３．６６ － ３．７１ （ｍ， ３ Ｈ） ３．７９ （ｓ， ３ Ｈ） ６．５７ （ｄｄ， Ｊ＝８．８４， ２．７８ Ｈｚ， １ Ｈ） ６．７２ （ｄ， Ｊ＝２．７８Ｈｚ， １ Ｈ） ７．２０ （ｄ， Ｊ＝８．８４ Ｈｚ， １ Ｈ） ７．５６ － ７．６１ （ｍ， １ Ｈ） ７．６２ － ７．６９ （ｍ， １ Ｈ） ７．９６ （ｄ， Ｊ＝８．０８ Ｈｚ， １ Ｈ） ８．３２ （ｓ， １ Ｈ） ８．５０ （ｄ， Ｊ＝２．２７ Ｈｚ， １ Ｈ） ８．６５ （ｄ，Ｊ＝１．５２ Ｈｚ， １ Ｈ） １０．９３ （ｓ， １ Ｈ）． Step 2: Synthesis of 2- (2,4-dimethoxyphenoxy) -N- [3- (N, S-dimethylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridine-3-carboxamide

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

The following compounds were synthesized according to Method R.

(Example 174: 2- (2,4-difluorophenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridine-3-carboxamide)
[Method S]

磁気撹拌子を備えた丸底フラスコに２－クロロ－５－（トリフルオロメチル）ピリジン－３－カルボン酸（１．５ｇ、６．７ｍｍｏｌ）を加え、アセトニトリル（１５ｍＬ）を加えた。炭酸セシウム（４．３ｇ、１３．３ｍｍｏｌ）及び２，４－ジフルオロフェノール（９５２ｍｇ、７．３ｍｍｏｌ）を加え、混合液を１２時間還流させた。溶媒を減圧除去し、得られた残留物を水に溶解させた。２ＮのＨＣｌを加えてｐＨを約３に調整し、得られた沈殿物を濾過で回収し、水で洗浄し、乾燥するまで吸引し、目的の生成物を白色固体として得た（１．９ｇ、２．１ｍｍｏｌ、９１％収率）。ＭＳ， ＥＳ＋ ｍ／ｚ ３２０ ［Ｍ＋Ｈ］＋． Step 1: 2- (2,4-difluorophenoxy) -5- (trifluoromethyl) pyridine-3-carboxylic acid

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 stir bar, 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 refluxed 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, washed with water and aspirated to dryness to give the desired product as a white solid (1.9 g). , 2.1 mmol, 91% yield). MS, ES + m / z 320 [M + H] +.

２－（２，４－ジフルオロフェノキシ）－５－（トリフルオロメチル）ピリジン－３－カルボン酸（１５０ｍｇ、０．４４ｍｍｏｌ）をスクリューキャップバイアルに加え、ＤＭＦ（３ｍＬ）に溶解させた。トリエチルアミン（１２２μＬ、０．８７ｍｍｏｌ）及びＨＢＴＵ（２００ｍｇ、０．５２ｍｍｏｌ）を加え、混合液を室温で１０分間撹拌した。３－（Ｎ、Ｓ－ジメチルスルホンイミドイル）アニリン（７５ｍｇ、０．４４ｍｍｏｌ）を加え、さらに１２時間撹拌を続けた。分取逆相ＨＰＬＣ（高ｐＨ法）で精製し、表題化合物をベージュ色の固体として得た。（９７ｍｇ、０．２１ｍｍｏｌ、４７％収率）。ＭＳ， ＥＳ＋ ｍ／ｚ ４７２．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ３．０７ （ｓ， ３ Ｈ） ７．４６ － ７．５９ （ｍ， ２ Ｈ） ７．５９ － ７．６６ （ｍ， １ Ｈ） ７．６７ － ７．７４ （ｍ， １ Ｈ） ７．９６ （ｄ， Ｊ＝８．０８ Ｈｚ， １ Ｈ） ８．３９ （ｔ， Ｊ＝１．７７ Ｈｚ， １ Ｈ） ８．６１ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ） ８．７２ （ｄ， Ｊ＝１．５２ Ｈｚ， １ Ｈ） １１．０３ （ｓ， １ Ｈ）． Step 2: Synthesis of 2- (2,4-difluorophenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridine-3-carboxamide

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

The following compounds were synthesized according to Method S.

(Example 177: 5-cyano-2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridine-3-carboxamide)

ＭｅＣＮ（５ｍＬ）中の２－クロロ－５－シアノ－６－メチル－ピリジン－３－カルボン酸エチル（１５０ｍｇ、０．６６８ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（９５．１μＬ、０．８３５ｍｍｏｌ）及び炭酸セシウム（６５３ｍｇ、２．００ｍｍｏｌ）の混合液を６０℃で１時間撹拌た。冷却後、内容物を水で処理し、室温で一晩撹拌した。沈殿物を濾過で集め、水で洗浄し、真空乾燥させ、５－シアノ－２－（４－フルオロ－２－メトキシ－フェノキシ）－６－メチル－ピリジン－３－カルボン酸エチル（１３５ｍｇ、０．４０９ｍｍｏｌ、収率６１．２％）を緑がかった灰色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３３１．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ８．６４ （ｓ， １ Ｈ）， ７．２０ （ｄｄ， Ｊ＝８．９７， ５．９４ Ｈｚ， １ Ｈ）， ７．１１ （ｄｄ， Ｊ＝１０．４８， ２．６５ Ｈｚ， １ Ｈ）， ６．８２ （ｔｄ， Ｊ＝８．４６， ２．７８ Ｈｚ， １ Ｈ）， ４．３３ （ｑ， Ｊ＝７．０７ Ｈｚ， ２ Ｈ）， ３．７０ （ｓ， ３ Ｈ）， ２．４６ （ｓ， ３ Ｈ）， １．３２ （ｔ， Ｊ＝７．０７ Ｈｚ， ３ Ｈ）． Step 1: Synthesis of ethyl 5-cyano-2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-pyridine-3-carboxylate

Ethyl 2-chloro-5-cyano-6-methyl-pyridine-3-carboxylate (150 mg, 0.668 mmol) in MeCN (5 mL), 4-fluoro-2-methoxyphenol (95.1 μL, 0.835 mmol) And a mixed solution of cesium carbonate (653 mg, 2.00 mmol) was stirred at 60 ° C. for 1 hour. After cooling, the contents were treated with water and stirred at room temperature overnight. The precipitate is collected by filtration, washed with water, vacuum dried and ethyl 5-cyano-2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-pyridine-3-carboxylate (135 mg, 0. 409 mmol, yield 61.2%) was obtained as a greenish-gray solid. MS, ES + m / z 331.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1 H), 7.20 (dd, J = 8.97, 5.94 Hz, 1 H), 7.11 (dd, J) = 10.48, 2.65 Hz, 1 H), 6.82 (td, J = 8.46, 2.78 Hz, 1 H), 4.33 (q, J = 7.07 Hz, 2 H) ), 3.70 (s, 3H), 2.46 (s, 3H), 1.32 (t, J = 7.07 Hz, 3H).

ＴＨＦ（２ｍＬ）及び水（０．１ｍＬ）中の５－シアノ－２－（４－フルオロ－２－メトキシ－フェノキシ）－６－メチル－ピリジン－３－カルボン酸エチル（１３５ｍｇ、０．４０９ｍｍｏｌ）及び水酸化リチウム一水和物（１８．９ｍｇ、０．４５０ｍｍｏｌ）の混合液を室温で２時間撹拌した。Ｎ_２気流下で溶媒を除去し、残留物を水に溶解させた。６ＮのＨＣｌを慎重に加えてｐＨをｐＨ５に下げ、生成物をＣＨＣｌ_３（４ｘ）で抽出し、溶媒を真空除去して残渣を得、これを自動順相クロマトグラフィー（０－１００％ＥｔＯＡｃ／ヘプタン、４ｇシリカゲルカートリッジ）で精製し、５－シアノ－２－（４－フルオロ－２－メトキシ－フェノキシ）－６－メチル－ピリジン－３－カルボン酸（７７．２ｍｇ、０．２５５ｍｍｏｌ、収率６２．５％）を黄色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３０３．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １３．５５ （ｂｒ． ｓ．， １ Ｈ）， ８．５７ （ｓ， １ Ｈ）， ７．１９ （ｄｄ， Ｊ＝８．８４， ６．０６ Ｈｚ， １ Ｈ）， ７．１１ （ｄｄ， Ｊ＝１０．７４， ２．９１ Ｈｚ， １ Ｈ）， ６．８２ （ｔｄ， Ｊ＝８．５３， ２．９１ Ｈｚ， １ Ｈ）， ３．７０ （ｓ， ３ Ｈ）， ２．４４ （ｓ， ３ Ｈ）． Step 2: Synthesis of 5-cyano-2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-pyridine-3-carboxylic acid

Ethyl 5-cyano-2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-pyridine-3-carboxylate (135 mg, 0.409 mmol) in THF (2 mL) and water (0.1 mL) and A mixture of lithium hydroxide monohydrate (18.9 mg, 0.450 mmol) was stirred at room temperature for 2 hours. The solvent was removed under _N2 airflow and the residue was dissolved in water. Carefully add 6N HCl to lower the pH to pH 5, extract the product with CHCl ₃ (4x) and vacuum remove the solvent to give a residue, which is subjected to automatic normal phase chromatography (0-100% EtOAc /). Purified with heptane (4 g silica gel cartridge), 5-cyano-2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-pyridine-3-carboxylic acid (77.2 mg, 0.255 mmol, yield 62). .5%) was obtained as a yellow solid. MS, ES + m / z 303.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 13.55 (br. S., 1 H), 8.57 (s, 1 H), 7.19 (dd, J = 8.84, 6.06) Hz, 1H), 7.11 (dd, J = 10.74, 2.91 Hz, 1H), 6.82 (td, J = 8.53, 2.91 Hz, 1H), 3. 70 (s, 3H), 2.44 (s, 3H).

