JPWO2020128925A5 - - Google Patents

Description

The present invention relates to macrocyclic compounds containing an optionally substituted divalent N-(pyridin-2-yl)pyridinyl-sulfonamide moiety, and pharmaceutically acceptable salts thereof. The invention further relates to the use of such macrocycles in the treatment of respiratory diseases. The invention further relates to the use of such macrocycles in the treatment of pancreatitis. The invention further relates to pharmaceutical compositions comprising such macrocyclic compounds, a pharmaceutically acceptable carrier and optionally at least one additional therapeutic agent. The invention further relates to combinations comprising such macrocyclic compounds and at least one additional therapeutic agent. The invention further relates to the use of such pharmaceutical compositions and combinations in the treatment of respiratory diseases. The invention further relates to the use of such pharmaceutical compositions and combinations in treating pancreatitis.

Cystic fibrosis (CF) is an autosomal genetic disease that affects about 30,000 people in the United States and about 70,000 people worldwide. About 1,000 new patients with CF are diagnosed each year. Most patients are diagnosed with CF by age 2, and more than half of the CF population is 18 years and older. Despite advances in treating CF, there is no cure.

Cystic fibrosis (CF) is characterized by the CF transmembrane conductance regulator (CFTR) protein, a cAMP-regulated chloride channel expressed primarily in the apical plasma membrane of secretory epithelia in the airways, pancreas, intestine, and other tissues. caused by loss-of-function mutations in CFTR is a large multidomain glycoprotein consisting of two transmembrane domains, two nucleotide-binding domains (NBD1 and NBD2) that bind and hydrolyze ATP, and a regulatory (R) domain that gates the channel by phosphorylation. is. Approximately 2000 mutations in the CFTR gene have been identified that result in loss-of-function phenotypes by impairing its translation, cellular processing, and/or chloride channel gating. The F508del mutation, present in at least one allele in approximately 90% of CF patients, impairs CFTR folding, stability in the endoplasmic reticulum and plasma membrane, and chloride channel gating (Dalemans et al. 1991; Denning et al. 1992; Lukacs et al. 1993; Du et al. 2005). Other mutations primarily alter channel gating (eg G551D), conductance (eg R117H), or translation (eg G542X) (Welsh and Smith 1993). A fundamental premise of CFTR collector and potentiator therapy for CF is that correction of the underlying defects in cellular processing and chloride channel function of CF-induced mutant CFTR alleles is clinically effective. The collector is primarily targeted to F508del cell misprocessing, whereas the potentiator is intended to restore the cAMP-dependent chloride channel activity of mutant CFTR at the cell surface. In contrast to current therapies such as antibiotics, anti-inflammatory drugs, mucolytics, nebulized hypertonic saline, and pancreatic enzyme replacement that treat the symptoms of CF disease, collectors and potentiators are the underlying CFTR anion channels. Correct imperfections.

There remains a need for new treatments and therapies for cystic fibrosis and related diseases, including asthma, COPD, chronic bronchitis and emphysema. Additionally, there remains a need for new treatments and therapies for pancreatitis. The present invention provides compounds of formula (I) and subformulae thereof, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, wherein the compound of formula (I) and subformulaes thereof is , CFTR collector. The invention further provides a method of treating, preventing, or ameliorating cystic fibrosis and related disorders, comprising administering to a subject in need thereof an effective amount of the CFTR collector of the invention in combination with a CFTR potentiator ( two combinations) or in combination with a CFTR potentiator and a different CFTR collector (three combinations). Various embodiments of the invention are described herein.

（式中、Ａ _１ 、Ａ _２ Ａ _３ 、Ｌ _１ 、Ｌ _２ 及びＸ _Ａ が、本明細書において定義されるとおりである）の構造を有する化合物、又はその薬学的に許容できる塩である。 In one aspect of the invention, formula (I):

wherein A ₁ , A _{2 A 3} , L ₁ , L ₂ and XA are as defined herein, or a pharmaceutically acceptable salt thereof.

（式中：Ｘ _１ａ 、Ｘ _１ｂ 、Ｘ _１ｃ 、Ｘ _１ｄ 、Ｘ _２ａ 、Ｘ _２ｂ 、Ｘ _２ｃ 、Ｘ _２ｄ 、Ｘ _３ａ 、Ｘ _３ｂ 、Ｘ _３ｃ 、Ｘ _３ｄ 、Ｘ _４ 及びＬ _２ が、本明細書において定義されるとおりである）の構造を有する化合物、又はその薬学的に許容できる塩である。 Another aspect of the invention is a compound of formula (Ia):

(wherein: X _1a , X _1b , X _1c , X _1d , X _2a , X _2b , X _2c , X _2d , X _3a , X _3b , X _3c , X _3d , X ₄ and L ₂ are or a pharmaceutically acceptable salt thereof.

（式中、Ｘ _１ａ 、Ｘ _２ａ 、Ｘ _３ａ 、Ｘ _４ 、Ｌ _２ 、Ｒ ^１ 及びＲ ^２ が、本明細書において定義されるとおりである）の式の構造を有する化合物、又はその薬学的に許容できる塩である。 Another aspect of the invention is a compound of formula (Ib)

^{or a} _{pharmaceutically acceptable _ _ _} Acceptable salt.

In another aspect, the invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a method for treating a cystic fibrosis transmembrane conductance regulator (CFTR)-mediated disease in a subject, comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable compound thereof. A method is provided comprising administering to a subject a salt capable of

In another aspect, the invention provides a method for treating a cystic fibrosis transmembrane conductance regulator (CFTR)-mediated disease in a subject, comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, to A method is provided comprising administering to

In another aspect, the invention provides use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated disease. do.

In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated diseases.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in treating cystic fibrosis transmembrane conductance regulator (CFTR)-mediated disease.

In another aspect, the invention provides a method for treating a cystic fibrosis transmembrane conductance regulator (CFTR)-mediated disease in a subject, comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable compound thereof. A method is provided comprising administering to a subject a pharmaceutical composition comprising a salt that can be formed.

In another aspect, the invention provides a method for treating a cystic fibrosis transmembrane conductance regulator (CFTR)-mediated disease in a subject comprising a compound of the invention, or a pharmaceutically acceptable salt thereof A method is provided comprising administering a pharmaceutical composition to a subject.

In another aspect, the invention provides the use of a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated diseases. offer.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in treating a cystic fibrosis transmembrane conductance regulator (CFTR)-mediated disease. offer.

In another aspect, the invention comprises a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, optionally with a pharmaceutically acceptable carrier. Further provided is a pharmaceutical combination comprising:

In another aspect, the invention provides a pharmaceutical combination comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, optionally further comprising a pharmaceutically acceptable carrier. I will provide a.

In another aspect, the invention provides the use of a pharmaceutical combination of the invention in the treatment of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated diseases.

Various enumerated embodiments of the invention are described herein. It will be appreciated that features defined in each embodiment can be combined with other defined features to provide further embodiments of the invention.

DEFINITIONS The term "alkyl" as used herein refers to a saturated branched or straight chain hydrocarbon. In certain embodiments, alkyl groups are defined as "C ₁ -C ₃ alkyl", "C ₁ -C ₄ alkyl", "C ₁ -C ₅ alkyl", "C ₁ -C ₆ alkyl", "C ₁ - "C 1 -C ₈ alkyl", "C ₁ -C ₈ alkyl", "C ₁ -C ₉ alkyl" or "C ₁ -C ₁₀ alkyl", where as used herein "C ₁ - C ₃ alkyl", "C ₁ -C ₄ alkyl", "C ₁ -C ₅ alkyl", "C ₁ -C ₆ alkyl", "C ₁ -C ₇ alkyl", "C ₁ -C ₈ alkyl", The terms “C ₁ -C ₉ alkyl” and “C ₁ -C ₁₀ alkyl” contain at least 1 and no more than 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, respectively. Refers to an alkyl group. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl. etc. In certain embodiments, such alkyl groups are optionally substituted.

The term "alkylene," as used herein, refers to a saturated branched or straight chain divalent hydrocarbon radical derived from an alkyl group. In certain embodiments, the alkylene group is defined as "C ₁ -C ₃ alkylene", "C ₁ -C ₄ alkylene", "C ₁ -C ₅ alkylene", "C ₁ -C ₆ alkylene", "C ₁ - "C ₇ alkylene", "C ₁ -C ₈ alkylene", "C ₁ -C ₉ alkylene" or "C ₁ -C ₁₀ alkylene", wherein "C ₁ - C ₃ alkylene”, “C ₁ -C ₄ alkylene”, “C ₁ -C ₅ alkylene”, “C ₁ -C ₆ alkylene”, “C ₁ -C ₇ alkylene” and “C ₁ -C ₈ alkylene” The term refers to alkylene groups containing at least 1 and no more than 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, respectively. Non-limiting examples of alkylene groups as used herein include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, t-butylene, n-pentylene, isopentylene , hexylene, heptylene, octylene, nonylene, and decylene. In certain embodiments, such alkylene groups are optionally substituted.

The term "alkoxy" as used herein refers to -O-alkyl or -alkyl-O-, where the "alkyl" group is as defined herein. In certain embodiments, alkoxy groups are defined as "C ₁ -C ₃ alkoxy", "C ₁ -C ₄ alkoxy", "C ₁ -C ₅ alkoxy", "C ₁ -C ₆ alkoxy", "C ₁ - "C ₇ alkoxy", "C ₁ -C ₈ alkoxy", "C ₁ -C ₉ alkoxy" or "C ₁ -C ₁₀ alkoxy", wherein "C ₁ - C ₃ alkoxy", "C ₁ -C ₄ alkoxy", "C ₁ -C ₅ alkoxy", "C ₁ -C ₆ alkoxy", "C ₁ -C ₇ alkoxy", "C ₁ -C ₈ alkoxy", The terms "C ₁ -C ₉ alkoxy" and "C ₁ -C ₁₀ alkoxy" refer to -O-C ₁ -C ₃ alkyl, -O-C ₁ -C ₄ alkyl, -O-C ₁ -C ₅ respectively. alkyl, —O—C ₁ -C ₆ alkyl, —O—C ₁ -C ₇ alkyl, —O—C ₁ -C ₈ alkyl, —O—C ₁ -C ₉ alkyl or —O—C ₁ -C ₁₀ refers to alkyl. Non-limiting examples of "alkoxy" groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, hexoxy, heptoxy, octoxy, Examples include nonoxy and deoxy. In certain embodiments, such alkoxy groups are optionally substituted.

The term “alkoxylene,” as used herein, refers to —O-alkylene- or —alkylene-O—, a divalent radical derived from an alkoxy group, where the “alkylene” group is , as defined herein. In certain embodiments, the alkoxylene group is defined as "C ₁ -C ₃ alkoxylene", "C ₁ -C ₄ alkoxylene", "C ₁ -C ₅ alkoxylene", "C ₁ -C ₆ alkoxylene" , “C ₁ -C ₇ alkoxylenes”, “C ₁ -C ₈ alkoxylenes”, “C ₁ -C ₉ alkoxylenes” or “C ₁ -C ₁₀ alkoxylenes”, wherein “C ₁ -C ₃ alkoxylenes”, “C ₁ -C ₄ alkoxylenes”, “C ₁ -C ₅ alkoxylenes”, “C ₁ -C ₆ alkoxylenes”, “C ₁ -C alkoxylenes” when used. The terms "C 1 -C ₈ alkoxylen", "C ₁ -C ₈ alkoxylen", "C ₁ -C ₉ alkoxylen" and "C ₁ -C ₁₀ alkoxylen" refer respectively to -O-C ₁ -C ₃ alkylene, - OC ₁ -C ₄ alkylene, -OC ₁ -C ₅ alkylene, -OC ₁ -C ₆ alkylene, -OC ₁ -C ₇ alkylene, -OC ₁ -C ₈ alkylene, - It refers to O—C ₁ -C ₉ alkylene or —O—C ₁ -C ₁₀ alkylene. In certain embodiments, the alkoxylene group is defined as "C ₁ -C ₃ alkoxylene", "C ₁ -C ₄ alkoxylene", "C ₁ -C ₅ alkoxylene", "C ₁ -C ₆ alkoxylene" , “C ₁ -C ₇ alkoxylenes”, “C ₁ -C ₈ alkoxylenes”, “C ₁ -C ₉ alkoxylenes” or “C ₁ -C ₁₀ alkoxylenes”, wherein “C ₁ -C ₃ alkoxylenes”, “C ₁ -C ₄ alkoxylenes”, “C ₁ -C ₅ alkoxylenes”, “C ₁ -C ₆ alkoxylenes”, “C ₁ -C alkoxylenes” when used. The terms "C ₁ -C ₈ alkoxylen", "C ₁ -C _{9 alkoxylen} " and "C ₁ -C ₁₀ alkoxylen" refer to -C ₁ -C ₃ alkylene-O, - C ₁ -C ₄ alkylene-O, -C ₁ -C ₅ alkylene-O, -C ₁ -C ₆ alkylene-O, -C ₁ -C ₇ alkylene-O, -C ₁ -C ₈ alkylene-O, - It refers to C ₁ -C ₉ alkylene-O or -C ₁ -C ₁₀ alkylene-O. Non-limiting examples of "alkoxylene" groups include methoxylylene, ethoxylylene, n-propxylene, isopropxylene, n-butxylene, isobutxylene, sec-butxylene, tert-butxylene, n-pentyloxylene, iso- Pentyloxylene, hexyloxylene, heptyloxylene, octyloxylene, nonyloxylene, decyloxylene and the like. In certain embodiments, such alkoxylene groups are optionally substituted.

The term "alkylene oxide" as used herein refers to the following divalent group -alkylene-O-alkylene-, where the "alkylene" group is as defined herein. be.

The term "aminoalkylene" as used herein refers to the divalent group -NH-alkylene- or -alkylene-NH-, where the "alkylene" group is As defined. In certain embodiments, such aminoalkylene groups are optionally substituted.

The term "aryl" as used herein includes aromatic monocyclic ring systems having 6 carbon atoms as ring members, aromatic fused bicyclic ring systems having 9-10 carbon atoms as ring members , or an aromatic fused tricyclic ring system having 14 carbon atoms as ring members. Non-limiting examples of aryl groups as used herein include phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, anthracenyl, phenanthrenyl, and the like. In certain embodiments, such aryl groups are optionally substituted. In preferred embodiments, the aryl group is phenyl.

The term "arylene" as used herein refers to a divalent radical derived from an aryl group as defined herein. Non-limiting examples of arylene groups as used herein include phenylene, naphthalenylene, indenylene, azulenylene, anthracenylene, phenanthrenylene, and the like. In certain embodiments, such arylene groups are optionally substituted. In preferred embodiments, the arylene group is phenylene.

The term “C ₃ -C ₈ cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon ring system having 3 to 8 carbon atoms as ring members. Non _- limiting examples of such "C3 _- C8 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. In certain embodiments, such cycloalkyl groups are optionally substituted.

The term "C3 _- C8 cycloalkylene" as used herein refers to a divalent saturated monocyclic hydrocarbon ring derived from " _{C3 - C8} cycloalkyl" as defined herein. refers to the system. Non _- limiting examples of such "C3 _- C8 cycloalkylene" groups include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene and cyclooctylene groups. In certain embodiments, such cycloalkylene groups are optionally substituted.

The term “deuterium-substituted C ₁ -C ₆ alkyl” as used herein refers to a “C ₁ -C ₆ alkyl” having at least one of its hydrogen atoms replaced with a deuterium atom. refers to each “C ₁ -C ₆ alkyl” defined in . A deuterium-substituted C ₁ -C ₆ alkyl group can be monoteiated, wherein one hydrogen atom of the "C ₁ -C ₆ alkyl" is replaced with one deuterium atom. A deuterium-substituted C ₁ -C ₆ alkyl group can be dihydrogenated, wherein each of the two hydrogen atoms of the “C ₁ -C ₆ alkyl” is replaced with a deuterium atom. Deuterium-substituted C ₁ -C ₆ alkyl groups can be tritiated, wherein each of the three hydrogen atoms of the "C ₁ -C ₆ alkyl" is replaced with a deuterium atom. Additionally, deuterium-substituted C ₁ -C ₆ alkyl groups can be multiply hydrogenated, wherein four or more hydrogen atoms of the “C ₁ -C ₆ alkyl” are each replaced with a deuterium atom. Non-limiting examples of "deuterium-substituted C ₁ -C ₆ alkyl" groups include -CH ₂ D, -CHD ₂ , -CD ₃ , -CH ₂ CH ₂ D, -CH ₂ CHD ₂ , -CH ₂ CD ₃ and -CD ₂ CD ₃ are included.

The terms "halo-substituted C ₁ -C ₆ alkyl" and "C ₁ -C ₆ haloalkyl" are used interchangeably herein and, as used herein, "C ₁ -C ₆ alkyl" refers to each “C ₁ -C ₆ alkyl” as defined herein, wherein at least one of the hydrogen atoms of is replaced with a halo atom. A halo-substituted C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl group can be a mono C ₁ -C ₆ haloalkyl, wherein such C ₁ -C ₆ haloalkyl group comprises one iodo, one It has bromo, one chloro or one fluoro. Additionally, a C ₁ -C ₆ haloalkyl group can be a diC ₁ -C ₆ haloalkyl group, wherein such C ₁ -C ₆ haloalkyl group is independently selected from iodo, bromo, chloro or fluoro. can have two halo atoms. Additionally, a C ₁ -C ₆ haloalkyl group can be a polyC ₁ -C ₆ haloalkyl group, wherein such C ₁ -C ₆ haloalkyl group comprises two or more of the same halo atoms or two or more different It may have a combination of halo atoms. Such polyC ₁ -C ₆ haloalkyls can be perhaloC ₁ -C ₆ haloalkyls, wherein all hydrogen atoms of each C ₁ -C ₆ alkyl are replaced with halo atoms, and halo The atoms can be the same or a combination of different halo atoms. Non-limiting examples of “halo-substituted C ₁ -C ₆ alkyl” and “C ₁ -C ₆ haloalkyl” groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoro Ethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The terms “halo-substituted C ₁ -C ₆ alkoxy” and “C ₁ -C ₆ haloalkoxy” are used interchangeably herein and as used herein “C ₁ -C ₆ halo Refers to each “C ₁ -C ₆ alkoxy” as defined herein, wherein at least one of the hydrogen atoms of the “C ₁ -C ₆ alkyl” of the alkoxy” is replaced with a halo atom. Halo-substituted C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy groups can be mono C ₁ -C ₆ haloalkoxy, wherein such C ₁ -C ₆ haloalkoxy groups are substituted with one iodo , one bromo, one chloro or one fluoro. Additionally, a C ₁ -C ₆ haloalkoxy group can be a diC ₁ -C ₆ haloalkoxy, wherein such C ₁ -C ₆ haloalkoxy group independently from iodo, bromo, chloro or fluoro can have two halo atoms selected by Additionally, a C ₁ -C ₆ haloalkoxy group can be a polyC ₁ -C ₆ haloalkoxy group, wherein such C ₁ -C ₆ haloalkoxy group comprises two or more or two of the same halo atoms. It can have combinations of different halo atoms from above. Such polyC ₁ -C ₆ haloalkoxy may be perhaloC ₁ -C ₆ haloalkoxy wherein all of the hydrogen atoms of each C ₁ -C ₆ alkoxy are replaced with halo atoms and may be a combination of the same or different halo atoms. Non-limiting examples of “halo-substituted C ₁ -C ₆ alkoxy” and “C ₁ -C ₆ haloalkoxy” groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, penta fluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, trifluoroethoxy, difluoropropoxy, dichloroethoxy and dichloropropoxy.

The term "halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo.

The term “heteroaryl” as used herein includes i) an aromatic, 5- to 6-membered monocyclic ring system (wherein the 1-4 ring members are independently heteroatoms N, O and S), ii) an aromatic, 9-10 membered fused bicyclic ring system, wherein the 1-4 ring members are independently selected from heteroatoms N, O and S, and iii) ) refers to an aromatic, fused 14-membered tricyclic ring system, wherein the 1-4 ring members are independently selected from the heteroatoms N, O and S. Non-limiting examples of heteroaryl groups as used herein include benzofuranyl, benzofurazanyl, benzoxazolyl, benzopyranyl, benzthiazolyl, benzothienyl, benzazepinyl, benzimidazolyl, benzothiopyranyl, benzo[b ] furyl, benzo[b]thienyl, cinnolinyl, furazanyl, furyl, furopyridinyl, imidazolyl, indolyl, indolizinyl, indolin-2-one, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, isothiazolyl, 1,8-naphthyridinyl, oxazolyl, oxindolyl , oxadiazolyl, pyrazolyl, pyrrolyl, phthalazinyl, pteridinyl, purinyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinoxalinyl, quinolinyl, quinazolinyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, triazolyl and tetrazolyl. In certain embodiments, such heteroaryl groups are optionally substituted. In preferred embodiments, the heteroaryl group is pyridyl.

The term "heteroarylene" when used herein refers to a divalent radical derived from a heteroaryl group as defined herein. Non-limiting examples of arylene groups as used herein include phenylene, naphthalenylene, benzofuranylene, benzofurazanylene, benzoxazolylene, benzopyranylene, benzthiazolylene, benzothienylene, benzazepinylene, benzimidazolylene. , benzothiopyranylene, benzo[b]furylene, benzo[b]thienylene, cinolinylene, furazanylene, furylene, furopyridinylene, imidazolylene, indolylene, indolizinylene, indolin-2-one, indazolylene, isoindolylene, isoquinolinylene, isoxa zolylene, isothiazolylene, 1,8-naphthyridinylene, oxazolylene, oxindolylene, oxadiazolylene, pyrazolylene, pyrrolylene, phthalazinylene, pteridinylene, purinylene, pyridylene, pyridazinylene, pyrazinylene, pyrimidinylene, quinoxalinylene, quinolinylene, quinazolinylene, thiazolylene, thiadiazolylene, thienylene , triazinylene, triazolylene and tetrazolylene. In certain embodiments, such heteroarylene groups are optionally substituted. In preferred embodiments, the heteroarylene group is pyridylene.

The term "heteroatom" as used herein refers to nitrogen (N), oxygen (O) or sulfur (S) atoms.

The term “heterocycloalkyl” as used herein refers to i) a monocyclic ring structure having 4-6 ring members, wherein 1-2 of the ring members are independently N, NH, NR ¹⁶ , O or —S—, wherein R ¹⁶ is C ₁ -C ₆ alkyl) and ii) a fused bicyclic ring structure having 8-10 ring members (wherein the ring 1-2 of the members are independently selected from N, NH, NR ¹⁶ , O or -S-, wherein R ¹⁶ is C ₁ -C ₆ alkyl. Non-limiting examples of 4- to 6-membered heterocycloalkyl groups as used herein include azetazinyl, azetazin-1-yl, azetazin-2-yl, azetazin-3-yl, oxetanyl, oxetane- 2-yl, oxetan-3-yl, oxetan-4-yl, thietanyl, thietane-2-yl, thietane-3-yl, thietane-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl, pyrrolidin-5-yl, tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-5-yl, tetrahydrothienyl, tetrahydrothien -2-yl, tetrahydrothien-3-yl, tetrahydrothien-4-yl, tetrahydrothien-5-yl, piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4- yl, piperidin-5-yl, piperidin-6-yl, tetrahydropyranyl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-5-yl, tetrahydropyran-6 -yl, tetrahydrothiopyranyl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-5-yl, tetrahydrothiopyran-6-yl, piperazinyl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, piperazin-5-yl, piperazin-6-yl, morpholinyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, morpholin-5-yl, morpholin-6-yl, thiomorpholinyl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, thiomorpholin-5-yl, thiomorpholine -6-yl, oxathianyl, oxathian-2-yl, oxathian-3-yl, oxathian-5-yl, oxathian-6-yl, dithianyl, dithian-2-yl, dithian-3-yl, dithian-5-yl , Dithian-6-yl, Dioxolanyl, Dioxolan-2-yl, Dioxolan-4-yl, Dioxolan-5-yl, Thioxanyl, Thioxan-2-yl, Thioxan-3- yl, thioxan-4-yl, thioxan-5-yl, dithiolanyl, dithiolan-2-yl, dithiolan-4-yl, dithiolan-5-yl, pyrazolidinyl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidine- 3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, 2-azabicyclo[4.2.0]octanyl, octahydro-1H-cyclopenta[b]pyridine and decahydroquinoline. In certain embodiments, such heterocycloalkyl groups are optionally substituted.

The term "heterocycloalkylene," as used herein, refers to a divalent radical derived from a heterocycloalkyl group as defined herein.

The term "hydroxyl" as used herein refers to the -OH group.

The term "optionally substituted" as used herein means that the group referred to is an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, individually and independently from mercaptyl, cyano, halo, carbonyl, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, monosubstituted and disubstituted amino groups and amino, and protected derivatives thereof; which may or may not be substituted with one or more additional groups selected for. Non-limiting examples of optional substituents include halo, -CN, =O, =N-OH, =N-OR, =N-R, -OR, -C(O)R, -C (O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR ₂ , -OC(O)NHR, -OC(O)NR ₂ , - SR—, —S(O)R, —S(O) ₂ R, —NHR, —N(R) ₂ , —NHC(O)R, —NRC(O)R, —NHC(O)OR, — NRC(O)OR, S(O) _2NHR , -S(O)2N ₍ R) ₂ , _{-NHS (} O) _2NR2 , _-NRS (O) _2NR2 , -NHS(O)2R , —NRS(O) ₂ R, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo-substituted C ₁ -C ₈ alkyl, and halo-substituted C ₁ - C ₈ alkoxy, where each R is independently H, halo, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo substituted selected from C ₁ -C ₈ alkyl, and halo-substituted C ₁ -C ₈ alkoxy; The placement and number of such substituents are subject to the well-understood valence constraints of each group, eg =O is a preferred substituent for alkyl groups, but not for aryl groups.

The term "polyalkylene oxide" as used herein refers to the divalent group -(alkylene-O-alkylene) _n -, where the "alkylene" group is defined herein. and n is an integer from 1 to 10.

As used herein, "CFTR" stands for cystic fibrosis transmembrane conductance regulator.

As used herein, "mutation" can refer to mutations in the CFTR gene or CFTR protein. A "CFTR mutation" refers to a mutation in the CFTR gene and a "CFTR mutation" refers to a mutation in the CFTR protein. A genetic abnormality or mutation, or generally a nucleotide change in a gene, results in a mutation of the CFTR protein translated from that gene.

As used herein, "F508del mutation" or "F508del" is a specific mutation within the CFTR protein. The mutation is a three nucleotide deletion including the codon for the amino acid phenylalanine at position 508, resulting in a CFTR protein lacking this phenylalanine residue.

The term "CFTR gating mutation" as used herein means a CFTR mutation whose primary defect results in the production of a CFTR protein with a lower channel opening probability compared to normal CFTR. (Van Goor, F., Hadida S. and Grootenhuis P., "Pharmacological Rescue of Mutant CFTR function for the Treatment of Cystic Fibrosis", Top. Med. Chem. 3:91-120) (2008). Gating mutations include, but are not limited to, G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D.

As used herein, a patient who is "homozygous" for a particular mutation, eg, F508del, has the same mutation on each allele.

As used herein, a patient who is "atypical" for a particular mutation, eg, F508del, has this mutation on one allele and a different mutation on the other allele.

As used herein, the term "modulator" refers to compounds that increase the activity of biological compounds such as proteins. For example, a CFTR modulator is a compound that increases the activity of CFTR. Increased activity resulting from CFTR modulators may be through collector or potentiator mechanisms as described below.

As used herein, the term "CFTR collector" refers to compounds that increase the amount of functional CFTR protein on the cell surface, resulting in enhanced ion transport.

As used herein, the term "CFTR potentiator" refers to a compound that increases the channel activity of the CFTR protein located on the cell surface, resulting in enhanced ion transport.

As used herein, the term "modulate" as used herein means to increase or decrease by a measurable amount.

As used herein, the term "induction", such as inducing CFTR activity, refers to increasing CFTR activity, whether by a collector, potentiator, or other mechanism. .

As used herein, "asthma" includes both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise Includes induced asthma, occupational asthma and asthma induced after bacterial infection. Treatment of asthma is also diagnosed or diagnosable in the “wheezy infant,” an established patient category of great medical interest who presents with symptoms of wheezing and is now often in early Alternatively, it should be understood to include the treatment of subjects under the age of 4 or 5 years who are identified as having early stage asthma. (For convenience, this particular asthma symptom is called "wheezy-infant syndrome"). Prophylactic efficacy in the treatment of asthma is evidenced by reduced frequency or severity of symptomatic attacks (eg, acute asthmatic or bronchoconstrictive attacks), improved lung function, or improved airway hyperreactivity. It includes other symptomatic treatments, i.e. treatments for or intended to suppress or stop symptomatic seizures when they occur, e.g. anti-inflammatory drugs (e.g. corticosteroids) or bronchodilators can be further evidenced by the reduced need for A prophylactic effect in asthma may be particularly apparent in subjects prone to "morning dipping". The "morning dip" is a well-recognized asthma syndrome, common to a significant proportion of asthmatics, e.g. characterized by an asthma attack at a time well distant from symptomatic treatment.

The term "combination" or "pharmaceutical combination" as used herein refers to either a fixed combination or co-administration in one dosage unit form, wherein a compound of the invention and a combination partner (eg, another agent described below, also referred to as a “therapeutic agent” or “co-agent”) can be administered simultaneously or separately and independently within a time interval; The time interval allows the combination partners to exhibit synergistic effects, eg synergistic effects. Single components may be packaged in a kit or separately. One or both of the components (eg, powder or liquid) may be reconstituted or diluted to the desired dose prior to administration. Terms such as "co-administration" or "co-administration" as used herein are intended to encompass administration of the selected combination partner to a single subject (e.g., patient) in need thereof. are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination," as used herein, means a product resulting from mixing or combining two or more therapeutic agents, including both fixed and non-fixed combinations of therapeutic agents. Including both. The term "constant combination" means that both a therapeutic agent, eg, a compound of the invention, and a combination partner are administered to a patient at the same time in a single entity or dosage form. The term "non-constant combination" means that both the therapeutic agent, e.g., a compound of the invention and the combination partner, are administered to the patient simultaneously, in parallel, or sequentially, without specific time limits, as separate entities. , wherein such administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, eg the administration of three or more therapeutic agents.

The term "combination therapy" or "in conjunction with" or "pharmaceutical combination" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents at about the same time, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration includes multiple containers for each active ingredient, or co-administration in separate containers (eg, capsules, powders, and liquids). Powders and/or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration encompasses the use of each type of therapeutic agent administered before, after, in parallel with, or sequentially with respect to each other without a specified time limit. In either case, the therapeutic regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

As used herein, the term "co-administer" refers to the presence of two active agents in the blood of an individual. Co-administered active agents can be delivered simultaneously or sequentially.

The term "composition" or "pharmaceutical composition" as used herein refers to the composition of the present invention together with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration. A compound, or a pharmaceutically acceptable salt thereof.

"Patient", "subject" or "individual" are used interchangeably and refer to either a human or non-human animal. The term includes mammals such as humans. Typically the animal is a mammal. Subject also refers to, for example, primates (eg, humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. Preferably, the subject is human.

As used herein, the terms "inhibit," "inhibit" or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or Refers to a significant decrease in baseline activity of the process.

As used herein, the term "pharmaceutically acceptable carrier" refers to substances useful in the preparation or use of pharmaceutical compositions, and as known to those skilled in the art (e.g., Remington the Science and Practice of Pharmacy, 22 ^nd Ed. agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof.

The phrase "pharmaceutically acceptable" means that a substance, composition or dosage form is chemically and/or toxicologically compatible with the other ingredients that make up the formulation and/or the mammal treated therewith. Indicates what must be done.

The term "subject in need of such treatment" refers to a subject who would benefit biologically, medically or in quality of life from such treatment.

The term "therapeutically effective amount" as used herein means ameliorating symptoms, alleviating condition, slowing or retarding disease progression, preventing disease, or cause a medical response, e.g., increase the amount of functional CFTR protein on the cell surface, resulting in enhanced ion transport, or increase the channel activity of CFTR protein located on the cell surface, resulting in enhanced ion transport; It refers to the amount of a compound of the invention.

As used herein, the term "treating" or "treatment" of any disease or disorder refers to the management and care of a patient aimed at addressing the disease, condition, or disorder; Includes administration of a compound of the invention to prevent the development of symptoms or complications, alleviate symptoms or complications, or eliminate the disease, condition, or disorder.

Furthermore, the terms "treatment" and "treating" as used herein generally refer to ameliorating CF or symptoms thereof or reducing the severity of CF or symptoms thereof in a subject. "Treatment" as used herein includes, but is not limited to: (i) ameliorating the disease or disorder (i.e., slowing the onset of at least one of the disease or its clinical symptoms; (ii) reduce or ameliorate at least one physical parameter, including one that is not discernible by the patient; or (iii) prevent the onset or occurrence or progression of a disease or disorder. or delay. (iii) increased growth, increased weight gain, decreased mucus in the lungs, improved pancreatic and/or liver function, decreased symptoms of pulmonary infections, and/or decreased frequency of coughing or shortness of breath in the subject. Amelioration or reduction in severity of any of these conditions can be readily assessed according to standard methods and techniques known in the art.

As used herein, the terms “prevent,” “preventing,” or “prevention” of any disease or disorder refer to prophylactic treatment of the disease or disorder; means to delay

As used herein, a subject is "in need of treatment" if such subject would benefit biologically, medically or in quality of life from such treatment. ”.

The compound names given herein were obtained using ChemDraw Ultra version 14.0 (CambridgeSoft®) or JChem version 17.2.1300.1489 (ChemAxon).

As used herein, the terms "a", "an", "the" and similar terms used in the context of the present invention (particularly in the context of the claims) are shall be construed to include both the singular and the plural unless otherwise indicated herein or unless the context clearly contradicts.

（式中：
Ａ _１ 、Ａ _２ 及びＡ _３ がそれぞれ、独立して、任意選択的に置換されるアリーレン及び任意選択的に置換されるヘテロアリーレンから選択され；
Ｌ _１ が、スルホンアミド、アミド、カルボニル又は尿素であり；
Ｌ _２ が、任意選択的に置換されるアルキレン、任意選択的に置換されるアルコキシレン、任意選択的に置換されるポリアルキレンオキシド、任意選択的に置換されるアルキレンオキシド、任意選択的に置換されるアミノアルキレン又は任意選択的に置換されるＣ _３～８ シクロアルキレンであり；
Ｘ _Ａ が、任意選択的に置換される二価アミノ、任意選択的に置換される二価アミド、任意選択的に置換されるヘテロシクロアルキレン又は－Ｏ－である）
の構造を有する化合物、
又はその薬学的に許容できる塩を提供する。 Compounds of the Invention The present invention relates to compounds of formula (I):

(in the formula:
A ₁ , A ₂ and A ₃ are each independently selected from optionally substituted arylene and optionally substituted heteroarylene;
L ₁ is sulfonamide, amide, carbonyl or urea;
L ₂ is optionally substituted alkylene, optionally substituted alkoxylen, optionally substituted polyalkylene oxide, optionally substituted alkylene oxide, optionally substituted is an aminoalkylene or an optionally substituted C _3-8 cycloalkylene;
X _A is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-)
a compound having the structure of
or a pharmaceutically acceptable salt thereof.

Unless otherwise specified, the terms "compound of the invention", "compounds of the invention", "compound of the present invention" or "compound of the invention" The term "(compounds of the present invention)" refers to formula (I), sub-formulas thereof (formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), formula (Ij), formula (Ik), formula ( Il), Formula (Im), Formula (In), Formula (Io), Formula (Ip) and Formula (Iq), etc.) and exemplified and salts thereof, and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), and the essence It refers to naturally formed moieties (eg, polymorphs, solvates and/or hydrates).

Specific aspects and examples of compounds of the invention are provided in the following list of further enumerated embodiments. It will be appreciated that features defined in each embodiment can be combined with other defined features to provide further embodiments of the invention.

Embodiment 1. Formula (I)
(in the formula:
A ₁ is arylene or heteroarylene, wherein arylene and heteroarylene of A ₁ are unsubstituted or H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, substituted with 1 to 2 groups independently selected from deuterated C ₁ -C ₆ alkyl, nitrile, hydroxyl, C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
A ₂ is arylene or heteroarylene, wherein arylene and heteroarylene of A ₂ are unsubstituted or H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, substituted with 1 to 2 groups independently selected from deuterated C ₁ -C ₆ alkyl, nitrile, hydroxyl, C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
A ₃ is arylene or heteroarylene, wherein arylene and heteroarylene of A ₃ are unsubstituted or H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, substituted with 1 to 2 groups independently selected from deuterated C ₁ -C ₆ alkyl, nitrile, hydroxyl, C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
L ₁ is -NR ^A S(O) _1-2 - ^* , -S(O) _1-2 NR ^A - ^* , -NR ^A C(=O)- ^* , -C(=O)NR ^A - ^* , -C(=O)-, or -NR ^A C(=O)NR ^A -, where ^* indicates the point of attachment to A ₂ ;
L ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene or C ₃ -C ₈ cycloalkylene, where L ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene and C ₃ -C ₈ cycloalkylene is unsubstituted or C ₁ -C ₆ alkyl, —OH, —(CH ₂ ) _m C(=O)OR ^A , C ₁ -C ₆ alkoxy, 1-6 with 1 to 3 groups independently selected from C ₁ -C ₆ alkyl substituted with one hydroxyl group, deuterium, deuterium-substituted C ₁ -C ₆ alkyl, and spiro-bonded C ₃ -C ₈ cycloalkyl; replaced;
X _A is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-;
R ^A is H or C ₁ -C ₆ alkyl;
m is 1, 2, 3, 4, 5, or 6)
or a pharmaceutically acceptable salt thereof.

Embodiment 2. Formula (I)
(in the formula:
A ₁ is arylene or heteroarylene, wherein arylene and heteroarylene of A ₁ are unsubstituted or H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, substituted with 1 to 2 groups independently selected from deuterated C ₁ -C ₆ alkyl, nitrile, hydroxyl, C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
A ₂ is arylene or heteroarylene, wherein arylene and heteroarylene of A ₂ are unsubstituted or H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, substituted with 1 to 2 groups independently selected from deuterated C ₁ -C ₆ alkyl, nitrile, hydroxyl, C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
A ₃ is arylene or heteroarylene, wherein arylene and heteroarylene of A ₃ are unsubstituted or H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, substituted with 1 to 2 groups independently selected from deuterated C ₁ -C ₆ alkyl, nitrile, hydroxyl, C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
L ₁ is -NR ^A S(O) _1-2 - ^* or -S(O) _1-2 NR ^A - ^* , where ^* indicates the point of attachment to A ₂ ;
L ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene or C ₃ -C ₈ cycloalkylene, where L ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene and C ₃ -C ₈ cycloalkylene is unsubstituted or C ₁ -C ₆ alkyl, —OH, deuterium, —(CH ₂ ) _m C(=O)OR ^A , C ₁ -C ₆ alkoxy, with 1 to 3 groups independently selected from C ₁ -C ₆ alkyl substituted with 1 to 6 hydroxyl groups, deuterium-substituted C ₁ -C ₆ alkyl, and spiro-linked C ₃ -C ₈ cycloalkyl; replaced;
X _A is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-;
R ^A is H or C ₁ -C ₆ alkyl;
m is 1, 2, 3, 4, 5, or 6)
or a pharmaceutically acceptable salt thereof.