クロロホルム（３ｍＬ）中の５－シアノ－２－（４－フルオロ－２－メトキシ－フェノキシ）－６－メチル－ピリジン－３－カルボン酸（７５．０ｍｇ、０．２４８ｍｍｏｌ）、３－メチルスルホニルアニリン（４６．７ｍｇ、０．２７３ｍｍｏｌ）、ＨＢＴＵ（１１３ｍｇ、０．２９８ｍｍｏｌ）及びＤＩＰＥＡ（１３０μＬ、０．７４４ｍｍｏｌ）の混合液を、室温で１９時間撹拌した。内容物をＥｔＯＡｃで希釈し、水（３ｘ）、ブライン（１ｘ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、溶媒を真空除去して残渣を得、これを自動順相クロマトグラフィー（０－１００％ＥｔＯＡｃ／ヘプタン、４ｇシリカゲルカートリッジ）で精製し、５－シアノ－２－（４－フルオロ－２－メトキシ－フェノキシ）－６－メチル－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（４９．０ｍｇ、０．１０８ｍｍｏｌ、４３．４％収率）を淡黄色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４５６．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．８９ （ｓ， １ Ｈ）， ８．５７ （ｓ， １ Ｈ）， ８．３９ （ｓ， １ Ｈ）， ７．９４ － ７．９９ （ｍ， １ Ｈ）， ７．６４ － ７．７２ （ｍ， ２ Ｈ）， ７．３１ （ｄｄ， Ｊ＝８．８４， ５．８１ Ｈｚ， １ Ｈ）， ７．１１ （ｄｄ， Ｊ＝１０．７４， ２．９１ Ｈｚ， １ Ｈ）， ６．８４ （ｔｄ， Ｊ＝８．５３， ２．９１ Ｈｚ， １ Ｈ）， ３．７１ （ｓ， ３ Ｈ）， ３．２２ （ｓ， ３ Ｈ）． Step 3: Synthesis of 5-cyano-2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridine-3-carboxamide

5-Cyano-2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-pyridine-3-carboxylic acid (75.0 mg, 0.248 mmol) in chloroform (3 mL), 3-methylsulfonylaniline ( A mixture of 46.7 mg, 0.273 mmol), HBTU (113 mg, 0.298 mmol) and DIPEA (130 μL, 0.744 mmol) was stirred at room temperature for 19 hours. The contents are diluted with EtOAc, washed with water (3x), brine (1x), dried on silica gel ₄ , filtered, the solvent vacuum removed to give a residue, which is subjected to automatic normal phase chromatography (0-). Purified with 100% EtOAc / Heptane, 4 g silica gel cartridge) and 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) was obtained as a pale yellow solid. MS, ES + m / z 456.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 7.94-7.99 ( m, 1H), 7.64-772 (m, 2H), 7.31 (dd, J = 8.84, 5.81 Hz, 1H), 7.11 (dd, J = 10) .74, 2.91 Hz, 1 H), 6.84 (td, J = 8.53, 2.91 Hz, 1 H), 3.71 (s, 3 H), 3.22 (s, 3) H).

(Example 178: 5-fluoro-2- (4-fluoro-2-methoxy-phenoxy) -6-methoxy-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide)

ＭｅＣＮ（８ｍＬ）中の２－クロロ－５－フルオロ－６－メトキシ－ピリジン－３－カルボン酸メチル（２００ｍｇ、０．９１１ｍｍｏｌ）、４－フルオロ－２－メトキシフェノール（１１４μＬ、１．００ｍｍｏｌ）及び炭酸セシウム（７４２ｍｇ、２．２８ｍｍｏｌ）の混合液を８０℃で３時間撹拌した後、撹拌しながら室温まで冷却した。水（３０ｍＬ）及びメタノール（５ｍＬ）を加え、得られた混合液を短時間超音波処理した後、４時間撹拌した。沈殿物を濾過によって回収し、水で洗浄し、真空乾燥させ、５－フルオロ－２－（４－フルオロ－２－メトキシ－フェノキシ）－６－メトキシ－ピリジン－３－カルボン酸メチル（２３７ｍｇ、０．７２７ｍｍｏｌ、収率７９．９％）をベージュ色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３２６．０ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ８．１２ （ｄ， Ｊ＝１０．１１ Ｈｚ， １ Ｈ）， ７．１８ （ｄｄ， Ｊ＝８．７２， ５．９４ Ｈｚ， １ Ｈ）， ７．０９ （ｄｄ， Ｊ＝１０．７４， ２．９１ Ｈｚ， １ Ｈ）， ６．８１ （ｔｄ， Ｊ＝８．４６， ２．７８ Ｈｚ， １ Ｈ）， ３．８３ （ｓ， ３ Ｈ）， ３．７２ （ｓ， ３ Ｈ）， ３．５７ （ｓ， ３ Ｈ）． Step 1: Synthesis of methyl 5-fluoro-2- (4-fluoro-2-methoxy-phenoxy) -6-methoxy-pyridin-3-carboxylate

Methyl 2-chloro-5-fluoro-6-methoxy-pyridine-3-carboxylate (200 mg, 0.911 mmol), 4-fluoro-2-methoxyphenol (114 μL, 1.00 mmol) and carbonate in MeCN (8 mL) The mixed solution of cesium (742 mg, 2.28 mmol) was stirred at 80 ° C. for 3 hours, and then cooled to room temperature with stirring. Water (30 mL) and methanol (5 mL) were added, and the obtained mixture was sonicated for a short time and then stirred for 4 hours. The precipitate is collected by filtration, washed with water, vacuum dried and methyl 5-fluoro-2- (4-fluoro-2-methoxy-phenoxy) -6-methoxy-pyridine-3-carboxylate (237 mg, 0). .727 mmol, yield 79.9%) was obtained as a beige solid. MS, ES + m / z 326.0 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 10.11 Hz, 1 H), 7.18 (dd, J = 8.72, 5.94 Hz, 1 H), 7.09 (dd, J = 10.74, 2.91 Hz, 1 H), 6.81 (td, J = 8.46, 2.78 Hz, 1 H), 3.83 (s, 3 H) ), 3.72 (s, 3H), 3.57 (s, 3H).

ＴＨＦ（３ｍＬ）及び水（０．１ｍＬ）中の５－フルオロ－２－（４－フルオロ－２－メトキシ－フェノキシ）－６－メトキシ－ピリジン－３－カルボン酸メチル（２３１ｍｇ、０．７１０ｍｍｏｌ）及び水酸化リチウム一水和物（３２．８ｍｇ、０．７８１ｍｍｏｌ）の混合液を、室温で４８時間撹拌した。溶媒をＮ_２気流下で除去し、内容物を水（１５ｍＬ）で希釈した。内容物を濾過し、２ＮのＨＣｌを慎重に加えて濾液のｐＨをｐＨ４に下げた。１時間撹拌した後、沈殿物を濾過で集め、水で洗浄し、真空乾燥させ、５－フルオロ－２－（４－フルオロ－２－メトキシ－フェノキシ）－６－メトキシ－ピリジン－３－カルボン酸（２０１ｍｇ、０．６４６ｍｍｏｌ、９０．９％収率）を白色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３１２．０ ［Ｍ＋Ｈ］＋．
１Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １３．０５ （ｂｒ． ｓ．， １ Ｈ）， ８．０８ （ｄ， Ｊ＝１０．１１ Ｈｚ， １ Ｈ）， ７．１７ （ｄｄ， Ｊ＝８．８４， ６．０６ Ｈｚ， １ Ｈ）， ７．０８ （ｄｄ， Ｊ＝１０．７４， ２．９１ Ｈｚ， １ Ｈ）， ６．８０ （ｔｄ， Ｊ＝８．５３， ２．９１ Ｈｚ， １ Ｈ）， ３．７２ （ｓ， ３ Ｈ）， ３．５６ （ｓ， ３ Ｈ）． Step 2: Synthesis of 5-fluoro-2- (4-fluoro-2-methoxy-phenoxy) -6-methoxy-pyridin-3-carboxylic acid

Methyl 5-fluoro-2- (4-fluoro-2-methoxy-phenoxy) -6-methoxy-pyridine-3-carboxylate (231 mg, 0.710 mmol) in THF (3 mL) and water (0.1 mL) and A mixture of lithium hydroxide monohydrate (32.8 mg, 0.781 mmol) was stirred at room temperature for 48 hours. The solvent was removed under _N2 airflow and the contents were diluted with water (15 mL). The contents were filtered and 2N HCl was carefully added to reduce the pH of the filtrate to pH 4. After stirring for 1 hour, the precipitate is collected by filtration, washed with water, vacuum dried and 5-fluoro-2- (4-fluoro-2-methoxy-phenoxy) -6-methoxy-pyridine-3-carboxylic acid. (201 mg, 0.646 mmol, 90.9% yield) was obtained as a white solid. MS, ES + m / z 312.0 [M + H] +.
1H-NMR (400 MHz, DMSO-d6) δ 13.05 (br. S., 1 H), 8.08 (d, J = 10.11 Hz, 1 H), 7.17 (dd, J = 8.84, 6.06 Hz, 1 H), 7.08 (dd, J = 10.74, 2.91 Hz, 1 H), 6.80 (td, J = 8.53, 2.91 Hz) , 1 H), 3.72 (s, 3 H), 3.56 (s, 3 H).

クロロホルム（２ｍＬ）中の５－フルオロ－２－（４－フルオロ－２－メトキシ－フェノキシ）－６－メトキシ－ピリジン－３－カルボン酸（４０ｍｇ、０．１２９ｍｍｏｌ）、３－メチルスルホニルアニリン（２４．２ｍｇ、０．１４１ｍｍｏｌ）、ＨＢＴＵ（５３．６ｍｇ、０．１４１ｍｍｏｌ）及びＤＩＰＥＡ（５６．０μＬ、０．３２１ｍｍｏｌ）の混合液を、室温で２２時間撹拌した。ＬＣＭＳにより、反応は約２５％のみ完了した。５０℃で５４時間撹拌した。Ｎ_２気流下で溶媒を除去し、残留物を水／ＭｅＯＨ（３：１）で処理した。この混合液を短時間超音波処理した後、室温で２４時間撹拌した。得られた沈殿物を濾過して回収し、水で洗浄し、真空乾燥させ、５－フルオロ－２－（４－フルオロ－２－メトキシ－フェノキシ）－６－メトキシ－Ｎ－（３－メチルスルホニルフェニル）ピリジン－３－カルボキサミド（４５．８ｍｇ、０．０９８６ｍｍｏｌ、収率７６．７％）を白色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４６５．１ ［Ｍ＋Ｈ］＋． １Ｈ－ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．５２ （ｓ， １ Ｈ）， ８．３８ （ｓ， １ Ｈ）， ８．１４ （ｄ， Ｊ＝９．８５ Ｈｚ， １ Ｈ）， ７．９９ （ｄ， Ｊ＝７．０７ Ｈｚ， １ Ｈ）， ７．６３ － ７．７０ （ｍ， ２ Ｈ）， ７．３９ － ７．４４ （ｍ， １ Ｈ）， ７．１１ （ｄｄ， Ｊ＝１０．７４， ２．６５ Ｈｚ， １ Ｈ）， ６．８５ （ｔｄ， Ｊ＝８．５９， ２．７８ Ｈｚ， １ Ｈ）， ３．７５ （ｓ， ３ Ｈ）， ３．６４ （ｓ， ３ Ｈ）， ３．２２ （ｓ， ３ Ｈ）． Step 3: Synthesis of 5-fluoro-2- (4-fluoro-2-methoxy-phenoxy) -6-methoxy-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide

5-Fluoro-2- (4-fluoro-2-methoxy-phenoxy) -6-methoxy-pyridin-3-carboxylic acid (40 mg, 0.129 mmol) in chloroform (2 mL), 3-methylsulfonylaniline (24. A mixture of 2 mg (0.141 mmol), HBTU (53.6 mg, 0.141 mmol) and DIPEA (56.0 μL, 0.321 mmol) was stirred at room temperature for 22 hours. By LCMS, the reaction was only about 25% complete. The mixture was stirred at 50 ° C. for 54 hours. The solvent was removed under _N2 airflow and the residue was treated with water / MeOH (3: 1). The mixture was sonicated for a short time and then stirred at room temperature for 24 hours. The resulting precipitate is filtered and collected, washed with water, vacuum dried and 5-fluoro-2- (4-fluoro-2-methoxy-phenoxy) -6-methoxy-N- (3-methylsulfonyl). Pyridine) pyridine-3-carboxamide (45.8 mg, 0.0986 mmol, yield 76.7%) was obtained as a white solid. MS, ES + m / z 465.1 [M + H] +. 1H-NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1 H), 8.38 (s, 1 H), 8.14 (d, J = 9.85 Hz, 1 H), 7 .99 (d, J = 7.07 Hz, 1H), 7.63-7.70 (m, 2H), 7.39-7.44 (m, 1H), 7.11 (dd, 1H) J = 10.74, 2.65 Hz, 1 H), 6.85 (td, J = 8.59, 2.78 Hz, 1 H), 3.75 (s, 3 H), 3.64 ( s, 3H), 3.22 (s, 3H).

(Example 179: 5- (difluoromethoxy) -2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide)

磁気撹拌子を備えた丸底フラスコに５－ブロモ－６－クロロ－ピリジン－３－オール（１．０ｇ、４．８ｍｍｏｌ）を入れ、その後アセトニトリル（２０ｍＬ）及び水（２０ｍＬ）を加えた。固体水酸化カリウム（５．４ｇ、９６ｍｍｏｌ）を加え、混合液をドライアイス／アセトン浴で冷却した。混合液が凍り始めたところで、１－［［ブロモ（ジフルオロ）メチル］－エトキシ－ホスホリル］オキシエタン（２．６ｇ、９．６ｍｍｏｌ）を加え、混合液を室温まで温めた。クルード混合液を水及びジエチルエーテル間で分配し、エーテル層を回収、乾燥、濃縮して目的の生成物を含む無色の油を得て、これをさらに精製することなく使用した。 Step 1: Synthesis of 3-bromo-2-chloro-5- (difluoromethoxy) pyridine

5-bromo-6-chloro-pyridine-3-ol (1.0 g, 4.8 mmol) was placed in a round bottom flask equipped with a magnetic stir bar, and then acetonitrile (20 mL) and water (20 mL) were added. Solid potassium hydroxide (5.4 g, 96 mmol) was added and the mixture was cooled in a dry ice / acetone bath. When the mixture began to freeze, 1-[[bromo (difluoro) methyl] -ethoxy-phosphoryl] oxyethane (2.6 g, 9.6 mmol) was added and the mixture was warmed to room temperature. The crude mixture was partitioned between water and diethyl ether, and the ether layer was recovered, dried and concentrated to give a colorless oil containing the product of interest, which was used without further purification.

磁気撹拌子を備えた丸底フラスコに工程１のクルード生成物（１．２ｇ、４．６ｍｍｏｌ）を加え、アセトニトリル（２０ｍＬ）に溶解させた。４－フルオロ－２－メトキシ－フェノール（７２６ｍｇ、５．１１ｍｍｏｌ）及び炭酸セシウム（１．７ｇ、５．１ｍｍｏｌ）を加え、混合液を６０℃で２４時間加熱した。室温まで冷却した後、クルード混合液を水で希釈し、ジクロロメタンで抽出した。合わせた有機層を乾燥、濃縮し、シリカゲルクロマトグラフィー（ヘプタン中０－３５％ＥｔＯＡｃ）で精製し、目的の生成物を無色の油として得て、これを静置させると固化した（１．１ｇ、３．１ｍｍｏｌ）。ＭＳ， ＥＳ＋ ｍ／ｚ ３６４．０／３６５．０ ［Ｍ＋Ｈ］＋． Step 2: Synthesis of 3-bromo-2-chloro-5- (difluoromethoxy) pyridine

The crudo product of Step 1 (1.2 g, 4.6 mmol) was added to a round bottom flask equipped with a magnetic stir bar and dissolved in acetonitrile (20 mL). 4-Fluoro-2-methoxy-phenol (726 mg, 5.11 mmol) and cesium carbonate (1.7 g, 5.1 mmol) were added, and the mixture was heated at 60 ° C. for 24 hours. After cooling to room temperature, the crude mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried, concentrated and purified by silica gel chromatography (0-35% EtOAc in heptane) to give the desired product as a colorless oil, which solidified when allowed to stand (1.1 g). 3.1 mmol). MS, ES + m / z 364.0 / 365.0 [M + H] +.

磁気撹拌子を備えたマイクロ波バイアルに、３－ブロモ－５－（ジフルオロメトキシ）－２－（４－フルオロ－２－メトキシ－フェノキシ）ピリジン（２５０ｍｇ、０．６９ｍｍｏｌ）、ＤＰＥＰｈｏｓ（２７．７）ｍｇ、０．０５ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（３．８５ｍｇ、０．０２ｍｍｏｌ）、３－メチルスルホニルアニリン（２３５ｍｇ、１．３７ｍｍｏｌ）及び水酸化セシウム（１．２ｇ、６．９ｍｍｏｌ）を加えた。バイアルを密閉し、真空にして窒素を３回逆流させた後、トルエン（４ｍＬ）及びクロロホルム（０．１７ｍＬ）を加えた。得られた混合液を８０℃で１８時間加熱し、室温まで冷却した後、ジクロロメタンで希釈し、セライトのプラグで濾過した。透明な濾液を濃縮し、分取逆相ＨＰＬＣ（高ｐＨ法）で精製して、目的の生成物を無色の固体として得た（１６６ｍｇ、収率５０．１％）。ＭＳ， ＥＳ＋ ｍ／ｚ ４８３．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ３．１８ － ３．２６ （ｍ， ３ Ｈ） ３．６８ － ３．７２ （ｍ， ３ Ｈ） ６．８３ （ｔｄ， Ｊ＝８．５３， ２．９１ Ｈｚ， １ Ｈ） ７．０６ － ７．１１ （ｍ， １ Ｈ） ７．３２ （ｄｄ， Ｊ＝８．７２， ５．９４ Ｈｚ， １ Ｈ） ７．６４ － ７．７３ （ｍ， ２ Ｈ） ７．９３ － ８．０２ （ｍ， １ Ｈ） ８．０７ （ｄ， Ｊ＝３．０３ Ｈｚ， １ Ｈ） ８．１６ （ｄ， Ｊ＝２．７８ Ｈｚ， １ Ｈ） ８．４１ （ｓ， １ Ｈ） １０．９０ （ｓ， １ Ｈ） Step 3: Synthesis of 5- (difluoromethoxy) -2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide

In a microwave vial equipped with a magnetic stir bar, 3-bromo-5- (difluoromethoxy) -2- (4-fluoro-2-methoxy-phenoxy) pyridine (250 mg, 0.69 mmol), DPEPhos (27.7). mg, 0.05 mmol), palladium (II) acetate (3.85 mg, 0.02 mmol), 3-methylsulfonylaniline (235 mg, 1.37 mmol) and cesium hydroxide (1.2 g, 6.9 mmol) were added. .. The vial was sealed, evacuated and backflowed with nitrogen three times, after which toluene (4 mL) and chloroform (0.17 mL) were added. The resulting mixture was heated at 80 ° C. for 18 hours, cooled to room temperature, diluted with dichloromethane and filtered through a plug of Celite. The clear filtrate was concentrated and purified by preparative reverse phase HPLC (high pH method) to give the desired product as a colorless solid (166 mg, 50.1% yield). MS, ES + m / z 483.0 [M + H] +. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.18-3.26 (m, 3H) 3.68-3.72 (m, 3H) 6.83 (td, J = 8.53, 2.91 Hz, 1 H) 7.06-7.11 (m, 1 H) 7.32 (dd, J = 8.72, 5.94 Hz, 1 H) 7.64-7.73 (m) , 2 H) 7.93-8.02 (m, 1 H) 8.07 (d, J = 3.03 Hz, 1 H) 8.16 (d, J = 2.78 Hz, 1 H) 8 .41 (s, 1H) 10.90 (s, 1H)

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

ジクロロメタン（２００ｍＬ）中の２－クロロ－５－ニトロ－ピリジン－３－カルボン酸（１０ｇ、４９．３７ｍｍｏｌ）の撹拌溶液に、塩化オキサリル（６．３５ｍＬ、７４．０６ｍｍｏｌ）を加えた。ＤＭＦ（ｇ， ２．４７ ｍｍｏｌ）（３滴）を加えた。この溶液を、溶液からの泡が見られなくなるまで、室温で５時間撹拌した。３－メチルスルホニルアニリン（１０．１４ｇ、５９．２４ｍｍｏｌ）を加えた。Ｎ，Ｎ－ジイソプロピルエチルアミン（１７．７２ｍＬ、９８．７４ｍｍｏｌ）を溶液に滴加した。この溶液を室温で１時間撹拌した。ＤＣＭ（２００ｍＬ）を加え、溶液を塩酸溶液（１Ｎ、２×１００ｍＬ）、ブライン（１００ｍＬ）で抽出した後、硫酸ナトリウムで乾燥させた。この溶液を濾過し、濃縮した。残留物を酢酸エチル／ヘプタン（３０－１００％グラジエント）で溶出するシリカゲルクロマトグラフィーで精製し、２－クロロ－Ｎ－（３－メチルスルホニルフェニル）－５－ニトロ－ピリジン－３－カルボキサミド（１１．２８ｇ、２２．１９５ｍｍｏｌ、収率４４．９５７％）を紫色の固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ３５６．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， クロロホルム－ｄ） δ ｐｐｍ ３．０２ － ３．１１ （ｍ， ３ Ｈ） ７．６０ － ７．８２ （ｍ， ３ Ｈ） ７．９４ － ８．０５ （ｍ， １ Ｈ） ８．６１ （ｄ， Ｊ＝２．７８ Ｈｚ， １ Ｈ） ９．２２ － ９．３１（ｍ， １ Ｈ）． Step 1: Synthesis of 2-chloro-N- (3-methylsulfonylphenyl) -5-nitro-pyridin-3-carboxamide

Oxalyl chloride (6.35 mL, 74.06 mmol) was added to a stirred solution of 2-chloro-5-nitro-pyridine-3-carboxylic acid (10 g, 49.37 mmol) in dichloromethane (200 mL). DMF (g, 2.47 mmol) (3 drops) was added. The solution was stirred at room temperature for 5 hours until no bubbles were seen from the solution. 3-Methylsulfonylaniline (10.14 g, 59.24 mmol) was added. N, N-diisopropylethylamine (17.72 mL, 98.74 mmol) was added dropwise to the solution. The solution was stirred at room temperature for 1 hour. DCM (200 mL) was added and the solution was extracted with hydrochloric acid solution (1N, 2 x 100 mL) and brine (100 mL) and then dried over sodium sulfate. The solution was filtered and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate / heptane (30-100% gradient) and 2-chloro-N- (3-methylsulfonylphenyl) -5-nitro-pyridine-3-carboxamide (11. 28 g, 22.195 mmol, yield 44.957%) was obtained as a purple solid. MS, ES + m / z 356.0 [M + H] +. 1H 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, 1 H) 9.22-9.31 (m, 1 H).