Embodiment 3. Formula (I)
(in the formula:
A ₁ is phenylene or pyridylene, wherein A ₁ phenylene or pyridylene is unsubstituted or H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, deuterium substituted with 1 to 2 groups independently selected from substituted C ₁ -C ₆ alkyl, nitrile, hydroxyl, C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
A ₂ is phenylene or pyridylene, wherein A ₂ phenylene or pyridylene is unsubstituted or H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, deuterium substituted with 1 to 2 groups independently selected from substituted C ₁ -C ₆ alkyl, nitrile, hydroxyl, C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
A ₃ is phenylene or pyridylene, wherein A ₃ phenylene or pyridylene is unsubstituted or H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, deuterium substituted with 1 to 2 groups independently selected from substituted C ₁ -C ₆ alkyl, nitrile, hydroxyl, C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
L ₁ is -NR ^A S(O) _1-2 - ^* or -S(O) _1-2 NR ^A - ^* , where ^* indicates the point of attachment to A ₂ ;
L ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene or C ₃ -C ₈ cycloalkylene, where L ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene and C ₃ -C ₈ cycloalkylene is unsubstituted or C ₁ -C ₆ alkyl, —OH, deuterium, —(CH ₂ ) _m C(=O)OR ^A , C ₁ -C ₆ alkoxy, with 1 to 3 groups independently selected from C ₁ -C ₆ alkyl substituted with 1 to 6 hydroxyl groups, deuterium-substituted C ₁ -C ₆ alkyl, and spiro-linked C ₃ -C ₈ cycloalkyl; replaced;
X _A is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-;
R ^A is H or C ₁ -C ₆ alkyl;
m is 1, 2, 3, 4, 5, or 6)
or a pharmaceutically acceptable salt thereof.

Embodiment 4. Formula (I)
(in the formula:
A ₁ is pyridylene, wherein pyridylene of A ₁ is H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, deuterium-substituted C ₁ -C ₆ alkyl, nitrile, hydroxyl, substituted with 1 to 2 groups independently selected from C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
A ₂ is pyridylene, wherein the pyridylene of A ₂ is unsubstituted;
A ₃ is phenylene or pyridylene, wherein A ₃ phenylene or pyridylene is unsubstituted or H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, deuterium substituted with 1 to 2 groups independently selected from substituted C ₁ -C ₆ alkyl, nitrile, hydroxyl, C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
L ₁ is -NR ^A S(O) _1-2 - ^* or -S(O) _1-2 NR ^A - ^* , where ^* indicates the point of attachment to A ₂ ;
L ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene or C ₃ -C ₈ cycloalkylene, where L ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene and C ₃ -C ₈ cycloalkylene is unsubstituted or C ₁ -C ₆ alkyl, —OH, deuterium, —(CH ₂ ) _m C(=O)OR ^A , C ₁ -C ₆ alkoxy, with 1 to 3 groups independently selected from C ₁ -C ₆ alkyl substituted with 1 to 6 hydroxyl groups, deuterium-substituted C ₁ -C ₆ alkyl, and spiro-linked C ₃ -C ₈ cycloalkyl; replaced;
X _A is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-;
R ^A is H or C ₁ -C ₆ alkyl;
m is 1, 2, 3, 4, 5, or 6)
or a pharmaceutically acceptable salt thereof.

（式中：
Ｘ _１ａ 、Ｘ _１ｂ 、Ｘ _１ｃ 及びＸ _１ｄ がそれぞれ、独立して、ＣＲ ^１ 又はＮから選択され、ここで、Ｘ _１ａ 、Ｘ _１ｂ 、Ｘ _１ｃ 及びＸ _１ｄ のうちの１つ又は２つのみがＮであり得、その他がＣＲ ^１ であり；
Ｘ _２ａ 、Ｘ _２ｂ 、Ｘ _２ｃ 及びＸ _２ｄ がそれぞれ、独立して、ＣＲ ^１ 又はＮから選択され、ここで、Ｘ _２ａ 、Ｘ _２ｂ 、Ｘ _２ｃ 及びＸ _２ｄ のうちの１つ又は２つのみがＮであり得、その他がＣＲ ^１ であり；
Ｘ _３ａ 、Ｘ _３ｂ 、Ｘ _３ｃ 及びＸ _３ｄ がそれぞれ、独立して、ＣＲ ^２ 又はＮから選択され、ここで、Ｘ _３ａ 、Ｘ _３ｂ 、Ｘ _３ｃ 及びＸ _３ｄ のうちの１つ又は２つのみがＮであり得、その他がＣＲ ^２ であり；
Ｘ _４ が、

又は－Ｏ－であり、ここで、 ^＊ が、Ｌ _２ への結合点を示し；
Ｌ _２ が、－（ＣＲ ^４ Ｒ ^５ ） _ｎ －、－Ｏ（ＣＲ ^４ Ｒ ^５ ） _ｎ － ^＊＊ 、－ＮＲ ^７ （ＣＲ ^４ Ｒ ^５ ） _ｎ － ^＊＊ 、－（ＣＲ ^４ Ｒ ^５ ） _ｎ Ｏ（ＣＲ ^６ Ｒ ^１０ ） _ｐ － ^＊＊ 、－（ＣＲ ^４ Ｒ ^５ ） _ｎ （ＣＲ ^６ Ｒ ^１８ ）－ ^＊＊ 、－（ＣＲ ^４ Ｒ ^５ ） _ｎ （ＣＲ ^８ Ｒ ^９ ） _ｐ （ＣＲ ^４ Ｒ ^５ ） _ｍ －、－（ＣＲ ^４ Ｒ ^５ ） _ｐ ＮＲ ^７ （ＣＲ ^６ Ｒ ^１０ ） _ｎ － ^＊＊ 、－（ＣＲ ^４ Ｒ ^５ ） _ｎ Ｏ） _ｔ （ＣＲ ^６ Ｒ ^１０ ） _ｐ － ^＊＊ 、又は－Ｏ－Ｃ _３ ～Ｃ _８ シクロアルキレン－ ^＊＊ であり、ここで、 ^＊＊ が、Ｘ _４ 中で ^＊ によって示される結合点におけるＸ _４ への結合点を示し；
各Ｒ ^１ が、独立して、Ｈ、ハロ、ハロ置換Ｃ _１ ～Ｃ _６ アルキル、Ｃ _１ ～Ｃ _６ アルキル、重水素置換Ｃ _１ ～Ｃ _６ アルキル、ニトリル、ヒドロキシル、Ｃ _１ ～Ｃ _６ アルコキシ及びハロ置換Ｃ _１ ～Ｃ _６ アルコキシから選択され；
各Ｒ ^２ が、独立して、Ｈ、ハロ、ニトリル、ヒドロキシル、ハロ置換Ｃ _１ ～Ｃ _６ アルキル、Ｃ _１ ～Ｃ _６ アルキル、重水素置換Ｃ _１ ～Ｃ _６ アルキル、ヒドロキシ置換Ｃ _１ ～Ｃ _６ アルキル、Ｃ _１ ～Ｃ _６ アルコキシ及びハロ置換Ｃ _１ ～Ｃ _６ アルコキシから選択され；
Ｒ ^３ が、Ｈ、－Ｃ _１ ～Ｃ _６ アルキル、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｒ ^１６ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｃ（＝Ｏ）ＯＲ ^１３ 、－（（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｏ（ＣＲ ^１４ Ｒ ^１５ ） _ｚ Ｃ（＝Ｏ）ＯＲ ^１３ 、－（（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｏ（ＣＲ ^１４ Ｒ ^１５ ） _ｚ ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｃ（＝Ｏ）Ｒ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ （ＣＲ ^８ Ｒ ^９ ） _ｚ Ｃ（＝Ｏ）ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ （ＣＲ ^８ Ｒ ^９ ） _ｚ ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ （ＣＲ ^８ Ｒ ^９ ） _ｚ （ＣＲ ^１４ Ｒ ^１５ ） _ｑ ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ ＮＲ ^１０ （ＣＲ ^１４ Ｒ ^１５ ） _ｑ Ｃ（＝Ｏ）ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ ＮＲ ^１３ Ｒ ^１４ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｒ ^２０ 、－（（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｏ） _ｑ （ＣＲ ^１４ Ｒ ^１５ ） _ｚ Ｃ（＝Ｏ）ＯＲ ^１３ 、－（（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｏ） _ｑ （ＣＲ ^１４ Ｒ ^１５ ） _ｚ ＯＲ ^１３ 、

であり；
各Ｒ ^４ が、独立して、Ｈ、Ｄ、重水素置換Ｃ _１ ～Ｃ _６ アルキル及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^５ が、独立して、Ｈ、Ｄ重水素置換Ｃ _１ ～Ｃ _６ アルキル及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^６ が、独立して、Ｈ、Ｄ重水素置換Ｃ _１ ～Ｃ _６ アルキル及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^７ が、独立して、Ｈ、及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^８ 及びＲ ^９ が、独立して、Ｈ、Ｄ、重水素置換Ｃ _１ ～Ｃ _６ アルキル、Ｃ _１ ～Ｃ _６ アルキル、又は－ＯＨから選択され；
又はＲ ^８ 及びＲ ^９ が、ＣＲ ^８ Ｒ ^９ 中の炭素と一緒に、Ｃ _３ ～Ｃ _８ シクロアルキルを形成し；
各Ｒ ^１０ が、独立して、Ｈ、Ｄ及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^１１ が、独立して、Ｈ、Ｄ及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^１２ が、独立して、Ｈ、Ｄ、重水素置換Ｃ _１ ～Ｃ _６ アルキル及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^１３ が、独立して、Ｈ、及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^１４ が、独立して、Ｈ、Ｄ、重水素置換Ｃ _１ ～Ｃ _６ アルキル及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^１５ が、独立して、Ｈ、Ｄ、重水素置換Ｃ _１ ～Ｃ _６ アルキル及びＣ _１ ～Ｃ _６ アルキルから選択され；
Ｒ ^１６ が、Ｎ、Ｏ、及びＳから独立して選択される１～２つの環員を有する４～６員ヘテロシクロアルキルであり、ここで、４～６員ヘテロシクロアルキルが、非置換であるか、又は１～２つのＲ ^１７ 基で置換され；
各Ｒ ^１７ が、独立して、Ｃ _１ ～Ｃ _６ アルキル及びヒドロキシルから選択され；
Ｒ ^１８ が、Ｈ、Ｃ _１ ～Ｃ _６ アルキル、－Ｃ（Ｒ ^４ Ｒ ^５ ） _ｍ ＯＲ ^１９ 、又は－（ＣＨ _２ ） _ｍ Ｃ（＝Ｏ）ＯＲ ^１９ であり；
各Ｒ ^１９ が、独立して、Ｈ及びＣ _１ ～Ｃ _６ アルキルから選択され；
Ｒ ^２０ が、

であり；
各ｍが、独立して、１、２、３、４、５、６、７、８、９及び１０から選択され；
各ｎが、独立して、１、２、３、４、５、６、７、８、９及び１０から選択され；
各ｐが、独立して、１、２、３、４、５、６、７、８、９及び１０から選択され；
各ｔが、独立して、１、２、３、４、５、６、７、８、９及び１０から選択され．
各ｗが、独立して、１、２、３、４、５、６、７、８、９及び１０から選択され；
各ｙが、独立して、１、２、３、４、５、６、７、８、９及び１０から選択され；
各ｚが、独立して、１、２、３、４、５、６、７、８、９及び１０から選択され；
各ｑが、独立して、１、２、３、４、５、６、７、８、９及び１０から選択される）
の構造を有する式（Ｉ）の化合物、又はその薬学的に許容できる塩。 Embodiment 5. Formula (Ia), or a pharmaceutically acceptable salt thereof

(in the formula:
X _1a , X _1b , X _1c and X _1d are each independently selected from CR ¹ or N, wherein only one or two of X _1a , X _1b , X _1c and X _1d are N, the others being CR ¹ ;
X _2a , X _2b , X _2c and X _2d are each independently selected from CR ¹ or N, wherein only one or two of X _2a , X _2b , X _2c and X _2d are N, the others being CR ¹ ;
X _3a , X _3b , X _3c and X _3d are each independently selected from CR ² or N, wherein only one or two of X _3a , X _3b , X _3c and X _3d are ^N , the others being CR2;
_X4 is

or -O-, where ^* indicates the point of attachment to _L2 ;
L ₂ is —(CR ⁴ R ⁵ ) _n —, —O(CR ⁴ R ⁵ ) _n — ^** , —NR ⁷ (CR ⁴ R ⁵ ) _n — ^** , —(CR ⁴ R ⁵ ) _n O (CR ⁶ R ¹⁰ ) _p − ^** , −(CR ⁴ R ⁵ ) _n (CR ⁶ R ¹⁸ ) − ^** , −(CR ⁴ R ⁵ ) _n (CR ⁸ R ⁹ ) _p (CR ⁴ R ⁵ ) _m -, -(CR ⁴ R ⁵ ) _p NR ⁷ (CR ⁶ R ¹⁰ ) _n - ^** , -(CR ⁴ R ⁵ ) _n O) _t (CR ⁶ R ¹⁰ ) _p - ^** , or -O- C ₃ -C ₈ cycloalkylene- ^** , wherein ^** indicates the point of attachment to X ₄ at the point of attachment indicated by ^* in X ₄ ;
Each R ¹ is independently H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, deuterium-substituted C ₁ -C ₆ alkyl, nitrile, hydroxyl, C ₁ -C ₆ alkoxy and selected from halo-substituted C ₁ -C ₆ alkoxy;
each R ² is independently H, halo, nitrile, hydroxyl, halo substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, deuterium substituted C ₁ -C ₆ alkyl, hydroxy substituted C ₁ -C ₆ selected from alkyl, C ₁ -C ₆ alkoxy and halo-substituted C ₁ -C ₆ alkoxy;
R ³ is H, —C ₁ -C ₆ alkyl, —(CR ¹¹ R ¹² ) _y R ¹⁶ , —(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , —((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z C(=O) OR ¹³ , —((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z OR ¹³ , —(CR ¹¹ R ¹² ) _y C(=O) R ¹³ , -(CR ¹¹ R ¹² ) _y OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ , -(CR ¹¹ R ¹² ) _y NR ¹⁰ (CR ¹⁴ R ¹⁵ ) _q C(=O )OR ¹³ , -(CR ¹¹ R ¹² ) _y NR ¹³ R ¹⁴ , -(CR ¹¹ R ¹² ) _y R ²⁰ , -((CR ¹¹ R ¹² ) _y O) _q (CR ¹⁴ R ¹⁵ ) _z C(= O) OR ¹³ , —((CR ¹¹ R ¹² ) _y O) _q (CR ¹⁴ R ¹⁵ ) _z OR ¹³ ,

is;
each R ⁴ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl and C ₁ -C ₆ alkyl;
each R ⁵ is independently selected from H, D deuterated C ₁ -C ₆ alkyl and C ₁ -C ₆ alkyl;
each R ⁶ is independently selected from H, D deuterated C ₁ -C ₆ alkyl and C ₁ -C ₆ alkyl;
each R ⁷ is independently selected from H and C ₁ -C ₆ alkyl;
each R ⁸ and R ⁹ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, or —OH;
or R ⁸ and R ⁹ together with the carbon in CR ⁸ R ⁹ form a C ₃ -C ₈ cycloalkyl;
each R ¹⁰ is independently selected from H, D and C ₁ -C ₆ alkyl;
each R ¹¹ is independently selected from H, D and C ₁ -C ₆ alkyl;
each R ¹² is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl and C ₁ -C ₆ alkyl;
each R ¹³ is independently selected from H and C ₁ -C ₆ alkyl;
each R ¹⁴ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl and C ₁ -C ₆ alkyl;
each R ¹⁵ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl and C ₁ -C ₆ alkyl;
R ¹⁶ is a 4- to 6-membered heterocycloalkyl having 1-2 ring members independently selected from N, O, and S, wherein the 4- to 6-membered heterocycloalkyl is unsubstituted is or is substituted with 1-2 R ¹⁷ groups;
each R ¹⁷ is independently selected from C ₁ -C ₆ alkyl and hydroxyl;
R ¹⁸ is H, C ₁ -C ₆ alkyl, —C(R ⁴ R ⁵ ) _m OR ¹⁹ , or —(CH ₂ ) _m C(=O)OR ¹⁹ ;
each R ¹⁹ is independently selected from H and C ₁ -C ₆ alkyl;
^R20 is

is;
each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each p is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.
each w is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each y is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each z is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each q is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10)
or a pharmaceutically acceptable salt thereof.

（式中、Ｘ _１ａ 、Ｘ _２ａ 、Ｘ _３ａ 、Ｘ _４ 、Ｌ _２ 、Ｒ ^１ 及びＲ ^２ が、実施形態５において定義されるとおりである）
の式の構造を有する、実施形態５に記載の化合物、又はその薬学的に許容できる塩。 Embodiment 6. Formula (Ib)

(wherein X _1a , X _2a , X _3a , X ₄ , L ₂ , R ¹ and R ² are as defined in Embodiment 5)
or a pharmaceutically acceptable salt thereof, according to embodiment 5, having the structure of the formula:

（式中、Ｌ _２ 、Ｒ ^１ 及びＲ ^２ が、実施形態５において定義されるとおりであり、Ｘ _１ａ が、ＣＨ又はＮであり；Ｘ _２ａ が、ＣＨ又はＮであり；Ｘ _３ａ が、ＣＨ又はＮである）
の式の構造を有する、実施形態５又は実施形態６に記載の化合物、又はその薬学的に許容できる塩。 Embodiment 7. Formula (Ic) or Formula (Id)

(wherein L ₂ , R ¹ and R ² are as defined in Embodiment 5; X _1a is CH or N; X _2a is CH or N; X _3a is CH or N)
or a pharmaceutically acceptable salt thereof, according to Embodiment 5 or Embodiment 6, having the structure of the formula:

（式中、Ｌ _２ 、Ｒ ^１ 及びＲ ^２ が、実施形態５において定義されるとおりであり、Ｘ _１ａ が、ＣＨ又はＮであり；Ｘ _２ａ が、ＣＨ又はＮである）
の構造を有する、実施形態５～７のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 8. Formula (Ie), Formula (If), Formula (Ig) or Formula (Ih):

(wherein L ₂ , R ¹ and R ² are as defined in Embodiment 5, X _1a is CH or N; X _2a is CH or N)
or a pharmaceutically acceptable salt thereof, according to any one of embodiments 5-7, having the structure

（式中、Ｌ _２ 、Ｒ ^１ 及びＲ ^２ が、実施形態５において定義されるとおりである）
の式の構造を有する、実施形態５～８のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 9. formula (Ii), formula (Ij), formula (Ik) or formula (Il)

(wherein L ₂ , R ¹ and R ² are as defined in Embodiment 5)
or a pharmaceutically acceptable salt thereof, according to any one of embodiments 5-8, having a structure of the formula:

（式中、Ｌ _２ 、Ｒ ^１ 及びＲ ^２ が、実施形態５において定義されるとおりである）
の式の構造を有する、実施形態５～８のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 10. formula (Im), formula (In), formula (Io) or formula (Ip)

(wherein L ₂ , R ¹ and R ² are as defined in Embodiment 5)
or a pharmaceutically acceptable salt thereof, according to any one of embodiments 5-8, having a structure of the formula:

（式中、Ｌ _２ 、Ｒ ^１ 及びＲ ^２ が、実施形態５において定義されるとおりである）
の構造を有する、実施形態５～８のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 11. Formula (Ii),

(wherein L ₂ , R ¹ and R ² are as defined in Embodiment 5)
or a pharmaceutically acceptable salt thereof, according to any one of embodiments 5-8, having the structure

（式中、Ｌ _２ 、Ｒ ^１ 及びＲ ^２ が、実施形態５において定義されるとおりである）
の構造を有する、実施形態５～８のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 12. Formula (Im),

(wherein L ₂ , R ¹ and R ² are as defined in Embodiment 5)
or a pharmaceutically acceptable salt thereof, according to any one of embodiments 5-8, having the structure

又は－Ｏ－であり、ここで、 ^＊ が、Ｌ _２ への結合点を示し；
Ｌ _２ が、－（ＣＲ ^４ Ｒ ^５ ） _ｎ －、－Ｏ（ＣＲ ^４ Ｒ ^５ ） _ｎ － ^＊＊ 、－ＮＲ ^７ （ＣＲ ^４ Ｒ ^５ ） _ｎ － ^＊＊ 、－（ＣＲ ^４ Ｒ ^５ ） _ｎ Ｏ（ＣＲ ^６ Ｒ ^１０ ） _ｐ － ^＊＊ 、－（ＣＲ ^４ Ｒ ^５ ） _ｎ （ＣＲ ^６ Ｒ ^１８ ）－ ^＊＊ 、－（ＣＲ ^４ Ｒ ^５ ） _ｎ （ＣＲ ^８ Ｒ ^９ ） _ｐ （ＣＲ ^４ Ｒ ^５ ） _ｍ －、－（ＣＲ ^４ Ｒ ^５ ） _ｐ ＮＲ ^７ （ＣＲ ^６ Ｒ ^１０ ） _ｎ － ^＊＊ 、又は－Ｏ－Ｃ _３ ～Ｃ _８ シクロアルキレン－ ^＊＊ であり、ここで、 ^＊＊ が、Ｘ _４ 中で ^＊ によって示される結合点におけるＸ _４ への結合点を示し；
Ｒ ^１ が、Ｈ、ハロ、ハロ置換Ｃ _１ ～Ｃ _６ アルキル、Ｃ _１ ～Ｃ _６ アルキル、又はＣ _１ ～Ｃ _６ アルコキシであり；
Ｒ ^２ が、Ｈ、又はハロであり；
Ｒ ^３ が、Ｈ、－Ｃ _１ ～Ｃ _６ アルキル、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｒ ^１６ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｃ（＝Ｏ）ＯＲ ^１３ 、－（（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｏ（ＣＲ ^１４ Ｒ ^１５ ） _ｚ Ｃ（＝Ｏ）ＯＲ ^１３ 、－（（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｏ（ＣＲ ^１４ Ｒ ^１５ ） _ｚ ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｃ（＝Ｏ）Ｒ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ （ＣＲ ^８ Ｒ ^９ ） _ｚ Ｃ（＝Ｏ）ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ （ＣＲ ^８ Ｒ ^９ ） _ｚ ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ （ＣＲ ^８ Ｒ ^９ ） _ｚ （ＣＲ ^１４ Ｒ ^１５ ） _ｑ ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ ＮＲ ^１０ （ＣＲ ^１４ Ｒ ^１５ ） _ｑ Ｃ（＝Ｏ）ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ ＮＲ ^１３ Ｒ ^１４ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｒ ^２０ 、

であり；
各Ｒ ^４ がＨであり；
各Ｒ ^５ がＨであり；
各Ｒ ^６ がＨであり；
各Ｒ ^７ が、独立して、Ｈ、及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^８ 及びＲ ^９ が、独立して、Ｈ、Ｃ _１ ～Ｃ _６ アルキル、又は－ＯＨから選択され；
又はＲ ^８ 及びＲ ^９ が、ＣＲ ^８ Ｒ ^９ 中の炭素と一緒に、Ｃ _３ ～Ｃ _８ シクロアルキルを形成し；
各Ｒ ^１０ がＨであり；
各Ｒ ^１１ がＨであり；
各Ｒ ^１２ がＨであり；
各Ｒ ^１３ が、独立して、Ｈ、及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^１４ がＨであり；
各Ｒ ^１５ がＨであり；
Ｒ ^１６ が、Ｎ、又はＯから独立して選択される１～２つの環員を有する４～６員ヘテロシクロアルキルであり、ここで、前記４～６員ヘテロシクロアルキルが、非置換であるか、又は１～２つのＲ ^１７ 基で置換され；
各Ｒ ^１７ が、独立して、Ｃ _１ ～Ｃ _６ アルキル及びヒドロキシルから選択され；
Ｒ ^１８ が、－Ｃ（Ｒ ^４ Ｒ ^５ ） _ｍ ＯＲ ^１９ 、又は－（ＣＨ _２ ） _ｍ Ｃ（＝Ｏ）ＯＲ ^１９ であり；
各Ｒ ^１９ がＨであり；
Ｒ ^２０ が、

であり；
各ｍが、独立して、１、２及び３から選択され；
各ｎが、独立して、１、２、３、４、５、６、７、８、及び９から選択され；
各ｐが、独立して、１、２及び３から選択され；
各ｗが、独立して、１及び２から選択され；
各ｙが、独立して、１、２、３、４及び５から選択され；
各ｚが、独立して、１、２及び３から選択され；
各ｑが、独立して、１及び２から選択される、実施形態５～１２のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 13.
_X4 is

or -O-, where ^* indicates the point of attachment to _L2 ;
L ₂ is —(CR ⁴ R ⁵ ) _n —, —O(CR ⁴ R ⁵ ) _n — ^** , —NR ⁷ (CR ⁴ R ⁵ ) _n — ^** , —(CR ⁴ R ⁵ ) _n O (CR ⁶ R ¹⁰ ) _p − ^** , −(CR ⁴ R ⁵ ) _n (CR ⁶ R ¹⁸ ) − ^** , −(CR ⁴ R ⁵ ) _n (CR ⁸ R ⁹ ) _p (CR ⁴ R ⁵ ) _m -, -(CR ⁴ R ⁵ ) _p NR ⁷ (CR ⁶ R ¹⁰ ) _n - ^** or -O-C ₃ -C ₈ cycloalkylene- ^** where ^** is X ₄ indicates the point of attachment to _X4 at the point of attachment indicated by ^* in;
R ¹ is H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy;
R ² is H or halo;
R ³ is H, —C ₁ -C ₆ alkyl, —(CR ¹¹ R ¹² ) _y R ¹⁶ , —(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , —((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z C(=O) OR ¹³ , —((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z OR ¹³ , —(CR ¹¹ R ¹² ) _y C(=O) R ¹³ , -(CR ¹¹ R ¹² ) _y OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ , -(CR ¹¹ R ¹² ) _y NR ¹⁰ (CR ¹⁴ R ¹⁵ ) _q C(=O ) OR ¹³ , —(CR ¹¹ R ¹² ) _y NR ¹³ R ¹⁴ , —(CR ¹¹ R ¹² ) _y R ²⁰ ,

is;
each R ⁴ is H;
each R ⁵ is H;
each R ⁶ is H;
each R ⁷ is independently selected from H and C ₁ -C ₆ alkyl;
each R ⁸ and R ⁹ is independently selected from H, C ₁ -C ₆ alkyl, or —OH;
or R ⁸ and R ⁹ together with the carbon in CR ⁸ R ⁹ form a C ₃ -C ₈ cycloalkyl;
each R ¹⁰ is H;
each R ¹¹ is H;
each R ¹² is H;
each R ¹³ is independently selected from H and C ₁ -C ₆ alkyl;
each R ¹⁴ is H;
each R ¹⁵ is H;
R ¹⁶ is a 4-6 membered heterocycloalkyl having 1-2 ring members independently selected from N or O, wherein said 4-6 membered heterocycloalkyl is unsubstituted or substituted with 1-2 R ¹⁷ groups;
each R ¹⁷ is independently selected from C ₁ -C ₆ alkyl and hydroxyl;
R ¹⁸ is —C(R ⁴ R ⁵ ) _m OR ¹⁹ or —(CH ₂ ) _m C(=O)OR ¹⁹ ;
each R ¹⁹ is H;
^R20 is

is;
each m is independently selected from 1, 2 and 3;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;
each p is independently selected from 1, 2 and 3;
each w is independently selected from 1 and 2;
each y is independently selected from 1, 2, 3, 4 and 5;
each z is independently selected from 1, 2 and 3;
A compound according to any one of embodiments 5-12, or a pharmaceutically acceptable salt thereof, wherein each q is independently selected from 1 and 2.

又は－Ｏ－であり、ここで、 ^＊ が、Ｌ _２ への結合点を示し；
Ｌ _２ が、－（ＣＲ ^４ Ｒ ^５ ） _ｎ －、－Ｏ（ＣＲ ^４ Ｒ ^５ ） _ｎ － ^＊＊ 、又は－（ＣＲ ^４ Ｒ ^５ ） _ｎ Ｏ（ＣＲ ^６ Ｒ ^１０ ） _ｐ － ^＊＊ であり、ここで、 ^＊＊ が、Ｘ _４ 中で ^＊ によって示される結合点におけるＸ _４ への結合点を示し；
Ｒ ^１ が、ハロ又はハロ置換Ｃ _１ ～Ｃ _６ アルキルであり；
Ｒ ^２ が、Ｈ、又はハロであり；
Ｒ ^３ が、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｃ（＝Ｏ）ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ （ＣＲ ^８ Ｒ ^９ ） _ｚ Ｃ（＝Ｏ）ＯＲ ^１３ 、又は－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ （ＣＲ ^８ Ｒ ^９ ） _ｚ （ＣＲ ^１４ Ｒ ^１５ ） _ｑ ＯＲ ^１３ であり；
各Ｒ ^４ がＨであり；
各Ｒ ^５ がＨであり；
各Ｒ ^６ がＨであり；
各Ｒ ^８ 及びＲ ^９ が、独立して、Ｈ又はＣ _１ ～Ｃ _６ アルキルから選択され；
又はＲ ^８ 及びＲ ^９ が、ＣＲ ^８ Ｒ ^９ 中の炭素と一緒に、Ｃ _３ ～Ｃ _８ シクロアルキルを形成し；
各Ｒ ^１０ がＨであり；
各Ｒ ^１１ がＨであり；
各Ｒ ^１２ がＨであり；
各Ｒ ^１３ が、独立して、Ｈ及びＣ _１ ～Ｃ _６ アルキルから選択され；
各Ｒ ^１４ がＨであり；
各Ｒ ^１５ がＨであり；
各ｎが、独立して、１、２、３、４、５、６、７、８、及び９から選択され；
各ｐが、独立して、１、２及び３から選択され；
各ｙが、独立して、１、２、３、４及び５から選択され；
各ｚが、独立して、１、２及び３から選択され；
各ｑが、独立して、１及び２から選択される、実施形態５～１３のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 14.
_X4 is

or -O-, where ^* indicates the point of attachment to _L2 ;
L2 is -( _CR4R5 ) _{n-, -O(CR4R5)n -} ^** _, ^or - ^{( CR4R5} ) ^{nO ( CR6R10 )} _p - ^{** ;} where ^** indicates the point of attachment to _X4 at the point of attachment indicated by ^* in _X4 ;
R ¹ is halo or halo-substituted C ₁ -C ₆ alkyl;
R ² is H or halo;
R ³ is -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O )OR ¹³ , or -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ ;
each R ⁴ is H;
each R ⁵ is H;
each R ⁶ is H;
each R ⁸ and R ⁹ is independently selected from H or C ₁ -C ₆ alkyl;
or R ⁸ and R ⁹ together with the carbon in CR ⁸ R ⁹ form a C ₃ -C ₈ cycloalkyl;
each R ¹⁰ is H;
each R ¹¹ is H;
each R ¹² is H;
each R ¹³ is independently selected from H and C ₁ -C ₆ alkyl;
each R ¹⁴ is H;
each R ¹⁵ is H;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;
each p is independently selected from 1, 2 and 3;
each y is independently selected from 1, 2, 3, 4 and 5;
each z is independently selected from 1, 2 and 3;
A compound according to any one of embodiments 5-13, or a pharmaceutically acceptable salt thereof, wherein each q is independently selected from 1 and 2.

又は－Ｏ－であり、ここで、 ^＊ が、Ｌ _２ への結合点を示し；
Ｌ _２ が、－（ＣＲ ^４ Ｒ ^５ ） _ｎ －、－Ｏ（ＣＲ ^４ Ｒ ^５ ） _ｎ － ^＊＊ 、又は－（ＣＲ ^４ Ｒ ^５ ） _ｎ Ｏ（ＣＲ ^６ Ｒ ^１０ ） _ｐ であり、ここで、 ^＊＊ が、Ｘ _４ 中で ^＊ によって示される結合点におけるＸ _４ への結合点を示し；
Ｒ ^１ が、Ｃｌ、Ｆ又はＣＦ _３ であり；
Ｒ ^２ が、Ｈ又はＦであり；
Ｒ ^３ が、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｃ（＝Ｏ）ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ ＯＲ ^１３ 、－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ （ＣＲ ^８ Ｒ ^９ ） _ｚ Ｃ（＝Ｏ）ＯＲ ^１３ 、又は－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ （ＣＲ ^８ Ｒ ^９ ） _ｚ （ＣＲ ^１４ Ｒ ^１５ ） _ｑ ＯＲ ^１３ であり；
各Ｒ ^４ がＨであり；
各Ｒ ^５ がＨであり；
各Ｒ ^６ がＨであり；
各Ｒ ^８ 及びＲ ^９ が、独立して、Ｈ又はメチルから選択され；
又はＲ ^８ 及びＲ ^９ が、ＣＲ ^８ Ｒ ^９ 中の炭素と一緒に、シクロプロピルを形成し；
各Ｒ ^１０ がＨであり；
各Ｒ ^１１ がＨであり；
各Ｒ ^１２ がＨであり；
各Ｒ ^１３ が、独立して、Ｈ、メチル及びエチルから選択され；
各Ｒ ^１４ がＨであり；
各Ｒ ^１５ がＨであり；
各ｎが、独立して、１、２、３、４、５、６、７、８、及び９から選択され；
各ｐが、独立して、１、２及び３から選択され；
各ｙが、独立して、１、２、３、４及び５から選択され；
ｚが１であり；
ｑが１である、実施形態５～１４のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 15.
_X4 is

or -O-, where ^* indicates the point of attachment to _L2 ;
L ₂ is —(CR ⁴ R ⁵ ) _n —, —O(CR ⁴ R ⁵ ) _n — ^** , or —(CR ⁴ R ⁵ ) _n O(CR ⁶ R ¹⁰ ) _p , wherein ^** indicates the point of attachment to _X4 at the point of attachment indicated by ^* in _X4 ;
R ¹ is Cl, F or _CF3 ;
R ² is H or F;
R ³ is -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O )OR ¹³ , or -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ ;
each R ⁴ is H;
each R ⁵ is H;
each R ⁶ is H;
each R ⁸ and R ⁹ is independently selected from H or methyl;
or R ⁸ and R ⁹ together with the carbon in CR ⁸ R ⁹ form cyclopropyl;
each R ¹⁰ is H;
each R ¹¹ is H;
each R ¹² is H;
each R ¹³ is independently selected from H, methyl and ethyl;
each R ¹⁴ is H;
each R ¹⁵ is H;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;
each p is independently selected from 1, 2 and 3;
each y is independently selected from 1, 2, 3, 4 and 5;
z is 1;
A compound according to any one of embodiments 5-14, or a pharmaceutically acceptable salt thereof, wherein q is 1.

であり、ここで、 ^＊ が、Ｌ _２ への結合点を示し；
Ｌ _２ が－（ＣＲ ^４ Ｒ ^５ ） _ｎ －であり；
Ｒ ^１ がＣＦ _３ であり；
Ｒ ^２ がＨであり；
Ｒ ^３ が－（ＣＲ ^１１ Ｒ ^１２ ） _ｙ Ｃ（＝Ｏ）ＯＲ ^１３ であり；
各Ｒ ^４ がＨであり；
各Ｒ ^５ がＨであり；
各Ｒ ^１１ がＨであり；
各Ｒ ^１２ がＨであり；
各Ｒ ^１３ がＨであり；
ｎが、１、２、３、４、５、６、７、８、又は９であり；
ｙが、２、３又は４である、実施形態５～１５のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 16.
_X4 is

where ^* indicates the point of attachment to _L2 ;
L ₂ is -(CR ⁴ R ⁵ ) _n -;
R ¹ is CF ₃ ;
R ² is H;
R ³ is -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ ;
each R ⁴ is H;
each R ⁵ is H;
each R ¹¹ is H;
each R ¹² is H;
each R ¹³ is H;
n is 1, 2, 3, 4, 5, 6, 7, 8, or 9;
A compound according to any one of embodiments 5-15, wherein y is 2, 3 or 4, or a pharmaceutically acceptable salt thereof.

（式中、Ｘ _３ａ が、ＣＨ又はＮであり；Ｘ _４ 、Ｌ _２ 、Ｒ ^１ 及びＲ ^２ が、実施形態１３において定義されるとおりである）
の式の構造を有する、実施形態５に記載の化合物、又はその薬学的に許容できる塩。 Embodiment 17. Formula (Iq)

(wherein X _3a is CH or N; X ₄ , L ₂ , R ¹ and R ² are as defined in Embodiment 13)
or a pharmaceutically acceptable salt thereof, according to embodiment 5, having the structure of the formula:

Embodiment 18. Compounds according to embodiment 17, wherein X _3a is CH or N; X ₄ , L ₂ , R ¹ and R ² are as defined in embodiment 14.

であり、ここで、 ^＊ が、Ｌ _２ への結合点を示す、実施形態５～１８のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 19.
_X4 is

A compound according to any one of embodiments _5-18 , or a pharmaceutically acceptable salt thereof, wherein ^* indicates the point of attachment to L2.

Embodiment 20. A compound according to any one of Embodiments 5-15 or Embodiments 17-18, or a pharmaceutically acceptable salt thereof, wherein X ₄ is -O-.

Embodiment 21. L ₂ is —(CR ⁴ R ⁵ ) _n —, —O(CR ⁴ R ⁵ ) _n — ^** , —NR ⁷ (CR ⁴ R ⁵ ) _n — ^** , —(CR ⁴ R ⁵ ) _n O (CR ⁶ R ¹⁰ ) _p − ^** , −(CR ⁴ R ⁵ ) _n (CR ⁶ R ¹⁸ ) − ^** , −(CR ⁴ R ⁵ ) _n (CR ⁸ R ⁹ ) _p (CR ⁴ R ⁵ ) _m -, -(CR ⁴ R ⁵ ) _p NR ⁷ (CR ⁶ R ¹⁰ ) _n - ^** or -O-C ₃ -C ₈ cycloalkylene- ^** where ^** is X ₄ A compound according to any one of Embodiments 5-12 or Embodiments 17-18, or a pharmaceutically acceptable salt thereof, that exhibits a point of attachment to X ₄ at the point of attachment indicated by ^* in it.

Embodiment 22. L2 is -( _CR4R5 ) _{n-, -O(CR4R5)n -} ^** _, ^or - ^{( CR4R5} ) ^{nO ( CR6R10 )} _p - ^{** ;} wherein ^** indicates the point of attachment to X ₄ at the point of attachment indicated by ^* in X _4. The compound of any one of Embodiments 5-13 or Embodiments 17-20, or pharmaceutically acceptable salts.

Embodiment 23. A compound according to any one of Embodiments 5-15 or Embodiments 17-20, or a pharmaceutically acceptable salt thereof, wherein L ₂ is -(CR ⁴ R ⁵ ) _n -.

Embodiment 24. Embodiments 5-15 wherein L ₂ is -O(CR ⁴ R ⁵ ) _n - ^** , wherein ^** indicates the point of attachment to X ₄ at the point of attachment indicated by ^* in X ₄ or a compound according to any one of embodiments 17-20, or a pharmaceutically acceptable salt thereof.

Embodiment 25. L ₂ is -(CR ⁴ R ⁵ ) _n O(CR ⁶ R ¹⁰ ) _p - ^** where ^** points the point of attachment to X ₄ at the point of attachment indicated by ^* in X ₄ A compound according to any one of Embodiments 5-15 or Embodiments 17-20, or a pharmaceutically acceptable salt thereof, as shown.