アセトニトリル（１００ｍＬ）中の２－クロロ－Ｎ－（３－メチルスルホニルフェニル）－５－ニトロ－ピリジン－３－カルボキサミド（１１．１８ｇ、２２ｍｍｏｌ）の撹拌溶液に、４－（トリフルオロメトキシ）フェノール（５．８８ｇ、３３ｍｍｏｌ）及び炭酸カリウム（６．０８ｇ、４４ｍｍｏｌ）を加えた。この溶液を６０℃で一晩撹拌した。溶液を室温まで冷却し、濾過して固体を除去した。水（３００ｍＬ）を加えた。わずかに着色した固体を濾過により単離し、乾燥させて、Ｎ－（３－メチルスルホニルフェニル）－５－ニトロ－２－［４－（トリフルオロメトキシ）フェノキシ］ピリジン－３－カルボキサミド（１０．４３ｇ、２０．９６９ｍｍｏｌ、収率９５．３２％）をわずかに着色した固体として得た。１００ｍｇの少量のサンプルを酢酸エチル／ヘプタン（０－６０％）で溶出したＩＳＣＯで精製し、Ｎ－（３－メチルスルホニルフェニル）－５－ニトロ－２－［４－（トリフルオロメトキシ）フェノキシ］ピリジン－３－カルボキサミド（１０．４３ｇ、２０．９７ｍｍｏｌ、収率９５．３２％）を白色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４９８．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， クロロホルム－ｄ） ｄ ｐｐｍ ３．１２ （ｓ， ３ Ｈ） ７．２６ － ７．３８ （ｍ， ３ Ｈ） ７．４３ （ｄ， Ｊ＝８．８４ Ｈｚ， ２ Ｈ） ７．６１ － ７．７０ （ｍ， １ Ｈ） ７．７９ （ｄｄ， Ｊ＝７．８３， １．２６ Ｈｚ， １ Ｈ） ８．１０ － ８．２１ （ｍ， ２ Ｈ） ９．１２ （ｄ， Ｊ＝２．７８ Ｈｚ， １ Ｈ） ９．４８ （ｄ， Ｊ＝２．７８ Ｈｚ， １ Ｈ） ９．６８ （ｓ， １ Ｈ）．（ｍ， １ Ｈ）． Step 2: Synthesis of N- (3-methylsulfonylphenyl) -5-nitro-2- [4- (trifluoromethoxy) phenoxy] pyridine-3-carboxamide

4- (Trifluoromethoxy) phenol (trifluoromethoxy) phenol in a stirred solution of 2-chloro-N- (3-methylsulfonylphenyl) -5-nitro-pyridine-3-carboxamide (11.18 g, 22 mmol) in acetonitrile (100 mL). 5.88 g, 33 mmol) and potassium carbonate (6.08 g, 44 mmol) were added. The solution was stirred at 60 ° C. overnight. The solution was cooled to room temperature and filtered to remove solids. Water (300 mL) was added. The slightly colored solid was isolated by filtration and dried to dry N- (3-methylsulfonylphenyl) -5-nitro-2- [4- (trifluoromethoxy) phenoxy] pyridine-3-carboxamide (10.43 g). , 20.696 mmol, yield 95.32%) as a slightly colored solid. A small sample of 100 mg was purified with ISCO eluted with ethyl acetate / heptane (0-60%) and N- (3-methylsulfonylphenyl) -5-nitro-2- [4- (trifluoromethoxy) phenoxy]. Pyridine-3-carboxamide (10.43 g, 20.97 mmol, yield 95.32%) was obtained as a white solid. MS, ES + m / z 498.0 [M + H] +. 1H NMR (400 MHz, chloroform-d) d ppm 3.12 (s, 3 H) 7.26-7.38 (m, 3 H) 7.43 (d, J = 8.84 Hz, 2 H) 7.61-7.70 (m, 1H) 7.79 (dd, J = 7.83, 1.26 Hz, 1H) 8.10-18.21 (m, 2H) 9.12 ( d, J = 2.78 Hz, 1 H) 9.48 (d, J = 2.78 Hz, 1 H) 9.68 (s, 1 H). (M, 1H).

(Example 181: 5-chloro-N- (3-methylsulfonylphenyl) -2- [4- (trifluoromethoxy) phenoxy] pyridine-3-carboxamide)

Ｎ－（３－メチルスルホニルフェニル）－５－ニトロ－２－［４－（トリフルオロメトキシ）フェノキシ］ピリジン－３－カルボキサミド（１０．３３ｇ、２０．７７ｍｍｏｌ）のＴＨＦ（５０ｍＬ）及びエタノール（１００ｍＬ）中の撹拌溶液に、パラジウム炭素１０％（ｇ、２０．７７ｍｍｏｌ）を加えた。この溶液に５分間窒素をバブリングした。溶液を水素バルーンで充填し、２日間撹拌した。溶液を濾過し、濃縮した。残留物をメタノール／ＤＣＭ（０－８％）で溶出したＩＳＣＯで精製し、５－アミノ－Ｎ－（３－メチルスルホニルフェニル）－２－［４－（トリフルオロメトキシ）フェノキシ］ピリジン－３－カルボキサミド（４．６４ｇ、９．９２６８ｍｍｏｌ、４７．７９９％収率）を白色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４６８．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） ｄ ｐｐｍ ３．１５ － ３．２６ （ｍ， ３ Ｈ） ５．４４ （ｓ， ２ Ｈ） ７．１２ － ７．２１ （ｍ， ２ Ｈ） ７．３０ － ７．４１ （ｍ， ３ Ｈ） ７．６０ － ７．７１ （ｍ， ３ Ｈ） ７．９２ （ｄ， Ｊ＝７．５８ Ｈｚ， １ Ｈ） ８．３８ （ｓ， １ Ｈ） １０．７６ （ｓ， １ Ｈ）． Step 1: Synthesis of 5-amino-N- (3-methylsulfonylphenyl) -2- [4- (trifluoromethoxy) phenoxy] pyridine-3-carboxamide

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) 10% (g, 20.77 mmol) of palladium carbon was added to the stirred solution in the mixture. The solution was bubbled with nitrogen for 5 minutes. The solution was filled with a hydrogen balloon and stirred for 2 days. The solution was filtered and concentrated. The residue was purified with ISCO eluted with methanol / DCM (0-8%) and 5-amino-N- (3-methylsulfonylphenyl) -2- [4- (trifluoromethoxy) phenoxy] pyridine-3-. Carboxamide (4.64 g, 9.9268 mmol, 47.799% yield) was obtained as a white solid. MS, ES + m / z 468.0 [M + H] +. 1H NMR (400 MHz, DMSO-d6) d ppm 3.15-3.26 (m, 3H) 5.44 (s, 2H) 7.12-7.21 (m, 2H) 7.30 -7.41 (m, 3H) 7.60-771 (m, 3H) 7.92 (d, J = 7.58 Hz, 1H) 8.38 (s, 1H) 10. 76 (s, 1H).

水（３ｍＬ）中の５－アミノ－Ｎ－（３－メチルスルホニルフェニル）－２－［４－（トリフルオロメトキシ）フェノキシ］ピリジン－３－カルボキサミド（２００ｍｇ、０．４３００ｍｍｏｌ）の撹拌溶液に、塩酸（２ｍＬ）を加えた。溶液を氷水浴で冷却し、水（０．２ｍＬ）に溶解した亜硝酸ナトリウム（３２．４８ｍｇ、０．４７００ｍｍｏｌ）を加えた。０℃で１５分撹拌した後、水（１ｍＬ）に溶解した塩化銅（ＩＩ）（１７２．５９ｍｇ、１．２８ｍｍｏｌ）を加えた。この溶液を室温で一晩撹拌した。溶液を酢酸エチル（２Ｘ３ｍＬ）で抽出した。合わせた有機溶液を水（２ｍＬ）、ブライン（２ｍＬ）で洗浄し、硫酸ナトリウムで乾燥させた。溶液を濾過し、濃縮した。残留物を酢酸エチル／ヘプタン（０－５０％）で溶出したＩＳＣＯで精製し、５－クロロ－Ｎ－（３－メチルスルホニルフェニル）－２－［４－（トリフルオロメトキシ）フェノキシ］ピリジン－３－カルボキサミド（４３ｍｇ、０．０８８３ｍｍｏｌ、収率２０．６４２％）を白色固体として得た。ＭＳ， ＥＳ＋ ｍ／ｚ ４８７．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＨＬＯＲＯＦＯＲＭ－ｄ） ｄ ｐｐｍ ３．１１ （ｓ， ３ Ｈ） ７．２４ － ７．３２ （ｍ， ２ Ｈ） ７．３９ （ｄ， Ｊ＝８．３４ Ｈｚ， ２ Ｈ） ７．５８ － ７．６８ （ｍ， １ Ｈ） ７．７４ － ７．８３ （ｍ， １ Ｈ） ８．１０ （ｄ， Ｊ＝８．０８ Ｈｚ， １ Ｈ） ８．１７ （ｔ， Ｊ＝１．８９ Ｈｚ， １ Ｈ） ８．２３ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ） ８．７０ （ｄ， Ｊ＝２．５３ Ｈｚ， １ Ｈ） ９．７９ （ｓ， １ Ｈ）． Step 2: Synthesis of 5-chloro-N- (3-methylsulfonylphenyl) -2- [4- (trifluoromethoxy) phenoxy] pyridine-3-carboxamide

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

(A assay method)
The ability of the pyridinecarboxamide derivative exemplified above to inhibit the Nav1.8 channel was measured using one or more of the methods described below.

(HEK Nav1.8 β1 / β2 stable expression cell line)
A HEK293 cell line was constructed that stably expresses human Nav1.8 (hNav1.8) ion channels with β1 / β2 subunits. This cell line is suitable for _IC50 measurements in fluorescence and electrophysiology-based assays. It is also suitable for conducting mechanism-of-action pharmacological studies in electrophysiological assays. DMEM / high glucose medium containing HEK293 Nav1.8 cells as an adhesive monolayer and selective agent G418 (400 mg / L) and puromycin (0.5 mg / L), 10% fetal bovine serum, Na pyruvate (2 mM) , Hepes (10 mM), culture at 37 ° C., 10% CO ₂ .

(Nav1.8 Fluorescence Inhibition Assay)
Compounds were supplied as 10- mM stock solution or as 10- mM stock solution using DMSO as a base. The concentration reaction curve was created using a multi-channel pipettor manufactured by Matrix. The compound source plate was made by diluting a 10 mM compound stock to make a 500 μM (100-fold) solution in DMSO of a 96-well V-bottom plate. The compound was then serially diluted with 100% DMSO to create a dose-response curve for a 5-point, 4-fold dilution scheme. Next, a 2 μL 100-fold dose-response curve was added to the pre-incubation and stimulation assay plates. Then, 100 μL of pre-incubation buffer and 200 μL of stimulus buffer were added to the plate to set the final assay test concentration range to 5 μM to 0.02 μM and the final DMSO concentration to 1%.