である、実施形態５～１３又は実施形態１７～２５のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 26. R ³ is H, —C ₁ -C ₆ alkyl, —(CR ¹¹ R ¹² ) _y R ¹⁶ , —(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , —((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z C(=O) OR ¹³ , —((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z OR ¹³ , —(CR ¹¹ R ¹² ) _y C(=O) R ¹³ , -(CR ¹¹ R ¹² ) _y OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ , -(CR ¹¹ R ¹² ) _y NR ¹⁰ (CR ¹⁴ R ¹⁵ ) _q C(=O ) OR ¹³ , —(CR ¹¹ R ¹² ) _y NR ¹³ R ¹⁴ , —(CR ¹¹ R ¹² ) _y R ²⁰ ,

or a pharmaceutically acceptable salt thereof, according to any one of Embodiments 5-13 or Embodiments 17-25.

Embodiment 27. A compound according to any one of Embodiments 5-13 or Embodiments 17-26, or a pharmaceutically acceptable salt thereof, wherein R ³ is H or —C ₁ -C ₆ alkyl.

Embodiment 28. A compound according to any one of Embodiments 5-13 or Embodiments 17-27, or a pharmaceutically acceptable salt thereof, wherein R ³ is H, methyl or ethyl.

Embodiment 29. A compound according to any one of Embodiments 5-13 or Embodiments 17-28, wherein R ³ is H, or a pharmaceutically acceptable salt thereof.

Embodiment 30. A compound according to any one of Embodiments 5-13 or Embodiments 17-28, or a pharmaceutically acceptable salt thereof, wherein R ³ is methyl.

Embodiment 31. A compound according to any one of Embodiments 5-13 or Embodiments 17-28, or a pharmaceutically acceptable salt thereof, wherein R ³ is ethyl.

Embodiment 32. R ³ is H, —(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , —((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z C(=O) OR ¹³ , —(( CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z OR ¹³ , —(CR ¹¹ R ¹² ) _y C(=O)R ¹³ , —(CR ¹¹ R ¹² ) _y OR ¹³ , —(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z any of Embodiments 5-13 or Embodiments 17-26 which is (CR ¹⁴ R ¹⁵ ) _q OR ¹³ or -(CR ¹¹ R ¹² ) _y NR ¹⁰ (CR ¹⁴ R ¹⁵ ) _q C(=O)OR ¹³ or a pharmaceutically acceptable salt thereof.

Embodiment 33. R ³ is -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O any one of Embodiments 5-15, Embodiments 17-26, or Embodiment 32, which is )OR ¹³ or -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ A compound according to 1, or a pharmaceutically acceptable salt thereof.

Embodiment 34. A compound according to any one of Embodiments 5-16, Embodiments 17-26, or Embodiments 32-33, wherein R ³ is -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ ; or pharmaceutically acceptable salts.

Embodiment 35. The compound according to any one of Embodiments 5-15, Embodiments 17-26, or Embodiments 32-33, or a pharmaceutically acceptable compound thereof, wherein R ³ is -(CR ¹¹ R ¹² ) _y OR ¹³ salt.

Embodiment 36. any one of Embodiments 5-15, Embodiments 17-26, or Embodiments 32-33 wherein R ³ is -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O)OR ¹³ The compound according to , or a pharmaceutically acceptable salt thereof.

Embodiment 37. any of Embodiments 5-15, Embodiments 17-26, or Embodiments 32-33 wherein R ³ is -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ A compound according to one, or a pharmaceutically acceptable salt thereof.

である、実施形態５～１２又は実施形態１７～２６のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 38. ^R3 is

or a pharmaceutically acceptable salt thereof, according to any one of Embodiments 5-12 or Embodiments 17-26.

Embodiment 39. The compound according to any one of Embodiments 5-13 or Embodiments 17-26, wherein R ³ is -(CR ¹¹ R ¹² ) _y R ¹⁶ or -(CR ¹¹ R ¹² ) _y R ²⁰ ; pharmaceutically acceptable salts.

Embodiment 40. Embodiments 5-13, Embodiments 17-26, or Embodiment 39 wherein R ¹⁶ is unsubstituted 4-6 membered heterocycloalkyl having 1-2 ring members independently selected from N or O or a pharmaceutically acceptable salt thereof.

Embodiment 41. A compound according to any one of Embodiments 5-13, Embodiments 17-26, or Embodiments 39-40, or a pharmaceutically acceptable salt thereof, wherein R ¹⁶ is unsubstituted morpholinyl.

Embodiment 42. A compound according to any one of Embodiments 5-13, Embodiments 17-26, or Embodiments 39-40, or a pharmaceutically acceptable salt thereof, wherein R ¹⁶ is unsubstituted pyrrolidinyl.

Embodiment 43. A compound according to any one of Embodiments 5-13, Embodiments 17-26, or Embodiments 39-40, or a pharmaceutically acceptable salt thereof, wherein R ¹⁶ is unsubstituted piperazinyl.

Embodiment 44. Embodiments 5- wherein R ¹⁶ is 4-6 membered heterocycloalkyl having 1-2 ring members independently selected from N, O and S, substituted with 1-2 R ¹⁷ groups 13, any one of embodiments 17-26 or embodiment 39, or a pharmaceutically acceptable salt thereof.

Embodiment 45. The compound according to any one of Embodiments 5-13, Embodiments 17-26, Embodiment 39, or Embodiment 44, or a pharmaceutically acceptable compound thereof, wherein R ¹⁶ is azetidinyl substituted with a hydroxyl group salt.

Embodiment 46. A compound according to any one of Embodiments 5-13, Embodiments 17-26, Embodiment 39, or Embodiment 44, or a pharmacological thereof, wherein R ¹⁶ is pyrrolidinyl substituted with 1-2 hydroxyl groups acceptable salt.

Embodiment 47. The compound of any one of Embodiments 5-13, Embodiments 17-26, Embodiment 39, or Embodiment 44, or a pharmaceutically acceptable compound thereof, wherein R ¹⁶ is piperazinyl substituted with a methyl group salt.

Embodiment 48. Embodiments 5-13, Embodiments 17-26, or wherein R ¹⁶ is morpholinyl, azetidinyl, pyrrolidinyl, or piperazinyl, each unsubstituted or substituted with 1-2 R ¹⁷ groups, or A compound according to any one of embodiment 39, or a pharmaceutically acceptable salt thereof.

Embodiment 49. Embodiments 5-13 wherein R ¹⁶ is morpholinyl, azetidinyl, pyrrolidinyl or piperazinyl, each of which is unsubstituted or substituted with 1-2 groups independently selected from hydroxyl and methyl , Embodiments 17-26, or Embodiment 39, or a pharmaceutically acceptable salt thereof.

Embodiment 50. 49. According to any one of Embodiments 5-13, Embodiments 17-26, or Embodiments 39, 44, or 48, wherein each R ¹⁷ is independently selected from C ₁ -C ₆ alkyl and hydroxyl. A compound, or a pharmaceutically acceptable salt thereof.

Embodiment 51. The compound according to any one of Embodiments 5-13, Embodiments 17-26, or Embodiments 39, 44, or 48, wherein each R ¹⁷ is independently selected from methyl, ethyl, propyl and hydroxyl. , or a pharmaceutically acceptable salt thereof.

Embodiment 52. A compound according to any one of Embodiments 5-13, Embodiments 17-24 or Embodiments 39, 44, or 48, wherein each R ¹⁷ is independently selected from methyl and hydroxyl, or a pharmaceutically acceptable compound thereof acceptable salt.

である、実施形態５～１３、実施形態１７～２６又は実施形態３９のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 53. ^R20 is

or a pharmaceutically acceptable salt thereof, according to any one of Embodiments 5-13, Embodiments 17-26, or Embodiment 39.

である、実施形態５～１３、実施形態１７～２６又は実施形態３９のいずれか１つに記載の化合物、又はその薬学的に許容できる塩。 Embodiment 54. ^R20 is

or a pharmaceutically acceptable salt thereof, according to any one of Embodiments 5-13, Embodiments 17-26, or Embodiment 39.

Embodiment 55. according to any one of Embodiments 5-13 or Embodiments 17-54, wherein R ¹⁸ is -C(R ⁴ R ⁵ ) _m OR ¹⁹ or -(CH ₂ ) _m C(=O)OR ¹⁹ A compound as described, or a pharmaceutically acceptable salt thereof.

Embodiment 56. A compound according to any one of Embodiments 5-13 or Embodiments 17-55, or a pharmaceutically acceptable salt thereof, wherein R ¹⁸ is —C(R ⁴ R ⁵ ) _m OR ¹⁹ .

Embodiment 57. A compound according to any one of Embodiments 5-13 or Embodiments 17-55, or a pharmaceutically acceptable salt thereof, wherein R ¹⁸ is —(CH ₂ ) _m C(=O)OR ¹⁹ .

Embodiment 58. any one of Embodiments 6-13 or Embodiments 17-57, wherein R ¹ is H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy The compound according to , or a pharmaceutically acceptable salt thereof.

Embodiment 59. A compound according to any one of Embodiments 6-13 or Embodiments 17-58, wherein R ¹ is H, or a pharmaceutically acceptable salt thereof.

Embodiment 60. A compound according to any one of Embodiments 6-14 or Embodiments 17-58, or a pharmaceutically acceptable salt thereof, wherein R ¹ is halo.

Embodiment 61. A compound according to any one of Embodiments 6-14, Embodiments 17-58 or Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein R ¹ is F.

Embodiment 62. A compound according to any one of Embodiments 6-14, Embodiments 17-58 or Embodiment 60, or a pharmaceutically acceptable salt thereof, wherein R ¹ is Cl.

Embodiment 63. A compound according to any one of Embodiments 6-14 or Embodiments 17-58, or a pharmaceutically acceptable salt thereof, wherein R ¹ is halo-substituted C ₁ -C ₆ alkyl.

Embodiment 64. A compound according to any one of Embodiments 6-14, Embodiments 17-58, or Embodiment 63, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CF ₃ .

Embodiment 65. A compound according to any one of Embodiments 6-14, Embodiments 17-58, or Embodiment 63, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CHF ₂ .

Embodiment 66. A compound according to any one of Embodiments 6-13 or Embodiments 17-58, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₆ alkyl.

Embodiment 67. A compound according to any one of Embodiments 6-13, Embodiments 17-58, or Embodiment 66, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl.

Embodiment 68. A compound according to any one of Embodiments 6-13 or Embodiments 17-58, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₆ alkoxy.

Embodiment 69. A compound according to any one of Embodiments 6-13, Embodiments 17-58, or Embodiment 68, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methoxy.

Embodiment 70. A compound according to embodiment 5, wherein each R ¹ is independently selected from H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy; or pharmaceutically acceptable salts.

Embodiment 71. A compound according to embodiment 5, or a pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from H and halo.

Embodiment 72. A compound according to embodiment 5, or a pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from H and F.

Embodiment 73. A compound according to embodiment 5, or a pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from H and Cl.

Embodiment 74. A compound according to embodiment 5, or a pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from H and halo-substituted C ₁ -C ₆ alkyl.

Embodiment 75. A compound according to embodiment 5, or a pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from H and —CF ₃ .

Embodiment 76. A compound according to embodiment 5, or a pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from H and —CHF ₂ .

Embodiment 77. A compound according to embodiment 5, or a pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from H and C ₁ -C ₆ alkyl.

Embodiment 78. A compound according to embodiment 5, a pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from H and methyl.

Embodiment 79. A compound according to embodiment 5, a pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from H and C ₁ -C ₆ alkoxy.

Embodiment 80. A compound according to embodiment 5, a pharmaceutically acceptable salt thereof, wherein each R ¹ is independently selected from H and methoxy.

Embodiment 81. A compound according to any one of Embodiments 6-14 or Embodiments 17-80, or a pharmaceutically acceptable salt thereof, wherein R ² is H or halo.

Embodiment 82. A compound according to any one of Embodiments 6-14 or Embodiments 17-81, or a pharmaceutically acceptable salt thereof, wherein R ² is halo.

Embodiment 83. A compound according to any one of Embodiments 6-14 or Embodiments 17-82, wherein R ² is F, or a pharmaceutically acceptable salt thereof.

Embodiment 84. A compound according to any one of embodiments 6-81, or a pharmaceutically acceptable salt thereof, wherein R ² is H.

Embodiment 85. A compound according to embodiment 5, or a pharmaceutically acceptable salt thereof, wherein each ^R2 is independently selected from H and halo.

Embodiment 86. A compound according to embodiment 5, or a pharmaceutically acceptable salt thereof, wherein each ^R2 is independently selected from H and F.

Embodiment 87. 87. A compound according to any one of embodiments 5-86, or a pharmaceutically acceptable salt thereof, wherein each ^R4 is H.

Embodiment 88. ^88. A compound according to any one of embodiments 5-87, or a pharmaceutically acceptable salt thereof, wherein each R5 is H.

Embodiment 89. ^89. A compound according to any one of embodiments 5-88, or a pharmaceutically acceptable salt thereof, wherein each R6 is H.

Embodiment 90. 90. A compound according to any one of embodiments 5-89, or a pharmaceutically acceptable salt thereof, wherein each R ⁷ is independently selected from H and C ₁ -C ₆ alkyl.

Embodiment 91. A compound according to any one of embodiments 5-90, or a pharmaceutically acceptable salt thereof, wherein each R ⁷ is independently selected from H and methyl.

Embodiment 92. A compound according to any one of embodiments 5-91, or a pharmaceutically acceptable compound thereof, wherein each R ⁸ and R ⁹ is independently selected from H, C ₁ -C ₆ alkyl, or —OH can salt.

Embodiment 93. A compound according to any one of embodiments 5-92, or a pharmaceutically acceptable salt thereof, wherein each R ⁸ and R ⁹ is independently selected from H, methyl or —OH.

Embodiment 94. A compound according to any one of embodiments 5-91, or a pharmaceutically acceptable compound according to any one of embodiments 5-91, wherein R ⁸ and R ⁹ together with the carbon in CR ⁸ R ⁹ form a C ₃ -C ₈ cycloalkyl can salt.

Embodiment 95. The compound of any one of Embodiments 5-91 or Embodiment 93, or a pharmaceutically acceptable compound thereof, wherein R ⁸ and R ⁹ together with the carbon in CR ⁸ R ⁹ form cyclopropyl salt.

Embodiment 96. 96. A compound according to any one of embodiments 5-95, or a pharmaceutically acceptable salt thereof, wherein each R ¹⁰ is H.

Embodiment 97. 97. A compound according to any one of embodiments 5-96, or a pharmaceutically acceptable salt thereof, wherein each R ¹¹ is H.

Embodiment 98. 98. A compound according to any one of embodiments 5-97, or a pharmaceutically acceptable salt thereof, wherein each R ¹² is H.

Embodiment 99. A compound according to any one of embodiments 5-98, or a pharmaceutically acceptable salt thereof, wherein each R ¹³ is independently selected from H and C ₁ -C ₆ alkyl.

Embodiment 100. A compound according to any one of embodiments 5-98, or a pharmaceutically acceptable salt thereof, wherein each R ¹³ is independently selected from H, methyl and ethyl.

Embodiment 101. 101. A compound according to any one of embodiments 5-100, or a pharmaceutically acceptable salt thereof, wherein each R ¹⁴ is H.

Embodiment 102. 101. A compound according to any one of embodiments 5-100, or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is H.

Embodiment 103. A compound according to any one of embodiments 5-102, or a pharmaceutically acceptable salt thereof, wherein each R ¹⁹ is H.

Embodiment 104. A compound according to any one of embodiments 5-102, or a pharmaceutically acceptable salt thereof, wherein each R ¹⁹ is C ₁ -C ₆ alkyl.

Embodiment 105. A compound according to any one of embodiments 5-102, or a pharmaceutically acceptable salt thereof, wherein each R ¹⁹ is methyl or ethyl.

Embodiment 106. A compound according to any one of Embodiments 2-13 or Embodiments 17-105, wherein each m is independently selected from 1, 2 and 3, or a pharmaceutically acceptable salt thereof.

Embodiment 107. A compound according to any one of Embodiments 5-13 or Embodiments 17-106, wherein each w is independently selected from 1 and 2, or a pharmaceutically acceptable salt thereof.

Embodiment 108. A compound according to any one of Embodiments 5-14 or Embodiments 17-107, wherein each z is independently selected from 1, 2 and 3, or a pharmaceutically acceptable salt thereof.

Embodiment 109. A compound according to any one of Embodiments 5-14 or Embodiments 17-108, wherein each z is 1, or a pharmaceutically acceptable salt thereof.

Embodiment 110. A compound according to any one of Embodiments 5-15 or Embodiments 17-109, wherein each q is independently selected from 1 and 2, or a pharmaceutically acceptable salt thereof.

Embodiment 111. A compound according to any one of Embodiments 5-15 or Embodiments 17-109, wherein each q is 1, or a pharmaceutically acceptable salt thereof.

Embodiment 112. A compound according to any one of Embodiments 5-15 or Embodiments 17-111, or a pharmaceutically acceptable salt thereof, wherein each p is independently selected from 1, 2 and 3.

Embodiment 113. A compound according to any one of embodiments 5-112, or a pharmaceutically acceptable salt thereof, wherein each y is independently selected from 1, 2, 3, 4 and 5.

Embodiment 114. A compound according to any one of embodiments 5-112, or a pharmaceutically acceptable salt thereof, wherein each y is independently selected from 2, 3 and 4.

Embodiment 115. 115. A compound according to any one of embodiments 5-114, or a pharmaceutical compound thereof, wherein each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9 acceptable salt.

Embodiment 116. 6-(2-morpholinoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphane 4,4-dioxide;
2 ^3- (Trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4 - a dioxide;
2-(4,4-dioxide-2 ³ -(trifluoromethyl)-1 ¹ -oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphan-6-yl)acetic acid;
2 ^3- (trifluoromethyl)-4-thia-3,6,1 ¹ -triaza-1(3,2),2,5(2,6)-tripyridinacycloundecaphane 4,4-dioxide ;
2 ³ -(trifluoromethyl)-1 ² -oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4- dioxide;
4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphan-6-yl)butanoic acid;
3-(2-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Nacycloundecaphan-6-yl)ethoxy)propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca phan-6-yl)butanoic acid;
2 ^3- (Trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4 - a dioxide;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphan-6-yl)butanoic acid;
6-(2-(3-hydroxypropoxy)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphane 4,4-dioxide;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)butanoic acid;
4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzeneacyclododecaphan-6-yl)butanoic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphan-6-yl)propanoic acid;
6-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)hexanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphan-6-yl)butanoic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca phan-6-yl)propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid;
4-(2 ³ -methyl-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-6 - yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)butanal;
2-(2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Nacycloundecaphan-6-yl)ethoxy)acetic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphan-6-yl)propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)butanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)pentanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)pentanoic acid;
4-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-6 - yl)butanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca phan-6-yl)pentanoic acid;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphan-6-yl)propanoic acid;
6-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-6 - yl) hexanoic acid;
4-(2 ³ -methoxy-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-6 - yl)butanoic acid;
6-(5-hydroxypentyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
6-(5-hydroxypentyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca fan 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)propanoic acid;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca fan 4,4-dioxide;
6-(4-hydroxybutyl)-2 ³ -methoxy-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
6-ethyl-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane4,4 - a dioxide;
6-(4-hydroxybutyl)-2 ³ -methyl-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzeneacyclododecaphan-6-yl)propanoic acid;
4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphan-6-yl)butanoic acid;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca fan 4,4-dioxide;
3-(2 ^3- (difluoromethyl)-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane -6-yl)propanoic acid;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca fan 4,4-dioxide;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid;
3-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-6 - yl) propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca phan-6-yl)butanoic acid;
1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphane 4,4-dioxide;
4-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane-6- yl)butanoic acid;
1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)propanoic acid;
2 ³ -chloro-6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
2 ^3- (trifluoromethyl)-6,12-dioxa-4-thia-3-aza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide ;
2 ³ -chloro-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
3-(4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propanoic acid ;
1-((4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenenacyclo ndecafane-6-yl)methyl)cyclopropane-1-carboxylic acid;
1-((4,4-dioxide-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzeneacyclododecaphan-6-yl)methyl)cyclopropane-1-carboxylic acid;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzeneacycloundecaphan-6-yl)-2,2-dimethylpropanoic acid;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzenacycloundecaphan-6-yl)propanoic acid;
6-(2-hydroxyethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca fan 4,4-dioxide;
6-(2-hydroxyethyl)-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)propanoic acid;
2 ³ -chloro-14-methyl-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6,13-triaza-1(3,2),2,5(2,6)-tripyridinacyclotridecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)-2,2-dimethylpropanoic acid;
1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphane 4,4-dioxide;
6-(3-hydroxy-2,2-dimethylpropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)-2,2-dimethylpropanoic acid;
6-(3-hydroxy-2,2-dimethylpropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacyclododecaphane 4,4-dioxide;
6,13-dimethyl-2 ^3- (trifluoromethyl)-4-thia-3,6,13-triaza-1(3,2),2,5(2,6)-tripyridinacyclotridecaphane 4,4-dioxide;
2 ³ -chloro-12-oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
6-(2-hydroxyethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenacin crowndecaphan-7-yl)propanoic acid;
6,10-dimethyl-2 ^3- (trifluoromethyl)-4-thia-3,6,10-triaza-1(3,2),2,5(2,6)-tripyridinacyclodecaphane 4 , 4-dioxide;
(4 ¹ s,4 ⁵ s)-1 ³ -(trifluoromethyl)-3,5-dioxa-7-thia-8-aza-1,6(2,6),2(3,2)-tripyridina -4(1,5)-cyclooctanacyclooctaphane 7,7-dioxide;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphane 4,4-dioxide;
1 ⁵ -fluoro-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6,10-triaza-1(3,2),2,5(2,6)-tripyridinacyclodecaphane 4,4-dioxide;
7-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenacin crownedecaphane 4,4-dioxide;
Ethyl 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclo dodecaphan-6-yl)-2,2-dimethylpropanoate;
2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide;
2-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)acetic acid;
2 ^3- (trifluoromethyl)-6-((2S,3S)-2,3,4-trihydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 1(1,2)-Benzenacycloundecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
8-hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4- dioxide;
6-(2-(piperazin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphane 4,4-dioxide;
6-(2-(4-methylpiperazin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphane 4,4-dioxide;
(2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenenacyclo ndecafane-6-yl)ethyl)glycine;
6-(2-(3-hydroxyazetidin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 (1,2)-Benzenacycloundecaphane 4,4-dioxide;
^23- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide ;
6-(2-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2 ,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide;
6-(((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ^3- (trifluoromethyl)-4-thia-3 ,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide;
6-methyl-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4- dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
Ethyl 2-(4,4-dioxide-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphan-6-yl)acetate;
6-(2,3-dihydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacin crownedecaphane 4,4-dioxide;
6-(2-(pyrrolidin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphane 4,4-dioxide;
Methyl (2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacin Crown Decaphan-6-yl)ethyl)glycinate;
6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6) - dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(2-aminoethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca fan 4,4-dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6,9-triaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclononaphane 4,4-dioxide;
8-Hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4 - a dioxide;
6-(2-aminoethyl)-2 ^3- (difluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundeca fan 4,4-dioxide;
2-(3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Nacycloundecaphan-6-yl)propyl)isoindoline-1,3-dione;
2-(3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene nacycloundecaphan-6-yl)propyl)hexahydro-1H-isoindole-1,3(2H)-dione;
Methyl 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclo dodecaphan-6-yl)acetate 6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1 , 2)-Benzenacyclotridecaphane 4,4-dioxide;
6-(5-hydroxypentyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca fan 4,4-dioxide;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphane 4,4-dioxide;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphane 4,4-dioxide;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphane 4,4-dioxide;
2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacyclododecaphane 4,4-dioxide;
6-(6-hydroxyhexyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
6-(2-(2-hydroxyethoxy)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphane 4,4-dioxide;
6-(5-hydroxypentyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca fan 4,4-dioxide;
2 ³ -chloro-6-(6-hydroxyhexyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacyclododecaphane 4,4-dioxide;
1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca fan 4,4-dioxide;
2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4 - a dioxide;
6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1, 2)-Benzenacycloundecaphane 4,4-dioxide;
6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 1(1,2)-Benzenacyclododecaphane 4,4-dioxide;
1 ⁵ -fluoro-6-(3-hydroxy-2,2-dimethylpropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 1(1,2)-Benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca phan-6-yl)propanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca phan-6-yl)pentanoic acid;
6-(2-aminoethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide and (R)-3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)- The compound according to any one of embodiments 5-12, which is selected from dipyridina-1(1,2)-benzeneacycloundecaphan-7-yl)propanoic acid.

Embodiment 117.4-(1 ⁵ -Fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)- dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca phan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)butanoic acid;
4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzeneacyclododecaphan-6-yl)butanoic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphan-6-yl)propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphan-6-yl)butanoic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca phan-6-yl)propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphan-6-yl)propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)butanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)pentanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)pentanoic acid;
4-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-6 - yl)butanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca phan-6-yl)pentanoic acid;
6-(5-hydroxypentyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca fan 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)propanoic acid,
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca fan 4,4-dioxide;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzeneacyclododecaphan-6-yl)propanoic acid;
4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid;
1-((4,4-dioxide-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzeneacyclododecaphan-6-yl)methyl)cyclopropane-1-carboxylic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)-2,2-dimethylpropanoic acid;
1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)-2,2-dimethylpropanoic acid;
6-(3-hydroxy-2,2-dimethylpropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacyclododecaphane 4,4-dioxide;
6-(2-hydroxyethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphane 4,4-dioxide;
Ethyl 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclo dodecaphan-6-yl)-2,2-dimethylpropanoate;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenacyclododecaphane 4,4-dioxide and methyl 2- (4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane- The compound according to any one of embodiments 5-12, which is selected from 6-yl)acetates.

Embodiment 118. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)butanoic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphan-6-yl)propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphan-6-yl)butanoic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca phan-6-yl)propanoic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphan-6-yl)propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)butanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)pentanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)pentanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca phan-6-yl)pentanoic acid and 3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 The compound according to any one of embodiments 5-12, which is selected from (1,2)-benzeneacyclododecaphan-6-yl)propanoic acid.

Embodiment 119. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca phan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphan-6-yl)butanoic acid and 6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2 ,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide.

Depending on the choice of starting materials and procedures, compounds may be present in one of the possible stereoisomeric forms or as mixtures thereof, e.g. as pure optical isomers or, depending on the number of asymmetric carbon atoms, in racemates. and as mixtures of stereoisomers, such as mixtures of diastereomers. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent can have a cis- or trans-configuration. All tautomers are also intended to be included.

As used herein, the terms "salt" or "salts" refer to acid or base addition salts of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salts" as used herein typically refers to biologically or otherwise Refers to one or more salts that retain the biological effectiveness and properties of the compounds of this invention that are not harmful in form. In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Organic or inorganic acids used to form pharmaceutically acceptable acid addition salts of compounds of the invention include, but are not limited to, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfone Acid, carbonic acid, camphorsulfonic acid, capric acid, chloroteophylinate, citric acid, ethanedisulfonic acid, fumaric acid, D-glycero-D-gulo-heptonic acid, galactaric acid, galactaric/mucilic acid, gluceptic acid, glucoheptone Acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfate, malic acid, maleic acid, malonic acid , mandelic acid, mesylic acid, methanesulfonic acid, mucic acid, naphthoic acid, 1-hydroxy-2-naphthoic acid, naphthalenesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, nitric acid, octadecanoic acid, oleic acid, oxalic acid, Palmitic acid, pamoic acid, phosphoric acid, polygalacturonic acid, propionic acid, sebacic acid, stearic acid, succinic acid, sulfosalicylic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid and triphenylacetic acid.

Salt forms of the compounds of the invention may be converted to the free compounds by treatment with a suitable basic agent.

Pharmaceutically acceptable acid addition salts of the compounds of the present invention include, but are not limited to, acetate, adipate, ascorbate, aspartate, benzoate, besylate, benzenesulfonate, polyacidate, Carbonate/carbonate, bisulfate/sulfate, bromide/hydrobromide, camphorsulfonate, camsylate, caprate, chloride/hydrochloride, chloroteophylinate, citrate, edisyl acid, ethanedisulfonate, fumarate, gluceptate, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodine isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methyl sulfate, mucus, Naphthoate, napsylate, 2-napsylate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoic acid Salts, Phosphates/Hydrogen Phosphates/Dihydrogen Phosphates, Polygalacturonates, Propionates, Sebacates, Stearates, Succinates, Sulfosalicylates, Sulfates, Tartrates, Tosylates Salt, p-toluenesulfonate, trifluoroacetate, triphenate, triphenylacetate and xinafoate forms.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Organic bases used to form pharmaceutically acceptable base addition salts of compounds of the invention include, but are not limited to, primary, secondary, and tertiary amines, naturally substituted amines. including substituted amines, cyclic amines, basic ion exchange resins, and the like. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine. Inorganic bases used to form pharmaceutically acceptable base addition salts of compounds of the present invention include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, ammonium salts and I of the periodic table. to XII column metals. Pharmaceutically acceptable base addition salts of the compounds of this invention include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper salts. particularly suitable salts include the ammonium, potassium, sodium, calcium and magnesium salts.

In another aspect, the present invention provides 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2, in the sodium or potassium salt form). 6) -Dipyridina-1(1,2)-Benzenacyclodecaphan-6-yl)butanoic acid.

In another aspect, the present invention provides 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2, in the sodium or potassium salt form). 6) -Dipyridina-1(1,2)-Benzenacycloundecaphan-6-yl)butanoic acid.

In another aspect, the present invention provides 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2, in the sodium or potassium salt form). 6) -Dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)butanoic acid.

In another aspect, the present invention provides 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2, in the sodium or potassium salt form). 6) -Dipyridina-1(1,2)-Benzenacyclotridecaphan-6-yl)butanoic acid.

In another aspect, the present invention provides 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2, in the sodium or potassium salt form). 6) -Dipyridina-1(1,2)-Benzenacyclotetradecaphan-6-yl)butanoic acid.

In another aspect, the present invention provides 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2, in the sodium or potassium salt form). 6) -Dipyridina-1(1,2)-Benzenacyclopentadecan-6-yl)butanoic acid.

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically-labeled compounds have structures depicted by the formulas depicted herein, except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into compounds of the present invention include, for example, isotopes of hydrogen.

Furthermore, incorporation of certain isotopes, particularly deuterium (i.e., ² H or D), may result in higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements or therapeutic index or tolerability. can provide certain therapeutic benefits resulting from improvements in It is understood that deuterium in this context is considered a substituent of the compounds of the invention. The concentration of deuterium can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the invention is designated to be deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5 at each designated deuterium atom). % deuterium uptake), at least 4000 (60% deuterium uptake), at least 4500 (67.5% deuterium uptake), at least 5000 (75% deuterium uptake), at least 5500 (82.5% deuterium uptake), at least 6000 (90% deuterium uptake), at least 6333.3 (95% deuterium uptake), at least 6466.7 (97% deuterium uptake), at least 6600 (99% deuterium uptake) uptake), or at least 6633.3 (99.5% deuterium uptake). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as it is described for deuterium.

Other examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine ( ^3H , ^11C , ^13C , ^14C , ^15C , respectively). N, ¹⁸ F ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²³ I, ¹²⁴ I, ¹²⁵ I, etc.). Accordingly, the present invention provides any one of the above isotopes, including those in which radioactive isotopes such as ³ H and ¹⁴ C or non-radioactive isotopes such as ² H and ¹³ C are present. or a compound that incorporates a plurality. Such isotopically labeled compounds can be used in detection or imaging techniques including metabolic studies (with ¹⁴ C), kinetic studies (e.g. with ² H or ³ H), drug or substrate tissue distribution assays (Positron Emission Tomography (Positron Emission Tomography)). PET) or single photon emission computed tomography (SPECT)), or radiation treatment of a patient. In particular, ¹⁸ F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of the present invention can be prepared by conventional techniques known to those skilled in the art, or by using suitable isotopically-labeled reagents in place of previously used unlabeled reagents, as described in the accompanying Examples and preparations. can generally be prepared by methods analogous to those described.

By way of example, compounds of the invention may exist in the deuterated forms shown below.

Any asymmetric atom (such as carbon) of the compounds of the invention may be in a racemic or enantiomerically enriched, e.g. (R)-, (S)- or (R,S)-configuration. can exist. In certain embodiments, each asymmetric atom is in the (R)- or (S)-configuration with at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess , at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. Substituents at atoms with unsaturated double bonds may, where possible, be present in cis-(Z)- or trans-(E)-form.

Thus, as used herein, the compounds of the invention are in one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, e.g. It can be as pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

Any resulting mixture of isomers may be pure or substantially pure geometric or optical isomers, diastereomers, It can be separated into racemates.

Either the final product or the resulting racemate of the intermediate can be separated by known methods, e.g., separation of its diastereomeric salts with optically active acids or bases, and liberation of optically active acidic or basic compounds. can be resolved into the optical antipodes. Thus, in particular, basic moieties are, for example, with optically active acids such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. The compounds of this invention can be used to resolve their optical antipodes by fractional crystallization of the salts formed. Racemic products can also be resolved by chiral chromatography, eg, high performance liquid chromatography (HPLC), using a chiral adsorbent.

Methods for Making the Compounds of the Invention General procedures for preparing the compounds of the invention are described herein. In the reactions described, reactive functional groups such as hydroxy, amino, imino or carboxy groups, if desired in the final product, may be protected to avoid their undesired participation in the reaction. Within this context, unless the context indicates otherwise, only readily removable groups that are not components of the particular desired end product of the compounds of this invention are designated as "protecting groups." The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described, for example, in J. Am. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; W. Greene andP. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999.

The compounds of the invention were made by the methods described herein and as shown in the examples. Non-limiting examples of synthetic schemes used to make compounds of the invention are shown in Schemes 1-12 below.

Scheme 1 shows one embodiment for making compounds of the present invention, wherein amination of intermediate (1a) with a vinyl-terminated amine yields intermediate (1b) with a vinyl-terminated group. can get. Catalytic ring-closing metathesis (RCM) with a Ru catalyst gives the cyclic intermediate (1c), followed by hydrogenation to give compounds of formula (Ib).

Scheme 2 shows another embodiment for making compounds of the invention, wherein amination of intermediate (2a) with a diamine provides compounds of formula (Ib).

Scheme 3 shows another embodiment for making compounds of the invention, wherein compounds of formula (Ib) undergo ring closure upon ether formation via reaction of intermediate (3a) with a diol. obtained by

Scheme 4 shows another embodiment for making compounds of the invention, wherein the initial amination of intermediate (4a) forms intermediate (4b) containing a pendant alcohol group. Ring closure is accomplished by intramolecular ether formation, thereby affording compounds of formula (Ib).

Scheme 5 shows another embodiment for making compounds of the invention, wherein ring closure by amination of intermediate (5a) provides compounds of formula (Ib).

Scheme 6 shows another embodiment for making compounds of the invention, in which intermediate (6a) is first N-alkylated to form intermediate (6b). Ring closure is achieved by intramolecular amination, which gives intermediate (6c), which is then acidified to give certain compounds of formula (Ib).

Scheme 7 shows another embodiment for making compounds of the present invention wherein the amination of intermediate (7a) with a vinyl-terminated amine yields vinyl-terminated intermediate (7b). is obtained. Catalytic ring-closing metathesis (RCM) with a Ru catalyst gives the cyclic intermediate (7c), followed by hydrogenation to give compounds of formula (Ib).

Compounds of the invention and intermediates can also be converted into each other according to methods commonly known to those skilled in the art. Reaction Schemes 8-12 below show general reactions that can be used to convert certain compounds of the present invention to other compounds of the present invention.

The compounds of the invention can be produced as shown in the examples below. The following examples are intended to illustrate the invention and should not be construed as limitations thereon. Temperatures are given in °C. Unless otherwise stated, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, eg microanalysis and spectroscopic properties eg MS, IR, NMR. Abbreviations used are conventional in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the invention are either commercially available or made by organic synthetic methods known to those skilled in the art. or can be produced by the organic synthetic methods described herein.

For illustrative purposes, the general reaction schemes presented herein indicate possible routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are shown in the schemes and described below, other starting materials and reagents can be readily substituted to provide various derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those of ordinary skill in the art.

Abbreviations:
Abbreviations used are conventional in the art or are as follows.

Analytical Methods ESI-MS data (also reported herein simply as MS) were recorded using a Waters System (Acquity UPLC and Micromass ZQ mass spectrometer); all reported masses are not specifically recorded. is the m/z of the protonated parent ion.

LC/MS:
Samples are dissolved in a suitable solvent such as MeCN, DMSO or MeOH and injected directly onto the column using an automated sample handler. Analysis is performed using one of the following methods.

HPLC conditions:
Condition 1: Agilent 1200 Series HPLC system:
- Agilent binary gradient manager with degasser - Agilent diode array detector - Agilent 6140 quadrupole LC/MS
- SoftA ELS detector HPLC column: Waters Acquity HSS T3 C18 1.8um, 2.1 x 50mm
Flow rate: 0.9 mL/min Temperature: 60°C (column temperature)
Mobile phase composition: A: 0.05% trifluoroacetic acid in water.
B: 0.035% trifluoroacetic acid in acetonitrile.

工程１．Ｎ－（２－モルホリノエチル）－２－ニトロベンゼンスルホンアミドの合成
ＤＣＭ（２０ｍＬ）中の２－モルホリノエタンアミン（０．６５１ｇ、５ｍｍｏｌ）及びＥｔ _３ Ｎ（２．１ｍＬ、１５ｍｍｏｌ）の冷（０℃）溶液に、２－ニトロベンゼン－１－スルホニルクロリド（１．５５１ｇ、７ｍｍｏｌ）を加え、室温で一晩撹拌した。ＬＣＭＳにより、反応が完了したことが示された。反応溶液を、水、塩水で洗浄し、Ｎａ _２ ＳＯ _４ 上で乾燥させた。有機相をろ過し、濃縮し、４０ｇのＧｏｌｄ ＩＳＣＯカラム（ＥｔＯＡｃ／ヘプタン０～１００％）上で精製して、表題化合物（１．５３６ｇ、９７％）を褐色の結晶として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ３１６．２［Ｍ＋Ｈ］ ^＋ 、０．４１分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ８．０５（ｍ，１Ｈ）、７．９８（ｍ，１Ｈ）、７．８７（ｍ，３Ｈ）、３．４３（ｍ，４Ｈ）、３．０４（ｑ，Ｊ＝６．３Ｈｚ、２Ｈ）、２．３１（ｔ，Ｊ＝６．５Ｈｚ、２Ｈ）、２．２３（ｍ，４Ｈ）． Synthesis of intermediates Synthesis of intermediate N-(2-morpholinoethyl)pent-4-en-1-amine (intermediate a1)

Step 1. Synthesis of N-(2-morpholinoethyl)-2-nitrobenzenesulfonamide 2-morpholinoethanamine (0.651 g, 5 mmol) and Et ₃ N (2.1 mL, 15 mmol) in DCM (20 mL) were cooled (0° ) solution, 2-nitrobenzene-1-sulfonyl chloride (1.551 g, 7 mmol) was added and stirred overnight at room temperature. LCMS indicated the reaction was complete. The reaction solution was washed with water, _brine and dried over _Na2SO4 . The organic phase was filtered, concentrated and purified on a 40 g Gold ISCO column (EtOAc/heptane 0-100%) to give the title compound (1.536 g, 97%) as brown crystals. LCMS (conditions 1): m/z 316.2 [M+H] ⁺ , 0.41 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (m, 1H), 7.98 (m, 1H), 7.87 (m, 3H), 3.43 (m, 4H), 3. 04 (q, J=6.3 Hz, 2H), 2.31 (t, J=6.5 Hz, 2H), 2.23 (m, 4H).

Step 2. Synthesis of N-(2-morpholinoethyl)-2-nitro-N-(pent-4-en-1-yl)benzenesulfonamide N-(2-morpholinoethyl)-2-nitrobenzenesulfone in DMF (8 mL) A mixture of amide (631 mg, 2 mmol), 5-bromopent-1-ene (332 μL, 2.8 mmol), and K ₂ CO ₃ (553 mg, 4.00 mmol) was stirred at 100° C. for 2 hours. LCMS indicated the reaction was complete. Water was then added to the cold reaction solution, extracted with EtOAc, washed with water ( _x3 ), brine and dried over _Na2SO4 . The combined extracts were filtered, concentrated and purified on a 24 g Gold ISCO column (EtOAc/Heptane 0-100%) to give the title compound (771 mg, 1.95 mmol, 98% yield) as a colorless oil. obtained as LCMS (conditions 1): m/z 384.2 [M+H] ⁺ , 1.19 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (m, 1H), 7.97 (m, 1H), 7.86 (m, 2H), 5.77 (ddt, J = 6.6 , 10.2, 16.8Hz, 1H), 4.98 (m, 2H), 3.48 (m, 4H), 3.38 (t, J = 6.6Hz, 2H), 3.29 (m , 2H), 2.41 (t, J = 6.6Hz, 2H), 2.33 (m, 4H), 1.98 (m, 2H), 1.60 (p, J = 7.5Hz, 2H) ).

Step 3. Synthesis of N-(2-morpholinoethyl)pent-4-en-1-amine (intermediate a1) N-(2-morpholinoethyl)-2-nitro-N-(pent-4- A mixture of en-1-yl)benzenesulfonamide (748 mg, 1.95 mmol), K ₂ CO ₃ (809 mg, 5.85 mmol), and thiophenol (0.24 mL, 2.34 mmol) was stirred at room temperature for 2 days. did. LC-MS indicated the reaction was complete. The reaction solution was filtered, concentrated and purified on an ISCO column (MeOH/DCM 0-10%) to give the title compound (344 mg, 89% yield) as an oil. LCMS (conditions 1): m/z 199.3 [M+H] ⁺ , 0.23 min. ¹ H NMR (400 MHz, DMSO-d6) 5.81 (ddt, J= _6.6 , 10.2, 16.9 Hz, 1H), 5.01 (m, 1H), 4.94 (ddt, J = 1.2, 2.3, 10.2Hz, 1H), 3.56 (m, 4H), 2.57 (t, J = 6.5Hz, 2H), 2.49 (m, 2H), 2 .35 (m, 6H), 2.04 (m, 2H), 1.57 (s, 1H), 1.47 (m, 2H).

工程１において、２－モルホリノエタンアミンを、３－（２－アミノエトキシ）プロパン－１－オールで置き換えたことを除いて、中間体（中間体ａ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １８８．２［Ｍ＋Ｈ］ ^＋ 、０．２８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ５．８０（ｄｄｔ，Ｊ＝１６．９、１０．２、６．６Ｈｚ、１Ｈ）、５．０１（ｍ，１Ｈ）、４．９４（ｄｄｔ，Ｊ＝１０．２、２．３、１．２Ｈｚ、１Ｈ）、３．４１（ｍ，７Ｈ）、２．６５（ｔ，Ｊ＝５．７Ｈｚ、２Ｈ）、２．５２（ｍ，２Ｈ）、２．０２（ｍ，２Ｈ）、１．６３（ｐ，Ｊ＝６．４Ｈｚ、２Ｈ）、１．４８（ｐ，Ｊ＝７．３Ｈｚ、２Ｈ）． Synthesis of intermediate 3-(2-(pent-4-en-1-ylamino)ethoxy)propan-1-ol (intermediate a2)

Synthesized using the procedure used for intermediate (intermediate a1) except that in step 1 2-morpholinoethanamine was replaced with 3-(2-aminoethoxy)propan-1-ol. LCMS (conditions 1): m/z 188.2 [M+H] ⁺ , 0.28 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.80 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.01 (m, 1H), 4.94 (ddt, J = 10.2, 2.3, 1.2Hz, 1H), 3.41 (m, 7H), 2.65 (t, J = 5.7Hz, 2H), 2.52 (m, 2H), 2.02 (m, 2H), 1.63 (p, J=6.4Hz, 2H), 1.48 (p, J=7.3Hz, 2H).

工程１において、２－モルホリノエタンアミンを、６－アミノヘキサン－１－オールで置き換えたことを除いて、中間体（中間体ａ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １８６．３［Ｍ＋Ｈ］ ^＋ 、１．０９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ５．８０（ｄｄｔ，Ｊ＝１６．９、１０．２、６．６Ｈｚ、１Ｈ）、５．００（ｄｑ，Ｊ＝１７．２、１．７Ｈｚ、１Ｈ）、４．９３（ｄｄｔ，Ｊ＝１０．２、２．４、１．２Ｈｚ、１Ｈ）、４．３１（ｓ，１Ｈ）、３．３７（ｔ，Ｊ＝６．５Ｈｚ、２Ｈ）、２．４６（ｍ，４Ｈ）、２．０３（ｍ，２Ｈ）、１．４６（ｐ，Ｊ＝７．３Ｈｚ、２Ｈ）、１．３８（ｍ，４Ｈ）、１．２６（ｍ，４Ｈ）． Synthesis of intermediate 6-(pent-4-en-1-ylamino)hexan-1-ol (intermediate a3)

Synthesized using the procedure used for intermediate (intermediate a1) except that in step 1 2-morpholinoethanamine was replaced with 6-aminohexan-1-ol. LCMS (conditions 1): m/z 186.3 [M+H] ⁺ , 1.09 min. ¹ H NMR (400 MHz, DMSO-d6) δ 5.80 ( _ddt , J=16.9, 10.2, 6.6 Hz, 1 H), 5.00 (dq, J=17.2, 1.7 Hz , 1H), 4.93 (ddt, J = 10.2, 2.4, 1.2 Hz, 1H), 4.31 (s, 1H), 3.37 (t, J = 6.5Hz, 2H) , 2.46 (m, 4H), 2.03 (m, 2H), 1.46 (p, J = 7.3 Hz, 2H), 1.38 (m, 4H), 1.26 (m, 4H ).

工程１において、２－モルホリノエタンアミンを、２－（２－アミノエトキシ）エタン－１－オールで置き換えたことを除いて、中間体（中間体ａ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １７４．２［Ｍ＋Ｈ］ ^＋ 、０．３８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ５．８１（ｄｄｔ，Ｊ＝１６．９、１０．２、６．６Ｈｚ、１Ｈ）、５．０１（ｍ，１Ｈ）、４．９４（ｄｄｔ，Ｊ＝１０．１、２．３、１．２Ｈｚ、１Ｈ）、３．４９（ｍ，２Ｈ）、３．４５（ｔ，Ｊ＝５．７Ｈｚ、２Ｈ）、３．４０（ｍ，２Ｈ）、２．６５（ｔ，Ｊ＝５．７Ｈｚ、２Ｈ）、２．５２（ｍ，２Ｈ）、２．０４（ｍ，２Ｈ）、１．４８（ｐ，Ｊ＝７．３Ｈｚ、２Ｈ）． Synthesis of intermediate 2-(2-(pent-4-en-1-ylamino)ethoxy)ethan-1-ol (intermediate a4)

Synthesized using the procedure used for intermediate (intermediate a1) except that in step 1 2-morpholinoethanamine was replaced with 2-(2-aminoethoxy)ethan-1-ol. LCMS (conditions 1): m/z 174.2 [M+H] ⁺ , 0.38 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.81 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.01 (m, 1H), 4.94 (ddt, J = 10.1, 2.3, 1.2Hz, 1H), 3.49 (m, 2H), 3.45 (t, J = 5.7Hz, 2H), 3.40 (m, 2H), 2.65 (t, J=5.7 Hz, 2H), 2.52 (m, 2H), 2.04 (m, 2H), 1.48 (p, J=7.3 Hz, 2H).

工程１において、２－モルホリノエタンアミンを、５－アミノペンタン－１－オールで置き換え、工程２において、５－ブロモペンタ－１－エンを、４－ブロモブタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １５８．２［Ｍ＋Ｈ］ ^＋ 、０．３２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ５．８０（ｄｄｔ，Ｊ＝１７．０、１０．２、６．８Ｈｚ、１Ｈ）、５．０３（ｄｑ，Ｊ＝１７．２、１．６Ｈｚ、１Ｈ）、４．９７（ｄｄｔ，Ｊ＝１０．２、２．３、１．２Ｈｚ、１Ｈ）、４．３３（ｓ，１Ｈ）、３．３７（ｔ，Ｊ＝６．５Ｈｚ、２Ｈ）、２．５５（ｔ，Ｊ＝７．２Ｈｚ、２Ｈ）、２．４７（ｍ，２Ｈ）、２．１５（ｑｔ，Ｊ＝７．１、１．４Ｈｚ、２Ｈ）、１．３８（ｍ，４Ｈ）、１．２９（ｍ，２Ｈ）． Synthesis of intermediate 5-(but-3-en-1-ylamino)pentan-1-ol (intermediate a5)

except that in step 1 2-morpholinoethanamine was replaced with 5-aminopentan-1-ol and in step 2 5-bromopent-1-ene was replaced with 4-bromobut-1-ene; Synthesized using the procedure used for intermediate (intermediate a1). LCMS (conditions 1): m/z 158.2 [M+H] ⁺ , 0.32 min. ¹ H NMR (400 MHz, DMSO-d6) δ 5.80 ( _ddt , J=17.0, 10.2, 6.8 Hz, 1 H), 5.03 (dq, J=17.2, 1.6 Hz , 1H), 4.97 (ddt, J = 10.2, 2.3, 1.2 Hz, 1H), 4.33 (s, 1H), 3.37 (t, J = 6.5Hz, 2H) , 2.55 (t, J=7.2 Hz, 2H), 2.47 (m, 2H), 2.15 (qt, J=7.1, 1.4 Hz, 2H), 1.38 (m, 4H), 1.29(m, 2H).

工程１において、２－モルホリノエタンアミンを、４－アミノブタン－１－オールで置き換え、工程２において、５－ブロモペンタ－１－エンを、３－（２－ブロモエトキシ）プロパ－１－エンで置き換えたことを除いて、中間体（中間体ａ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １７４．３［Ｍ＋Ｈ］ ^＋ 、０．３２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ５．８８（ｄｄｔ，Ｊ＝１７．３、１０．６、５．４Ｈｚ、１Ｈ）、５．２４（ｄｑ，Ｊ＝１７．３、１．８Ｈｚ、１Ｈ）、５．１３（ｍ，１Ｈ）、３．９２（ｄｔ，Ｊ＝５．３、１．６Ｈｚ、２Ｈ）、３．４２（ｔ，Ｊ＝５．８Ｈｚ、２Ｈ）、３．３７（ｍ，２Ｈ）、２．６４（ｔ，Ｊ＝５．８Ｈｚ、２Ｈ）、２．４８（ｍ，２Ｈ）、１．４１（ｍ，４Ｈ）． Synthesis of intermediate 4-((2-(allyloxy)ethyl)amino)butan-1-ol (intermediate a6)

In step 1, 2-morpholinoethanamine was replaced with 4-aminobutan-1-ol and in step 2, 5-bromopent-1-ene was replaced with 3-(2-bromoethoxy)prop-1-ene. Synthesized using the procedure used for the intermediate (intermediate a1), except that LCMS (conditions 1): m/z 174.3 [M+H] ⁺ , 0.32 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.88 (ddt, J=17.3, 10.6, 5.4 Hz, 1 H), 5.24 (dq, J=17.3, 1.8 Hz , 1H), 5.13 (m, 1H), 3.92 (dt, J = 5.3, 1.6Hz, 2H), 3.42 (t, J = 5.8Hz, 2H), 3.37 (m, 2H), 2.64 (t, J=5.8 Hz, 2H), 2.48 (m, 2H), 1.41 (m, 4H).

工程１において、２－モルホリノエタンアミンを、４－アミノブタン－１－オールで置き換え、工程２において、５－ブロモペンタ－１－エンを、４－ブロモブタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １４４．２［Ｍ＋Ｈ］ ^＋ 、０．３９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ５．８０（ｄｄｔ，Ｊ＝１７．１、１０．２、６．８Ｈｚ、１Ｈ）、５．０３（ｍ，１Ｈ）、４．９７（ｄｄｔ，Ｊ＝１０．２、２．４、１．２Ｈｚ、１Ｈ）、３．３７（ｍ，２Ｈ）、２．５４（ｍ，２Ｈ）、２．４６（ｍ，２Ｈ）、２．１４（ｑｔ，Ｊ＝７．１、１．４Ｈｚ、２Ｈ）、１．４１（ｍ，４Ｈ）． Synthesis of intermediate 4-(but-3-en-1-ylamino)butan-1-ol (intermediate a7)

Intermediate, except that in step 1 2-morpholinoethanamine was replaced with 4-aminobutan-1-ol and in step 2 5-bromopent-1-ene was replaced with 4-bromobut-1-ene. Synthesized using the procedure used for the compound (intermediate a1). LCMS (conditions 1): m/z 144.2 [M+H] ⁺ , 0.39 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.80 (ddt, J=17.1, 10.2, 6.8 Hz, 1H), 5.03 (m, 1H), 4.97 (ddt, J = 10.2, 2.4, 1.2 Hz, 1H), 3.37 (m, 2H), 2.54 (m, 2H), 2.46 (m, 2H), 2.14 (qt, J=7.1, 1.4 Hz, 2H), 1.41 (m, 4H).

工程１において、２－モルホリノエタンアミンを、（１－（アミノメチル）シクロプロピル）メタノールで置き換えたことを除いて、中間体（中間体ａ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １７０．３［Ｍ＋Ｈ］ ^＋ 、０．３２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ５．８０（ｄｄｔ，Ｊ＝６．６、１０．２、１６．９Ｈｚ、１Ｈ）、５．０１（ｄｄｔ，Ｊ＝１．６、２．１、１７．２Ｈｚ、１Ｈ）、４．９５（ｄｄｔ，Ｊ＝１．２、２．３、１０．２Ｈｚ、１Ｈ）、４．２２（ｂｓ、２Ｈ）、３．３２（ｓ，２Ｈ）、２．５６（ｍ，４Ｈ）、２．０３（ｍ，２Ｈ）、１．５１（ｐ，Ｊ＝７．４Ｈｚ、２Ｈ）、０．３４（ｍ，４Ｈ）． Synthesis of intermediate (1-((pent-4-en-1-ylamino)methyl)cyclopropyl)methanol (intermediate a8)

Synthesized using the procedure used for intermediate (intermediate a1) except that in step 1 2-morpholinoethanamine was replaced with (1-(aminomethyl)cyclopropyl)methanol. LCMS (conditions 1): m/z 170.3 [M+H] ⁺ , 0.32 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.80 (ddt, J = 6.6, 10.2, 16.9 Hz, 1 H), 5.01 (ddt, J = 1.6, 2.1 , 17.2Hz, 1H), 4.95 (ddt, J = 1.2, 2.3, 10.2Hz, 1H), 4.22 (bs, 2H), 3.32 (s, 2H), 2 .56 (m, 4H), 2.03 (m, 2H), 1.51 (p, J=7.4Hz, 2H), 0.34 (m, 4H).

工程１において、２－モルホリノエタンアミンを、３－アミノプロパン－１－オールで置き換え、工程２において、５－ブロモペンタ－１－エンを、３－（２－ブロモエトキシ）プロパ－１－エンで置き換えたことを除いて、中間体（中間体ａ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １６０．２［Ｍ＋Ｈ］ ^＋ 、０．２８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ５．８８（ｄｄｔ，Ｊ＝５．３、１０．６、１７．３Ｈｚ、１Ｈ）、５．２４（ｄｑ，Ｊ＝１．８、１７．３Ｈｚ、１Ｈ）、５．１３（ｍ，１Ｈ）、３．９２（ｄｔ，Ｊ＝１．５、５．３Ｈｚ、２Ｈ）、３．４３（ｍ，４Ｈ）、２．６４（ｔ，Ｊ＝５．７Ｈｚ、２Ｈ）、２．５６（ｔ，Ｊ＝６．８Ｈｚ、２Ｈ）、１．５３（ｐ，Ｊ＝６．６Ｈｚ、２Ｈ）． Synthesis of Intermediate 3-((2-(allyloxy)ethyl)amino)propan-1-ol (Intermediate a9)

In step 1 2-morpholinoethanamine is replaced with 3-aminopropan-1-ol and in step 2 5-bromopent-1-ene is replaced with 3-(2-bromoethoxy)prop-1-ene Synthesized using the procedure used for intermediate (intermediate a1), except that LCMS (conditions 1): m/z 160.2 [M+H] ⁺ , 0.28 min. ¹ H NMR (400 MHz, DMSO-d6) δ 5.88 ( _ddt , J = 5.3, 10.6, 17.3 Hz, 1H), 5.24 (dq, J = 1.8, 17.3 Hz , 1H), 5.13 (m, 1H), 3.92 (dt, J = 1.5, 5.3 Hz, 2H), 3.43 (m, 4H), 2.64 (t, J = 5 .7Hz, 2H), 2.56 (t, J = 6.8Hz, 2H), 1.53 (p, J = 6.6Hz, 2H).

工程１において、２－モルホリノエタンアミンを、（２，２－ジメチル－１，３－ジオキソラン－４－イル）メタンアミンで置き換えたことを除いて、中間体（中間体ａ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １６０．２［Ｍ＋Ｈ］ ^＋ 、０．２８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ５．８０（ｄｄｔ，Ｊ＝６．６、１０．２、１６．９Ｈｚ、１Ｈ）、５．００（ｍ，１Ｈ）、４．９３（ｄｄｔ，Ｊ＝１．２、２．３、１０．２Ｈｚ、１Ｈ）、４．０８（ｐ，Ｊ＝６．１Ｈｚ、１Ｈ）、３．９５（ｄｄ，Ｊ＝６．３、８．０Ｈｚ、１Ｈ）、３．５８（ｄｄ，Ｊ＝６．５、８．０Ｈｚ、１Ｈ）、２．６２（ｄｄ，Ｊ＝５．９、１１．９Ｈｚ、１Ｈ）、２．５２（ｍ，３Ｈ）、２．０２（ｍ，２Ｈ）、１．５６（ｓ，１Ｈ）、１．４６（ｐ，Ｊ＝７．４Ｈｚ、２Ｈ）、１．３０（ｓ，３Ｈ）、１．２５（ｓ，３Ｈ）． Synthesis of intermediate N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)pent-4-en-1-amine (intermediate a10)

The procedure used for intermediate (intermediate a1) was followed except that in step 1 2-morpholinoethanamine was replaced with (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine. Synthesized using LCMS (conditions 1): m/z 160.2 [M+H] ⁺ , 0.28 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.80 (ddt, J = 6.6, 10.2, 16.9 Hz, 1H), 5.00 (m, 1H), 4.93 (ddt, J = 1.2, 2.3, 10.2Hz, 1H), 4.08 (p, J = 6.1Hz, 1H), 3.95 (dd, J = 6.3, 8.0Hz, 1H) , 3.58 (dd, J=6.5, 8.0 Hz, 1 H), 2.62 (dd, J=5.9, 11.9 Hz, 1 H), 2.52 (m, 3 H), 2. 02 (m, 2H), 1.56 (s, 1H), 1.46 (p, J=7.4Hz, 2H), 1.30 (s, 3H), 1.25 (s, 3H).

工程１において、２－モルホリノエタンアミンを、（１－（アミノメチル）シクロプロピル）メタノールで置き換え、工程２において、５－ブロモペンタ－１－エンを、３－（２－ブロモエトキシ）プロパ－１－エンで置き換えたことを除いて、中間体（中間体ａ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １８６．３［Ｍ＋Ｈ］ ^＋ 、０．３１分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ５．８８（ｄｄｔ，Ｊ＝５．３、１０．５、１７．３Ｈｚ、１Ｈ）、５．２４（ｄｑ，Ｊ＝１．７、１７．３Ｈｚ、１Ｈ）、５．１３（ｄｄｔ，Ｊ＝１．４、２．１、１０．５Ｈｚ、１Ｈ）、３．９３（ｄｔ，Ｊ＝１．５、５．３Ｈｚ、２Ｈ）、３．４２（ｔ，Ｊ＝５．７Ｈｚ、２Ｈ）、３．３０（ｓ，２Ｈ）、２．６５（ｔ，Ｊ＝５．７Ｈｚ、２Ｈ）、２．５１（ｓ，２Ｈ）、０．３１（ｍ，２Ｈ）、０．２７（ｍ，２Ｈ）． Synthesis of intermediate (1-(((2-(allyloxy)ethyl)amino)methyl)cyclopropyl)methanol (intermediate a11)

In step 1, 2-morpholinoethanamine is replaced with (1-(aminomethyl)cyclopropyl)methanol, and in step 2, 5-bromopent-1-ene is replaced with 3-(2-bromoethoxy)prop-1- Synthesized using the procedure used for intermediate (intermediate a1), except replacing with ene. LCMS (conditions 1): m/z 186.3 [M+H] ⁺ , 0.31 min. ¹ H NMR (400 MHz, DMSO-d6) δ 5.88 ( _ddt , J=5.3, 10.5, 17.3 Hz, 1 H), 5.24 (dq, J=1.7, 17.3 Hz , 1H), 5.13 (ddt, J = 1.4, 2.1, 10.5 Hz, 1H), 3.93 (dt, J = 1.5, 5.3 Hz, 2H), 3.42 ( t, J = 5.7 Hz, 2H), 3.30 (s, 2H), 2.65 (t, J = 5.7 Hz, 2H), 2.51 (s, 2H), 0.31 (m, 2H), 0.27(m, 2H).

５－ブロモペンタ－１－エンを、４－ブロモブタ－１－エンで置き換え、２－アミノエタノールを、ｔｅｒｔ－ブチル（２－アミノエチル）カルバメートで置き換えたことを除いて、中間体（中間体ａ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：）：ｍ／ｚ ２００．３［Ｍ＋Ｈ］ ^＋ 。１．１８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ５．７９（ｄｄｔ，Ｊ＝１６．９、１０．２、６．７Ｈｚ、１Ｈ）、５．００（ｍ，１Ｈ）、４．９３（ｄｄｔ，Ｊ＝１０．２、２．３、１．２Ｈｚ、１Ｈ）、３．３７（ｔ，Ｊ＝６．５Ｈｚ、２Ｈ）、２．４８（ｍ，４Ｈ）、２．００（ｍ，２Ｈ）、１．３２（ｍ，１２Ｈ）． Synthesis of intermediate 5-(hept-6-en-1-ylamino)pentan-1-ol (intermediate a12)

Intermediate (intermediate a1) except 5-bromopent-1-ene was replaced with 4-bromobut-1-ene and 2-aminoethanol was replaced with tert-butyl (2-aminoethyl)carbamate Synthesized using the procedure used for LCMS (conditions 1): ): m/z 200.3 [M+H] ⁺ . 1.18 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.79 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.00 (m, 1H), 4.93 (ddt, J = 10.2, 2.3, 1.2Hz, 1H), 3.37 (t, J = 6.5Hz, 2H), 2.48 (m, 4H), 2.00 (m, 2H), 1.32(m, 12H).

工程１．（（４Ｓ，５Ｓ）－５－（ヒドロキシメチル）－２，２－ジメチル－１，３－ジオキソラン－４－イル）メチル４－メチブベンゼンスルホネートの合成
（（４Ｓ，５Ｓ）－２，２－ジメチル－１，３－ジオキソラン－４，５－ジイル）ジメタノール（１．６２２ｇ、１０ｍｍｏｌ）、テトラブチルアンモニウム硫酸水素塩（０．３５２ｇ、１．０３７ｍｍｏｌ）及びＤＣＭ（４１ｍＬ）の溶液に、水（２．８７ｍＬ）中のＮａＯＨ（０．４４ｇ、１１ｍｍｏｌ）の溶液、続いて、ＤＣＭ（１０ｍＬ）中のＴｓＣｌ（２．１ｇ、１１ｍｍｏｌ）の溶液を加えた。得られた反応溶液を室温で７０分間撹拌した。ＬＣＭＳにより、反応が完了したことが示された。反応溶液を、水、飽和ＮａＨＣＯ _３ 溶液、塩水で洗浄し、Ｎａ _２ ＳＯ _４ 上で乾燥させ、ろ過した。ろ液を濃縮し、ＩＳＣＯカラム（ＥｔＯＡｃ／ヘプタン０～５０％）上で精製して、表題化合物（２．８０５ｇ、８９％の収率）を油として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ３１７．２［Ｍ＋Ｈ］ ^＋ 、１．３０分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ７．７９（ｍ，２Ｈ）、７．４９（ｍ，２Ｈ）、４．８９（ｓ，１Ｈ）、４．２０（ｄｄ，Ｊ＝２．７、１０．８Ｈｚ、１Ｈ）、４．０５（ｍ，１Ｈ）、３．９６（ｄｄｄ，Ｊ＝２．６、６．３、８．１Ｈｚ、１Ｈ）、３．７５（ｄｔ，Ｊ＝５．１、８．０Ｈｚ、１Ｈ）、３．４８（ｄｄ，Ｊ＝４．８、１１．４Ｈｚ、１Ｈ）、３．４３（ｄｄ，Ｊ＝５．３、１１．４Ｈｚ、１Ｈ）、２．４３（ｓ，３Ｈ）、１．２７（ｓ，３Ｈ）、１．２３（ｓ，３Ｈ）． Synthesis of intermediate ((4S,5S)-2,2-dimethyl-5-((pent-4-en-1-ylamino)methyl)-1,3-dioxolan-4-yl)methanol (intermediate a13)

Step 1. Synthesis of ((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methibubenzenesulfonate ((4S,5S)-2,2- To a solution of dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (1.622 g, 10 mmol), tetrabutylammonium hydrogensulfate (0.352 g, 1.037 mmol) and DCM (41 mL) was added water ( A solution of NaOH (0.44 g, 11 mmol) in DCM (10 mL) was added followed by a solution of TsCl (2.1 g, 11 mmol) in DCM (10 mL). The resulting reaction solution was stirred at room temperature for 70 minutes. LCMS indicated the reaction was complete. The reaction solution was washed with water, saturated _NaHCO3 solution, _brine , dried over _Na2SO4 and filtered. The filtrate was concentrated and purified on an ISCO column (EtOAc/heptane 0-50%) to give the title compound (2.805 g, 89% yield) as an oil. LCMS (conditions 1): m/z 317.2 [M+H] ⁺ , 1.30 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (m, 2H), 7.49 (m, 2H), 4.89 (s, 1H), 4.20 (dd, J = 2.7 , 10.8 Hz, 1 H), 4.05 (m, 1 H), 3.96 (ddd, J=2.6, 6.3, 8.1 Hz, 1 H), 3.75 (dt, J=5. 1, 8.0Hz, 1H), 3.48 (dd, J = 4.8, 11.4Hz, 1H), 3.43 (dd, J = 5.3, 11.4Hz, 1H), 2.43 (s, 3H), 1.27(s, 3H), 1.23(s, 3H).

Step 2. N-(((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2-nitro-N-(pent-4-ene-1 -yl)benzenesulfonamide 2-Nitro-N-(pent-4-en-1-yl)benzenesulfonamide (0.811 g, 3 mmol), ((4S,5S)-5 in DMF (10 mL) -(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methibubenzenesulfonate (1.234 g, 3.9 mmol) and K ₂ CO ₃ (1.244 g, 9 mmol) ) was stirred at 100° C. for 5 hours. LCMS indicated the reaction was complete. Water was added to the cold reaction mixture and extracted with EtOAc. The combined extracts were washed with water ( _3x ), brine, dried over _Na2SO4 and filtered. The filtrate was concentrated and purified on an ISCO column (EtOAc/heptane 0-100%) to give the title compound (459 mg, 37% yield) as a brown oil. LCMS (conditions 1): m/z 415.3 [M+H] ⁺ , 1.47 min, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (dd, J=1.6, 7.6 Hz, 1H), 7.97 (dd, J = 1.4, 7.8 Hz, 1H), 7.88 (td, J = 1.6, 7.6 Hz, 1H), 7.84 (td, J = 1 .6, 7.6 Hz, 1H), 5.74 (ddt, J = 6.5, 10.2, 16.8 Hz, 1H), 4.96 (m, 2H), 4.89 (t, J = 5.4Hz, 1H), 3.91 (td, J = 2.7, 8.1Hz, 1H), 3.70 (dt, J = 4.8, 8.1Hz, 1H), 3.58 (dd , J = 2.6, 15.1 Hz, 1H), 3.49 (t, J = 5.3 Hz, 2H), 3.38 (m, 2H), 3.28 (m, 1H), 1.95 (q, J = 6.9 Hz, 2H), 1.60 (p, J = 7.6 Hz, 2H), 1.26 (s, 3H), 1.25 (s, 3H).

Step 3. Synthesis of ((4S,5S)-2,2-dimethyl-5-((pent-4-en-1-ylamino)methyl)-1,3-dioxolan-4-yl)methanol (Intermediate a13) ACN ( N-(((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2-nitro-N-(penta -4-en-1-yl)benzenesulfonamide (458 mg, 1.11 mmol), K ₂ CO ₃ (458 mg, 3.32 mmol), and thiophenol (0.148 mL, 1.437 mmol) at room temperature. Stir overnight. LCMS indicated the reaction was complete. The reaction was cooled to room temperature and the precipitate was filtered and washed with ACN. The filtrate was concentrated and purified on an ISCO column (MeOH/DCM 0-10%) to give the title compound (233 mg, 92% yield) as a colorless oil. LCMS (conditions 1): m/z 230.3 [M+H] ⁺ , 0.78 min. ¹ H NMR (400 MHz, DMSO-d6) 5.80 (ddt, J = _6.6 , 10.2, 16.9 Hz, 1H), 5.01 (m, 1H), 4.94 (ddt, J = 1.2, 2.3, 10.2Hz, 1H), 3.77 (dt, J = 5.7, 8.0Hz, 1H), 3.68 (ddd, J = 4.8, 5.7 , 8.0 Hz, 1 H), 3.51 (dd, J = 4.7, 11.2 Hz, 1 H), 3.45 (dd, J = 5.7, 11.2 Hz, 1 H), 2.72 ( dd, J = 5.6, 12.0 Hz, 1H), 2.62 (dd, J = 5.8, 12.0 Hz, 1H), 2.45-2.58 (m, 2H), 2.03 (m, 2H), 1.47 (p, J=7.2 Hz, 2H), 1.30 (s, 3H), 1.29 (s, 3H).

工程１．Ｎ－アリル－２－ニトロベンゼンスルホンアミドの合成
無水ＤＣＭ（１００ｍＬ）中のアリルアミン（５．００ｍＬ、６６．６ｍｍｏｌ）及びトリエチルアミン（１８．５８ｍＬ、１３３ｍｍｏｌ）の混合物に、２－ニトロベンゼン－１－スルホニルクロリド（１４．７７ｇ、６６．６ｍｍｏｌ）を０℃で少しずつ加えた。得られた混合物を室温で一晩撹拌した。ＬＣＭＳにより、反応が完了したことが示された。混合物を水で希釈し、１ＮのＨＣｌ（５０ｍＬ）を用いてｐＨを８～９に調整した。層を分離し、有機層をＭｇＳＯ _４ 上で乾燥させ、ろ過し、濃縮して、表題化合物（１５ｇ、５５．７ｍｍｏｌ、８４％の収率）を、さらに精製せずに褐色の油として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ２４３．２［Ｍ＋Ｈ］ ^＋ 、１．１８分。 Synthesis of intermediate ethyl 2-(allylamino)acetate (intermediate a14)

Step 1. Synthesis of N-allyl-2-nitrobenzenesulfonamide To a mixture of allylamine (5.00 mL, 66.6 mmol) and triethylamine (18.58 mL, 133 mmol) in anhydrous DCM (100 mL) was added 2-nitrobenzene-1-sulfonyl chloride ( 14.77 g, 66.6 mmol) was added in portions at 0°C. The resulting mixture was stirred overnight at room temperature. LCMS indicated the reaction was complete. The mixture was diluted with water and pH was adjusted to 8-9 using 1N HCl (50 mL). The layers _were separated and the organic layer was dried over MgSO4, filtered and concentrated to give the title compound (15 g, 55.7 mmol, 84% yield) as a brown oil without further purification. . LCMS (conditions 1): m/z 243.2 [M+H] ⁺ , 1.18 min.

Step 2. Synthesis of ethyl 2-(N-allyl-2-nitrophenylsulfonamide)acetate N-allyl-2-nitrobenzenesulfonamide (2.00 g, 8.26 mmol), K ₂ CO ₃ (2.0 g, 8.26 mmol) in DMF (15 mL). 28 g, 16.50 mmol) and ethyl 2-bromoacetate (1.10 mL, 9.91 mmol) was stirred at room temperature for 4 days to give an orange suspension. The mixture was diluted with EtOAc (50 mL) and saturated aqueous NH ₄ Cl. The organic layer was washed with water ₍ 3x) and brine, dried over MgSO4, filtered, concentrated and purified by ISCO column (EtOAc/heptane 0-100%) to give the title compound (2.5 g). , 7.23 mmol, 88% yield) as a pale yellow oil. LCMS (conditions 1): m/z 329.2 [M+H] ⁺ , 1.45 min.

Step 3 Synthesis of ethyl 2-(allylamino)acetate (intermediate a14) Ethyl 2-(N-allyl-2-nitrophenylsulfonamido)acetate (2.5 g, 7.61 mmol) and K in ACN (50 mL) To a mixture of ₂ CO ₃ (3.16 g, 22.84 mmol) was added benzenethiol (0.784 mL, 7.61 mmol) and the mixture was stirred overnight at room temperature to give a yellow suspension. The mixture was diluted with DCM (50 mL) and then filtered. The filtrate was concentrated and purified by ISCO column (100% EtOAc; fractions were confirmed by LCMS and _KMnO4 staining) to give the title compound (580 mg, 4.05 mmol, 53% yield) as an oil. Obtained. LCMS (conditions 1): m/z 144.2 [M+H] ⁺ , 0.24 min.

工程２において、２－ブロモ酢酸エチルを、２－ブロモエタン－１－オールで置き換えたことを除いて、中間体（中間体ａ１４）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １０２．２［Ｍ＋Ｈ］ ^＋ 、０．２２分。 Synthesis of intermediate 2-(allylamino)ethan-1-ol (intermediate a15)

Synthesized using the procedure used for intermediate (intermediate a14) except that in step 2 ethyl 2-bromoacetate was replaced with 2-bromoethan-1-ol. LCMS (conditions 1): m/z 102.2 [M+H] ⁺ , 0.22 min.

工程１において、アリルアミンを、ペンタ－４－エン－１－アミンで置き換え、工程２において、２－ブロモ酢酸エチルを、ベンジル（２－ブロモエチル）カルバメートで置き換えたことを除いて、中間体（中間体ａ１４）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ２６３．３［Ｍ＋Ｈ］＋、１．１２分。 Synthesis of intermediate benzyl (2-(pent-4-en-1-ylamino)ethyl)carbamate (intermediate a16)

Intermediate (Intermediate Synthesized using the procedure used for a14). LCMS (conditions 1): m/z 263.3 [M+H]+, 1.12 min.

ＡＣＮ（７５ｍＬ）中の３－アミノプロパン－１－オール（１．１３ｇ、１５．００ｍｍｏｌ）、６－ブロモヘキサ－１－エン（１．６３ｇ、１０．００ｍｍｏｌ）及びＫ _２ ＣＯ _３ （２．７６ｇ、２０．００ｍｍｏｌ）の混合物を、７０℃で一晩撹拌した。ＬＣＭＳにより、反応がほぼ完了したことが示され、２つの生成物が形成された（ＴＬＣにより、所望のモノ－アルキル化生成物が、形成された主要な生成物であったことが示された）。次に、反応物を、セライトパッドに通してろ過し、ろ液を濃縮し、残渣を、ＩＳＣＯ精製（ＭｅＯＨ／ＤＣＭ ０～１０％）に供して、所望の表題化合物（１．０３ｇ、６５％の収率）を得た。ジ－アルキル化副生成物は、収集されなかった。ＬＣＭＳ（条件１）：ｍ／ｚ １５８．２［Ｍ＋１］＋、０．４９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ５．８３（ｄｄｔ，Ｊ＝１６．９、１０．２、６．７Ｈｚ、１Ｈ）、５．０５（ｄｑ，Ｊ＝１７．１、１．６Ｈｚ、１Ｈ）、４．９９（ｄｄｔ，Ｊ＝１０．２、２．２、１．２Ｈｚ、１Ｈ）、３．７２－３．６４（ｍ，２Ｈ）、３．１６－３．０８（ｍ，２Ｈ）、３．０５－２．９５（ｍ，２Ｈ）、２．１７－２．０８（ｍ，２Ｈ）、１．９５－１．８４（ｍ，２Ｈ）、１．７７－１．６４（ｍ，２Ｈ）、１．５５－１．４４（ｍ，２Ｈ）． Synthesis of intermediate 3-(hex-5-en-1-ylamino)propan-1-ol (intermediate a17)

3-Aminopropan-1-ol (1.13 g, 15.00 mmol), 6-bromohex-1-ene (1.63 g, 10.00 mmol) and K ₂ CO ₃ (2.76 g, 20.00 mmol) was stirred at 70° C. overnight. LCMS showed the reaction to be nearly complete with two products formed (TLC showed the desired mono-alkylated product was the major product formed. ). The reaction was then filtered through a celite pad, the filtrate was concentrated and the residue was subjected to ISCO purification (MeOH/DCM 0-10%) to give the desired title compound (1.03 g, 65% yield) was obtained. No di-alkylated byproducts were collected. LCMS (conditions 1): m/z 158.2 [M+1]+, 0.49 min. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 5.83 (ddt, J=16.9, 10.2, 6.7 Hz, 1 H), 5.05 (dq, J=17.1, 1.6 Hz , 1H), 4.99 (ddt, J = 10.2, 2.2, 1.2 Hz, 1H), 3.72-3.64 (m, 2H), 3.16-3.08 (m, 2H), 3.05-2.95 (m, 2H), 2.17-2.08 (m, 2H), 1.95-1.84 (m, 2H), 1.77-1.64 ( m, 2H), 1.55-1.44 (m, 2H).

３－アミノプロパン－１－オールを、メチル２－アミノ－２－メチルプロパノエートで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ２００．３［Ｍ＋Ｈ］ ^＋ 、０．３０分。 Synthesis of intermediate methyl 2-(hex-5-en-1-ylamino)-2-methylpropanoate (intermediate a18)

Synthesized using the procedure used for intermediate (intermediate a17) except that 3-aminopropan-1-ol was replaced with methyl 2-amino-2-methylpropanoate. LCMS (conditions 1): m/z 200.3 [M+H] ⁺ , 0.30 min.

３－アミノプロパン－１－オールを、グリシン酸メチルで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １７２．２［Ｍ＋Ｈ］ ^＋ 、０．２７分。 Synthesis of Intermediate Methylhex-5-en-1-ylglycinate (Intermediate a19)

Synthesized using the procedure used for intermediate (intermediate a17) except that 3-aminopropan-1-ol was replaced with methyl glycinate. LCMS (conditions 1): m/z 172.2 [M+H] ⁺ , 0.27 min.