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 CaCl ₂ , 1 mM MgCl ₂ , 10 mM HEPES, pH 7.4) and the cell culture medium was removed. The Na-sensitive fluorescent dye Asante Natrium Green-2 (ANG-2) is incubated for 60 minutes for equilibration and then washed with 2K EBSS. The plate is transferred to a fluorescent plate reader (FLIPR ^TM , Molecular Devices), and fluorescence measurement is performed using an excitation wavelength of 490 nm and an emission wavelength of 565 nm. The compound is preincubated in the presence of ouabain (30 μM) at the final test concentration for 5 minutes to suppress Na + efflux via the Na + / K + exchanger. Following the pre-incubation step, the hNav1.8 channel is stimulated with 10 μM pyrethroid deltamethrin to prevent channel inactivation. The assay was performed for 15 minutes using the base and 30 μM tetracaine as negative and positive controls, respectively. The peak change in fluorescence for the wells of the negative and positive controls was calculated and fitted to the logistic equation to determine the _IC50 .

(Nav 1.8 inhibition assay by _PatchXpress )
HEK-Nav1.8 β1 / β2 cells were recorded in whole cell cell patch clamp using the PatchXpress automatic patch clamp platform (Molecular Devices). Cell suspensions were obtained by trypsinizing the attached monolayer and then gently rocking for at least 30 minutes. Compounds were prepared from 10 mM DMSO stock.

Variants of the Nav1.8 channel were evaluated using Protocol 1, in which cells were first voltage-fixed at a holding potential of -100 mV to keep Nav1.8 closed and quiescent. After the current amplitude stabilized, a series of 5-second adjustment steps to the gradually depolarizing voltage (-100-0 mV) was used to determine the steady-state inactivation midpoint voltage for each cell. The holding potential was then reset to a voltage that was approximately 50% inactive (automatically set by the V- _half -PatchXpress script) so that inhibition of closed and inactivated channels could be assessed. .. Protocol 1 was run at a frequency of 0.1 Hz until the current amplitude stabilized (automatically determined by the PatchXpress script). The effect of the test reagents on the current amplitude of Nav was monitored using a custom PatchXpress stability script to determine the timing of compound addition and washout.

Data was processed and analyzed using DataXpress 2.0 (Molecular Devices). The rate of inhibition is according to the formula:% inhibition = (((control + washout) / 2) -drug) / ((control + washout) / 2) * 100 (see schematic diagram above). Calculated using Microsoft Excel so that it is normalized to the average of control and washout currents. Normalized concentration-response relationships were fitted using a 4-parameter logistic model or sigmoid dose-response model from XLfit software (IDBS).

(HNa _V 1.8 Automatic Patch Clamp-IonFlux ^HT Assay)
An IonFlex HT automatic whole cell patch clamp device (Fluxion Biosciences, Alameda, USA, USA) was used to record the inward sodium current.

Cells HEK-293 cells were stably transfected with human NaV1.8 cDNA (X-type voltage-gated sodium channel α subunit, transfection number NM_006514) and human β subunit 1 (acsession number NM_001037). Cells were harvested with trypsin and maintained at room temperature in serum-free medium prior to recording. The cells were washed, resuspended in extracellular solution and then filled into the device.

Test Concentration: The stock solution was prepared in DMSO at 300 times the final assay concentration and stored at −80 ° C. until the day of the assay. On the day of the assay, the aliquot of the stock solution was thawed and diluted with an external solution to give the final test concentration. The final concentration of 0.33% DMSO was maintained at each concentration of assay compound and control.

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

Extracellular solution (mM): 150 NaCl, 4 BaCl, 1 MgCl ₂ , 1.8 CaCl ₂ , 10 HEPES, 5 glucose, (titrated with pH 7.4, 10 M NaOH).

When the sodium channel is held at the depolarized membrane potential, it remains inactivated until the channel opens and inactivates, the membrane potential returns to the hyperpolarized membrane potential, and the inactivated channel recovers to a closed state. Will be. A compound that exhibits greater inhibition at pulse 2 than at pulse 1 is a state-dependent inhibitor. One example is tetracaine, which is a more potent inhibitor in the inactivated state than in the tense or open state.

The cells were held at -120 mV for 50 ms and then stepped to -10 mV over 2 seconds to completely inactivate the sodium channels (pulse 1) and return to -120 mV for 10 ms (complete recovery from inactivity). However, the channel to which the inhibitor is bound may not recover from inactivation) and was stepped to -10 mV for 50 ms (Pulse 2). The sweep interval is 20 seconds (0.05 Hz). It was applied to each concentration of compound for 2 minutes. The assay was performed at room temperature.

Reference compound: Tetracaine was used as a positive control and the test was performed at the same time as the test compound.

Data analysis: Only current amplitudes above 3 nA were analyzed at the reference stage. The amplitude of the sodium current was calculated by measuring the difference between the peak inward current (ie, the peak of the current) when stepped to -10 mV and the remaining current at the end of the step. Sodium current was assessed under base control conditions and then at the end of each 2 minute compound application. The results of individual cell traps were normalized to the amplitude of the base control and a mean ± SEM was calculated for each compound concentration. These values were then plotted to calculate the estimated _IC50 curve fit.

Table 1 shows the estimated _IC50 values of the pyridinecarboxamide compounds exemplified above.

(Reference)
All publications, patent applications, patents and other references referred to herein represent the level of one of ordinary skill in the art to which the subject matter of this disclosure relates. All publications, patent applications, patents and other references are to the same extent as if specific and individually indicated that individual publications, patent applications, patents and other references are incorporated by reference. , Incorporated herein by reference. Many patent applications, patents and other references are referenced herein, but such references form part of the general knowledge of the art in any of these documents. It will be understood that it does not admit that.

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Jarvis, M.M. F. Honore, P.M. Shieh, C.I. C. Chapman, M. et al. Joshi, S.M. Zhang, X. F. Kort, M.M. Carroll, W. et al. Marron, B. Atkinson, R.M. Thomas, J.M. Liu, D. Krambis, M. et al. Liu, Y. McGarautty, S.M. Chu, K.K. Roeloffs, R.M. Zhong, C.I. M. Mikusa, J. et al. P. Hernandez, G.M. Gauvin, D.I. Wade, C.I. Zhu, C.I. Pai, M. et al. Scanio, M. et al. Shi, L. Drizin, I. Gregg, R.M. Matulenko, M. et al. Hakeem, A. Grosst, M. et al. Johnson, M.D. Marsh, K.K. Wagoner, P.M. K. Sullivan, J.M. P. Faltinek, C.I. R. Krafte, D.I. S. , A-803467, a potent and selective Na (v) 1.8 sodium channel blocker, attendates neuropathic and inflammation pain in the rat. P Natl Acad Sci USA 2007, 104 (20), 8520-8525.
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The above-mentioned subjects have been described in some detail using examples and examples for the purpose of clarifying understanding, but those skilled in the art will make certain changes and amendments within the scope of the attached claims. You will understand what you get.

Claims (49)

Compound of formula (I):

[During the ceremony,
X is -CH- or nitrogen;
Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;
R ₁ is an aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl. , C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C1 _- C ₈ alkoxyl, mono-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and arylalkoxyl. Substituted with one or more groups selected from the group consisting of;
_R2 is selected from the group consisting of aryls, heteroaryls and heterocycles, wherein the aryls, heteroaryls and heterocycles are unsubstituted or mono-, di- and trihalo-C1 _{- C4} alkyls. Substituent or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C1 _- C ₈ alkoxyl, mono-, di- or trihaloalkenyl. , Arylalkenyl, oxo, alkylsulfinyl, alkylsulfonyls, alkyliminosulfanonyls, alkylsulfoxides, sulfonamides, morpholinyls and oxazolyls substituted with one or more groups selected from the group;
R ₃ is hydrogen, cyano, halogen, C1-C ₈ alkoxyl, mono-, di- and trihalo-C ₁ -C ₄ alkyl, mono-, di- and trihalo-C _{1 -} C when Y is carbon. Selected from the group consisting of ₄ alkoxyls, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ , not present when Y is nitrogen;
_R4 is hydrogen, cyano, halogen, C1 _- C8 alkoxyl, mono-, di- and trihalo-C _{1 -} C ₄ alkyl, mono-, di- and trihalo _{-C 1-4 alkoxyl} , substituted or non-substituted. Selected from the group consisting of substituted C1 _- C8 alkyl and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or R ₃ and R ₄ together _{, R 3 and} R. Form a C3 _{- C5} carbon ring containing the carbon atom to which ₄ is bonded];
And its pharmaceutically acceptable salt. The compound according to claim 1 [in the formula,
X is -CH- or nitrogen;
Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;
R ₁ is phenyl or pyridinyl, and the phenyl or pyridinyl is unsubstituted, or substituted or unsubstituted C ₁ -C ₈ alkyl, halogen, -OR ₅ (in the formula, R ₅ is C). ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ and-(CH ₂ ) _p -CF ₃ (in the formula, p is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8). (Selected from the group consisting of) and -S-CF ₃ substituted with one or more groups selected from the group consisting of 3;
_R2 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazolyl, pyridin-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl. , Pyridyl, pyrimidinyl, pyridadinyl, pyridin- ₁ -oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzothiazolyl are unsubstituted, unsubstituted or substituted C1- C ₈ alkyl, halogen, cyano, oxo, -O-R ₅ (in the formula, R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ and -CHF ₂ ),-(CH ₂ ). ) _Q -OH (in the formula, q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8), -NR ₆ R ₇ (in the formula, R ₆ and R ₇ is selected from the group consisting of H and C ₁ -C ₄ alkyl), morpholinyl, oxazolyl, -C (= O) -R ₈ (in the formula, R ₈ is -NR ₆ R ₇ (in the formula). , R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl) and (selected from the group consisting of C ₁ -C ₄ alkyl), -S (= O) -R ₉ , -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the equation, each R ₉ is independent. Thus, C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), R. ₁₀ is H or C1 _{- C4} alkyl and _R11 is C1- _C4 alkyl) and is substituted with _one or more groups selected from the group, where Y is nitrogen and If R ₂ is phenyl or pyridyl, then R ₈ cannot be -NR ₆ R ₇ ;
R ₃ is hydrogen, cyano, halogen, -CF ₃ , C ₁ -C ₈ alkoxyl, -O-CH (F) ₂ , substituted or unsubstituted C ₁ -C ₈ alkyl, C _3- , when Y is carbon. Selected from the group consisting of C8 cycloalkyl, -N ⁺ ₍ = O) ^-O- , not present when Y is nitrogen;
R ₄ is selected from the group consisting of hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, -CF ₃ , substituted or unsubstituted C ₁ -C ₈ alkyl, and morpholinyl, with R ₃ and R ₄ simultaneously. Subject to non-hydrogen; or R ₃ and R ₄ together form a C ₃ -C ₅ carbon ring containing the carbon atom to which R ₃ and R ₄ are attached];
And its pharmaceutically acceptable salt. The compound according to claim 1, which has the following structure:

[During the ceremony,
X is -CH- or nitrogen;
Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen;
_R2 is selected from the group consisting of aryls, heteroaryls and heterocycles, wherein the aryls, heteroaryls and heterocycles are unsubstituted or mono-, di- and trihalo-C1 _{- C4} alkyls. Substituent or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C1 _- C ₈ alkoxyl, mono-, di- or trihaloalkenyl. , Arylalkenyl, Oxo, Alkylsulfinyl, Alksulfonyl, Alkyliminosulfanonyl, Alkylsulfoxide, Sulfonamide, Morphorinyl and Oxazolyl and is substituted with one or more groups selected from the group;
R ₃ is hydrogen, cyano, halogen, C1-C ₈ alkoxyl, mono-, di- and trihalo-C ₁ -C ₄ alkyl, mono-, di- and trihalo-C _{1 -} C when Y is carbon. Selected from the group consisting of ₄ alkoxyls, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ , not present when Y is nitrogen;
_R4 is hydrogen, cyano, halogen, C1 _- C8 alkoxyl, mono-, di- and trihalo-C _{1 -} C ₄ alkyl, mono-, di- and trihalo _{-C 1-4 alkoxyl} , substituted or non-substituted. Selected from the group consisting of substituted C1 _- C8 alkyl and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or R ₃ and R ₄ together _{, R 3 and} R. Form a C3 _{- C5} carbon ring containing the carbon atom to which ₄ is bonded;
n is an integer selected from 0, 1, 2, 3, 4 and 5;
Each R ₂₄ is independently mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, Selected from the group consisting of amino, nitro, aryloxyl, aryl, C1 _- C8 _alkoxyl , mono-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and arylalkoxyl];
And its pharmaceutically acceptable salt. The compound according to claim 3 , wherein R ₂ is selected from the group consisting of the following:

[During the ceremony,
m is an integer selected from the group consisting of 0, 1, 2, 3 and 4;
R ₂₅ is selected from the group consisting of H, morpholinyl, oxazolyl, halogen, cyano,-(CH ₂ ) _q -OH (in the formula, q is 1, 2, 3, 4, 5, 6, 7 and 8). (Integer), -C (= O) -R ₈ (in the equation, R ₈ is selected from the group consisting of -NR ₆ R ₇ and C ₁ -C ₄ alkyl, R ₆ and R ₇ are H and (Selected from the group consisting of C ₁ -C ₄ alkyl), -S (= O) -R ₉ , -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ And -N = S (= O)-(R ₁₁ ) ₂ (in the formula, each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ ). And R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), R ₁₀ is H or C ₁ -C ₄ alkyl, and R ₁₁ is C ₁ -C ₄ alkyl). Selected from the group consisting of, provided that if Y is nitrogen and R ₂ is phenyl or pyridyl, then R ₈ cannot be -NR ₆ R ₇ ;
_R26 is a halogen or cyano;
Each R ₂₇ is independently selected from the group consisting of H, halogen, C ₁ -C ₈ alkoxyl, cyano and -NR ₆ R ₇ ;
Each R ₂₈ is independently an H or C1 _{- C4} alkyl]. The compound according to claim 1, wherein the compound of the formula (I) is a compound of the formula (IF):

[During the ceremony,
R ₂ is selected from the group consisting of aryl and heteroaryl, and the aryl or heteroaryl is optionally cyano, heterocycloalkyl, —S (= O) —R ₉ , —S (= O) ₂ −. R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the equation, each R ₉ is independently C ₁ -C ₄ Alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), where R ₁₀ is H or C ₁ -C. It is ₄ -alkyl and R ₁₁ is substituted with a substituent selected from the group consisting of C1 _{- C4} alkyl);
R ₁₂ is a halogen;
R ₁₃ is _a C1- _C4 alkyl]. The aryls and heteroaryls are selected from the group consisting of phenyl, benzothiazolyl, pyridyl, pyridyl N-oxide and pyrimidinyl, respectively, optionally cyano, heterocycloalkyl, -S (= O) -R ₉ ,-. S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the equation, each R ₉ is independent. C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl) and R ₁₀ Is H or C1 _{- C4} alkyl and _R11 is substituted with a substituent selected from the group consisting of C1 _{- C4} alkyl);
R ₁₂ is fluorine;
The compound according to claim 5, wherein R ₁₃ is methyl. _R2 is 1,3-benzothiazole-6-yl, 3-morpholinophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-pyridyl, 4-pyridyl, 6-cyano-3-pyridyl, 3-methylsulfinyl. Phenyl, 3-oxazol-5-ylphenyl, 3-dimethylsulfamoylphenyl, 1,3-benzothiazole-2-yl, pyrimidine-4-yl, (trifluorosulfonyl) phenyl, 3- (methylsulfonimideyl) ) Phenyl, 2-methoxy-4-pyridyl, 3- (N, S-dimethylsulfonimideyl) phenyl, 2-methyl-4-pyridyl, 6-methyl-3-pyridyl, pyridazine-4-yl and dimethyl (oxo) )-Λ ⁶ -Sulfanilidene] Amino] The compound according to claim 6 selected from the group consisting of phenyl. The compound according to claim 1, wherein the compound is a compound of the formula (IG):

[During the ceremony,
R ₁ is a phenyl substituted with _one or more of the C1-C8 alkyl, halogen and C1-C _{- 8} alkoxyl, wherein the C1 _{-C-8 alkoxyl is} optionally one or more. Substituted with multiple halogens;
R ₁₄ is _a C1- _C4 alkyl]. The R ₁ is 2,4-dichlorophenyl, 2,4-dimethylphenyl, 2-chloro-4-methoxyphenyl, 2-propylphenyl, 2-methoxy-4-methylphenyl, 2-methoxy-4-chlorophenyl, 2 -Selected from the group consisting of isopropoxyphenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2-chloro-4-methoxyphenyl, 3,4-difluorophenyl and 2-chloro-4-fluorophenyl. The compound according to claim 8. The compound according to claim 1, wherein the compound is a compound of the formula (I-Hi):

[During the ceremony,
R ₁ is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazole- _4yl , wherein the phenyl and pyridyl may be unsubstituted or halogen, C1 _- C8 alkyl, -O-. R ₅ (in the formula, R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ and-(CH ₂ ) _p -CF ₃ (in the formula, p is 1, 2, 3, 4, 5). , Which is an integer selected from the group consisting of 6, 7 and 8), -S-CF ₃ , -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are H and It may be substituted with one or more of (selected from the group consisting of C1 _{- C4} alkyl);
R ₃ and R ₄ are H or -CF ₃ , but if R ₃ is H, then R ₄ is -CF ₃ , and if R ₄ is H, then R ₃ is -CF ₃ . year;
R ₁₄ is _a C1- _C4 alkyl;
R ₁₅ is O or NR ₁₀ (in the formula, R ₁₀ is H or C1 _{- C4} alkyl)]. R ₁ is 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-flulophenyl, 2-isopropylphenyl, 3,4-difluorophenyl, 2 , 4-Difluorophenyl, 3,5-difluorophenyl, 4- (2,2,2-trifluoroethoxy) phenyl, 4- (trifluoromethylsulfanyl) phenyl, 2-dimethylaminophenyl, 2-triflulomethylphenyl , 2,4-Dimethoxyphenyl, 3,4,5-trifluorophenyl, 3,5-dichlorophenyl, 6-trifluoromethyl-3-pyridyl, 1,3-benzothiazole-4-yl, 4-difluoromethoxyphenyl The compound according to claim 10, which is selected from the group consisting of 2-chloro-4-fluorophenyl, 2-chloro-4-methoxyphenyl and 2-chlorophenyl. The compound according to claim 1, wherein the compound is a compound of the formula (IH-ii):

[During the ceremony,
R ₁ is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazole- _4yl , wherein the phenyl and pyridyl may be unsubstituted or halogen, C1 _- C8 alkyl, -O-. R ₅ (in the formula, R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ and-(CH ₂ ) _p -CF ₃ (in the formula, p is 1, 2, 3, 4, 5). , Which is an integer selected from the group consisting of 6, 7 and 8), -S-CF ₃ , -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are H and It may be substituted with one or more of (selected from the group consisting of C1 _{- C4} alkyl);
R ₃ and R ₄ are H or -CF ₃ , but if R ₃ is H, then R ₄ is -CF ₃ , and if R ₄ is H, then R ₃ is -CF ₃ . Let]. The compound according to claim 12, wherein _R1 is selected from the group consisting of 2,4-dichlorophenyl, 4-difluoromethoxyphenyl and 2-chloro-4-methoxyphenyl. The compound according to claim 1, wherein the compound is a compound of the formula (I):

[During the ceremony,
R ₂ is selected from the group consisting of phenyl, pyridadinyl and pyridyl, wherein the phenyl is halogen, —S (= O) —R ₉ , —S (= O) ₂ -R ₉ and —S (= O) ( = NR ₁₀ ) -R ₁₁ (In the formula, each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are H and C. (Selected from the group consisting of ₁ -C ₄ alkyl), where R ₁₀ is H or C ₁ -C ₄ alkyl and R ₁₁ is C ₁ -C ₄ alkyl). May be;
R ₁₆ is a halogen;
R ₁₇ is _a C1- _C4 alkyl]. 14. According to claim 14, _R2 is selected from the group consisting of 3-methylsulfinylphenyl, 2-fluoro-5-methylsulfonylphenyl, 3- (N, S-dimethylsulfonimideyl) phenyl, pyridadinyl and pyridyl. Compound. The compound according to claim 1, wherein the compound is a compound of the formula (IJ):

[During the ceremony,
R ₂ is selected from the group consisting of phenyl and pyridyl, wherein the phenyl is halogen, -C (= O) -R ₈ (in the formula, R ₈ is -NR ₆ R ₇ (in the formula, R ₆ and R). ₇ is selected from the group consisting of H and C1 _{- C4} alkyl) and C1 _{- C4} alkyl (selected from the group), -S (= O) _-R9 , -S (= O). ) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the formula, each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), where R ₁₀ is H or C. ₁ - _C4 alkyl and _R11 is C1- _C4 alkyl) substituted with _one or more;
R ₁₈ is a halogen]. _R2 is 3-methylsulfonylphenyl, 3-methylsulfinylphenyl, 3- (dimethylsulfamoyl) phenyl, 2-fluoro-5-methylsulfonylphenyl, 3- (methylsulfonimideyl) phenyl, 3-carbamoylphenyl. 3, (N, S-dimethylsulfoneimideyl) The compound according to claim 16, which is selected from the group consisting of phenyl, 3-pyridyl and 4-pyridyl. The compound according to claim 1, wherein the compound is a compound of the formula (IK):

[During the ceremony,
R ₁ is halogen, C ₁ -C ₈ alkyl, -OR ₅ (in the formula, R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ and-(CH ₂ ) _p -CF ₃ Substituted with one or more of (in the formula, p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8). It is phenyl]. _R1 is 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,4-difluorophenyl and 3 , 4-The compound according to claim 18, selected from the group consisting of 4-difluorophenyl. The compound according to claim 1, wherein the compound is a compound of the formula (IL):

[During the ceremony,
R ₂ is selected from the group consisting of phenyl, pyridyl and pyridazine-4-yl, wherein the phenyl is -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the formula, each R ₉ is independently C1 _{-C 4 alkyl} or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are respectively. H, R ₁₀ is H or C ₁ -C ₄ alkyl, and R ₁₁ is C ₁ -C ₄ alkyl). The compound according to claim 1, wherein the compound is a compound of the formula (IMi):