３－アミノプロパン－１－オールを、エチル３－アミノ－２，２－ジメチルプロパノエートで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ２２８．３［Ｍ＋Ｈ］ ^＋ 、１．０４分。 Synthesis of intermediate ethyl 3-(hex-5-en-1-ylamino)-2,2-dimethylpropanoate (intermediate a20)

Synthesized using the procedure used for intermediate (intermediate a17) except that 3-aminopropan-1-ol was replaced with ethyl 3-amino-2,2-dimethylpropanoate. LCMS (conditions 1): m/z 228.3 [M+H] ⁺ , 1.04 min.

３－アミノプロパン－１－オールを、グリシン酸エチルで置き換え、６－ブロモヘキサ－１－エンを、５－ブロモペンタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １７２．２［Ｍ＋Ｈ］ ^＋ 、０．５０分。 Synthesis of intermediate ethyl pent-4-en-1-ylglycinate (intermediate a21)

As used for intermediate (intermediate a17) except that 3-aminopropan-1-ol was replaced with ethyl glycinate and 6-bromohex-1-ene was replaced with 5-bromopent-1-ene. Synthesized using the procedure described in LCMS (conditions 1): m/z 172.2 [M+H] ⁺ , 0.50 min.

３－アミノプロパン－１－オールを、グリシン酸エチルで置き換え、６－ブロモヘキサ－１－エンを、３－（２－ブロモエトキシ）プロパ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １８８．２［Ｍ＋Ｈ］ ^＋ 、０．３２分。 Synthesis of Intermediate Ethyl (2-(allyloxy)ethyl)glycinate (Intermediate a22)

Intermediate (Intermediate Synthesized using the procedure used for body a17). LCMS (conditions 1): m/z 188.2 [M+H] ⁺ , 0.32 min.

３－アミノプロパン－１－オールを、４－アミノブタン酸エチルで置き換え、６－ブロモヘキサ－１－エンを、５－ブロモペンタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ２００．３［Ｍ＋Ｈ］ ^＋ 、０．９６分。 Synthesis of intermediate ethyl 4-(pent-4-en-1-ylamino)butanoate (intermediate a23)

For the intermediate (intermediate a17) except that 3-aminopropan-1-ol was replaced by ethyl 4-aminobutanoate and 6-bromohex-1-ene was replaced by 5-bromopent-1-ene Synthesized using the procedure used. LCMS (conditions 1): m/z 200.3 [M+H] ⁺ , 0.96 min.

６－ブロモヘキサ－１－エンを、５－ブロモペンタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ２００．３［Ｍ＋Ｈ］ ^＋ 、０．９６分。 Synthesis of intermediate 3-(pent-4-en-1-ylamino)propan-1-ol (intermediate a24)

Synthesized using the procedure used for intermediate (intermediate a17) except 6-bromohex-1-ene was replaced with 5-bromopent-1-ene. LCMS (conditions 1): m/z 200.3 [M+H] ⁺ , 0.96 min.

３－アミノプロパン－１－オールを、３－アミノ－２，２－ジメチルプロパン－１－オールで置き換え、６－ブロモヘキサ－１－エンを、５－ブロモペンタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １７２．３［Ｍ＋Ｈ］ ^＋ 、０．８７分。 Synthesis of intermediate 2,2-dimethyl-3-(pent-4-en-1-ylamino)propan-1-ol (intermediate a25)

except that 3-aminopropan-1-ol was replaced with 3-amino-2,2-dimethylpropan-1-ol and 6-bromohex-1-ene was replaced with 5-bromopent-1-ene. , was synthesized using the procedure used for intermediate (intermediate a17). LCMS (conditions 1): m/z 172.3 [M+H] ⁺ , 0.87 min.

３－アミノプロパン－１－オールを、３－アミノ－２，２－ジメチルプロパン－１－オールで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １８６．３［Ｍ＋Ｈ］ ^＋ 、０．４９分。 Synthesis of intermediate 3-(hex-5-en-1-ylamino)-2,2-dimethylpropan-1-ol (intermediate a26)

Synthesized using the procedure used for intermediate (intermediate a17) except 3-aminopropan-1-ol was replaced with 3-amino-2,2-dimethylpropan-1-ol. LCMS (conditions 1): m/z 186.3 [M+H] ⁺ , 0.49 min.

３－アミノプロパン－１－オールを、（３－（アミノメチル）オキセタン－３－イル）メタノールで置き換え、６－ブロモヘキサ－１－エンを、５－ブロモペンタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １８６．２［Ｍ＋Ｈ］ ^＋ 、０．３５分。 Synthesis of intermediate (3-((pent-4-en-1-ylamino)methyl)oxetan-3-yl)methanol (intermediate a27)

except that 3-aminopropan-1-ol was replaced with (3-(aminomethyl)oxetan-3-yl)methanol and 6-bromohex-1-ene was replaced with 5-bromopent-1-ene. , was synthesized using the procedure used for intermediate (intermediate a17). LCMS (conditions 1): m/z 186.2 [M+H] ⁺ , 0.35 min.

６－ブロモヘキサ－１－エンを、４－ブロモブタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １３０．２［Ｍ＋Ｈ］ ^＋ 、０．３３分。 Synthesis of intermediate 3-(but-3-en-1-ylamino)propan-1-ol (intermediate a28)

Synthesized using the procedure used for intermediate (intermediate a17) except 4-bromobut-1-ene was substituted for 6-bromohex-1-ene. LCMS (conditions 1): m/z 130.2 [M+H] ⁺ , 0.33 min.

６－ブロモヘキサ－１－エンを、５－ブロモペンタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １５８．３［Ｍ＋Ｈ］ ^＋ 、０．５０分。 Synthesis of intermediate 4-(pent-4-en-1-ylamino)butan-1-ol (intermediate a29)

Synthesized using the procedure used for intermediate (intermediate a17) except 6-bromohex-1-ene was replaced with 5-bromopent-1-ene. LCMS (conditions 1): m/z 158.3 [M+H] ⁺ , 0.50 min.

６－ブロモヘキサ－１－エンを、３－ブロモプロパ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １１６．２［Ｍ＋Ｈ］ ^＋ 、０．３７分。 Synthesis of intermediate 3-(allylamino)propan-1-ol (intermediate a30)

Synthesized using the procedure used for intermediate (intermediate a17), except that 6-bromohex-1-ene was replaced with 3-bromoprop-1-ene. LCMS (conditions 1): m/z 116.2 [M+H] ⁺ , 0.37 min.

３－アミノプロパン－１－オールを、４－アミノブタン－１－オールで置き換え、６－ブロモヘキサ－１－エンを、３－ブロモプロパ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １３０．２［Ｍ＋Ｈ］ ^＋ 、０．２２分。 Synthesis of intermediate 4-(allylamino)butan-1-ol (intermediate a31)

Intermediate (intermediate a17 ) were synthesized using the procedure used for LCMS (conditions 1): m/z 130.2 [M+H] ⁺ , 0.22 min.

３－アミノプロパン－１－オールを、エタンアミンで置き換え、６－ブロモヘキサ－１－エンを、５－ブロモペンタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １１４．２［Ｍ＋Ｈ］ ^＋ 、０．３８分。 Synthesis of intermediate N-ethylpent-4-en-1-amine (intermediate a32)

Procedure used for intermediate (intermediate a17) except 3-aminopropan-1-ol was replaced with ethanamine and 6-bromohex-1-ene was replaced with 5-bromopent-1-ene was synthesized using LCMS (conditions 1): m/z 114.2 [M+H] ⁺ , 0.38 min.

３－アミノプロパン－１－オールを、５－アミノペンタン－１－オールで置き換え、６－ブロモヘキサ－１－エンを、５－ブロモペンタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １７２．２［Ｍ＋Ｈ］ ^＋ 、０．７１分。 Synthesis of intermediate 5-(pent-4-en-1-ylamino)pentan-1-ol (intermediate a33)

Intermediate (Intermediate Synthesized using the procedure used for a17). LCMS (conditions 1): m/z 172.2 [M+H] ⁺ , 0.71 min.

３－アミノプロパン－１－オールを、５－アミノペンタン－１－オールで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １８６．２［Ｍ＋Ｈ］ ^＋ 、０．５７分。 Synthesis of intermediate 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34)

Synthesized using the procedure used for intermediate (intermediate a17) except 3-aminopropan-1-ol was replaced with 5-aminopentan-1-ol. LCMS (conditions 1): m/z 186.2 [M+H] ⁺ , 0.57 min.

３－アミノプロパン－１－オールを、４－アミノブタン－１－オールで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １７２．２［Ｍ＋Ｈ］ ^＋ 、０．４４分。 Synthesis of intermediate 4-(hex-5-en-1-ylamino)butan-1-ol (intermediate a35)

Synthesized using the procedure used for intermediate (intermediate a17), except that 3-aminopropan-1-ol was replaced with 4-aminobutan-1-ol. LCMS (conditions 1): m/z 172.2 [M+H] ⁺ , 0.44 min.

３－アミノプロパン－１－オールを、４－アミノブタン－１－オールで置き換え、６－ブロモヘキサ－１－エンを、７－ブロモヘプタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １８６．３［Ｍ＋Ｈ］ ^＋ 、１．０４分。 Synthesis of intermediate 4-(hept-6-en-1-ylamino)butan-1-ol (intermediate a36)

Intermediate (intermediate a17 ) were synthesized using the procedure used for LCMS (conditions 1): m/z 186.3 [M+H] ⁺ , 1.04 min.

３－アミノプロパン－１－オールを、４－アミノブタン－１－オールで置き換え、６－ブロモヘキサ－１－エンを、８－ブロモオクタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ２００．３［Ｍ＋Ｈ］ ^＋ 、１．２４分。 Synthesis of intermediate 4-(oct-7-en-1-ylamino)butan-1-ol (intermediate a37)

Intermediate (intermediate a17 ) were synthesized using the procedure used for LCMS (conditions 1): m/z 200.3 [M+H] ⁺ , 1.24 min.

３－アミノプロパン－１－オールを、４－アミノブタン－１－オールで置き換え、６－ブロモヘキサ－１－エンを、９－ブロモノナ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ２１４．３［Ｍ＋Ｈ］ ^＋ 、１．３０分。 Synthesis of intermediate 4-(non-8-en-1-ylamino)butan-1-ol (intermediate a38)

Intermediate (intermediate a17 ) were synthesized using the procedure used for LCMS (conditions 1): m/z 214.3 [M+H] ⁺ , 1.30 min.

６－ブロモヘキサ－１－エンを、７－ブロモヘプタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １７２．２［Ｍ＋Ｈ］ ^＋ 、０．５９分。 Synthesis of intermediate 3-(hept-6-en-1-ylamino)propan-1-ol (intermediate a39)

Synthesized using the procedure used for intermediate (intermediate a17) except 6-bromohept-1-ene was replaced with 7-bromohept-1-ene. LCMS (conditions 1): m/z 172.2 [M+H] ⁺ , 0.59 min.

６－ブロモヘキサ－１－エンを、８－ブロモオクタ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ １８６．３［Ｍ＋Ｈ］ ^＋ 、１．１３分。 Synthesis of intermediate 3-(oct-7-en-1-ylamino)propan-1-ol (intermediate a40)

Synthesized using the procedure used for intermediate (intermediate a17) except 6-bromohex-1-ene was replaced with 8-bromooct-1-ene. LCMS (conditions 1): m/z 186.3 [M+H] ⁺ , 1.13 min.

６－ブロモヘキサ－１－エンを、９－ブロモノナ－１－エンで置き換えたことを除いて、中間体（中間体ａ１７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ２００．３［Ｍ＋Ｈ］ ^＋ 、１．２７分。 Synthesis of intermediate 3-(non-8-en-1-ylamino)propan-1-ol (intermediate a41)

Synthesized using the procedure used for intermediate (intermediate a17) except 6-bromohex-1-ene was replaced with 9-bromonon-1-ene. LCMS (conditions 1): m/z 200.3 [M+H] ⁺ , 1.27 min.

ＥｔＯＨ（４０ｍＬ）中の５－ブロモペンタ－１－エン（２．０ｍＬ、１６．８０ｍｍｏｌ）及び２－アミノエタノール（５．０ｍＬ、８３ｍｍｏｌ）の溶液に、ＮａＩ（０．２５ｇ、１．６８ｍｍｏｌ）を加えた。反応混合物を室温で４日間撹拌し、次に、１時間にわたって還流状態で加熱した。次に、混合物を室温に冷まし、減圧下で蒸発させた。残渣を、飽和ＮＨ _４ Ｃｌ水溶液とＥｔＯＡｃ（主に、ジアルキル化生成物を含有する）とに分けた。水性層を、４０％の水酸化ナトリウム（３ｍＬ）を用いてｐＨ約１０になるまで塩基性化し、ＥｔＯＡｃ（３回）で抽出した。組み合わされた有機層をＭｇＳＯ _４ 上で乾燥させ、濃縮して、表題化合物（１．６０ｇ、１２．３８ｍｍｏｌ、７４％の収率）を黄褐色の油として得た。ＬＣＭＳ（条件１）：ｍ／ｚ １３０．２［Ｍ＋Ｈ］ ^＋ 、０．７０分。 Synthesis of intermediate 2-(pent-4-en-1-ylamino)ethan-1-ol (intermediate a42)

NaI (0.25 g, 1.68 mmol) was added to a solution of 5-bromopent-1-ene (2.0 mL, 16.80 mmol) and 2-aminoethanol (5.0 mL, 83 mmol) in EtOH (40 mL). rice field. The reaction mixture was stirred at room temperature for 4 days and then heated at reflux for 1 hour. The mixture was then cooled to room temperature and evaporated under reduced pressure. The residue was partitioned between saturated aqueous NH ₄ Cl and EtOAc (mainly containing the dialkylated product). The aqueous layer was basified with 40% sodium hydroxide (3 mL) to pH~10 and extracted with EtOAc (3x). The combined organic layers _were dried over MgSO4 and concentrated to give the title compound (1.60 g, 12.38 mmol, 74% yield) as a tan oil. LCMS (conditions 1): m/z 130.2 [M+H] ⁺ , 0.70 min.

５－ブロモペンタ－１－エンを、４－ブロモブタ－１－エンで置き換え、２－アミノエタノールを、ｔｅｒｔ－ブチル（２－アミノエチル）カルバメートで置き換えたことを除いて、中間体（中間体ａ４２）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ２１５．２［Ｍ＋Ｈ］ ^＋ 、１．１８分。 Synthesis of intermediate tert-butyl (2-(but-3-en-1-ylamino)ethyl)carbamate (intermediate a43)

Intermediate (Intermediate a42) except 5-bromopent-1-ene was replaced with 4-bromobut-1-ene and 2-aminoethanol was replaced with tert-butyl (2-aminoethyl)carbamate Synthesized using the procedure used for LCMS (conditions 1): m/z 215.2 [M+H] ⁺ , 1.18 min.

工程１．ＤＣＭ（１００ｍＬ）中の（Ｓ）－５－（ヒドロキシメチル）ピロリジン－２－オン（５．１５ｇ、４４．７ｍｍｏｌ）の溶液に、４－メチルベンゼン－１－スルホニルクロリド（１０．２３ｇ、５３．７ｍｍｏｌ）、トリエチルアミン（９．０５ｇ、８９ｍｍｏｌ）及びＤＭＡＰ（０．５４６ｇ、４．４７ｍｍｏｌ）を加えた。透明の溶液を室温で一晩撹拌し、反応を停止させ、ＤＣＭ（１００ｍＬ）で希釈した。次に、水（２５０ｍＬ）を加えた後、濃ＨＣｌ（４ｍＬ）を加えた。水性相を分離し、ＤＣＭ（２×５０ｍＬ）で抽出した。ＤＣＭを組み合わせて、Ｎａ _２ ＳＯ _４ 上で乾燥させた。シリカゲル（１２ｇ）を溶液に加え、溶媒を蒸発させた。シリカゲルを短いカラムに移し、（ＭｅＯＨ：ＥｔＯＡｃ／１：２０）で溶離して、（Ｓ）－（５－オキソピロリジン－２－イル）メチル４－メチブベンゼンスルホネートを白色の固体として得た：ＭＳ ２７０．１［Ｍ＋Ｈ］＋、ｒｔ＝０．９６分。 Synthesis of (R)-5-(but-3-en-1-yl)pyrrolidin-2-one (Intermediate a44)

Step 1. To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (5.15 g, 44.7 mmol) in DCM (100 mL) was added 4-methylbenzene-1-sulfonyl chloride (10.23 g, 53.7 mmol). 7 mmol), triethylamine (9.05 g, 89 mmol) and DMAP (0.546 g, 4.47 mmol) were added. The clear solution was stirred overnight at room temperature, quenched and diluted with DCM (100 mL). Water (250 mL) was then added followed by concentrated HCl (4 mL). The aqueous phase was separated and extracted with DCM (2 x 50 mL). DCM was combined and _dried over _Na2SO4 . Silica gel (12 g) was added to the solution and the solvent was evaporated. Transferred silica gel to a short column and eluted with (MeOH:EtOAc/1:20) to give (S)-(5-oxopyrrolidin-2-yl)methyl 4-methibubenzenesulfonate as a white solid: MS 270.1 [M+H]+, rt=0.96 min.

Step 2. Allylmagnesium bromide (74.3 mL, 74.3 mmol) in ether was added to (S)-(5-oxopyrrolidin-2-yl)methyl 4-methyl-4-methyl-4-methyl-4-methyl-4-methyl-4 in THF (150 mL) at 0° C. over a period of 30 minutes. Added to a solution of bubenzenesulfonate (4 g, 14.85 mmol). The reaction was then stirred at 70° C. for 3 hours, then the reaction was quenched by careful addition of saturated NH ₄ Cl (150 mL). The aqueous phase was separated and extracted with DCM (4 x 50 mL). The organic phases _were combined, dried over _Na2SO4 and evaporated. The resulting liquid was purified by flash chromatography (EtOAc:heptane/4:1) with the addition of 0.5% TEA to give (R)-5-(but-3-en-1-yl) Pyrrolidin-2-one (intermediate a44) was obtained. MS 140.1 [M+H]+ ^, rt=0.82 min; 1H NMR (500 MHz, chloroform-d) δ 5.82 (ddt, J=17.0, 10.2, 6.7 Hz, 1H), 5 .73 (s, 1H), 5.08 (dq, J=17.1, 1.6Hz, 1H), 5.06-4.99 (m, 1H), 3.68 (p, J=6. 6Hz, 1H), 2.43-2.24 (m, 3H), 2.14 (m, 2H), 1.81-1.71 (m, 1H), 1.71-1.61 (m, 2H).

工程１．６－（５－フルオロ－２－ビニルフェニル）－５－（トリフルオロメチル）ピリジン－２－アミン
６－クロロ－５－（トリフルオロメチル）ピリジン－２－アミン（５ｇ、２５．４ｍｍｏｌ）及び（５－フルオロ－２－ビニルフェニル）ボロン酸（５．２８ｇ、３１．８ｍｍｏｌ）を、ジオキサン（６０ｍＬ）及び水（９ｍＬ）に溶解させ、炭酸ナトリウム（１０．７８ｇ、１０２ｍｍｏｌ）で処理した。混合物を、アルゴンを用いて脱気した。テトラキス（トリフェニルホスフィノ）パラジウム（０）（２．９４ｇ、２．５４ｍｍｏｌ）を加え、混合物を再度脱気した。混合物を１１５℃で１８時間撹拌した。ＬＣＭＳにより、反応が完了したことが示された。混合物を冷却し、ろ過した。固体をさらなるジオキサン（２５ｍＬ）で洗浄した。組み合わされたろ液をＮａ _２ ＳＯ _４ 上で乾燥させ、ろ過し、濃縮して、赤みがかった油を得た。粗生成物を、シリカゲルクロマトグラフィー（３３０ｇのＩＳＣＯカラム）（ＥｔＯＡｃ／ヘプタン１０～４０％）によって精製して、表題化合物を黄色の固体（６．１０ｇ、２１．６１ｍｍｏｌ、８５％の収率）として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ２８３．２［Ｍ＋Ｈ］ ^＋ 、１．２８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、クロロホルム－ｄ）δ ７．７７（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、７．６２（ｄｄ，Ｊ＝５．６、８．７Ｈｚ、１Ｈ）、７．０９（ｔｄ，Ｊ＝２．７、８．５Ｈｚ、１Ｈ）、６．９４（ｄｄ，Ｊ＝２．７、８．９Ｈｚ、１Ｈ）、６．５４（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、６．３２（ｄｄ，Ｊ＝１１．０、１７．５Ｈｚ、１Ｈ）、５．５９（ｄ，Ｊ＝１７．４Ｈｚ、１Ｈ）、５．１２（ｄ，Ｊ＝１１．０Ｈｚ、１Ｈ）、４．８８（ｓ，２Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、クロロホルム－ｄ）δ－５７．６７（ｓ，３Ｆ）、－１１４．９３（ｓ，１Ｆ）． Synthesis for intermediate 6-fluoro-N-(6-(5-fluoro-2-vinylphenyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b1) procedure

Step 1. 6-(5-Fluoro-2-vinylphenyl)-5-(trifluoromethyl)pyridin-2-amine 6-chloro-5-(trifluoromethyl)pyridin-2-amine (5 g, 25.4 mmol ) and (5-fluoro-2-vinylphenyl)boronic acid (5.28 g, 31.8 mmol) were dissolved in dioxane (60 mL) and water (9 mL) and treated with sodium carbonate (10.78 g, 102 mmol). . The mixture was degassed with argon. Tetrakis(triphenylphosphino)palladium(0) (2.94 g, 2.54 mmol) was added and the mixture was again degassed. The mixture was stirred at 115° C. for 18 hours. LCMS indicated the reaction was complete. The mixture was cooled and filtered. The solid was washed with additional dioxane (25 mL). The combined _filtrate was dried over _Na2SO4 , filtered and concentrated to give a reddish oil. The crude product was purified by silica gel chromatography (330 g ISCO column) (EtOAc/heptane 10-40%) to give the title compound as a yellow solid (6.10 g, 21.61 mmol, 85% yield). Obtained. LCMS (conditions 1): m/z 283.2 [M+H] ⁺ , 1.28 min. ¹ H NMR (400 MHz, chloroform-d) δ 7.77 (d, J=8.7 Hz, 1 H), 7.62 (dd, J=5.6, 8.7 Hz, 1 H), 7.09 (td , J=2.7, 8.5 Hz, 1 H), 6.94 (dd, J=2.7, 8.9 Hz, 1 H), 6.54 (d, J=8.7 Hz, 1 H), 6. 32 (dd, J=11.0, 17.5 Hz, 1 H), 5.59 (d, J=17.4 Hz, 1 H), 5.12 (d, J=11.0 Hz, 1 H), 4.88 (s, 2H). ¹⁹ F NMR (376 MHz, chloroform-d) δ -57.67 (s, 3F), -114.93 (s, 1F).

Step 2. 6-Fluoro-N-(6-(5-fluoro-2-vinylphenyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide (Intermediate b1)
6-(5-Fluoro-2-vinylphenyl)-5-(trifluoromethyl)pyridin-2-amine (6.1 g, 21.61 mmol) was dissolved in pyridine (30 mL) to give 6-fluoropyridine-2 - treated with sulfonyl chloride (5.50 g, 28.1 mmol). The resulting red solution was stirred at 20° C. for 2 days. LCMS indicated the reaction was complete. The reaction mixture was diluted with EtOAc (200 mL) and 1N HCl (50 mL). It was extracted with EtOAc (2 x 100 mL). The combined extracts _were dried over _Na2SO4 and concentrated. The resulting oil was treated with toluene (70 mL) and concentrated to give a brown paste. The residue was taken up in DCM (30 mL). A white precipitate (desired product) was formed. It was collected by filtration, washed with a small amount of DCM and air dried. The DCM filtrates were combined and purified by silica gel chromatography (330 g ISCO column) (EtOAc/heptane 10-40%). The desired material thus obtained was combined with the previously obtained precipitated product. The title compound was obtained as an off-white powder (8.63g, 19.52mmol, 90%). The desired product and by-product 6-fluoro-N-(6-(5-fluoro-2-vinylphenyl)-5-(trifluoromethyl)pyridin-2-yl)-N-((6- A mixture of fluoropyridin-2-yl)sulfonyl)pyridine-2-sulfonamides was also obtained (1.2 g, 30% desired product and 70% by-product based on ¹ H NMR). LCMS (conditions 1): m/z 441.9 [M+H] ⁺ , 1.68 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.19 (s, 1H), 8.20 (d, J = 8.9 Hz, 1 H), 8.11 (q, J = 7.7 Hz, 1 H) , 7.83 (dd, J=1.7, 7.5 Hz, 1 H), 7.71 (dd, J=5.7, 8.8 Hz, 1 H), 7.48 (dd, J=1.9 , 8.3 Hz, 1H), 7.29 (td, J = 2.8, 8.5 Hz, 2H), 6.95 (d, J = 8.7 Hz, 1H), 5.81 (dd, J = 11.1, 17.4 Hz, 1 H), 5.55 (d, J = 17.4 Hz, 1 H), 4.99 (d, J = 11.1 Hz, 1 H). ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -57.13 (s, 3F), -66.34 (s, 1F), -114.95 (s, 1F).

工程１において、５－フルオロ－２－ビニルフェニル）ボロン酸を、（２－ビニルフェニル）ボロン酸で置き換えたことを除いて、中間体（中間体ｂ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４２４．１［Ｍ＋Ｈ］ ^＋ 、１．３７分。 Synthesis of intermediate 6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2)

Synthesized using the procedure used for intermediate (intermediate b1) except that in step 1 5-fluoro-2-vinylphenyl)boronic acid was replaced with (2-vinylphenyl)boronic acid . LCMS (conditions 1): m/z 424.1 [M+H] ⁺ , 1.37 min.

工程１において、５－フルオロ－２－ビニルフェニル）ボロン酸を、（２－ビニルフェニル）ボロン酸で置き換え、６－クロロ－５－（トリフルオロメチル）ピリジン－２－アミンを、（５，６－ジクロロピリジン－２－アミンで置き換えたことを除いて、中間体（中間体ｂ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ３９０．１［Ｍ＋Ｈ］ ^＋ 、１．５５分。 Synthesis of intermediate N-(5-chloro-6-(2-vinylphenyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b3)

In step 1, 5-fluoro-2-vinylphenyl)boronic acid is replaced with (2-vinylphenyl)boronic acid and 6-chloro-5-(trifluoromethyl)pyridin-2-amine is replaced with (5,6 Synthesized using the procedure used for intermediate (intermediate b1) except replacing -dichloropyridin-2-amine LCMS (conditions 1): m/z 390.1 [M+H] ⁺ , 1.55 minutes.

工程１において、５－フルオロ－２－ビニルフェニル）ボロン酸を、（２－ビニルフェニル）ボロン酸で置き換え、６－クロロ－５－（トリフルオロメチル）ピリジン－２－アミンを、６－クロロ－５－メチルピリジン－２－アミンで置き換えたことを除いて、中間体（中間体ｂ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ３９０．１［Ｍ＋Ｈ］ ^＋ 、１．５５分。 Synthesis of intermediate 6-fluoro-N-(5-methyl-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b4)

In step 1, 5-fluoro-2-vinylphenyl)boronic acid is replaced with (2-vinylphenyl)boronic acid and 6-chloro-5-(trifluoromethyl)pyridin-2-amine is replaced with 6-chloro- Synthesized using the procedure used for intermediate (intermediate b1), except substituting 5-methylpyridin-2-amine. LCMS (conditions 1): m/z 390.1 [M+H] ⁺ , 1.55 min.

工程１において、５－フルオロ－２－ビニルフェニル）ボロン酸を、（２－ビニルフェニル）ボロン酸で置き換え、６－クロロ－５－（トリフルオロメチル）ピリジン－２－アミンを、６－クロロ－５－メトキシピリジン－２－アミンで置き換えたことを除いて、中間体（中間体ｂ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ３８６．２［Ｍ＋Ｈ］ ^＋ 、１．５２分。 Synthesis of intermediate 6-fluoro-N-(5-methoxy-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b5)

In step 1, 5-fluoro-2-vinylphenyl)boronic acid is replaced with (2-vinylphenyl)boronic acid and 6-chloro-5-(trifluoromethyl)pyridin-2-amine is replaced with 6-chloro- Synthesized using the procedure used for intermediate (intermediate b1), except substituting 5-methoxypyridin-2-amine. LCMS (conditions 1): m/z 386.2 [M+H] ⁺ , 1.52 min.

工程１において、５－フルオロ－２－ビニルフェニル）ボロン酸を、（２－ビニルフェニル）ボロン酸で置き換え、６－クロロ－５－（トリフルオロメチル）ピリジン－２－アミンを、６－クロロピリジン－２－アミンで置き換えたことを除いて、中間体（中間体ｂ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ３５６．１［Ｍ＋Ｈ］ ^＋ 、１．６６分。 Synthesis of intermediate 6-fluoro-N-(6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b6)

In step 1, 5-fluoro-2-vinylphenyl)boronic acid is replaced with (2-vinylphenyl)boronic acid and 6-chloro-5-(trifluoromethyl)pyridin-2-amine is replaced with 6-chloropyridine. Synthesized using the procedure used for intermediate (intermediate b1), except substituting -2-amine. LCMS (conditions 1): m/z 356.1 [M+H] ⁺ , 1.66 min.

工程１．２－（６－アミノ－３－（トリフルオロメチル）ピリジン－２－イル）フェノール
ジオキサン（４ｍＬ）及び水（１ｍＬ）中の６－クロロ－５－（トリフルオロメチル）ピリジン－２－アミン（１．５０ｇ、７．６３ｍｍｏｌ）、２－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノール（２．１０ｇ、９．１６ｍｍｏｌ）及びＮａ _２ ＣＯ _３ （０．０８１ｇ、０．７６ｍｍｏｌ）の混合物を含む１５０ｍＬの圧力フラスコを排気し、窒素（２回）をバックフィル（ｂａｃｋｆｉｌｌ）した。Ｐｄ（Ｐｈ _３ Ｐ） _４ （０．２５ｇ、０．２２ｍｍｏｌ）を加え、得られた混合物を、４時間にわたって１２０℃で、油浴中で加熱した。混合物を室温に冷まし、次に、ＥｔＯＡｃ（２回）で抽出し、水及び塩水で洗浄した。組み合わされた抽出物をＭｇＳＯ _４ 上で乾燥させ、ろ過し、濃縮した。残渣を、ＩＳＣＯカラム（ＥｔＯＡｃ／ヘプタン０～１００％）によって精製して、表題化合物（１．６０ｇ、６．２９ｍｍｏｌ、８２％の収率）を白色の固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ２５５．２［Ｍ＋Ｈ］ ^＋ 、０．９８分。 Synthesis of intermediate N-(6-(2-(allyloxy)phenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b7)

Step 1.2-(6-Amino-3-(trifluoromethyl)pyridin-2-yl)phenol 6-chloro-5-(trifluoromethyl)pyridine-2- in dioxane (4 mL) and water (1 mL) Amine (1.50 g, 7.63 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.10 g, 9.16 mmol) and Na ₂ A 150 mL pressure flask containing a mixture of CO ₃ (0.081 g, 0.76 mmol) was evacuated and backfilled with nitrogen (twice). Pd(Ph ₃ P) ₄ (0.25 g, 0.22 mmol) was added and the resulting mixture was heated in an oil bath at 120° C. for 4 hours. The mixture was cooled to room temperature, then extracted with EtOAc (2x), washed with water and brine. The combined extracts _were dried over MgSO4, filtered and concentrated. The residue was purified by ISCO column (EtOAc/heptane 0-100%) to give the title compound (1.60 g, 6.29 mmol, 82% yield) as a white solid. LCMS (conditions 1): m/z 255.2 [M+H] ⁺ , 0.98 min.

Step 2. Synthesis of 6-(2-(allyloxy)phenyl)-5-(trifluoromethyl)pyridin-2-amine 2-(6-amino-3-(trifluoromethyl)pyridine- in ACN (3 mL) A mixture of 2-yl)phenol (0.87 g, 3.42 mmol), Cs ₂ CO ₃ (3.35 g, 10.27 mmol) and allyl bromide (0.36 mL, 4.11 mmol) was heated at 60° C. for 3 hours. Stirred. The reaction mixture was quenched with water and acidified with 1N HCl (10 mL). The mixture was extracted with EtOAc (2x). The organic layers were combined, dried ₍ MgSO4), filtered and concentrated. The crude product was purified by ISCO column (EtOAc/heptane 0-100%) to give the title compound (530 mg, 1.80 mmol, 53% yield) as a white solid. LCMS (conditions 1): m/z 295.2 [M+H] ⁺ , 1.25 min.

Step 3. N-(6-(2-(allyloxy)phenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (Intermediate b7)
1 M LHMDS in THF (0.170 mL, 0.170 mmol) was added dropwise at 0° C. to give an orange solution. After 5 minutes, 6-fluoropyridine-2-sulfonyl chloride (0.35 mL, 2.7 mmol) in 2 mL of THF was added dropwise at 0°C. The reaction mixture was quenched with water and then acidified with 1N HCl (5 mL). The mixture was extracted with EtOAc (2x). The organic layers _were combined, dried over MgSO4, filtered and concentrated. The crude product was purified by ISCO column (EtOAc/heptane 0-100%) to give the title compound (480 mg, 1.1 mmol, 59% yield) as a brown solid. LCMS (conditions 1): m/z 454.2 [M+H] ⁺ , 1.54 min.

工程１において、２－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノールを、４－フルオロ－２－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノールで置き換えたことを除いて、中間体（中間体ｂ７）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４７２．１［Ｍ＋Ｈ］ ^＋ 、１．８１分。 Synthesis of intermediate N-(6-(2-(allyloxy)-5-fluorophenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b8)

In step 1, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol is converted to 4-fluoro-2-(4,4,5,5-tetramethyl Synthesized using the procedure used for intermediate (intermediate b7), except substituting -1,3,2-dioxaborolan-2-yl)phenol. LCMS (conditions 1): m/z 472.1 [M+H] ⁺ , 1.81 min.

ＤＭＦ（２ｍＬ）中のＮ－（５－クロロ－６－（２－ビニルフェニル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ３）（５９ｍｇ、０．１５ｍｍｏｌ）及びペンタ－４－エン－１－オール（３９ｍｇ、０．４５ｍｍｏｌ）の溶液に、ＮａＨ（３６ｍｇ、１．５ｍｍｏｌ）を窒素雰囲気下で加えた。混合物を室温で１時間撹拌し、水でクエンチした。反応物を、１０％のクエン酸溶液を用いて酸性化し、ＥｔＯＡｃで抽出し、水、ＮａＨＣＯ _３ 、塩水（２回）で洗浄し、Ｎａ _２ ＳＯ _４ 上で乾燥させた。生成物を、ＩＳＣＯシリカゲルカラム（ＥｔＯＡｃ／ヘプタン０～２０％）上で精製して、表題化合物（５３ｍｇ、７５％の収率）を油として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ４５６．２［Ｍ＋Ｈ］ ^＋ 、１．８０分、 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）１１．３８（ｓ，１Ｈ）、７．９５（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．９０（ｄｄ，Ｊ＝７．４、８．３Ｈｚ、１Ｈ）、７．６９（ｄ，Ｊ＝７．９Ｈｚ、１Ｈ）、７．５２（ｄ，Ｊ＝７．３Ｈｚ、１Ｈ）、７．４２（ｍ，１Ｈ）、７．３２（ｍ，２Ｈ）、７．０８（ｄ，Ｊ＝８．３Ｈｚ、１Ｈ）、６．９８（ｄ，Ｊ＝７．３Ｈｚ、１Ｈ）、６．１２（ｄｄ，Ｊ＝１１．０、１７．６Ｈｚ、１Ｈ）、５．７６（ｄｄｔ，Ｊ＝６．６、１０．３、１６．９Ｈｚ、１Ｈ）、５．６６（ｍ，１Ｈ）、５．０７（ｄ，Ｊ＝１１．２Ｈｚ、１Ｈ）、４．９５（ｍ，２Ｈ）、４．０６（ｔ，Ｊ＝６．６Ｈｚ、２Ｈ）、２．０５（ｍ，２Ｈ）、１．６７（ｍ，２Ｈ）． Synthesis of intermediate N-(5-chloro-6-(2-vinylphenyl)pyridin-2-yl)-6-(pent-4-en-1-yloxy)pyridine-2-sulfonamide (intermediate b9)

N-(5-chloro-6-(2-vinylphenyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b3) (59 mg, 0.15 mmol) in DMF (2 mL) and To a solution of pent-4-en-1-ol (39 mg, 0.45 mmol) was added NaH (36 mg, 1.5 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour and quenched with water. The reaction was acidified with 10% citric acid solution, extracted with EtOAc, washed with water, _NaHCO3 , brine ₍ twice) and dried over _Na2SO4 . The product was purified on an ISCO silica gel column (EtOAc/heptane 0-20%) to give the title compound (53 mg, 75% yield) as an oil. LCMS (conditions 1): m/z 456.2 [M+H] ⁺ , 1.80 min, ¹ H NMR (400 MHz, DMSO-d ₆ ) 11.38 (s, 1H), 7.95 (d, J= 8.8Hz, 1H), 7.90 (dd, J = 7.4, 8.3Hz, 1H), 7.69 (d, J = 7.9Hz, 1H), 7.52 (d, J = 7 .3Hz, 1H), 7.42 (m, 1H), 7.32 (m, 2H), 7.08 (d, J = 8.3Hz, 1H), 6.98 (d, J = 7.3Hz , 1H), 6.12 (dd, J = 11.0, 17.6Hz, 1H), 5.76 (ddt, J = 6.6, 10.3, 16.9Hz, 1H), 5.66 ( m, 1H), 5.07 (d, J = 11.2Hz, 1H), 4.95 (m, 2H), 4.06 (t, J = 6.6Hz, 2H), 2.05 (m, 2H), 1.67(m, 2H).

工程１．２’－フルオロ－３－（トリフルオロメチル）－［２，３’－ビピリジン］－６－アミンの合成
還流冷却器が取り付けられたフラスコ中で、６－クロロ－５－（トリフルオロメチル）ピリジン－２－アミン（４．００ｇ、２０．４ｍｍｏｌ）、２－フルオロピリジン－３－ボロン酸（４．３０ｇ、３０．５ｍｍｏｌ）、Ｎａ _２ ＣＯ _３ （６．４７ｇ、６１．１ｍｍｏｌ）、及びＰｄ（Ｐｈ _３ Ｐ） _４ （２．３５ｇ、２．０４ｍｍｏｌ）を、ジオキサン（１００ｍＬ）及びＨ _２ Ｏ（１６ｍＬ）の混合物に取り込んだ。続いて、混合物をアルゴンでスパージし、３日間にわたって１２０℃に加熱した。粗反応材料を、直接、シリカゲル上で蒸発させ、フラッシュカラムクロマトグラフィー（８０ｇのシリカゲルカラム、０～８％のＭｅＯＨ／ＤＣＭ、乾式化合物充填）によって精製して、表題化合物（３．５２ｇ、１３．７ｍｍｏｌ、６７％の収率）を黄色の固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ２５８．１［Ｍ＋Ｈ］ ^＋ 、１．２６分。 Synthesis of intermediate 6-fluoro-N-(2′-fluoro-3-(trifluoromethyl)-[2,3′-bipyridin]-6-yl)pyridine-2-sulfonamide (intermediate b10)

Step 1. Synthesis of 2′-fluoro-3-(trifluoromethyl)-[2,3′-bipyridin]-6-amine In a flask equipped with a reflux condenser, 6-chloro-5-(trifluoro methyl)pyridin-2-amine (4.00 g, 20.4 mmol), 2-fluoropyridine-3-boronic acid (4.30 g, 30.5 mmol), Na ₂ CO ₃ (6.47 g, 61.1 mmol), and Pd(Ph ₃ P) ₄ (2.35 g, 2.04 mmol) were taken in a mixture of dioxane (100 mL) and H ₂ O (16 mL). The mixture was subsequently sparged with argon and heated to 120° C. for 3 days. The crude reaction material was directly evaporated onto silica gel and purified by flash column chromatography (80 g silica gel column, 0-8% MeOH/DCM, dry compound loading) to give the title compound (3.52 g, 13.5 g, 13.5 g). 7 mmol, 67% yield) as a yellow solid. LCMS (conditions 1): m/z 258.1 [M+H] ⁺ , 1.26 min.

Step 2. Synthesis of 6-fluoro-N-(2′-fluoro-3-(trifluoromethyl)-[2,3′-bipyridin]-6-yl)pyridine-2-sulfonamide In a flask, 2′ -Fluoro-3-(trifluoromethyl)-[2,3'-bipyridin]-6-amine (3.52 g, 13.7 mmol) was taken in THF (100 mL) and the resulting solution was cooled to 0°C. did. The solution was treated with 1 M LiHMDS in THF (27.4 mL, 27.4 mmol) followed by a solution of 6-fluoropyridine-2-sulfonyl chloride (4.01 g, 20.5 mmol) dissolved in THF (10 mL). added. The reaction was stirred for 1 hour, then quenched with 1M HCl and extracted into EtOAc (x3). The organics _were then washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was evaporated onto silica gel and purified by flash column chromatography (80 g silica gel column, 0-80% EtOAc/heptane, dry compound loading) to give the title compound (2.49 g, 5.98 mmol, 44% yield) was obtained as a pale brown solid. LCMS (conditions 1): m/z 417.0 [M+H] ^<+ >, 1.49 min. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.28 (s, 1H), 8.39-8.32 (m, 1H), 8.24 (d, J=8.9Hz, 1H), 8 .20-8.14 (m, 1H), 7.88 (dd, J=7.5, 1.6Hz, 1H), 7.80-7.74 (m, 1H), 7.52 (dd, J=8.3, 1.8 Hz, 1 H), 7.48-7.43 (m, 1 H), 7.28 (d, J=8.7 Hz, 1 H).

工程１において、６－クロロ－５－（トリフルオロメチル）ピリジン－２－アミンを、６－ブロモ－５－クロロピリジン－２－イルアミンで置き換え、２－フルオロピリジン－３－ボロン酸を、２－クロロピリジン－３－ボロン酸で置き換えたことを除いて、中間体（中間体ｂ１０）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ＬＣＭＳ（条件１）：ｍ／ｚ ３９８．９［Ｍ＋Ｈ］ ^＋ 、１．４６分。 Synthesis of intermediate N-(2',3-dichloro-[2,3'-bipyridin]-6-yl)-6-fluoropyridine-2-sulfonamide (intermediate b11)

In step 1, 6-chloro-5-(trifluoromethyl)pyridin-2-amine is replaced with 6-bromo-5-chloropyridin-2-ylamine and 2-fluoropyridine-3-boronic acid is replaced with 2- Synthesized using the procedure used for intermediate (intermediate b10), except substituting chloropyridine-3-boronic acid. LCMS (conditions 1): LCMS (conditions 1): m/z 398.9 [M+H] ⁺ , 1.46 min.

工程１において、６－クロロ－５－（トリフルオロメチル）ピリジン－２－アミンを、６－ブロモ－５－クロロピリジン－２－イルアミンで置き換え、２－フルオロピリジン－３－ボロン酸を、２－クロロ－４－メチルピリジン－３－ボロン酸で置き換えたことを除いて、中間体（中間体ｂ１０）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４１２．９［Ｍ＋Ｈ］ ^＋ 、１．５９分。 Synthesis of intermediate N-(2',3-dichloro-4'-methyl-[2,3'-bipyridin]-6-yl)-6-fluoropyridine-2-sulfonamide (intermediate b12)

In step 1, 6-chloro-5-(trifluoromethyl)pyridin-2-amine is replaced with 6-bromo-5-chloropyridin-2-ylamine and 2-fluoropyridine-3-boronic acid is replaced with 2- Synthesized using the procedure used for the intermediate (intermediate b10), except substituting chloro-4-methylpyridine-3-boronic acid. LCMS (conditions 1): m/z 412.9 [M+H] ⁺ , 1.59 min.

工程１．ｔｅｒｔ－ブチル（３－（（２－（６－アミノ－３－（トリフルオロメチル）ピリジン－２－イル）ベンジル）オキシ）プロピル）カルバメートの合成
６－クロロ－５－（トリフルオロメチル）ピリジン－２－アミン（８０ｍｇ、０．２０ｍｍｏｌ）、ｔｅｒｔ－ブチル（３－（（２－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）ベンジル）オキシ）プロピル）カルバメート（１７５ｍｇ、０．４５）及びＫ _２ ＣＯ _３ （１１３ｍｇ、０．８１ｍｍｏｌ）を、マイクロ波バイアル中で、ジオキサン／水（３：１、４ｍＬ）中で懸濁させ、２分間にわたってＮ _２ でフラッシュした。Ｐｄ（ＰＰｈ _３ ） _４ （２４ｍｇ、０．０２ｍｍｏｌ）を加え、２分間にわたってＮ _２ でフラッシュし、バイアルを閉じた。次に、反応物を、４５分間にわたって１３５℃でマイクロ波にかけた。それをろ過し、ＥｔＯＡｃで洗浄した。ろ液を、塩水及び次に水で洗浄し、Ｎａ _２ ＳＯ _４ 上で乾燥させ、ろ過し、濃縮した。次に、それを、フラッシュカラムクロマトグラフィー（ＩＳＣＯ、２４ｇのカラム、ＥｔＯＡｃ／ヘプタン０～６０％）に供して、表題化合物（１２０ｍｇ、０．１４ｍｍｏｌ、７０％の収率）を得た。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ４２６．２［Ｍ＋Ｈ］ ^＋ 、１．９８分。 Intermediate N-(6-(2-((3-aminopropoxy)methyl)phenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (Intermediate b13) Synthesis of

Step 1. Synthesis of tert-butyl (3-((2-(6-amino-3-(trifluoromethyl)pyridin-2-yl)benzyl)oxy)propyl)carbamate 6-chloro-5-(trifluoromethyl)pyridine- 2-amine (80 mg, 0.20 mmol), tert-butyl (3-((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)propyl ) carbamate (175 mg, 0.45) and _K2CO3 (113 mg, 0.81 mmol) were suspended in dioxane/water (3:1, ₄ mL) in a microwave vial and stirred for 2 min with _N2 . flashed with Pd(PPh ₃ ) ₄ (24 mg, 0.02 mmol) was added, flushed with N ₂ for 2 minutes and the vial was closed. The reaction was then microwaved at 135° C. for 45 minutes. It was filtered and washed with EtOAc. The filtrate was washed with brine and then water, _dried over _Na2SO4 , filtered and concentrated. It was then subjected to flash column chromatography (ISCO, 24 g column, EtOAc/heptane 0-60%) to give the title compound (120 mg, 0.14 mmol, 70% yield). LC-MS (conditions 1): m/z 426.2 [M+H] ⁺ , 1.98 min.

Step 2. Synthesis of tert-butyl (3-((2-(6-((6-fluoropyridine)-2-sulfonamido)-3-(trifluoromethyl)pyridin-2-yl)benzyl)oxy)propyl)carbamate tert -Butyl (3-((2-(6-amino-3-(trifluoromethyl)pyridin-2-yl)benzyl)oxy)propyl)carbamate (100 mg, 0.24 mmol) was suspended in THF (5 mL). Turbid and cooled to 0° C. under N ₂ atmosphere. LiHMDS (79 mg, 0.47 mmol) was added dropwise. Stirring was continued for 30 minutes, 6-fluoropyridine-2-sulfonyl chloride (40 mg, 0.21 mmol) in THF (1 mL) was added dropwise and the reaction mixture was brought to room temperature and stirred for 3 hours. Poured into cold saturated NH ₄ Cl solution and worked up with EtOAc. Dried over Na ₂ SO ₄ and concentrated. It was purified by flash column chromatography (ISCO, 12 g column, EtOAc/heptane 0-10%) to give the title compound as a yellow solid (76 mg, 0.12 mmol, 50% yield). LCMS (conditions 1): m/z 585.3 [M+H] ⁺ , 1.78 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.17 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 8.09 (q, J = 7.8, 1H) , 7.84 (dd, J=7.3, 2.0 Hz, 1H), 7.52-7.38 (m, 3H), 7.30 (ddd, J=7.6, 5.1, 3 .7Hz, 1H), 7.27-7.20 (m, 1H), 7.04 (d, J = 7.5Hz, 1H), 6.70 (t, J = 5.6Hz, 1H), 3 .95 (s, 2H), 3.09 (dt, J = 21.7, 5.0 Hz, 2H), 2.85 (q, J = 6.6 Hz, 2H), 1.54-1.39 ( m, 2H), 1.35 (s, 9H).

Step 3. Synthesis of N-(6-(2-((3-aminopropoxy)methyl)phenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (Intermediate b13) tert-butyl (3-((2-(6-((6-fluoropyridine)-2-sulfonamido)-3-(trifluoromethyl)pyridin-2-yl)benzyl)oxy)-propyl)carbamate (55 mg , 0.09 mmol) was stirred in HCl in MeOH (3.0 M, 1.0 mL, 3.0 mmol) in a vial at 55° C. for 3 h. Solvent was removed and the residue was dried and washed with diethyl ether to give crude title compound (43 mg, 94% yield) as a brown solid. LCMS (conditions 1): m/z 485.2 [M+H] ⁺ , 1.39 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.27 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.14-7.97 (m, 3H), 7 .83 (dd, J=7.4, 2.1 Hz, 1H), 7.49 (dd, J=8.2, 2.2 Hz, 1H), 7.46-7.39 (m, 2H), 7.36-7.19 (m, 2H), 7.02 (d, J = 7.5Hz, 1H), 4.00 (s, 2H), 3.29-2.98 (m, 2H), 2.82-2.59 (m, 2H), 1.85-1.49 (m, 2H).

工程１において、５－フルオロ－２－ビニルフェニル）ボロン酸を、２－ビニルフェニル）ボロン酸で置き換え、工程２において、６－フルオロピリジン－２－スルホニルクロリドを、６－ブロモピリジン－２－スルホニルクロリドで置き換えたことを除いて、中間体（中間体ｂ１）について使用される手順を用いて合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４８３．９［Ｍ＋Ｈ］ ^＋ 、１．４１分。 Synthesis of 6-bromo-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b14)

In step 1 5-fluoro-2-vinylphenyl)boronic acid is replaced with 2-vinylphenyl)boronic acid and in step 2 6-fluoropyridine-2-sulfonyl chloride is replaced with 6-bromopyridine-2-sulfonyl Synthesized using the procedure used for intermediate (intermediate b1), except replacing with chloride. LCMS (conditions 1): m/z 483.9 [M+H] ⁺ , 1.41 min.

工程１．６－（アリルアミノ）－Ｎ－（６－（２－（アリルオキシ）フェニル）－５－（トリフルオロメチル）ピリジン－２－イル）ピリジン－２－スルホンアミドの合成
ジオキサン（５ｍＬ）中のＮ－（６－（２－（アリルオキシ）フェニル）－５－（トリフルオロメチル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ７）（１００ｍｇ、０．２２ｍｍｏｌ）、及びプロパ－２－エン－１－アミン（６３．０ｍｇ、１．１０ｍｍｏｌ）を含有する混合物を、１２０℃で１６時間加熱した。混合物を水で希釈し、１ＮのＨＣｌ水溶液（２ｍＬ）で希釈し、次に、ＥｔＯＡｃで抽出した。有機層を収集し、ＭｇＳＯ _４ 上で乾燥させ、ろ過し、濃縮した。残渣を、ＩＳＣＯカラム（ＥｔＯＡｃ／ヘプタン０～１００％）によって精製して、表題化合物をガラス質の固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ４９１．２［Ｍ＋Ｈ］ ^＋ 、１．６２分。 Synthesis of Exemplary Compounds Example 1: 2 ^3- (Trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Synthesis of Benzenacycloundecaphane 4,4-dioxide (1)

Step 1. Synthesis of 6-(allylamino)-N-(6-(2-(allyloxy)phenyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide N-(6-(2-(allyloxy)phenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b7) (100 mg, 0.22 mmol), and prop-2-en-1-amine (63.0 mg, 1.10 mmol) was heated at 120° C. for 16 hours. The mixture was diluted with water and diluted with 1N aqueous HCl (2 mL), then extracted with EtOAc. The organic layer was collected, dried over _MgSO4 , filtered and concentrated. The residue was purified by ISCO column (EtOAc/heptane 0-100%) to give the title compound as a glassy solid. LCMS (conditions 1): m/z 491.2 [M+H] ⁺ , 1.62 min.

Step 2. 23-(Trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane- Synthesis of 8-ene 4,4-dioxide 6-(allylamino)-N-(6-(2-(allyloxy)phenyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine in DCM (50 mL) -2-sulfonamide (80 mg, 0.163 mmol) was added to Grubbs II catalyst ((1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tri Cyclohexylphosphine)ruthenium) (40 mg, 0.047 mmol) was added under a nitrogen atmosphere. The mixture was heated at 50° C. in an oil bath for 2 hours and then left stirring at room temperature for 5 days. The mixture was concentrated under reduced pressure and the residue was purified by ISCO column (EtOAc/heptane 0-100%) to give the title compound as a brown solid. LCMS (conditions 1): m/z 463.2 [M+H] ⁺ , 1.53 min.

Step 3.2 ^3- (Trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane Synthesis of 4,4-dioxide (1) 2 ^3- (Trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina- in EtOAc (15 mL) To a solution of 1(1,2)-benzeneacycloundecaphan-8-ene 4,4-dioxide (55 mg, 0.119 mmol) was added PtO _dihydrate for 1.5 h at room temperature under a hydrogen atmosphere. (25 mg, 0.110 mmol). The mixture was filtered through Celite, rinsed with EtOAc, and the filtrate was concentrated under reduced pressure. The residue was purified by ISCO column (EtOAc/heptane 0-100%) to give the title compound as a white solid. LCMS (conditions 1): m/z 465.2 [M+H] ⁺ , 1.58 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.32 (s, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.56-7.45 (m, 2H), 7 .40 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 6.9 Hz, 1H), 7.13-6.94 (m, 4H), 6.62 (d, J = 8.5 Hz, 1H), 4.00-3.82 (m, 2H), 3.02-2.89 (m, 1H), 2.87-2.73 (m, 1H), 1.77- 1.61 (m, 1H), 1.62-1.44 (m, 2H), 1.42-1.26 (m, 1H).

工程１において、プロパ－２－エン－１－アミンを、２－（アリルアミノ）エタン－１－オール（中間体ａ１５）で置き換えたことを除いて、実施例１に記載される手順を用いて、６－（２－ヒドロキシエチル）－２ ^３ －（トリフルオロメチル）－１１－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５０９．２［Ｍ＋Ｈ］ ^＋ 、１．５２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６０（ｓ，１Ｈ）、８．０３（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．６７（ｄｄ，Ｊ＝８．６、７．３Ｈｚ、１Ｈ）、７．４０（ｔ，Ｊ＝７．７Ｈｚ、１Ｈ）、７．２４（ｔ，Ｊ＝７．６Ｈｚ、２Ｈ）、７．１６（ｄ，Ｊ＝６．２Ｈｚ、１Ｈ）、７．０５（ｄ，Ｊ＝８．３Ｈｚ、１Ｈ）、６．９８（ｔ，Ｊ＝７．４Ｈｚ、１Ｈ）、６．９０（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．７７（ｔ，Ｊ＝５．２Ｈｚ、１Ｈ）、４．００（ｓ，２Ｈ）、３．８６（ｓ，１Ｈ）、３．５５－３．４９（ｍ，２Ｈ）、３．３０－３．１９（ｍ，１Ｈ）、３．１０－２．９５（ｍ，１Ｈ）、１．７８（ｓ，１Ｈ）、１．５０（ｓ，２Ｈ）、１．３２－１．１０（ｍ，１Ｈ）、０．８９－０．８３（ｍ，１Ｈ）． Example 2: 6-(2-hydroxyethyl)-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1 ,2)-Synthesis of Benzenacycloundecaphane 4,4-dioxide (2)

Using the procedure described in Example 1, except that in step 1 prop-2-en-1-amine was replaced with 2-(allylamino)ethan-1-ol (intermediate a15) 6-(2-hydroxyethyl)-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphane 4,4-dioxide (2) was synthesized. LCMS (conditions 1): m/z 509.2 [M+H] ⁺ , 1.52 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.60 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.67 (dd, J = 8.6, 7. 3 Hz, 1 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.24 (t, J = 7.6 Hz, 2 H), 7.16 (d, J = 6.2 Hz, 1 H), 7.05 (d, J = 8.3 Hz, 1 H), 6.98 (t, J = 7.4 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 1 H), 4.77 (t , J = 5.2 Hz, 1H), 4.00 (s, 2H), 3.86 (s, 1H), 3.55-3.49 (m, 2H), 3.30-3.19 (m , 1H), 3.10-2.95 (m, 1H), 1.78 (s, 1H), 1.50 (s, 2H), 1.32-1.10 (m, 1H), 0. 89-0.83 (m, 1H).

工程１において、プロパ－２－エン－１－アミンを、エチル２－（アリルアミノ）アセテート（中間体ａ１４）で置き換えたことを除いて、実施例１に記載される手順を用いて、エチル２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－１１－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）アセテート（３）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５５１．２［Ｍ＋Ｈ］ ^＋ 、１．６５分。 Example 3: Ethyl 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-Benzenacycloundecaphan-6-yl)acetate (3)

Using the procedure described in Example 1, except that in step 1 prop-2-en-1-amine was replaced with ethyl 2-(allylamino)acetate (intermediate a14), ethyl 2- (4,4-dioxide-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacin Crowndecaphan-6-yl)acetate (3) was synthesized. LCMS (conditions 1): m/z 551.2 [M+H] ⁺ , 1.65 min.

ＭｅＯＨ（１．５ｍＬ）及び水（０．５ｍＬ）中のエチル２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－１１－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）アセテート（３）（１０ｍｇ、０．０１８ｍｍｏｌ）及びＬｉＯＨ（２．２ｍｇ、０．０９１ｍｍｏｌ）の混合物を、室温で一晩撹拌した。混合物を減圧下で濃縮して、ＭｅＯＨの大部分を除去した。残りの水性混合物を１ＮのＨＣｌ（０．５ｍＬ）で処理して、乳状の懸濁液を得た。次に、混合物をＤＣＭで抽出し、ＭｇＳＯ _４ 上で乾燥させ、ろ過し、濃縮し、１時間にわたって７０℃で加熱しながら、高真空下で乾燥させて、２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－１１－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）酢酸（４）を白色の固体として得た。ＬＣＭＳ９（条件１）：ｍ／ｚ ５２３．２［Ｍ＋Ｈ］ ^＋ 、１．５０分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．７５（ｓ，１Ｈ）、１１．６５（ｓ，１Ｈ）、８．０３（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．５、７．４Ｈｚ、１Ｈ）、７．４０（ｔ，Ｊ＝７．８Ｈｚ、１Ｈ）、７．３２（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、７．２４（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．１７（ｄ，Ｊ＝８．０Ｈｚ、１Ｈ）、７．０５（ｄ，Ｊ＝８．３Ｈｚ、１Ｈ）、６．９８（ｔ，Ｊ＝７．５Ｈｚ、１Ｈ）、６．６９（ｄ，Ｊ＝８．４Ｈｚ、１Ｈ）、４．２４－４．１９（ｍ，１Ｈ）、４．０７－４．０２（ｍ，２Ｈ）、３．８４（ｓ，１Ｈ）、２．９７（ｓ，１Ｈ）、１．８２（ｓ，１Ｈ）、１．５１（ｓ，２Ｈ）、１．２４（ｓ，２Ｈ）． Example 4: 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-1 ¹ -oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-Benzenacycloundecaphan-6-yl)acetic acid (4)

Ethyl 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2, in MeOH (1.5 mL) and water (0.5 mL) 5(2,6)-Dipyridina-1(1,2)-benzonacycloundecaphan-6-yl)acetate (3) (10 mg, 0.018 mmol) and LiOH (2.2 mg, 0.091 mmol). The mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to remove most of the MeOH. The remaining aqueous mixture was treated with 1N HCl (0.5 mL) to give a milky suspension. The mixture was then extracted with DCM, dried over MgSO ₄ , filtered, concentrated and dried under high vacuum with heating at 70° C. for 1 hour to give 2-(4,4-dioxide- 2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane-6- yl)acetic acid (4) was obtained as a white solid. LCMS 9 (conditions 1): m/z 523.2 [M+H] ^<+ >, 1.50 min. ¹ H NMR (400 MHz, DMSO _- d6) δ 12.75 (s, 1H), 11.65 (s, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.70 (dd , J = 8.5, 7.4 Hz, 1 H), 7.40 (t, J = 7.8 Hz, 1 H), 7.32 (d, J = 7.2 Hz, 1 H), 7.24 (d, J = 8.9Hz, 1H), 7.17 (d, J = 8.0Hz, 1H), 7.05 (d, J = 8.3Hz, 1H), 6.98 (t, J = 7.5Hz , 1H), 6.69 (d, J = 8.4 Hz, 1H), 4.24-4.19 (m, 1H), 4.07-4.02 (m, 2H), 3.84 (s , 1H), 2.97(s, 1H), 1.82(s, 1H), 1.51(s, 2H), 1.24(s, 2H).

マイクロ波バイアル中で、６－フルオロ－Ｎ－（２’－フルオロ－３－（トリフルオロメチル）－［２，３’－ビピリジン］－６－イル）ピリジン－２－スルホンアミド（中間体ｂ１０）（１３．１ｍｇ、０．０３１ｍｍｏｌ）及び１，４－ジアミノブタン（２．８ｍｇ、０．０３１ｍｍｏｌ）を、ＮＭＰ（３ｍＬ）に取り込み、次に、ＤＩＥＡ（１６μＬ、０．０９４ｍｍｏｌ）を加え、反応物を、マイクロ波中で、１時間にわたって２００℃に加熱した。粗反応材料をシリカゲル上で蒸発させ、フラッシュカラムクロマトグラフィー（ＩＳＣＯ、４ｇのＲｅｄｉＳｅｐ Ｒｆ Ｇｏｌｄカラム、ＥｔＯＡｃ／ヘプタン０～６０％、乾式充填）によって精製して、生成物２ ^３ －（トリフルオロメチル）－４－チア－３，６，１１－トリアザ－１（３，２），２，５（２，６）－トリピリジナシクロウンデカファン４，４－ジオキシド（５）をオフホワイトの固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ４６５．１［Ｍ＋Ｈ］ ^＋ 、１．２８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７９（ｓ，１Ｈ）、８．１８（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、８．１０（ｄｄ，Ｊ＝４．９、１．７Ｈｚ、１Ｈ）、７．５４－７．５０（ｍ，１Ｈ）、７．３９－７．３５（ｍ，３Ｈ）、７．１８（ｄ，Ｊ＝７．１Ｈｚ、１Ｈ）、６．６３（ｄｄ，Ｊ＝７．３、５．１Ｈｚ、２Ｈ）、５．６２（ｓ，１Ｈ）、３．２６－３．２４（ｍ，４Ｈ）、１．５４（ｓ，４Ｈ）． Example 5: 2 ^3- (trifluoromethyl)-4-thia-3,6,11-triaza-1(3,2),2,5(2,6)-tripyridinacycloundecaphane 4, Synthesis of 4-dioxide (5)

6-fluoro-N-(2′-fluoro-3-(trifluoromethyl)-[2,3′-bipyridin]-6-yl)pyridine-2-sulfonamide (intermediate b10) in a microwave vial (13.1 mg, 0.031 mmol) and 1,4-diaminobutane (2.8 mg, 0.031 mmol) were taken up in NMP (3 mL) followed by DIEA (16 μL, 0.094 mmol) and the reaction mixture was heated to 200° C. in a microwave for 1 hour. The crude reaction material is evaporated onto silica gel and purified by flash column chromatography (ISCO, 4 g RediSep Rf Gold column, EtOAc/heptane 0-60%, dry packed) to give the product 2 ³ -(trifluoromethyl). -4-thia-3,6,11-triaza-1(3,2),2,5(2,6)-tripyridinacycloundecaphane 4,4-dioxide (5) as an off-white solid Obtained. LCMS (conditions 1): m/z 465.1 [M+H] ⁺ , 1.28 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.79 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 8.10 (dd, J = 4.9, 1. 7Hz, 1H), 7.54-7.50 (m, 1H), 7.39-7.35 (m, 3H), 7.18 (d, J = 7.1Hz, 1H), 6.63 ( dd, J = 7.3, 5.1 Hz, 2H), 5.62 (s, 1H), 3.26-3.24 (m, 4H), 1.54 (s, 4H).

１，４－ジアミノブタンを、１，５－ジアミノペンタンで置き換えたことを除いて、実施例５に記載される手順を用いて、２ ^３ －（トリフルオロメチル）－４－チア－３，６，１２－トリアザ－１（３，２），２，５（２，６）－トリピリジナシクロドデカファン４，４－ジオキシド（６）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４７９．１［Ｍ＋Ｈ］ ^＋ 、１．２６分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７０（ｓ，１Ｈ）、８．２６（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、８．００（ｄｄ，Ｊ＝６．１、１．５Ｈｚ、１Ｈ）、７．７４（ｓ，２Ｈ）、７．６２（ｄ，Ｊ＝８．２Ｈｚ、１Ｈ）、７．４９（ｄｄ，Ｊ＝８．４、７．３Ｈｚ、１Ｈ）、７．０８（ｄ，Ｊ＝６．７Ｈｚ、２Ｈ）、６．９２（ｓ，１Ｈ）、６．６０（ｄ，Ｊ＝８．４Ｈｚ、１Ｈ）、３．５１（ｓ，２Ｈ）、３．３１（ｓ，２Ｈ）、１．４９（ｓ，２Ｈ）、１．３７－１．３６（ｍ，２Ｈ）、１．２２－１．２１（ｍ，２Ｈ）． Example 6: 2 ^3- (Trifluoromethyl)-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4 - Synthesis of the dioxide (6)

2 ³ -(Trifluoromethyl)-4-thia-3,6 was prepared using the procedure described in Example 5, except that 1,4-diaminobutane was replaced with 1,5-diaminopentane. ,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide (6) was synthesized. LCMS (conditions 1): m/z 479.1 [M+H] ⁺ , 1.26 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.70 (s, 1H), 8.26 (d, J = 9.0 Hz, 1H), 8.00 (dd, J = 6.1, 1. 5 Hz, 1 H), 7.74 (s, 2 H), 7.62 (d, J = 8.2 Hz, 1 H), 7.49 (dd, J = 8.4, 7.3 Hz, 1 H), 7. 08 (d, J = 6.7 Hz, 2H), 6.92 (s, 1H), 6.60 (d, J = 8.4 Hz, 1H), 3.51 (s, 2H), 3.31 ( s, 2H), 1.49 (s, 2H), 1.37-1.36 (m, 2H), 1.22-1.21 (m, 2H).

１，４－ジアミノブタンを、１，６－ジアミノヘキサンで置き換えたことを除いて、実施例５に記載される手順を用いて、２ ^３ －（トリフルオロメチル）－４－チア－３，６，１３－トリアザ－１（３，２），２，５（２，６）－トリピリジナシクロトリデカファン４，４－ジオキシド（７）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４９３．２［Ｍ＋Ｈ］ ^＋ 、１．３５分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．８８（ｓ，１Ｈ）、８．２１（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、８．０４（ｄｄ，Ｊ＝５．９、１．６Ｈｚ、１Ｈ）、７．６７（ｓ，１Ｈ）、７．５５（ｄｄ，Ｊ＝８．５、７．２Ｈｚ、１Ｈ）、７．３７（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．２２（ｄ，Ｊ＝７．１Ｈｚ、１Ｈ）、７．１２（ｄ，Ｊ＝５．０Ｈｚ、１Ｈ）、６．８８（ｓ，１Ｈ）、６．６７（ｄ，Ｊ＝８．５Ｈｚ、１Ｈ）、３．２９（ｓ，２Ｈ）、３．２１（ｓ，２Ｈ）、１．５３（ｓ，４Ｈ）、１．３１－１．２２（ｍ，４Ｈ）． Example 7: 2 ^3- (trifluoromethyl)-4-thia-3,6,13-triaza-1(3,2),2,5(2,6)-tripyridinacyclotridecaphane 4, Synthesis of 4-dioxide (7)

2 ³ -(Trifluoromethyl)-4-thia-3,6 was prepared using the procedure described in Example 5, except that 1,4-diaminobutane was replaced with 1,6-diaminohexane. ,13-triaza-1(3,2),2,5(2,6)-tripyridinacyclotridecaphane 4,4-dioxide (7) was synthesized. LCMS (conditions 1): m/z 493.2 [M+H] ⁺ , 1.35 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.88 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 8.04 (dd, J = 5.9, 1. 6 Hz, 1 H), 7.67 (s, 1 H), 7.55 (dd, J = 8.5, 7.2 Hz, 1 H), 7.37 (d, J = 9.0 Hz, 1 H), 7. 22 (d, J = 7.1 Hz, 1 H), 7.12 (d, J = 5.0 Hz, 1 H), 6.88 (s, 1 H), 6.67 (d, J = 8.5 Hz, 1 H ), 3.29 (s, 2H), 3.21 (s, 2H), 1.53 (s, 4H), 1.31-1.22 (m, 4H).

１，４－ジアミノブタンを、Ｎ ^１ ，Ｎ ^６ －ジメチルヘキサン－１，６－ジアミンで置き換えたことを除いて、実施例５に記載される手順を用いて、６，１３－ジメチル－２ ^３ －（トリフルオロメチル）－４－チア－３，６，１３－トリアザ－１（３，２），２，５（２，６）－トリピリジナシクロトリデカファン４，４－ジオキシド（８）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５２１．２［Ｍ＋Ｈ］ ^＋ 、１．４４分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７３（ｓ，１Ｈ）、８．２０（ｄｄ，Ｊ＝４．８、１．８Ｈｚ、１Ｈ）、８．１５（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６８（ｄｄ，Ｊ＝８．６、７．３Ｈｚ、１Ｈ）、７．５２－７．３６（ｍ，２Ｈ）、７．１４（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、６．８８（ｄｄ，Ｊ＝７．４、４．９Ｈｚ、１Ｈ）、６．８１（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．９５（ｓ，１Ｈ）、３．３８－３．３７（ｍ，１Ｈ）、２．８９（ｓ，３Ｈ）、２．６６（ｓ，４Ｈ）、２．３９－２．２５（ｍ，１Ｈ）、１．４７（ｓ，１Ｈ）、１．３３（ｓ，１Ｈ）、１．１０（ｓ，１Ｈ）、０．７６（ｓ，５Ｈ）． Example 8: 6,13-dimethyl-2 ³ -(trifluoromethyl)-4-thia-3,6,13-triaza-1(3,2),2,5(2,6)-tripyridi Synthesis of nacyclotridecaphane 4,4-dioxide (8)

Using the procedure described in Example 5, except replacing 1,4-diaminobutane with N ¹ ,N ⁶ -dimethylhexane-1,6-diamine, 6,13-dimethyl-2 ³ was prepared. -(trifluoromethyl)-4-thia-3,6,13-triaza-1(3,2),2,5(2,6)-tripyridinacyclotridecaphane 4,4-dioxide (8) was synthesized. LCMS (conditions 1): m/z 521.2 [M+H] ⁺ , 1.44 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.73 (s, 1H), 8.20 (dd, J=4.8, 1.8 Hz, 1H), 8.15 (d, J=8. 9Hz, 1H), 7.68 (dd, J = 8.6, 7.3Hz, 1H), 7.52-7.36 (m, 2H), 7.14 (d, J = 7.2Hz, 1H) ), 6.88 (dd, J = 7.4, 4.9 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 3.95 (s, 1H), 3.38-3 .37 (m, 1H), 2.89 (s, 3H), 2.66 (s, 4H), 2.39-2.25 (m, 1H), 1.47 (s, 1H), 1. 33 (s, 1H), 1.10 (s, 1H), 0.76 (s, 5H).

１，４－ジアミノブタンを、Ｎ ^１ ，Ｎ ^３ －ジメチルプロパン－１，３－ジアミンで置き換えたことを除いて、実施例５に記載される手順を用いて、６，１０－ジメチル－２ ^３ －（トリフルオロメチル）－４－チア－３，６，１０－トリアザ－１（３，２），２，５（２，６）－トリピリジナシクロデカファン４，４－ジオキシド（９）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４７９．１［Ｍ＋Ｈ］ ^＋ 、１．３５分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ８．１２（ｄｄ，Ｊ＝５．０、１．９Ｈｚ、１Ｈ）、７．６５－７．５２（ｍ，２Ｈ）、７．４１（ｄｄ，Ｊ＝７．３、１．９Ｈｚ、１Ｈ）、７．２０－７．１０（ｍ，２Ｈ）、６．８５（ｄｄ，Ｊ＝７．３、５．０Ｈｚ、１Ｈ）、６．５４（ｄ，Ｊ＝８．４Ｈｚ、１Ｈ）、３．５５－３．４８（ｍ，１Ｈ）、３．２６－３．１５（ｍ，１Ｈ）、３．００－２．９５（ｍ，１Ｈ）、２．９２（ｓ，３Ｈ）、２．８３（ｓ，３Ｈ）、２．６３－２．５１（ｍ，１Ｈ）、１．７３－１．６９（ｍ，１Ｈ）、０．８０－０．７６（ｍ，１Ｈ）． Example 9: 6,10-dimethyl-2 ³ -(trifluoromethyl)-4-thia-3,6,10-triaza-1(3,2),2,5(2,6)-tripyridina Synthesis of cyclodecaphane 4,4-dioxide (9)

6,10-dimethyl-2 ³ was prepared using the procedure described in Example 5, except that 1,4-diaminobutane was replaced with N ¹ ,N ³ -dimethylpropane-1,3-diamine. -(Trifluoromethyl)-4-thia-3,6,10-triaza-1(3,2),2,5(2,6)-tripyridinacyclodecaphane 4,4-dioxide (9) Synthesized. LCMS (conditions 1): m/z 479.1 [M+H] ⁺ , 1.35 min. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.12 (dd, J=5.0, 1.9 Hz, 1H), 7.65-7.52 (m, 2H), 7.41 (dd, J = 7.3, 1.9Hz, 1H), 7.20-7.10 (m, 2H), 6.85 (dd, J = 7.3, 5.0Hz, 1H), 6.54 (d , J = 8.4 Hz, 1H), 3.55-3.48 (m, 1H), 3.26-3.15 (m, 1H), 3.00-2.95 (m, 1H), 2 .92 (s, 3H), 2.83 (s, 3H), 2.63-2.51 (m, 1H), 1.73-1.69 (m, 1H), 0.80-0.76 (m, 1H).

１，４－ジアミノブタンを、１，３－ジアミノプロパンで置き換えたことを除いて、実施例５に記載される手順を用いて、２ ^３ －（トリフルオロメチル）－４－チア－３，６，１０－トリアザ－１（３，２），２，５（２，６）－トリピリジナシクロデカファン４，４－ジオキシド（１０）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４５１．１［Ｍ＋Ｈ］ ^＋ 、１．１９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．３３（ｓ，１Ｈ）、８．２７（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、８．０６（ｄｄ，Ｊ＝６．０、１．５Ｈｚ、１Ｈ）、７．８０（ｓ，１Ｈ）、７．５６－７．４４（ｍ，２Ｈ）、７．０２（ｄ，Ｊ＝７．２Ｈｚ、２Ｈ）、６．９１（ｓ，１Ｈ）、６．６３（ｄ，Ｊ＝８．５Ｈｚ、１Ｈ）、３．４４（ｓ，４Ｈ）、１．７３（ｓ，２Ｈ）． Example 10: 2 ^3- (Trifluoromethyl)-4-thia-3,6,10-triaza-1(3,2),2,5(2,6)-tripyridinacyclodecaphane 4,4 - Synthesis of the dioxide (10)

Using the procedure described in Example 5, except replacing 1,4-diaminobutane with 1,3-diaminopropane, 2 ³ -(trifluoromethyl)-4-thia-3,6 was prepared. ,10-triaza-1(3,2),2,5(2,6)-tripyridinacyclodecaphane 4,4-dioxide (10) was synthesized. LCMS (conditions 1): m/z 451.1 [M+H] ⁺ , 1.19 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.33 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.06 (dd, J = 6.0, 1. 5Hz, 1H), 7.80 (s, 1H), 7.56-7.44 (m, 2H), 7.02 (d, J = 7.2Hz, 2H), 6.91 (s, 1H) , 6.63 (d, J=8.5 Hz, 1H), 3.44 (s, 4H), 1.73 (s, 2H).

Ｎ－（６－（２－（（３－アミノプロポキシ）メチル）フェニル）－５－（トリフルオロメチル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ１３）（３１ｍｇ、０．０７ｍｍｏｌ）を、バイアル中でＮＭＰ（２ｍＬ）に溶解させ、ＤＩＥＡ（０．２７ｍＬ、１．５４ｍｍｏｌ）を加えた。バイアルを、窒素でフラッシュした後に閉じ、１３５℃で１６時間撹拌した。水に注ぎ、ＥｔＯＡｃで抽出した。Ｎａ _２ ＳＯ _４ 上で乾燥させ、ろ過し、濃縮した。それを、フラッシュカラムクロマトグラフィー（ＩＳＣＯ、１２ｇのカラム、ＭｅＯＨ／ＤＣＭ ０～１０％、乾式充填）によって精製して、２ ^３ －（トリフルオロメチル）－１０－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１１）を白色の固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ４６５．２［Ｍ＋Ｈ］ ^＋ 。１．７４分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．２７（ｓ，１Ｈ）、８．１８（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、８．１５－７．９７（ｍ，２Ｈ）、７．８３（ｄｄ，Ｊ＝７．４、２．１Ｈｚ、１Ｈ）、７．４９（ｄｄ，Ｊ＝８．２、２．２Ｈｚ、１Ｈ）、７．４３－７．３７（ｍ，２Ｈ）、７．３５－７．１９（ｍ，２Ｈ）、７．０２（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、４．００（ｓ，２Ｈ）、３．２９－３．０１（ｍ，２Ｈ）、２．８０－２．５４（ｍ，２Ｈ）、１．８２－１．５０（ｍ，２Ｈ）． Example 11: 2 ^3- (Trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundeca Synthesis of fan 4,4-dioxide (11)

N-(6-(2-((3-aminopropoxy)methyl)phenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b13) (31 mg , 0.07 mmol) was dissolved in NMP (2 mL) in a vial and DIEA (0.27 mL, 1.54 mmol) was added. The vial was closed after flushing with nitrogen and stirred at 135° C. for 16 hours. Poured into water and extracted with EtOAc. _Dried over _Na2SO4 , filtered and concentrated. It was purified by flash column chromatography (ISCO, 12 g column, MeOH/DCM 0-10%, dry packed) to give 2 ³ -(trifluoromethyl)-10-oxa-4-thia-3,6 -diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (11) was obtained as a white solid. LCMS (conditions 1): m/z 465.2 [M+H] ⁺ . 1.74 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.27 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.15-7.97 (m, 2H), 7 .83 (dd, J=7.4, 2.1 Hz, 1H), 7.49 (dd, J=8.2, 2.2 Hz, 1H), 7.43-7.37 (m, 2H), 7.35-7.19 (m, 2H), 7.02 (d, J = 7.5Hz, 1H), 4.00 (s, 2H), 3.29-3.01 (m, 2H), 2.80-2.54 (m, 2H), 1.82-1.50 (m, 2H).