[During the ceremony,
_R2 is 3- (N, S-dimethylsulfonimideyl) phenyl or pyrididin-4-yl;
R ₁₆ is a halogen;
R ₁₉ is _a C1- _C4 alkyl]. The compound according to claim 1, wherein the compound is a compound of the formula (IM-ii):

[In the formula, R ₁ is selected from the group consisting of 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl. Will be]. The compound according to claim 1, wherein the compound is a compound of the formula (IM-iii):

[During the ceremony,
_R1 is selected from the group consisting of 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl;
_R20 is _a C1- _C4 alkyl;
R ₂₁ is H or C1 _{- C4} alkyl]. The compound according to claim 1, wherein the compound is a compound of the formula (IM-iv):

[In the formula, R ₁ is selected from the group consisting of 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl. Will be]. The compound according to claim 1, wherein the compound is a compound of the formula (IN):

[During the ceremony,
_R2 is selected from the group consisting of 3- (N, S-dimethylsulfonimideyl) phenyl, 3- (methylsulfonimideyl) phenyl and pyridazine-4-yl;
R ₁₆ is a halogen;
R ₁₉ is _a C1- _C4 alkyl]. The compound according to claim 1, wherein the compound is a compound of the formula (IO):

[During the ceremony,
R ₂ is selected from the group consisting of phenyl, pyridyl and pyridazine-4-yl, wherein the phenyl is -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the formula, each R ₉ is independently C1 _{-C 4 alkyl} or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are respectively. H, R ₁₀ is H or C ₁ -C ₄ alkyl, and R ₁₁ is C ₁ -C ₄ alkyl). The compound according to claim 1, wherein the compound is a compound of the formula (IP):

[In the formula, R ₁ is 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl, 2,4-difluorophenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2-chloro- Selected from the group consisting of 4-methoxyphenyl, 3,4-diflulophenyl and 2-chloro-4-fluorophenyl]. The compound according to claim 1, wherein the compound is a compound of the formula (IQ):

[During the ceremony,
_R2 is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyridadinyl, thiadiazolyl, pyrazolyl and 1,2,4-triazolyl.
The phenyl is a group consisting of unsubstituted or substituted C ₁ -C ₈ alkyl, halogen, cyano, oxo, -OR ₅ (in the formula, R ₅ is C ₁ -C ₈ alkyl, -CF ₃ and -CHF ₂ ). (Selected from),-(CH ₂ ) _q -OH (in the equation, q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8), -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), morpholinyl, oxazolyl, -C (= O) -R ₈ (in the formula, R ₈ ). Is -NR ₆ R ₇ (in the formula, R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl) and C ₁ -C ₄ alkyl. -S (= O) -R ₉ , -S (= O) ₂ -R ₉ , -S (= O) (= NR ₁₀ ) -R ₁₁ and -N = S (= O)-(R ₁₁ ) ₂ (In the formula, each R ₉ independently consists of C ₁ -C ₄ alkyl, -CF ₃ or -NR ₆ R ₇ (in the formula, R ₆ and R ₇ consist of H and C ₁ -C ₄ alkyl. R ₁₀ is H or C ₁ -C ₄ alkyl and R ₁₁ is C ₁ -C ₄ alkyl) and is substituted with one or more groups selected from the group). Has been;
Pyridil is unsubstituted or substituted with C1 _{-C8 alkyl, oxo, C1-C-8 alkoxyl and halogen} ;
R ₁₈ is a halogen]. The compound according to claim 1, wherein the compound is a compound of the formula (IR):

[During the ceremony,
_R2 is 3- (methylsulfonimideyl) phenyl or pyridazine-4-yl;
R ₂₂ and R ₂₃ are C1 _{- C4} alkyl, respectively]. The compound according to claim 1, wherein the compound is a compound of the formula (IS):