工程１．６－（ヘキサ－５－エン－１－イル（５－ヒドロキシペンチル）アミノ）－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミドの合成
密閉管中で、ＮＭＰ（３ｍＬ）中の５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）（２６３ｍｇ、１．４１ｍｍｏｌ）、６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）（２００ｍｇ、０．４７ｍｍｏｌ）及びＤＩＥＡ（０．３３ｍＬ、１．８８ｍｍｏｌ）の混合物を、１５０℃で一晩撹拌し、ＬＣＭＳにより、反応がほぼ完了したことが示された。反応混合物を、５００ｍＬの分液漏斗中で、２００ｍＬのＥｔＯＡｃに注ぎ、１０％のクエン酸を用いて酸性化し、次に、水（２０ｍＬ×４）及び塩水（２０ｍＬ）で洗浄した。有機相をＮａ _２ ＳＯ _４ 上で乾燥させ、ろ過し、濃縮し、次に、残渣を、ＩＳＣＯ精製（４０ｇのカラム、ＥｔＯＡｃ／ヘプタン０～１００％）に供して、表題化合物（２２５ｍｇ、０．３８ｍｍｏｌ、８１％の収率）をわずかに褐色の固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ５８９．２［Ｍ＋１］ ^＋ 、１．９３分。 Example 12: 6-(5-Hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclododecaphane 4,4-dioxide (12)

Step 1. 6-(Hex-5-en-1-yl(5-hydroxypentyl)amino)-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) (263 mg, 1.41 mmol), 6 in NMP (3 mL) in a sealed tube. -fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) (200 mg, 0.47 mmol) and DIEA (0 .33 mL, 1.88 mmol) was stirred at 150° C. overnight and LCMS indicated the reaction was nearly complete. The reaction mixture was poured into 200 mL of EtOAc in a 500 mL separatory funnel, acidified with 10% citric acid, then washed with water (20 mL×4) and brine (20 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated, then the residue was subjected to ISCO purification (40 g column, EtOAc/heptane 0-100%) to give the title compound (225 mg, 0.100 g). 38 mmol, 81% yield) as a slightly brown solid. LCMS (conditions 1): m/z 589.2 [M+1] ⁺ , 1.93 min.

Step 2. 6-(5-Hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Nacyclododecaphan-11-ene 4,4-dioxide 6-(hex-5-en-1-yl(5-hydroxypentyl)amino)-N-(5-(tri Into a 500 mL flask containing a solution of fluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (220 mg, 0.37 mmol) was purged with argon. Grubbs II (64 mg, 0.075 mmol) catalyst was added and purged with argon again. The mixture was stirred at 55° C. overnight (or at 70-75° C. overnight in DCE). LC-MS indicated the reaction was complete. The reaction was concentrated and then the residue was subjected to ISCO purification (80 g column, EtOAc/hexanes 0-100%) to give the title compound (194 mg, 0.35 mmol, 94% yield) (cis- and A mixture of trans-products, but mainly the trans-product) was obtained as a white solid. LC-MS: m/z 561.2 [M+1] ⁺ , 1.88 min.

Step 3. 6-(5-Hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Nacyclododecaphane 4,4-dioxide (12)
6-(5-Hydroxypentyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) in EtOAc (24 mL) )-benzeneacyclododecaphan-11-ene 4,4-dioxide (a mixture of cis- and trans-products, but mainly the trans-product) (160 mg, 0.285 mmol) and PtO ₂ (65 mg, 0.285 mmol) was stirred at room temperature under hydrogen overnight and LC-MS indicated the reaction was complete. The reaction mixture was filtered through a layer of celite to remove platinum, then the filtrate was concentrated. The residue was subjected to ISCO purification (40 g column, 0-100% EtOAc in heptane) to give the title compound. LC-MS (conditions 1): m/z 563.2 [M+1] ⁺ , 1.92 min. ¹ H NMR (400 MHz, DMSO ^{-d6) 1} _H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.69 ( dd, J = 8.7, 7.2 Hz, 1H), 7.51-7.37 (m, 1H), 7.34 (td, J = 7.4, 1.5Hz, 1H), 7.29 -7.20 (m, 2H), 7.20-7.10 (m, 2H), 6.84 (d, J = 8.7Hz, 1H), 4.38 (t, J = 5.1Hz, 1H), 3.72-3.49 (m, 1H), 3.43-3.35 (m, 3H), 3.33-3.11 (m, 2H), 2.71-2.54 ( m, 1H), 2.14-1.91 (m, 1H), 1.55-1.17 (m, 9H), 1.17-0.98 (m, 3H), 0.96-0. 82 (m, 1H), 0.82-0.67 (m, 1H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、Ｎ－（２－モルホリノエチル）ペンタ－４－エン－１－アミン（中間体ａ１）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（２－モルホリノエチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１３）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５７６．３［Ｍ＋Ｈ］ ^＋ 、１．２６分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７７（ｓ，１Ｈ）、８．０９（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７２（ｄｄ，Ｊ＝７．３、８．７Ｈｚ、１Ｈ）、７．３６（ｔｄ，Ｊ＝１．４、７．５Ｈｚ、１Ｈ）、７．２９（ｍ，１Ｈ）、７．２３（ｍ，２Ｈ）、７．１９（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．１４（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、６．８４（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．９５（ｍ，１Ｈ）、３．５３（ｍ，４Ｈ）、３．３８（ｍ，３Ｈ）、２．８９（ｍ，１Ｈ）、２．４８（ｍ，１Ｈ）、２．４０（ｍ，６Ｈ）、１．９０（ｍ，１Ｈ）、１．７２（ｍ，１Ｈ）、１．３５（ｍ，２Ｈ）、１．１７（ｍ，１Ｈ）、１．０３（ｍ，１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ６）δ－５６．８８（ｓ）． Example 13: 6-(2-morpholinoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphane 4,4-dioxide (13)

5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was replaced with N-(2-morpholinoethyl)pent-4-en-1-amine (intermediate a1) Using the procedure described in Example 12, 6-(2-morpholinoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2 ,6)-Dipyridina-1(1,2)-Benzenacycloundecaphane 4,4-dioxide (13) was synthesized. LCMS (conditions 1): m/z 576.3 [M+H] ⁺ , 1.26 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.77 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.72 (dd, J = 7.3, 8. 7Hz, 1H), 7.36 (td, J = 1.4, 7.5Hz, 1H), 7.29 (m, 1H), 7.23 (m, 2H), 7.19 (d, J = 8.8Hz, 1H), 7.14 (d, J = 7.5Hz, 1H), 6.84 (d, J = 8.8Hz, 1H), 3.95 (m, 1H), 3.53 ( m, 4H), 3.38 (m, 3H), 2.89 (m, 1H), 2.48 (m, 1H), 2.40 (m, 6H), 1.90 (m, 1H), 1.72 (m, 1H), 1.35 (m, 2H), 1.17 (m, 1H), 1.03 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -56.88 (s).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（２－（ペンタ－４－エン－１－イルアミノ）エトキシ）プロパン－１－オール（中間体ａ２）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（２－（３－ヒドロキシプロポキシ）エチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１４）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６５．２［Ｍ＋Ｈ］ ^＋ 、１．８７分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７９（ｓ，１Ｈ）、８．０９（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．７、７．３Ｈｚ、１Ｈ）、７．３５（ｍ，１Ｈ）、７．２８（ｍ，１Ｈ）、７．２３（ｍ，２Ｈ）、７．１８（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．１４（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、６．９０（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．３５（ｔ，Ｊ＝５．２Ｈｚ、１Ｈ）、３．９４（ｍ，１Ｈ）、３．４２（ｍ，８Ｈ）、２．９１（ｍ，１Ｈ）、２．３９（ｍ，１Ｈ）、１．９１（ｍ，１Ｈ）、１．７３（ｍ，１Ｈ）、１．５８（ｐ，Ｊ＝６．４Ｈｚ、２Ｈ）、１．３２（ｍ，２Ｈ）、１．１０（ｍ，３Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ６）δ－５６．８６（ｓ）． Example 14: 6-(2-(3-hydroxypropoxy)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-Benzenacycloundecaphane 4,4-dioxide (14)

5-(Hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was converted to 3-(2-(pent-4-en-1-ylamino)ethoxy)propan-1-ol (intermediate 6-(2-(3-Hydroxypropoxy)ethyl)-2 ³ -(trifluoromethyl)-4-thia- using the procedure described in Example 12, except substituting with compound a2). 3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (14) was synthesized. LCMS (conditions 1): m/z 565.2 [M+H] ⁺ , 1.87 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.79 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.70 (dd, J = 8.7, 7. 3Hz, 1H), 7.35 (m, 1H), 7.28 (m, 1H), 7.23 (m, 2H), 7.18 (d, J = 8.8Hz, 1H), 7.14 (d, J = 7.5Hz, 1H), 6.90 (d, J = 8.8Hz, 1H), 4.35 (t, J = 5.2Hz, 1H), 3.94 (m, 1H) , 3.42 (m, 8H), 2.91 (m, 1H), 2.39 (m, 1H), 1.91 (m, 1H), 1.73 (m, 1H), 1.58 ( p, J = 6.4 Hz, 2H), 1.32 (m, 2H), 1.10 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -56.86 (s).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、５－（ペンタ－４－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３３）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（５－ヒドロキシペンチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１５）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５４９．２［Ｍ＋１］ ^＋ 、１．９４分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７７（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３６（ｔｄ，Ｊ＝７．４、１．４Ｈｚ、１Ｈ）、７．３１－７．２６（ｍ，１Ｈ）、７．２６－７．１７（ｍ，３Ｈ）、７．１４（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、６．８１（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．３６（ｔ，Ｊ＝５．１Ｈｚ、１Ｈ）、４．０４－３．８６（ｍ，１Ｈ）、３．４０－３．３４（ｍ，３Ｈ）、３．３３－３．１２（ｍ，２Ｈ）、２．９５－２．７９（ｍ，１Ｈ）、２．４６－２．３４（ｍ，１Ｈ）、１．９６－１．８１（ｍ，１Ｈ）、１．７９－１．６２（ｍ，１Ｈ）、１．５６－１．３６（ｍ，４Ｈ）、１．３６－１．２１（ｍ，３Ｈ）、１．２１－１．０８（ｍ，２Ｈ）、１．０８－０．９２（ｍ，１Ｈ）． Example 15: 6-(5-Hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphane 4,4-dioxide (15)

Replacing 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 5-(pent-4-en-1-ylamino)pentan-1-ol (intermediate a33) 6-(5-Hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (15) was synthesized. LC-MS (conditions 1): m/z 549.2 [M+1] ⁺ , 1.94 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.77 (s, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.71 (dd, J = 8.7, 7. 2Hz, 1H), 7.36 (td, J = 7.4, 1.4Hz, 1H), 7.31-7.26 (m, 1H), 7.26-7.17 (m, 3H), 7.14 (d, J = 7.6Hz, 1H), 6.81 (d, J = 8.7Hz, 1H), 4.36 (t, J = 5.1Hz, 1H), 4.04-3 .86 (m, 1H), 3.40-3.34 (m, 3H), 3.33-3.12 (m, 2H), 2.95-2.79 (m, 1H), 2.46 -2.34 (m, 1H), 1.96-1.81 (m, 1H), 1.79-1.62 (m, 1H), 1.56-1.36 (m, 4H), 1 .36-1.21 (m, 3H), 1.21-1.08 (m, 2H), 1.08-0.92 (m, 1H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ヘキサ－５－エン－１－イルアミノ）ブタン－１－オール（中間体ａ３５）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（１６）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５４９．２［Ｍ＋１］ ^＋ 、１．８７分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６７（ｓ，１Ｈ）、８．１６（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．８、７．２Ｈｚ、１Ｈ）、７．５１－７．３７（ｍ，１Ｈ）、７．３４（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．３０－７．２０（ｍ，２Ｈ）、７．２０－７．１０（ｍ，２Ｈ）、６．８５（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．４４（ｔ，Ｊ＝５．１Ｈｚ、１Ｈ）、３．７０－３．５０（ｍ，１Ｈ）、３．４５－３．３４（ｍ，３Ｈ）、３．３２－３．１１（ｍ，２Ｈ）、２．６８－２．５４（ｍ，１Ｈ）、２．１２－１．９２（ｍ，１Ｈ）、１．５８－１．１７（ｍ，８Ｈ）、１．１６－１．００（ｍ，２Ｈ）、０．９６－０．８２（ｍ，１Ｈ）、０．８２－０．６８（ｍ，１Ｈ）． Example 16: 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclododecaphane 4,4-dioxide (16)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 4-(hex-5-en-1-ylamino)butan-1-ol (intermediate a35) 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide (16) was synthesized. LC-MS (conditions 1): m/z 549.2 [M+1] ⁺ , 1.87 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.67 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.70 (dd, J = 8.8, 7.5). 2Hz, 1H), 7.51-7.37 (m, 1H), 7.34 (td, J = 7.4, 1.5Hz, 1H), 7.30-7.20 (m, 2H), 7.20-7.10 (m, 2H), 6.85 (d, J = 8.7Hz, 1H), 4.44 (t, J = 5.1Hz, 1H), 3.70-3.50 (m, 1H), 3.45-3.34 (m, 3H), 3.32-3.11 (m, 2H), 2.68-2.54 (m, 1H), 2.12-1 .92 (m, 1H), 1.58-1.17 (m, 8H), 1.16-1.00 (m, 2H), 0.96-0.82 (m, 1H), 0.82 -0.68 (m, 1H).

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、６－フルオロ－Ｎ－（５－メトキシ－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ５）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ペンタ－４－エン－１－イルアミノ）ブタン－１－オール（中間体ａ２９）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（４－ヒドロキシブチル）－２ ^３ －メトキシ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１７）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ４９７．３［Ｍ＋１］ ^＋ 、１．７０分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ７．６３（ｄｄｄ，Ｊ＝８．７、７．２、２．４Ｈｚ、１Ｈ）、７．４３（ｄｄ，Ｊ ＝９．０、２．５Ｈｚ、１Ｈ）、７．３５－７．２７（ｍ，１Ｈ）、７．２８－７．１７（ｍ，４Ｈ）、７．１５（ｄｔ，Ｊ＝７．６、１．９Ｈｚ、１Ｈ）、６．７４（ｄｄｄ，Ｊ＝８．８、１．６、０．６Ｈｚ、１Ｈ）、３．７０（ｓ，３Ｈ）、３．４５－３．３８（ｍ，２Ｈ）、２．４２（ｔ，Ｊ＝７．３Ｈｚ、２Ｈ）、２．３３（ｔ，Ｊ＝６．９Ｈｚ、２Ｈ）、１．８０－１．７４（ｍ，２Ｈ）、１．６８－１．３８（ｍ，５Ｈ）、１．２７（ｔ，Ｊ ＝７．７Ｈｚ、３Ｈ）、１．０９－０．９０（ｍ，２Ｈ）． Example 17: 6-(4-Hydroxybutyl)-2 ³ -methoxy-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloun Synthesis of Decaphane 4,4-dioxide (17)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to 6-fluoro-N-(5 -methoxy-6-(2-vinylphenyl)pyridin-2-yl)pyridin-2-sulfonamide (intermediate b5) to replace 5-(hex-5-en-1-ylamino)pentan-1-ol ( Using the procedure described in Example 12, except that intermediate a34) was replaced with 4-(pent-4-en-1-ylamino)butan-1-ol (intermediate a29), 6 -(4-hydroxybutyl)-2 ³ -methoxy-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4 -dioxide (17) was synthesized. LC-MS (conditions 1): m/z 497.3 [M+1] ⁺ , 1.70 min. ¹ H NMR (400 MHz, methanol- _d ) δ 7.63 (ddd, J = 8.7, 7.2, 2.4 Hz, 1 H), 7.43 (dd, J = 9.0, 2.5 Hz , 1H), 7.35-7.27 (m, 1H), 7.28-7.17 (m, 4H), 7.15 (dt, J = 7.6, 1.9Hz, 1H), 6 .74 (ddd, J=8.8, 1.6, 0.6 Hz, 1H), 3.70 (s, 3H), 3.45-3.38 (m, 2H), 2.42 (t, J = 7.3Hz, 2H), 2.33 (t, J = 6.9Hz, 2H), 1.80-1.74 (m, 2H), 1.68-1.38 (m, 5H), 1.27 (t, J = 7.7 Hz, 3H), 1.09-0.90 (m, 2H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、Ｎ－エチルペンタ－４－エン－１－アミン（中間体ａ３２）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－エチル－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１８）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ４９１．２［Ｍ＋１］ ^＋ 、１．９８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７７（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．４０－７．３２（ｍ，１Ｈ）、７．３１－７．２６（ｍ，１Ｈ）、７．２６－７．１７（ｍ，３Ｈ）、７．１４（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、６．８３（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．０４－３．８５（ｍ，１Ｈ）、３．４３－３．２２（ｍ，３Ｈ）、２．９３－２．７９（ｍ，１Ｈ）、２．４６－２．３４（ｍ，１Ｈ）、１．９４－１．８１（ｍ，１Ｈ）、１．７８－１．６２（ｍ，１Ｈ）、１．４２－１．２２（ｍ，２Ｈ）、１．２０－１．０９（ｍ，２Ｈ）、１．０４（ｔ，Ｊ＝７．０Ｈｚ、３Ｈ）． Example 18: 6-ethyl-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundeca Synthesis of fan 4,4-dioxide (18)

was carried out except that 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was replaced with N-ethylpent-4-en-1-amine (intermediate a32). Using the procedure described in Example 12, 6-ethyl-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphane 4,4-dioxide (18) was synthesized. LC-MS (conditions 1): m/z 491.2 [M+1] ⁺ , 1.98 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.77 (s, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.71 (dd, J = 8.7, 7. 2Hz, 1H), 7.40-7.32 (m, 1H), 7.31-7.26 (m, 1H), 7.26-7.17 (m, 3H), 7.14 (d, J = 7.6Hz, 1H), 6.83 (d, J = 8.7Hz, 1H), 4.04-3.85 (m, 1H), 3.43-3.22 (m, 3H), 2.93-2.79 (m, 1H), 2.46-2.34 (m, 1H), 1.94-1.81 (m, 1H), 1.78-1.62 (m, 1H) ), 1.42-1.22 (m, 2H), 1.20-1.09 (m, 2H), 1.04 (t, J = 7.0 Hz, 3H).

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、６－フルオロ－Ｎ－（５－メチル－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ４）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ペンタ－４－エン－１－イルアミノ）ブタン－１－オール（中間体ａ２９）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（４－ヒドロキシブチル）－２ ^３ －メチル－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１９）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４８１．２［Ｍ＋Ｈ］ ^＋ 、１．２７分； ^１ Ｈ ＮＭＲ（４００ＭＨｚ、クロロホルム－ｄ）δ ７．５６－７．４８（ｍ，２Ｈ）、７．４７－７．４２（ｍ，１Ｈ）、７．３９－７．３３（ｍ，１Ｈ）、７．３０－７．２８（ｍ，１Ｈ）、７．２６－７．２５（ｍ，１Ｈ）、７．１６－７．１０（ｍ，１Ｈ）、６．５４（ｄ，Ｊ＝８．７Ｈｚ、２Ｈ）、３．６７（ｔ，Ｊ＝５．８Ｈｚ、４Ｈ）、３．２５（ｔ，Ｊ＝７．３Ｈｚ、４Ｈ）、２．５１（ｓ，１Ｈ）、２．０５（ｓ，３Ｈ）、１．６５－１．５６（ｍ，２Ｈ）、１．３６（ｂｒ ｓ、６Ｈ）、１．１２（ｍ，３Ｈ）． Example 19: 6-(4-Hydroxybutyl)-2 ³ -methyl-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Synthesis of Decaphane 4,4-dioxide (19)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to 6-fluoro-N-(5 -methyl-6-(2-vinylphenyl)pyridin-2-yl)pyridin-2-sulfonamide (intermediate b4) to replace 5-(hex-5-en-1-ylamino)pentan-1-ol ( Using the procedure described in Example 12, except that intermediate a34) was replaced with 4-(pent-4-en-1-ylamino)butan-1-ol (intermediate a29), 6 -(4-hydroxybutyl)-2 ³ -methyl-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4 -dioxide (19) was synthesized. LCMS (conditions 1): m/z 481.2 [M+H] ⁺ , 1.27 min; ¹ H NMR (400 MHz, chloroform-d) δ 7.56-7.48 (m, 2H), 7.47- 7.42 (m, 1H), 7.39-7.33 (m, 1H), 7.30-7.28 (m, 1H), 7.26-7.25 (m, 1H), 7. 16-7.10 (m, 1H), 6.54 (d, J = 8.7Hz, 2H), 3.67 (t, J = 5.8Hz, 4H), 3.25 (t, J = 7 .3Hz, 4H), 2.51 (s, 1H), 2.05 (s, 3H), 1.65-1.56 (m, 2H), 1.36 (br s, 6H), 1.12 (m, 3H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（ブタ－３－エン－１－イルアミノ）プロパン－１－オール（中間体ａ２８）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン４，４－ジオキシド（２０）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５０７．２［Ｍ＋１］ ^＋ 、１．８１分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６７（ｓ，１Ｈ）、８．１５（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．７、７．３Ｈｚ、１Ｈ）、７．３９－７．３０（ｍ，２Ｈ）、７．３０－７．２０（ｍ，３Ｈ）、７．１６（ｄ，Ｊ＝７．１Ｈｚ、１Ｈ）、６．８３（ｄ，Ｊ＝８．６Ｈｚ、１Ｈ）、４．５６（ｔ，Ｊ＝４．９Ｈｚ、１Ｈ）、４．００－３．８２（ｍ，１Ｈ）、３．４５－３．３４（ｍ，３Ｈ）、３．３２－３．２０（ｍ，２Ｈ）、２．９３－２．８０（ｍ，１Ｈ）、２．６０－２．５１（ｍ，１Ｈ）、１．８１－１．６９（ｍ，１Ｈ）、１．６９－１．５３（ｍ，２Ｈ）、１．３９－１．１７（ｍ，２Ｈ）、０．７５－０．５７（ｍ，１Ｈ）． Example 20: 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclodecaphane 4,4-dioxide (20)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 3-(but-3-en-1-ylamino)propan-1-ol (intermediate a28) 6-(3-Hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide (20) was synthesized. LC-MS (conditions 1): m/z 507.2 [M+1] ⁺ , 1.81 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.67 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 8.7, 7. 3Hz, 1H), 7.39-7.30 (m, 2H), 7.30-7.20 (m, 3H), 7.16 (d, J = 7.1Hz, 1H), 6.83 ( d, J = 8.6Hz, 1H), 4.56 (t, J = 4.9Hz, 1H), 4.00-3.82 (m, 1H), 3.45-3.34 (m, 3H) ), 3.32-3.20 (m, 2H), 2.93-2.80 (m, 1H), 2.60-2.51 (m, 1H), 1.81-1.69 (m , 1H), 1.69-1.53 (m, 2H), 1.39-1.17 (m, 2H), 0.75-0.57 (m, 1H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（ヘキサ－５－エン－１－イルアミノ）プロパン－１－オール（中間体ａ１７）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（２１）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５３５．２［Ｍ＋１］ ^＋ 、１．８３分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６８（ｓ，１Ｈ）、８．１７（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．５１－７．３８（ｍ，１Ｈ）、７．３４（ｔｄ，Ｊ＝７．５、１．５Ｈｚ、１Ｈ）、７．２９－７．２０（ｍ，２Ｈ）、７．２０－７．１１（ｍ，２Ｈ）、６．８７（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．５６（ｔ，Ｊ＝４．９Ｈｚ、１Ｈ）、３．６９－３．５１（ｍ，１Ｈ）、３．４７－３．３５（ｍ，４Ｈ）、３．３２－３．１７（ｍ，１Ｈ）、２．６６－２．５５（ｍ，１Ｈ）、２．１２－１．９４（ｍ，１Ｈ）、１．７０－１．５５（ｍ，２Ｈ）、１．４４－０．９７（ｍ，６Ｈ）、０．９６－０．６８（ｍ，２Ｈ）． Example 21: 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclododecaphane 4,4-dioxide (21)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 3-(hex-5-en-1-ylamino)propan-1-ol (intermediate a17) 6-(3-Hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide (21) was synthesized. LC-MS (conditions 1): m/z 535.2 [M+1] ⁺ , 1.83 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.68 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.70 (dd, J = 8.7, 7.7. 2Hz, 1H), 7.51-7.38 (m, 1H), 7.34 (td, J = 7.5, 1.5Hz, 1H), 7.29-7.20 (m, 2H), 7.20-7.11 (m, 2H), 6.87 (d, J = 8.8Hz, 1H), 4.56 (t, J = 4.9Hz, 1H), 3.69-3.51 (m, 1H), 3.47-3.35 (m, 4H), 3.32-3.17 (m, 1H), 2.66-2.55 (m, 1H), 2.12-1 .94 (m, 1H), 1.70-1.55 (m, 2H), 1.44-0.97 (m, 6H), 0.96-0.68 (m, 2H).

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、Ｎ－（６－（２－（アリルオキシ）－５－フルオロフェニル）－５－（トリフルオロメチル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ８）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（ブタ－３－エン－１－イルアミノ）プロパン－１－オール（中間体ａ２８）で置き換えたことを除いて、実施例１２に記載される手順を用いて、１ ^５ －フルオロ－６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－１１－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２２）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５４１．１５［Ｍ＋１］ ^＋ 、１．７１分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６６（ｓ，１Ｈ）、８．０６（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６９（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３２－７．１９（ｍ，３Ｈ）、７．１４－７．０１（ｍ，２Ｈ）、６．８５（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．５７（ｔ，Ｊ＝４．９Ｈｚ、１Ｈ）、４．０４－３．７７（ｍ，３Ｈ）、３．５０－３．３８（ｍ，３Ｈ）、３．２９－３．１９（ｍ，１Ｈ）、３．０３－２．９０（ｍ，１Ｈ）、１．７７－１．５５（ｍ，３Ｈ）、１．５４－１．３５（ｍ，２Ｈ）、１．２７－１．１１（ｍ，１Ｈ）． Example 22: 1 ⁵ -Fluoro-6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)- Synthesis of dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (22)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to N-(6-(2- (allyloxy)-5-fluorophenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b8) to replace 5-(hex-5-ene- Example 12 except 1-ylamino)pentan-1-ol (intermediate a34) was replaced with 3-(but-3-en-1-ylamino)propan-1-ol (intermediate a28) 1 ⁵ -Fluoro-6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (22) was synthesized. LC-MS (conditions 1): m/z 541.15 [M+1] ⁺ , 1.71 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.66 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.69 (dd, J = 8.7, 7.6). 2Hz, 1H), 7.32-7.19 (m, 3H), 7.14-7.01 (m, 2H), 6.85 (d, J = 8.8Hz, 1H), 4.57 ( t, J = 4.9Hz, 1H), 4.04-3.77 (m, 3H), 3.50-3.38 (m, 3H), 3.29-3.19 (m, 1H), 3.03-2.90 (m, 1H), 1.77-1.55 (m, 3H), 1.54-1.35 (m, 2H), 1.27-1.11 (m, 1H) ).

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、Ｎ－（６－（２－（アリルオキシ）－５－フルオロフェニル）－５－（トリフルオロメチル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ８）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ブタ－３－エン－１－イルアミノ）ブタン－１－オール（中間体ａ７）で置き換えたことを除いて、実施例１２に記載される手順を用いて、１ ^５ －フルオロ－６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－１１－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２３）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５５５．２［Ｍ＋１］ ^＋ 、１．７１分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６５（ｓ，１Ｈ）、８．０５（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６８（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３１－７．１８（ｍ，３Ｈ）、７．１４－７．０１（ｍ，２Ｈ）、６．８２（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．４４（ｔ，Ｊ＝５．１Ｈｚ、１Ｈ）、４．０５－３．９５（ｍ，１Ｈ）、３．９５－３．８６（ｍ，１Ｈ）、３．８６－３．７５（ｍ，１Ｈ）、３．４７－３．３４（ｍ，３Ｈ）、３．２２－３．１０（ｍ，１Ｈ）、３．０４－２．９０（ｍ，１Ｈ）、１．７６－１．５９（ｍ，１Ｈ）、１．５７－１．３４（ｍ，６Ｈ）、１．２９－１．０９（ｍ，１Ｈ）． Example 23: 1 ⁵ -Fluoro-6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)- Synthesis of dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (23)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to N-(6-(2- (allyloxy)-5-fluorophenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b8) to replace 5-(hex-5-ene- Example 12 except 1-ylamino)pentan-1-ol (intermediate a34) was replaced with 4-(but-3-en-1-ylamino)butan-1-ol (intermediate a7) 1 ⁵ -Fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (23) was synthesized. LC-MS (conditions 1): m/z 555.2 [M+1] ⁺ , 1.71 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.65 (s, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.68 (dd, J = 8.7, 7. 2Hz, 1H), 7.31-7.18 (m, 3H), 7.14-7.01 (m, 2H), 6.82 (d, J = 8.8Hz, 1H), 4.44 ( t, J = 5.1 Hz, 1H), 4.05-3.95 (m, 1H), 3.95-3.86 (m, 1H), 3.86-3.75 (m, 1H), 3.47-3.34 (m, 3H), 3.22-3.10 (m, 1H), 3.04-2.90 (m, 1H), 1.76-1.59 (m, 1H) ), 1.57-1.34 (m, 6H), 1.29-1.09 (m, 1H).

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、Ｎ－（５－クロロ－６－（２－ビニルフェニル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ３）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（ペンタ－４－エン－１－イルアミノ）プロパン－１－オール（中間体ａ２４）で置き換えたことを除いて、実施例１２に記載される手順を用いて、２ ^３ －クロロ－６－（３－ヒドロキシプロピル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２４）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ４８７．２［Ｍ＋１］ ^＋ 、１．７５分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．３０（ｓ，１Ｈ）、７．８６（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６９（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．４０－７．２２（ｍ，３Ｈ）、７．２０－７．１３（ｍ，３Ｈ）、６．８２（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．５６（ｔ，Ｊ＝４．９Ｈｚ、１Ｈ）、３．８７－３．６９（ｍ，１Ｈ）、３．４４－３．３４（ｍ，３Ｈ）、３．３２－３．２４（ｍ，２Ｈ）、３．０５－２．８８（ｍ，１Ｈ）、２．１９－１．９７（ｍ，１Ｈ）、１．７１－１．４５（ｍ，４Ｈ）、１．４０－０．８３（ｍ，４Ｈ）． Example 24: 2 ³ -Chloro-6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Synthesis of Decaphane 4,4-dioxide (24)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to N-(5-chloro-6 -(2-vinylphenyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b3) to replace 5-(hex-5-en-1-ylamino)pentan-1-ol ( Using the procedure described in Example 12, except that intermediate a34) was replaced with 3-(pent-4-en-1-ylamino)propan-1-ol (intermediate a24), 2 ³ -chloro-6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4 -dioxide (24) was synthesized. LC-MS (conditions 1): m/z 487.2 [M+1] ⁺ , 1.75 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.30 (s, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.69 (dd, J = 8.7, 7.7. 2Hz, 1H), 7.40-7.22 (m, 3H), 7.20-7.13 (m, 3H), 6.82 (d, J = 8.7Hz, 1H), 4.56 ( t, J = 4.9 Hz, 1H), 3.87-3.69 (m, 1H), 3.44-3.34 (m, 3H), 3.32-3.24 (m, 2H), 3.05-2.88 (m, 1H), 2.19-1.97 (m, 1H), 1.71-1.45 (m, 4H), 1.40-0.83 (m, 4H) ).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ペンタ－４－エン－１－イルアミノ）ブタン－１－オール（中間体ａ２９）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２５）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５３５．２［Ｍ＋１］ ^＋ 、１．８７分。 ^１ Ｈ ＮＭＲ（６００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７６（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３６（ｔｄ，Ｊ＝７．５、１．４Ｈｚ、１Ｈ）、７．２９（ｄｄ，Ｊ＝７．７、１．３Ｈｚ、１Ｈ）、７．２５－７．１８（ｍ，３Ｈ）、７．１４（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、６．８２（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．４２（ｔ，Ｊ＝５．１Ｈｚ、１Ｈ）、４．０１－３．８９（ｍ，１Ｈ）、３．４０（ｔｄ，Ｊ＝６．２、５．１Ｈｚ、２Ｈ）、３．３２－３．２６（ｍ，２Ｈ）、３．２６－３．１８（ｍ，１Ｈ）、２．９４－２．８０（ｍ，１Ｈ）、２．４５－２．３５（ｍ，１Ｈ）、１．９４－１．８４（ｍ，１Ｈ）、１．７６－１．６６（ｍ，１Ｈ）、１．５６－１．２６（ｍ，５Ｈ）、１．１９－１．０９（ｍ，２Ｈ）、１．０７－０．９８（ｍ，１Ｈ）． Example 25: 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphane 4,4-dioxide (25)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 4-(pent-4-en-1-ylamino)butan-1-ol (intermediate a29) 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (25) was synthesized. LC-MS (conditions 1): m/z 535.2 [M+1] ⁺ , 1.87 min. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.76 (s, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.71 (dd, J = 8.7, 7. 2Hz, 1H), 7.36 (td, J = 7.5, 1.4Hz, 1H), 7.29 (dd, J = 7.7, 1.3Hz, 1H), 7.25-7.18 (m, 3H), 7.14 (d, J = 7.6Hz, 1H), 6.82 (d, J = 8.7Hz, 1H), 4.42 (t, J = 5.1Hz, 1H) , 4.01-3.89 (m, 1H), 3.40 (td, J = 6.2, 5.1Hz, 2H), 3.32-3.26 (m, 2H), 3.26- 3.18 (m, 1H), 2.94-2.80 (m, 1H), 2.45-2.35 (m, 1H), 1.94-1.84 (m, 1H), 1. 76-1.66 (m, 1H), 1.56-1.26 (m, 5H), 1.19-1.09 (m, 2H), 1.07-0.98 (m, 1H).

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、６－フルオロ－Ｎ－（６－（５－フルオロ－２－ビニルフェニル）－５－（トリフルオロメチル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ１）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（ペンタ－４－エン－１－イルアミノ）プロパン－１－オール（中間体ａ２４）で置き換えたことを除いて、実施例１２に記載される手順を用いて、１ ^５ －フルオロ－６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２６）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５３９．２［Ｍ＋Ｈ］ ^＋ 、１．５８分。 Example 26: 1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-Benzenacycloundecaphane 4,4-dioxide (26)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to 6-fluoro-N-(6 -(5-fluoro-2-vinylphenyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b1) to replace 5-(hex-5-ene-1- As described in Example 12, except that ylamino)pentan-1-ol (intermediate a34) was replaced with 3-(pent-4-en-1-ylamino)propan-1-ol (intermediate a24) 1 ⁵ -Fluoro-6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina -1(1,2)-Benzenacycloundecaphane 4,4-dioxide (26) was synthesized. LCMS (conditions 1): m/z 539.2 [M+H] ⁺ , 1.58 min.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、２，２－ジメチル－３－（ペンタ－４－エン－１－イルアミノ）プロパン－１－オール（中間体ａ２５）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（３－ヒドロキシ－２，２－ジメチルプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２７）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５４９．３［Ｍ＋１］ ^＋ 、１．８３分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７７（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．６７（ｄｄ，Ｊ＝８．８、７．２Ｈｚ、１Ｈ）、７．３５（ｔｄ，Ｊ＝７．５、１．４Ｈｚ、１Ｈ）、７．３０－７．１５（ｍ，４Ｈ）、７．１３（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、７．０８（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、４．７７（ｔ，Ｊ＝４．８Ｈｚ、１Ｈ）、３．９３－３．７６（ｍ，１Ｈ）、３．１５－３．０３（ｍ，３Ｈ）、３．０１－２．８８（ｍ，１Ｈ）、２．４１－２．２７（ｍ，１Ｈ）、１．９６－１．６９（ｍ，２Ｈ）、１．４５－１．１８（ｍ，３Ｈ）、１．１７－０．９１（ｍ，２Ｈ）、０．８９－０．８３（ｍ，１Ｈ）、０．８１（ｓ，３Ｈ）、０．８０（ｓ，３Ｈ）． Example 27: 6-(3-Hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 Synthesis of (1,2)-Benzenacycloundecaphane 4,4-dioxide (27)

5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was converted to 2,2-dimethyl-3-(pent-4-en-1-ylamino)propan-1-ol ( 6-(3-Hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4- using the procedure described in Example 12, except replacing intermediate a25) with Thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide (27) was synthesized. LC-MS (conditions 1): m/z 549.3 [M+1] ⁺ , 1.83 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.77 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 8.8, 7.5). 2Hz, 1H), 7.35 (td, J = 7.5, 1.4Hz, 1H), 7.30-7.15 (m, 4H), 7.13 (d, J = 7.6Hz, 1H) ), 7.08 (d, J = 8.9 Hz, 1H), 4.77 (t, J = 4.8 Hz, 1H), 3.93-3.76 (m, 1H), 3.15-3 .03 (m, 3H), 3.01-2.88 (m, 1H), 2.41-2.27 (m, 1H), 1.96-1.69 (m, 2H), 1.45 -1.18 (m, 3H), 1.17-0.91 (m, 2H), 0.89-0.83 (m, 1H), 0.81 (s, 3H), 0.80 (s , 3H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（ヘキサ－５－エン－１－イルアミノ）－２，２－ジメチルプロパン－１－オール（中間体ａ２６）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（３－ヒドロキシ－２，２－ジメチルプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（２８）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５６３．２［Ｍ＋１］ ^＋ 、１．９６分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７８－１１．３１（ｍ，１Ｈ）、８．１９（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６５（ｄｄ，Ｊ＝８．８、７．２Ｈｚ、１Ｈ）、７．６１－７．４４（ｍ，１Ｈ）、７．３８－７．３０（ｍ，１Ｈ）、７．２８－７．１９（ｍ，２Ｈ）、７．１５（ｄ，Ｊ＝７．３Ｈｚ、１Ｈ）、７．１１（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、７．０３（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．７４－４．５３（ｍ，１Ｈ）、３．７５－３．５２（ｍ，１Ｈ）、３．５０－３．３４（ｍ，２Ｈ）、３．１３－３．０５（ｍ，２Ｈ）、２．４５－２．２０（ｍ，１Ｈ）、２．１６－１．９２（ｍ，１Ｈ）、１．４３－０．９８（ｍ，６Ｈ）、０．９２－０．８２（ｍ，１Ｈ）、０．８１（ｓ，３Ｈ）、０．７９（ｓ，３Ｈ）、０．７５－０．６０（ｍ，１Ｈ）． Example 28: 6-(3-Hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 Synthesis of (1,2)-Benzenacyclododecaphane 4,4-dioxide (28)

5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was converted to 3-(hex-5-en-1-ylamino)-2,2-dimethylpropan-1-ol ( 6-(3-Hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4- was prepared using the procedure described in Example 12, except replacing intermediate a26). Thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacyclododecaphane 4,4-dioxide (28) was synthesized. LC-MS (conditions 1): m/z 563.2 [M+1] ⁺ , 1.96 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.78-11.31 (m, 1H), 8.19 (d, J=8.9 Hz, 1H), 7.65 (dd, J=8. 8, 7.2 Hz, 1H), 7.61-7.44 (m, 1H), 7.38-7.30 (m, 1H), 7.28-7.19 (m, 2H), 7. 15 (d, J = 7.3 Hz, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 7.03 (d, J = 8.7 Hz, 1 H), 4.74-4.53 (m, 1H), 3.75-3.52 (m, 1H), 3.50-3.34 (m, 2H), 3.13-3.05 (m, 2H), 2.45-2 .20 (m, 1H), 2.16-1.92 (m, 1H), 1.43-0.98 (m, 6H), 0.92-0.82 (m, 1H), 0.81 (s, 3H), 0.79 (s, 3H), 0.75-0.60 (m, 1H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（ペンタ－４－エン－１－イルアミノ）プロパン－１－オール（中間体ａ２４）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２９）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５２１．３［Ｍ＋１］ ^＋ 、１．７２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７８（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３６（ｔｄ，Ｊ＝７．４、１．４Ｈｚ、１Ｈ）、７．３１－７．２６（ｍ，１Ｈ）、７．２６－７．１７（ｍ，３Ｈ）、７．１４（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、６．８５（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．５６（ｔ，Ｊ＝４．９Ｈｚ、１Ｈ）、４．０３－３．８９（ｍ，１Ｈ）、３．４４－３．３４（ｍ，３Ｈ）、３．３３－３．２７（ｍ，１Ｈ）、２．９２－２．８１（ｍ，１Ｈ）、２．４６－２．３５（ｍ，１Ｈ）、１．９５－１．８１（ｍ，２Ｈ）、１．７８－１．６６（ｍ，１Ｈ）、１．６６－１．５２（ｍ，２Ｈ）、１．４５－１．２４（ｍ，２Ｈ）、１．２４－１．０８（ｍ，１Ｈ）、１．０８－０．９５（ｍ，１Ｈ）． Example 29: 6-(3-Hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphane 4,4-dioxide (29)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 3-(pent-4-en-1-ylamino)propan-1-ol (intermediate a24) 6-(3-Hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (29) was synthesized. LC-MS (conditions 1): m/z 521.3 [M+1] ⁺ , 1.72 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.78 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.71 (dd, J = 8.7, 7. 2Hz, 1H), 7.36 (td, J = 7.4, 1.4Hz, 1H), 7.31-7.26 (m, 1H), 7.26-7.17 (m, 3H), 7.14 (d, J = 7.6Hz, 1H), 6.85 (d, J = 8.8Hz, 1H), 4.56 (t, J = 4.9Hz, 1H), 4.03-3 .89 (m, 1H), 3.44-3.34 (m, 3H), 3.33-3.27 (m, 1H), 2.92-2.81 (m, 1H), 2.46 -2.35 (m, 1H), 1.95-1.81 (m, 2H), 1.78-1.66 (m, 1H), 1.66-1.52 (m, 2H), 1 .45-1.24 (m, 2H), 1.24-1.08 (m, 1H), 1.08-0.95 (m, 1H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（（２－（アリルオキシ）エチル）アミノ）プロパン－１－オール（中間体ａ９）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－９－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（３０）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５３７．３［Ｍ＋Ｈ］ ^＋ 、１．６２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．５０（ｓ，１Ｈ）、８．１５（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６０（ｍ，１Ｈ）、７．３６（ｍ，２Ｈ）、７．２１（ｍ，２Ｈ）、７．０９（ｄ，Ｊ＝７．０Ｈｚ、１Ｈ）、７．０３（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、６．９２（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．４３（ｔ，Ｊ＝４．８Ｈｚ、１Ｈ）、３．７２（ｍ，１Ｈ）、３．０．５－３．５０（ｍ，９Ｈ）、１．９９（ｍ，２Ｈ）、１．５７（ｍ，４Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．６０（ｓ）． Example 30: 6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1 ,2)-Synthesis of Benzenacyclododecaphane 4,4-dioxide (30)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 3-((2-(allyloxy)ethyl)amino)propan-1-ol (intermediate a9) 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza- 2,5(2,6)-Dipyridina-1(1,2)-Benzenacyclododecaphane 4,4-dioxide (30) was synthesized. LCMS (conditions 1): m/z 537.3 [M+H] ⁺ , 1.62 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.50 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.60 (m, 1H), 7.36 (m , 2H), 7.21 (m, 2H), 7.09 (d, J = 7.0 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.92 (d, J = 8.7Hz, 1H), 4.43 (t, J = 4.8Hz, 1H), 3.72 (m, 1H), 3.0.5-3.50 (m, 9H), 1.99 (m, 2H), 1.57 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.60 (s).