[During the ceremony,
_R2 is 3- (methylsulfonimideyl) phenyl or pyridazine-4-yl;
R ₁₆ and R ₁₈ are halogens, respectively]. The compound of the formula (I), which is the compound according to claim 1,
6-Chloro-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) Pyridine-3-carboxamide (Intermediate 3);
N- (1,3-Benzothiazole-6-yl) -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridin-3-carboxamide (1);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-morpholinophenyl) -5- (trifluoromethyl) pyridin-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) pyridin-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-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (6);
N- (6-cyano-3-pyridyl) -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide (7);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-methylsulfinylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (8);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-oxazole-5-ylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (9);
N- [3- (dimethylsulfamoyl) phenyl] -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridin-3-carboxamide (10);
N- (1,3-Benzothiazole-2-yl) -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridin-3-carboxamide (11);
2- (4-Fluoro-2-methoxy-phenoxy) -N-pyrimidine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (12);
2- (4-Fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) -N- [3- (trifluoromethylsulfonyl) phenyl] pyridin-3-carboxamide (13);
2- (4-Fluoro-2-methoxy-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (14);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (2-methoxy-4-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (15);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide (16);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (2-methyl-4-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (17);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (6-methyl-3-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (18);
2- (4-Fluoro-2-methoxy-phenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (19);
N- [3-[[dimethyl (oxo)]-λ ⁶ -sulfanilidene] amino] phenyl] -2- (4-fluoro-2-methoxy-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide ( 20);
2- (2,4-dichlorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (21);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-morpholinophenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (22);
2- (2-Chloro-4-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (23);
N- (3-Methylsulfonylphenyl) -2- (2-propylphenoxy) -5- (trifluoromethyl) pyridin-3-carboxamide (24);
2- (2-Methoxy-4-methyl-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (25);
2- (4-Chloro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (26);
2- (2-isopropoxyphenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-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) pyridin-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) pyridin-3-carboxamide (35);
2- (2-Chloro-4-fluoro-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (36);
N- (3-Methylsulfonylphenyl) -2- [2-methyl-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (37);
N- (3-Methylsulfonylphenyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (38);
2- [4- (Difluoromethoxy) phenoxy] -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (39);
2- [3-Fluoro-4- (trifluoromethoxy) phenoxy] -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (40);
N- (3-Methylsulfonylphenyl) -2-phenoxy-5- (trifluoromethyl) pyridin-3-carboxamide (41);
2- (3-Fluorophenoxy) -N- (3-Methylsulfonylphenyl) -5- (trifluoromethyl) Pyridine-3-carboxamide (42);
2- (2,5-difluorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-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) pyridin-3-carboxamide (45);
2- (2-Isopropylphenoxy) -N- (3-Methylsulfonylphenyl) -5- (Trifluoromethyl) Pyridine-3-Carboxamide (46);
2- (3,4-difluorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (47);
2- (2,4-difluorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (48);
2- (3,5-difluorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (49);
N- (3-Methylsulfonylphenyl) -2- [4- (2,2,2-trifluoroethoxy) phenoxy] -5- (trifluoromethyl) pyridin-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) pyridin-3-carboxamide (52);
N- (3-Methylsulfonylphenyl) -5- (trifluoromethyl) -2- [2- (trifluoromethyl) phenoxy] pyridin-3-carboxamide (53);
2- (2,4-dimethoxyphenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (54);
N- (3-Methylsulfonylphenyl) -5- (trifluoromethyl) -2- (3,4,5-trifluorophenoxy) pyridin-3-carboxamide (55);
2- (3,5-dichlorophenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (56);
N- (3-Methylsulfonylphenyl) -5- (trifluoromethyl) -2-[[6- (trifluoromethyl) -3-pyridyl] oxy] Pyridine-3-carboxamide (57);
2- (1,3-Benzothiazole-4-yloxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (58);
2- [4- (Difluoromethoxy) phenoxy] -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (59);
2- (2-Chloro-4-fluoro-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (60);
2- (2-Chloro-4-methoxy-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (61);
2- (2-Chlorophenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (62);
2- (2,4-dichlorophenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (63);
2- [4- (Difluoromethoxy) phenoxy] -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (64);
2- (2-Chloro-4-methoxy-phenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (65);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (66);
4- (4-Fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (67);
4- (4-Fluoro-2-methoxy-phenoxy) -N- (3-methylsulfinylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (68);
4- (4-Fluoro-2-methoxy-phenoxy) -N- (2-fluoro-5-methylsulfonyl-phenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (69);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -4- (4-fluoro-2-methoxy-phenoxy) -6- (trifluoromethyl) pyridin-3-carboxamide (70);
4- (4-Fluoro-2-methoxy-phenoxy) -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (71);
4- (4-Fluoro-2-methoxy-phenoxy) -N- (4-pyridyl) -6- (trifluoromethyl) pyridin-3-carboxamide (72);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [2- (dimethylamino) -4-pyridyl] -6- (trifluoromethyl) pyridin-3-carboxamide (73);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (3-methylsulfonylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (74);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (3-methylsulfinylphenyl) -6- (trifluoromethyl) pyridin-3-carboxamide (75);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (dimethylsulfamoyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (76);
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-pyridyl) -6- (trifluoromethyl) pyridin-3-carboxamide (78);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (4-pyridyl) -6- (trifluoromethyl) pyridin-3-carboxamide (79);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (80);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (N, S-dimethylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (82) ;
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (83);
4- (4-Fluoro-2-methoxy-phenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (84);
4- (4-Fluoro-2-methyl-phenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (85);
4- [4- (Difluoromethoxy) phenoxy] -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (86);
N- (1-oxide pyridine-1-ium-3-yl) -4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridine-3-carboxamide (87);
4- (2,4-Dimethoxyphenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (88);
4- (2,4-Difluorophenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -6- (trifluoromethyl) pyridine-3-carboxamide (89);
3- (4- (3,4-difluorophenoxy) -6- (trifluoromethyl) nicotinamide) pyridin 1-oxide (90);
N- [3- (Methylsulfonimideyl) phenyl] -4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridin-3-carboxamide (91);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridin-3-carboxamide (92);
4- (4-Fluoro-2-methyl-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (93);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -4- (4-fluoro-2-methyl-phenoxy) -6- (trifluoromethyl) pyridin-3-carboxamide (94);
4- (4-Fluoro-2-methyl-phenoxy) -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (95);
N-pyridazine-4-yl-4- [4- (trifluoromethoxy) phenoxy] -6- (trifluoromethyl) pyridin-3-carboxamide (96);
4- [4- (Difluoromethoxy) phenoxy] -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (97);
4- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (98);
4- (2,4-dimethoxyphenoxy) -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (99);
4- (2,4-difluorophenoxy) -N-pyridazine-4-yl-6- (trifluoromethyl) pyridin-3-carboxamide (100);
4- [4- (Difluoromethoxy) phenoxy] -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (101);
4- (2,4-dimethoxyphenoxy) -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (102);
4- (2,4-difluorophenoxy) -N- [3- (methylsulfonimideyl) phenyl] -6- (trifluoromethyl) pyridin-3-carboxamide (103);
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-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (109);
2- (4-Fluoro-2-methyl-phenoxy) -N- (2-oxo-1H-pyridin-4-yl) -5- (trifluoromethyl) pyridin-3-carboxamide (110);
5-bromo-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (111);
5-Cyclopropyl-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (112);
2- (4-Fluoro-2-methyl-phenoxy) -N- (3-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (113);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -2- (4-fluoro-2-methyl-phenoxy) -5- (trifluoromethyl) pyridine-3-carboxamide (114);
2- (4-Fluoro-2-methyl-phenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (115);
2- (4-Fluoro-2-methyl-phenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (116);
2- (4-Fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (117);
2- (4-Fluoro-2-methoxy-phenoxy) -5,6-dimethyl-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (118);
5-Chloro-2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (119);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) -6,7-dihydro-5H-cyclopentane [b] pyridin-3-carboxamide (120);
N- (3-Methylsulfinylphenyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (121);
N- (3-Sulfamoylphenyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (122);
N- [3- (Methylsulfonimideyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (123);
N- [3- (N, S-dimethylsulfonimideyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide (124);
N- (3-Ethylsulfonylphenyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (125);
N- (3-pyridyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (126);
N- (4-pyridyl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (127);
N-pyridazine-4-yl-2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (128);
N- [3-[[dimethyl (oxo)]-λ ⁶ -sulfanilidene] amino] phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide (129) );
N- [3- (Methylsulfonimideyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide, enantiomer A (130);
N- [3- (Methylsulfonimideyl) phenyl] -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide, enantiomer B (131);
N- (1-oxide pyridine-1-ium-3-yl) -2- [4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridine-3-carboxamide (132);
2- (4-Fluoro-2-methyl-phenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide (133);
2- (4-Fluoro-2-methoxy-phenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide (134);
2- (2,4-difluorophenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide (135);
3- (2- (4- (Difluoromethoxy) phenoxy) -5- (trifluoromethyl) nicotinamide) pyridin 1-oxide (136);
3- (2- (2,4-dimethoxy) phenoxy) -5- (trifluoromethyl) nicotinamide) Pyridine 1-oxide (137);
3- (2- (2-Chloro-4-methoxyphenoxy) -5- (trifluoromethyl) nicotinamide) pyridin 1-oxide (138);
3- (2- (3,4-difluorophenoxy) -5- (trifluoromethyl) nicotinamide) pyridin 1-oxide (139);
2- (2-Chloro-4-fluoro-phenoxy) -N- (1-oxide pyridine-1-ium-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide (140);
N- (1-oxide pyridine-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) pyridin-3-carboxamide (142);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (3-ethylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (143);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (N, S-dimethylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (144) ;
4-Pyridyl 2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxylate (145);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (3-cyanophenyl) -5- (trifluoromethyl) pyridine-3-carboxamide (146);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (1-methylpyrazole-4-yl) -5- (trifluoromethyl) pyridin-3-carboxamide (147);
N- (3-carbamoylphenyl) -2- [2-chloro-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (148);
N- (3-Acetylphenyl) -2- [2-chloro-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (149);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (1-methyl-2-oxo-4-pyridyl) -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) pyridin-3-carboxamide (152);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (4-methylsulfonylphenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (153);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (dimethylsulfamoyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (154);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (3,4-difluorophenyl) -5- (trifluoromethyl) pyridin-3-carboxamide (155);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (6-methoxy-3-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (156);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N-pyrimidine-5-yl-5- (trifluoromethyl) pyridin-3-carboxamide (157);
N- (2-Chloro-4-pyridyl) -2- [2-chloro-4- (trifluoromethoxy) phenoxy] -5- (trifluoromethyl) pyridin-3-carboxamide (158);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (6-fluoro-3-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (159);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- [3- (hydroxymethyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (160);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-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) pyridin-3-carboxamide (163);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (2-methyl-4-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (164);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (2-fluoro-4-pyridyl) -5- (trifluoromethyl) pyridin-3-carboxamide (165);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (thiadiazole-5-yl) -5- (trifluoromethyl) pyridin-3-carboxamide (166);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (2-methylpyrazole-3-yl) -5- (trifluoromethyl) pyridin-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-triazole-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide ( 169);
2- [2-Chloro-4- (trifluoromethoxy) phenoxy] -N- (1-methyl-1,2,4-triazole-3-yl) -5- (trifluoromethyl) pyridine-3-carboxamide ( 170);
2- (2,4-dimethoxyphenoxy) -N- [3- (N, S-dimethylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (171);
2- (2,4-dimethoxyphenoxy) -N- [3 (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (172);
2- (2,4-dimethoxyphenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (173);
2- (2,4-difluorophenoxy) -N- [3- (methylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (174);
2- (2,4-difluorophenoxy) -N- [3- (N, S-dimethylsulfonimideyl) phenyl] -5- (trifluoromethyl) pyridin-3-carboxamide (175);
2- (2,4-difluorophenoxy) -N-pyridazine-4-yl-5- (trifluoromethyl) pyridin-3-carboxamide (176);
5-Cyano-2- (4-fluoro-2-methoxy-phenoxy) -6-methyl-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (177);
5-Fluoro-2- (4-fluoro-2-methoxy-phenoxy) -6-methoxy-N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (178);
5- (Difluoromethoxy) -2- (4-fluoro-2-methoxy-phenoxy) -N- (3-methylsulfonylphenyl) pyridin-3-carboxamide (179);
N- (3-Methylsulfonylphenyl) -5-nitro-2- [4- (trifluoromethoxy) phenoxy] pyridin-3-carboxamide (180); and 5-chloro-N- (3-methylsulfonylphenyl)- 2- [4- (Trifluoromethoxy) Phenoxy] Pyridine-3-Carboxamide (181)
A compound selected from the group consisting of. A method for regulating Na _v 1.8 sodium ion channel, wherein a subject in need thereof is administered with the compound according to any one of claims 1 to 31 in a regulatory effective amount for the subject. The method, including that. A method for inhibiting Na _v 1.8, which comprises administering to a subject in need thereof an effective amount of the compound according to any one of claims 1 to 31. ,Method. A method of treating and / or alleviating the symptoms of a condition, disease or disorder associated with increased activity or expression of Na _v 1.8, which is therapeutically effective for the subject in need of the treatment. A method comprising administering the compound according to any one of claims 1-31 in an amount, treating and / or alleviating the symptoms of the pathology, disease or disorder. ₃₄ . the method of. The pains are neurogenic pain, inflammatory pain, visceral pain, cancerous pain, chemotherapy-induced pain, traumatic pain, surgical pain, postoperative pain, birth pain, labor pain, neurogenic bladder, and ulcerative pain. A group consisting of colitis, chronic pain, persistent pain, peripheral pain, central pain, chronic headache, migraine, headache due to sinusitis, tension headache, phantom limb pain, tooth pain, peripheral nerve injury and combinations thereof. 35. The method of claim 35, which is more selected. The disease or condition is HIV treatment-induced neuropathy, trigeminal nerve pain, post-herpes zoster nerve pain, eudynia, heat hypersensitivity, tosarcoidosis, hypersensitive bowel syndrome, Crohn's disease, multiple sclerosis (MS). , Muscle atrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndrome, myotension, malignant hyperthermia Symptoms Cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related disorders, familial erythromelalgia, primary limbs Erythromelalgia, familial rectal pain, cancer, epilepsy, partial and general tonic seizures, itching leg syndrome, arrhythmia, fibromyalgia, neuroprotection under ischemic conditions caused by stroke or nerve trauma, frequent 35. The method of claim 35, selected from the group consisting of pulsatile arrhythmia, atrial fibrillation, ventricular fibrillation and pithopkins syndrome (PTHS). 34. The method of claim 34, further comprising administering to the subject one or more additional therapeutic agents. 38. 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. Any of claims 1-31 in the manufacture of a drug for treating a subject suffering from such a disorder a condition, disease or disorder associated with increased activity or expression of Na _v 1.8. Use of the compound described in item 1 . The compound according to any one of claims 1 to 3.
When R3 is carbon, cyano, halogen, C1-C8 alkoxyl, mono-, di- and trihalo-C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alkoxyl, substituted or unsubstituted C1- Selected from the group consisting of C8alkyl, C3-C8cycloalkyl, -NO2, not present when Y is nitrogen;
R4 is hydrogen, cyano, halogen, C1-C8 alkoxyl, mono-, di- and trihalo-C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alkoxyl, substituted or unsubstituted C1-C8 alkyl and morpholinyl. A compound selected from the group consisting of. The compound according to any one of claims 1 to 3.
When R3 is carbon, hydrogen, cyano, halogen, C1-C8 alkoxyl, mono-, di- and trihalo-C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alkoxyl, substituted or unsubstituted. Selected from the group consisting of C1-C8alkyl, C3-C8cycloalkyl, -NO2, not present when Y is nitrogen;
R4 consists of cyano, halogen, C1-C8 alkoxyl, mono-, di- and trihalo-C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alkoxyl, substituted or unsubstituted C1-C8 alkyl and morpholinyl. A compound selected from the group. The compound according to any one of claims 1 to 3, wherein Y is carbon and R3 is CF3. The compound according to any one of claims 1 to 3, wherein Y is nitrogen and R4 is CF3. The compound according to any one of claims 1 to 3, wherein X is —CH— and Y is nitrogen. The compound according to any one of claims 1 to 3, wherein Y is carbon and X is nitrogen. The compound according to claim 2.
R1 is phenyl and the phenyl is unsubstituted, or substituted or unsubstituted C1-C8 alkyl, -O-R5 (in the formula, R5 is C1-C8 alkyl, -CF3, -CHF2 and-(in the formula. CH2) p-CF3 (in the formula, p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8) and -S- A compound substituted with one or more groups selected from the group consisting of CF3. The compound according to claim 2.
R2 is phenyl and said phenyl is unsubstituted or unsubstituted or substituted C1-C8 alkyl, halogen, cyano, oxo, -O-R5 (in the formula, R5 is C1-C8 alkyl and -CHF2). (Selected from the group consisting of),-(CH2) q-OH (in the equation, q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8),. -NR6R7 (in the formula, R6 and R7 are selected from the group consisting of H and C1-C4 alkyl), morpholinyl, oxazolyl, -C (= O) -R8 (in the formula, R8 is -NR6R7 (in the formula). , R6 and R7 are selected from the group consisting of H and C1-C4 alkyl) and from the group consisting of C1-C4 alkyl), -S (= O) -R9, -S (= O) 2. -R9, -S (= O) (= NR10) -R11 and -N = S (= O)-(R11) 2 (In the formula, each R9 is independently C1-C4 alkyl, -CF3 or- Group consisting of NR6R7 (in the formula, R6 and R7 are selected from the group consisting of H and C1-C4 alkyl), R10 is H or C1-C4 alkyl and R11 is C1-C4 alkyl). Substituted with one or more groups of choice, provided that if Y is nitrogen and R2 is phenyl, then R8 cannot be -NR6R7. The compound according to claim 3.
Each R24 is independently substituted or unsubstituted C1-C8alkyl, C3-C10cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C1-C8 alkoxyl, mono-, di- or A compound selected from the group consisting of trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and arylalkoxyl.