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、６－フルオロ－Ｎ－（６－（５－フルオロ－２－ビニルフェニル）－５－（トリフルオロメチル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ１）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、ペンタ－４－エン－１－アミン（購入した）で置き換えたことを除いて、実施例１２に記載される手順を用いて、１ ^５ －フルオロ－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（３１）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４８１．１［Ｍ＋Ｈ］ ^＋ 、１．８１分、 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ７．９８（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．５３－７．４１（ｍ，２Ｈ）、７．２７（ｄｄ，Ｊ＝８．６、５．６Ｈｚ、１Ｈ）、７．２２（ｄｄ，Ｊ＝７．２、０．６Ｈｚ、１Ｈ）、７．１２－７．０４（ｍ，１Ｈ）、６．８７（ｄｄ，Ｊ＝９．２、２．７Ｈｚ、１Ｈ）、６．５６（ｄｄ，Ｊ＝８．５、０．７Ｈｚ、１Ｈ）、３．８０－３．６２（ｍ，１Ｈ）、２．９２－２．８１（ｍ，１Ｈ）、２．４３－２．３１（ｍ，１Ｈ）、２．０７－１．９７（ｍ，１Ｈ）、１．７６－１．６０（ｍ，１Ｈ）、１．５２－１．４０（ｍ，１Ｈ）、１．４０－１．２７（ｍ，２Ｈ）、１．２９－１．１３（ｍ，２Ｈ）． Example 31: 1 ⁵ -Fluoro-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloun Synthesis of Decaphane 4,4-dioxide (31)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to 6-fluoro-N-(6 -(5-fluoro-2-vinylphenyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b1) to replace 5-(hex-5-ene-1- Using the procedure described in Example 12, except replacing ylamino)pentan-1-ol (intermediate a34) with pent-4-en-1-amine (purchased), 1 ⁵ - Fluoro-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (31) was synthesized. LCMS (conditions 1): m/z 481.1 [M+H] ⁺ , 1.81 min, ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.98 (d, J=8.9 Hz, 1 H), 7. .53-7.41 (m, 2H), 7.27 (dd, J = 8.6, 5.6Hz, 1H), 7.22 (dd, J = 7.2, 0.6Hz, 1H), 7.12-7.04 (m, 1H), 6.87 (dd, J = 9.2, 2.7Hz, 1H), 6.56 (dd, J = 8.5, 0.7Hz, 1H) , 3.80-3.62 (m, 1H), 2.92-2.81 (m, 1H), 2.43-2.31 (m, 1H), 2.07-1.97 (m, 1H), 1.76-1.60 (m, 1H), 1.52-1.40 (m, 1H), 1.40-1.27 (m, 2H), 1.29-1.13 ( m, 2H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、エチル３－（ヘキサ－５－エン－１－イルアミノ）－２，２－ジメチルプロパノエート（中間体ａ２０）で置き換えたことを除いて、実施例１２に記載される手順を用いて、エチル３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）－２，２－ジメチルプロパノエート（３２）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ６０５．３［Ｍ＋１］ ^＋ 、１．８９分。 Example 32: Ethyl 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Synthesis of Benzenacyclododecaphan-6-yl)-2,2-dimethylpropanoate (32)

5-(Hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was converted to ethyl 3-(hex-5-en-1-ylamino)-2,2-dimethylpropanoate (intermediate Ethyl 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6- was prepared using the procedure described in Example 12, except substituting with compound a20). Diaza-2,5(2,6)-dipyridina-1(1,2)-benzonacyclododecaphan-6-yl)-2,2-dimethylpropanoate (32) was synthesized. LC-MS (conditions 1): m/z 605.3 [M+1] ⁺ , 1.89 min.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、１－アミノブタ－３－エン－２－オール（ＣｈｅｍＢｒｉｄｇｅ（ｃａｔ．＃ ４０５５８７１））で置き換えたことを除いて、実施例１２に記載される手順を用いて、８－ヒドロキシ－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン４，４－ジオキシド（３３）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４６５．２［Ｍ＋Ｈ］ ^＋ 、１．４７分。 ^１ Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６５（ｓ，１Ｈ）、１１．２６（ｓ，０．３Ｈ）、８．１９（ｄ，Ｊ＝８．９Ｈｚ、０．３Ｈ）、８．１６（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６０（ｄｄ，Ｊ＝７．３、８．４Ｈｚ、１Ｈ）、７．５３（ｍ，０．７Ｈ）、７．３５（ｍ，３．７Ｈ）、７．２５（ｍ，３．７Ｈ）、７．１４（ｍ，１．３Ｈ）、７．０２（ｄ，Ｊ＝７．２Ｈｚ、０．３Ｈ）、６．７２（ｍ，１．３Ｈ）、４．６７（ｄ，Ｊ＝４．７Ｈｚ、０．３Ｈ）、４．５６（ｄ，Ｊ＝５．７Ｈｚ、１Ｈ）、３．７３（ｄｄ，Ｊ＝８．６、１３．０Ｈｚ、１Ｈ）、３．３８（ｍ，０．３Ｈ）、３．０３（ｍ，０．６Ｈ）、２．６０（ｍ，３Ｈ）、２．２０（ｍ，０．３Ｈ）、１．８４（ｍ，１Ｈ）、１．７０（ｍ，１Ｈ）、１．５４（ｍ，０．３Ｈ）、１．４３（ｍ，１Ｈ）、１．２８（ｍ，０．３Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．６８（ｓ，０．３Ｆ）、－５７．５４（ｓ，１Ｆ）．ジアステレオマー，７：３の比率． Example 33: 8-Hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane Synthesis of 4,4-dioxide (33)

Note that 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was replaced with 1-aminobut-3-en-2-ol (ChemBridge (cat.# 4055871)). 8-Hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 was prepared using the procedure described in Example 12, except that (1,2)-Benzenacyclodecaphane 4,4-dioxide (33) was synthesized. LCMS (conditions 1): m/z 465.2 [M+H] ⁺ , 1.47 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.65 (s, 1H), 11.26 (s, 0.3H), 8.19 (d, J=8.9Hz, 0.3H), 8 .16 (d, J = 8.9Hz, 1H), 7.60 (dd, J = 7.3, 8.4Hz, 1H), 7.53 (m, 0.7H), 7.35 (m, 3.7H), 7.25 (m, 3.7H), 7.14 (m, 1.3H), 7.02 (d, J = 7.2Hz, 0.3H), 6.72 (m, 1.3 H), 4.67 (d, J = 4.7 Hz, 0.3 H), 4.56 (d, J = 5.7 Hz, 1 H), 3.73 (dd, J = 8.6, 13 0 Hz, 1 H), 3.38 (m, 0.3 H), 3.03 (m, 0.6 H), 2.60 (m, 3 H), 2.20 (m, 0.3 H), 1. 84 (m, 1H), 1.70 (m, 1H), 1.54 (m, 0.3H), 1.43 (m, 1H), 1.28 (m, 0.3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.68 (s, 0.3 F), -57.54 (s, 1 F). Diastereomers, 7:3 ratio.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、（（４Ｓ，５Ｓ）－２，２－ジメチル－５－（（ペンタ－４－エン－１－イルアミノ）メチル）－１，３－ジオキソラン－４－イル）メタノール（中間体ａ１３）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（（（４Ｓ，５Ｓ）－５－（ヒドロキシメチル）－２，２－ジメチル－１，３－ジオキソラン－４－イル）メチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（３４）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ６０７．３［Ｍ＋Ｈ］ ^＋ 、１．７０分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．８１（ｍ，１Ｈ）、８．０９（ｍ，１Ｈ）、７．７１（ｍ，１Ｈ）、７．３５（ｍ，１Ｈ）、７．２５（ｍ，４Ｈ）、７．１４（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、６．９６（ｍ，１Ｈ）、５．０３及び４．９８（ｔ，Ｊ＝５．４Ｈｚ、１Ｈ）、３．９８（ｍ，２Ｈ）、３．７１（ｍ，１Ｈ）、３．５５（ｍ，４Ｈ）、２．９８（ｍ，１Ｈ）、２．３９（ｍ，１Ｈ）、１．８８（ｍ，１Ｈ）、１．７３（ｍ，１Ｈ）、０．９９－１．４５（ｍ，１１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．８０（ｓ）、－５６．８８（ｓ）．ジアステレオマー，１：１の比率． Example 34: 6-(((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ^3- (trifluoromethyl)-4 - synthesis of thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide (34)

5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was converted to ((4S,5S)-2,2-dimethyl-5-((pent-4-en-1- Using the procedure described in Example 12, except substituting ylamino)methyl)-1,3-dioxolan-4-yl)methanol (intermediate a13), 6-(((4S,5S) -5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5( 2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (34) was synthesized. LCMS (conditions 1): m/z 607.3 [M+H] ⁺ , 1.70 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.81 (m, 1H), 8.09 (m, 1H), 7.71 (m, 1H), 7.35 (m, 1H), 7. 25 (m, 4H), 7.14 (d, J = 7.5Hz, 1H), 6.96 (m, 1H), 5.03 and 4.98 (t, J = 5.4Hz, 1H), 3.98 (m, 2H), 3.71 (m, 1H), 3.55 (m, 4H), 2.98 (m, 1H), 2.39 (m, 1H), 1.88 (m , 1H), 1.73 (m, 1H), 0.99-1.45 (m, 11H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.80 (s), -56.88 (s). Diastereomers, 1:1 ratio.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、Ｎ－メチルヘキサ－５－エン－１－アミン（購入した）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－メチル－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（３５）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ４９１．２［Ｍ＋１］ ^＋ 、１．９８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６６（ｓ，１Ｈ）、８．１７（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７２（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．５１－７．３８（ｍ，１Ｈ）、７．３４（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．２８－７．２０（ｍ，２Ｈ）、７．２０－７．１０（ｍ，２Ｈ）、６．８５（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．７２－３．５４（ｍ，１Ｈ）、３．５０－３．３６（ｍ，１Ｈ）、３．３３－３．３０（ｍ，１Ｈ）、２．８６（ｓ，３Ｈ）、２．１０－１．８７（ｍ，１Ｈ）、１．４３－１．１７（ｍ，３Ｈ）、１．１４－０．９５（ｍ，３Ｈ）、０．９１－０．７６（ｍ，１Ｈ）、０．７６－０．６０（ｍ，１Ｈ）． Example 35: 6-Methyl-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane Synthesis of 4,4-dioxide (35)

Example except 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was replaced with N-methylhex-5-en-1-amine (purchased) 6-Methyl-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) using the procedure described in 12. -Benzenacyclododecaphane 4,4-dioxide (35) was synthesized. LC-MS (conditions 1): m/z 491.2 [M+1] ⁺ , 1.98 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.66 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.72 (dd, J = 8.7, 7.7). 2Hz, 1H), 7.51-7.38 (m, 1H), 7.34 (td, J = 7.4, 1.5Hz, 1H), 7.28-7.20 (m, 2H), 7.20-7.10 (m, 2H), 6.85 (d, J=8.7Hz, 1H), 3.72-3.54 (m, 1H), 3.50-3.36 (m , 1H), 3.33-3.30 (m, 1H), 2.86 (s, 3H), 2.10-1.87 (m, 1H), 1.43-1.17 (m, 3H) ), 1.14-0.95 (m, 3H), 0.91-0.76 (m, 1H), 0.76-0.60 (m, 1H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、ヘキサ－５－エン－１－アミン（購入した）で置き換えたことを除いて、実施例１２に記載される手順を用いて、２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（３６）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ４７７．２［Ｍ＋１］ ^＋ 、１．８９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６０（ｓ，１Ｈ）、８．１６（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．５５（ｄｄ，Ｊ＝８．５、７．１Ｈｚ、１Ｈ）、７．４５（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．３４（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．２９－７．２４（ｍ，１Ｈ）、７．２３（ｄｄ，Ｊ＝７．３、１．４Ｈｚ、１Ｈ）、７．１９－７．１２（ｍ，２Ｈ）、７．１０（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、６．６４（ｄ，Ｊ＝８．５Ｈｚ、１Ｈ）、３．２５－３．１３（ｍ，１Ｈ）、３．１２－２．９７（ｍ，１Ｈ）、２．７１－２．５８（ｍ，１Ｈ）、２．１５－１．９８（ｍ，１Ｈ）、１．３６－１．１４（ｍ，３Ｈ）、１．１４－０．９７（ｍ，４Ｈ）、０．９７－０．８０（ｍ，１Ｈ）． Example 36: 2 ³ -(Trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4- Synthesis of Dioxide (36)

Example 12 was followed except that 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was replaced with hex-5-en-1-amine (purchased). 2 ^3- (Trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacyclododecaphane using procedures described A 4,4-dioxide (36) was synthesized. LC-MS (conditions 1): m/z 477.2 [M+1] ⁺ , 1.89 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.60 (s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.55 (dd, J = 8.5, 7.5). 1Hz, 1H), 7.45 (d, J = 8.8Hz, 1H), 7.34 (td, J = 7.4, 1.5Hz, 1H), 7.29-7.24 (m, 1H) ), 7.23 (dd, J = 7.3, 1.4 Hz, 1 H), 7.19-7.12 (m, 2 H), 7.10 (d, J = 7.2 Hz, 1 H), 6 .64 (d, J = 8.5Hz, 1H), 3.25-3.13 (m, 1H), 3.12-2.97 (m, 1H), 2.71-2.58 (m, 1H), 2.15-1.98 (m, 1H), 1.36-1.14 (m, 3H), 1.14-0.97 (m, 4H), 0.97-0.80 ( m, 1H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、Ｎ－（（２，２－ジメチル－１，３－ジオキソラン－４－イル）メチル）ペンタ－４－エン－１－アミン（中間体ａ１０）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（（２，２－ジメチル－１，３－ジオキソラン－４－イル）メチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（３７）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５７７．３［Ｍ＋Ｈ］ ^＋ 、１．７８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．８０（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７１（ｍ，１Ｈ）、７．３５（ｍ，１Ｈ）、７．２８（ｍ，２Ｈ）、７．２２（ｍ，２Ｈ）、７．１４（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、６．９７（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．２３（ｍ，１Ｈ）、４．０１（ｍ，２Ｈ）、３．２８－３．５７（ｍ，３Ｈ）、２．９７（ｍ，１Ｈ）、２．３８（ｍ，１Ｈ）、１．８９（ｍ，１Ｈ）、１．７２（ｍ，１Ｈ）、１．２４（ｍ，１１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．８２（ｓ）、－５６．８６（ｓ）．ジアステレオマー，５２：４８の比率． Example 37: 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5( Synthesis of 2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (37)

5-(Hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was converted to N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)pent-4 6-((2,2-dimethyl-1,3-dioxolan-4-yl ) methyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4 -dioxide (37) was synthesized. LCMS (conditions 1): m/z 577.3 [M+H] ⁺ , 1.78 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.80 (s, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.71 (m, 1H), 7.35 (m , 1H), 7.28 (m, 2H), 7.22 (m, 2H), 7.14 (d, J = 7.5Hz, 1H), 6.97 (d, J = 8.8Hz, 1H ), 4.23 (m, 1H), 4.01 (m, 2H), 3.28-3.57 (m, 3H), 2.97 (m, 1H), 2.38 (m, 1H) , 1.89 (m, 1H), 1.72 (m, 1H), 1.24 (m, 11H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.82 (s), -56.86 (s). Diastereomers, 52:48 ratio.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、１－アミノペンタ－４－エン－２－オール（ＣｈｅｍＢｒｉｄｇｅ（ｃａｔ．＃ ４０８０１７５））で置き換えたことを除いて、実施例１２に記載される手順を用いて、８－ヒドロキシ－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（３８）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４７９．２［Ｍ＋Ｈ］ ^＋ 。１．５２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６０（ｍ，１．７Ｈ）、８．１２（ｄ，Ｊ＝２．４Ｈｚ、０．８Ｈ）、８．０９（ｄ，Ｊ＝２．４Ｈｚ、１Ｈ）、７．５４（ｍ，１．８Ｈ）、７．３２（ｍ，５．５Ｈ）、７．２３（ｍ，１．８Ｈ）、７．１４（ｍ，３．５Ｈ）、７．０７（ｄｄ，Ｊ＝４．０、６．９Ｈｚ、１Ｈ）、６．９５（ｄｄ，Ｊ＝３．３、７．８Ｈｚ、０．８Ｈ）、６．８０（ｄ，Ｊ＝８．５Ｈｚ、０．８Ｈ）、６．７４（ｍ，１Ｈ）、４．７１（ｄ，Ｊ＝４．２Ｈｚ、０．８Ｈ）、４．５６（ｄ，Ｊ＝４．７Ｈｚ、１Ｈ）、３．７３（ｍ，０．８Ｈ）、３．５８（ｍ，１．８Ｈ）、３．２３（ｍ，１Ｈ）、２．９０（ｍ，０．８Ｈ）、２．６５（ｍ，１Ｈ）、２．３５（ｍ，１．６Ｈ）、２．０７（ｍ，１Ｈ）、１．８９（ｍ，０．８Ｈ）、１．５５（ｍ，１Ｈ）、１．３２（ｍ，５．８Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５７．０５（ｓ，１Ｆ）、－５７．１７（ｓ，０．７５Ｆ）．ジアステレオマー，４：３の比率． Example 38: 8-Hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundeca Synthesis of fan 4,4-dioxide (38)

5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was replaced with 1-aminopent-4-en-2-ol (ChemBridge (cat.# 4080175)) 8-Hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 1(1,2)-Benzenacycloundecaphane 4,4-dioxide (38) was synthesized. LCMS (conditions 1): m/z 479.2 [M+H] ⁺ . 1.52 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.60 (m, 1.7H), 8.12 (d, J=2.4Hz, 0.8H), 8.09 (d, J=2. 4Hz, 1H), 7.54 (m, 1.8H), 7.32 (m, 5.5H), 7.23 (m, 1.8H), 7.14 (m, 3.5H), 7 .07 (dd, J=4.0, 6.9 Hz, 1 H), 6.95 (dd, J=3.3, 7.8 Hz, 0.8 H), 6.80 (d, J=8.5 Hz , 0.8H), 6.74 (m, 1H), 4.71 (d, J = 4.2Hz, 0.8H), 4.56 (d, J = 4.7Hz, 1H), 3.73 (m, 0.8H), 3.58 (m, 1.8H), 3.23 (m, 1H), 2.90 (m, 0.8H), 2.65 (m, 1H), 2. 35 (m, 1.6H), 2.07 (m, 1H), 1.89 (m, 0.8H), 1.55 (m, 1H), 1.32 (m, 5.8H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.05 (s, 1 F), -57.17 (s, 0.75 F). Diastereomers, 4:3 ratio.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（ヘプタ－６－エン－１－イルアミノ）プロパン－１－オール（中間体ａ３９）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５４９．２［Ｍ＋Ｈ］ ^＋ 。１．８８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７３（ｓ，１Ｈ）、８．１９（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７２（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．５５－７．４０（ｍ，１Ｈ）、７．３５（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．２９－７．２１（ｍ，２Ｈ）、７．２０－７．１２（ｍ，２Ｈ）、６．８９（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．５８（ｔ，Ｊ＝４．９Ｈｚ、１Ｈ）、３．７２－３．５７（ｍ，１Ｈ）、３．５４－３．４１（ｍ，４Ｈ）、３．４１－３．３４（ｍ，１Ｈ）、２．４２－２．２９（ｍ，１Ｈ）、２．１８－１．９９（ｍ，１Ｈ）、１．７１－１．５９（ｍ，２Ｈ）、１．４４－１．３０（ｍ，２Ｈ）、１．３０－０．９２（ｍ，６Ｈ）、０．９１－０．７０（ｍ，２Ｈ）． Example 39: 6-(3-Hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclotridecaphane 4,4-dioxide (39)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 3-(hept-6-en-1-ylamino)propan-1-ol (intermediate a39) 6-(3-Hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphane 4,4-dioxide (39) was synthesized. LCMS (conditions 1): m/z 549.2 [M+H] ⁺ . 1.88 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.73 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.72 (dd, J = 8.7, 7. 2Hz, 1H), 7.55-7.40 (m, 1H), 7.35 (td, J = 7.4, 1.5Hz, 1H), 7.29-7.21 (m, 2H), 7.20-7.12 (m, 2H), 6.89 (d, J = 8.8Hz, 1H), 4.58 (t, J = 4.9Hz, 1H), 3.72-3.57 (m, 1H), 3.54-3.41 (m, 4H), 3.41-3.34 (m, 1H), 2.42-2.29 (m, 1H), 2.18-1 .99 (m, 1H), 1.71-1.59 (m, 2H), 1.44-1.30 (m, 2H), 1.30-0.92 (m, 6H), 0.91 -0.70 (m, 2H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ヘプタ－６－エン－１－イルアミノ）ブタン－１－オール（中間体ａ３６）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（４０）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６３．２［Ｍ＋Ｈ］ ^＋ 。１．９２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７３（ｓ，１Ｈ）、８．１９（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７２（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．５５－７．３９（ｍ，１Ｈ）、７．３５（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．３０－７．２１（ｍ，２Ｈ）、７．２１－７．１１（ｍ，２Ｈ）、６．８７（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．４５（ｔ，Ｊ＝５．１Ｈｚ、１Ｈ）、３．７６－３．５６（ｍ，１Ｈ）、３．５５－３．４５（ｍ，１Ｈ）、３．４２（ｔｄ，Ｊ＝６．２、４．９Ｈｚ、２Ｈ）、３．３１－３．２０（ｍ，０Ｈ）、２．４５－２．２７（ｍ，１Ｈ）、２．１９－１．９９（ｍ，１Ｈ）、１．６３－１．２９（ｍ，６Ｈ）、１．２９－０．９２（ｍ，６Ｈ）、０．９１－０．６７（ｍ，２Ｈ）． Example 40: 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclotridecaphane 4,4-dioxide (40)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 4-(hept-6-en-1-ylamino)butan-1-ol (intermediate a36) 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphane 4,4-dioxide (40) was synthesized. LCMS (conditions 1): m/z 563.2 [M+H] ⁺ . 1.92 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.73 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.72 (dd, J = 8.7, 7. 2Hz, 1H), 7.55-7.39 (m, 1H), 7.35 (td, J = 7.4, 1.5Hz, 1H), 7.30-7.21 (m, 2H), 7.21-7.11 (m, 2H), 6.87 (d, J = 8.8Hz, 1H), 4.45 (t, J = 5.1Hz, 1H), 3.76-3.56 (m, 1H), 3.55-3.45 (m, 1H), 3.42 (td, J = 6.2, 4.9Hz, 2H), 3.31-3.20 (m, 0H) , 2.45-2.27 (m, 1H), 2.19-1.99 (m, 1H), 1.63-1.29 (m, 6H), 1.29-0.92 (m, 6H), 0.91-0.67 (m, 2H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、５－（ヘプタ－６－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ１２）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（５－ヒドロキシペンチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（４１）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５７７．３［Ｍ＋Ｈ］ ^＋ 。１．９７分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７２（ｓ，１Ｈ）、８．１９（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７２（ｍ，１Ｈ）、７．４５（ｍ，１Ｈ）、７．３５（ｍ，１Ｈ）、７．２５（ｍ，２Ｈ）、７．１６（ｍ，２Ｈ）、６．８６（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．３８（ｔ，Ｊ＝５．１Ｈｚ、１Ｈ）、３．６４（ｍ，１Ｈ）、３．４８（ｍ，１Ｈ）、３．３８（ｍ，２Ｈ）、３．２８（ｍ，１Ｈ）、２．３５（ｍ，１Ｈ）、２．０８（ｍ，１Ｈ）、０．９７－１．５４（ｍ，１６Ｈ）、０．８０（ｍ，１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．７０（ｓ）． Example 41: 6-(5-Hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclotridecaphane 4,4-dioxide (41)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 5-(hept-6-en-1-ylamino)pentan-1-ol (intermediate a12) 6-(5-Hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphane 4,4-dioxide (41) was synthesized. LCMS (conditions 1): m/z 577.3 [M+H] ⁺ . 1.97 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.72 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.72 (m, 1H), 7.45 (m , 1H), 7.35 (m, 1H), 7.25 (m, 2H), 7.16 (m, 2H), 6.86 (d, J = 8.8Hz, 1H), 4.38 ( t, J = 5.1 Hz, 1H), 3.64 (m, 1H), 3.48 (m, 1H), 3.38 (m, 2H), 3.28 (m, 1H), 2.35 (m, 1H), 2.08 (m, 1H), 0.97-1.54 (m, 16H), 0.80 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.70 (s).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ノナ－８－エン－１－イルアミノ）ブタン－１－オール（中間体ａ３８）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロペンタデカファン４，４－ジオキシド（４２）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５９１．３［Ｍ＋Ｈ］ ^＋ 。１．９６分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．５３（ｓ，１Ｈ）、８．２２（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７５－７．４９（ｍ，２Ｈ）、７．３５（ｔ，Ｊ＝７．５Ｈｚ、１Ｈ）、７．３０－７．１９（ｍ，２Ｈ）、７．１９－７．０５（ｍ，２Ｈ）、６．９１（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．４６（ｔ，Ｊ＝５．１Ｈｚ、１Ｈ）、３．９８－３．６１（ｍ，１Ｈ）、３．４５－３．３８（ｍ，３Ｈ）、３．３３－３．３１（ｍ，２Ｈ）、２．２６－２．０１（ｍ，２Ｈ）、１．６３－１．３７（ｍ，６Ｈ）、１．３７－０．７６（ｍ，１２Ｈ）． Example 42: 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclopentadecaphane 4,4-dioxide (42)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 4-(non-8-en-1-ylamino)butan-1-ol (intermediate a38) 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclopentadecaphane 4,4-dioxide (42) was synthesized. LCMS (conditions 1): m/z 591.3 [M+H] ⁺ . 1.96 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.53 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.75-7.49 (m, 2H), 7 .35 (t, J=7.5 Hz, 1H), 7.30-7.19 (m, 2H), 7.19-7.05 (m, 2H), 6.91 (d, J=8. 7Hz, 1H), 4.46 (t, J = 5.1Hz, 1H), 3.98-3.61 (m, 1H), 3.45-3.38 (m, 3H), 3.33- 3.31 (m, 2H), 2.26-2.01 (m, 2H), 1.63-1.37 (m, 6H), 1.37-0.76 (m, 12H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（オクタ－７－エン－１－イルアミノ）プロパン－１－オール（中間体ａ４０）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロテトラデカファン４，４－ジオキシド（４３）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６３．２［Ｍ＋Ｈ］ ^＋ 。１．９１分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６０（ｓ，１Ｈ）、８．２２（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．６８（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．６２－７．４３（ｍ，１Ｈ）、７．３９－７．３０（ｍ，１Ｈ）、７．２９－７．１９（ｍ，２Ｈ）、７．１６（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、７．１１（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、６．９０（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．５８（ｔ，Ｊ＝５．０Ｈｚ、１Ｈ）、３．９３－３．６８（ｍ，１Ｈ）、３．４９－３．４２（ｍ，２Ｈ）、３．４２－３．３６（ｍ，１Ｈ）、２．４６－２．２５（ｍ，３Ｈ）、２．１３－１．９１（ｍ，１Ｈ）、１．７５－１．５８（ｍ，２Ｈ）、１．４２－１．２１（ｍ，３Ｈ）、１．２１－０．７０（ｍ，９Ｈ）． Example 43: 6-(3-Hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclotetradecaphane 4,4-dioxide (43)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 3-(oct-7-en-1-ylamino)propan-1-ol (intermediate a40) 6-(3-Hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclotetradecaphane 4,4-dioxide (43) was synthesized. LCMS (conditions 1): m/z 563.2 [M+H] ⁺ . 1.91 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.60 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 8.7, 7.7. 2Hz, 1H), 7.62-7.43 (m, 1H), 7.39-7.30 (m, 1H), 7.29-7.19 (m, 2H), 7.16 (d, J = 7.5Hz, 1H), 7.11 (d, J = 7.2Hz, 1H), 6.90 (d, J = 8.8Hz, 1H), 4.58 (t, J = 5.0Hz , 1H), 3.93-3.68 (m, 1H), 3.49-3.42 (m, 2H), 3.42-3.36 (m, 1H), 2.46-2.25 (m, 3H), 2.13-1.91 (m, 1H), 1.75-1.58 (m, 2H), 1.42-1.21 (m, 3H), 1.21-0 .70(m, 9H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（オクタ－７－エン－１－イルアミノ）ブタン－１－オール（中間体ａ３７）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロテトラデカファン４，４－ジオキシド（４４）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５７７．３［Ｍ＋Ｈ］ ^＋ 。１．９６分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６０（ｓ，１Ｈ）、８．２１（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６８（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．５４（ｓ，１Ｈ）、７．３９－７．３０（ｍ，１Ｈ）、７．２９－７．２０（ｍ，２Ｈ）、７．１６（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、７．１１（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、６．８９（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．４５（ｔ，Ｊ＝５．１Ｈｚ、１Ｈ）、３．９２－３．６８（ｍ，１Ｈ）、３．４６－３．３５（ｍ，３Ｈ）、３．３２－３．１６（ｍ，２Ｈ）、２．４２－２．２７（ｍ，１Ｈ）、２．１２－１．９１（ｍ，１Ｈ）、１．６４－１．４９（ｍ，２Ｈ）、１．４９－１．３９（ｍ，２Ｈ）、１．３９－１．２０（ｍ，３Ｈ）、１．１９－０．７３（ｍ，７Ｈ）． Example 44: 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclotetradecaphane 4,4-dioxide (44)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 4-(oct-7-en-1-ylamino)butan-1-ol (intermediate a37) 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclotetradecaphane 4,4-dioxide (44) was synthesized. LCMS (conditions 1): m/z 577.3 [M+H] ⁺ . 1.96 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.60 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.68 (dd, J = 8.7, 7. 2Hz, 1H), 7.54 (s, 1H), 7.39-7.30 (m, 1H), 7.29-7.20 (m, 2H), 7.16 (d, J=7. 6 Hz, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 1 H), 4.45 (t, J = 5.1 Hz, 1 H), 3.92-3.68 (m, 1H), 3.46-3.35 (m, 3H), 3.32-3.16 (m, 2H), 2.42-2.27 (m, 1H) ), 2.12-1.91 (m, 1H), 1.64-1.49 (m, 2H), 1.49-1.39 (m, 2H), 1.39-1.20 (m , 3H), 1.19-0.73 (m, 7H).

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（ノナ－８－エン－１－イルアミノ）プロパン－１－オール（中間体ａ４１）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロペンタデカファン４，４－ジオキシド（４５）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５７７．３［Ｍ＋Ｈ］ ^＋ 。１．９７分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．５２（ｓ，１Ｈ）、８．２２（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．８２－７．４９（ｍ，２Ｈ）、７．３５（ｔ，Ｊ＝７．５Ｈｚ、１Ｈ）、７．２９－７．１９（ｍ，２Ｈ）、７．１９－７．０３（ｍ，２Ｈ）、６．９２（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．５７（ｔ，Ｊ＝４．９Ｈｚ、１Ｈ）、４．０１－３．６１（ｍ，１Ｈ）、３．５５－３．３４（ｍ，３Ｈ）、２．５７－２．５１（ｍ，２Ｈ）、２．２９－１．９９（ｍ，２Ｈ）、１．７９－１．５６（ｍ，２Ｈ）、１．５４－１．３９（ｍ，２Ｈ）、１．３７－０．７２（ｍ，１２Ｈ）． Example 45: 6-(3-Hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclopentadecaphane 4,4-dioxide (45)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 3-(non-8-en-1-ylamino)propan-1-ol (intermediate a41) 6-(3-Hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclopentadecaphane 4,4-dioxide (45) was synthesized. LCMS (conditions 1): m/z 577.3 [M+H] ⁺ . 1.97 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.52 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.82-7.49 (m, 2H), 7 .35 (t, J=7.5 Hz, 1H), 7.29-7.19 (m, 2H), 7.19-7.03 (m, 2H), 6.92 (d, J=8. 7Hz, 1H), 4.57 (t, J = 4.9Hz, 1H), 4.01-3.61 (m, 1H), 3.55-3.34 (m, 3H), 2.57- 2.51 (m, 2H), 2.29-1.99 (m, 2H), 1.79-1.56 (m, 2H), 1.54-1.39 (m, 2H), 1. 37-0.72 (m, 12H).

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、Ｎ－（５－クロロ－６－（２－ビニルフェニル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ３）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ペンタ－４－エン－１－イルアミノ）ブタン－１－オール（中間体ａ２９）で置き換えたことを除いて、実施例１２に記載される手順を用いて、２ ^３ －クロロ－６－（４－ヒドロキシブチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（４６）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５０１．２［Ｍ＋Ｈ］ ^＋ 。１．７７分。 Example 46: 2 ³ -Chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloun Synthesis of Decaphane 4,4-dioxide (46)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to N-(5-chloro-6 -(2-vinylphenyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b3) to replace 5-(hex-5-en-1-ylamino)pentan-1-ol ( Using the procedure described in Example 12, except that intermediate a34) was replaced with 4-(pent-4-en-1-ylamino)butan-1-ol (intermediate a29), 2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4 -dioxide (46) was synthesized. LCMS (conditions 1): m/z 501.2 [M+H] ⁺ . 1.77 minutes.

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、６－フルオロ－Ｎ－（６－（５－フルオロ－２－ビニルフェニル）－５－（トリフルオロメチル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ１）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ヘキサ－５－エン－１－イルアミノ）ブタン－１－オール（中間体ａ３５）で置き換えたことを除いて、実施例１２に記載される手順を用いて、１ ^５ －フルオロ－６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（４７）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６６．９［Ｍ＋Ｈ］ ^＋ 。１．７９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７３（ｓ，１Ｈ）、８．１９（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝７．４、８．６Ｈｚ、１Ｈ）、７．４４（ｄ，Ｊ＝８．１Ｈｚ、１Ｈ）、７．３１（ｄｄ，Ｊ＝５．９、８．５Ｈｚ、１Ｈ）、７．２３－７．１８（ｍ，１Ｈ）、７．１７（ｄ，Ｊ＝７．３Ｈｚ、１Ｈ）、７．０７（ｄ，Ｊ＝８．４Ｈｚ、１Ｈ）、６．８６（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．４５（ｔ，Ｊ＝５．１Ｈｚ、１Ｈ）、３．６９－３．５０（ｍ，１Ｈ）、３．４１（ｑ，Ｊ＝６．１Ｈｚ、２Ｈ）、３．３２－３．１４（ｍ，２Ｈ）、２．０２（ｄ，Ｊ＝３．５Ｈｚ、１Ｈ）、１．５９－１．４７（ｍ，２Ｈ）、１．４４（ｑ，Ｊ＝６．５Ｈｚ、２Ｈ）、１．３２（ｄｄｔ，Ｊ＝８．３、１１．９、３０．０Ｈｚ、３Ｈ）、１．１５－０．９５（ｍ，３Ｈ）、０．８４（ｄｄ，Ｊ＝６．７、９．４Ｈｚ、１Ｈ）、０．８０－０．６６（ｍ，１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．０２（ｓ，３Ｆ）、－１１７．９７（ｓ，１Ｆ） Example 47: 1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-Benzenacyclododecaphane 4,4-dioxide (47)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to 6-fluoro-N-(6 -(5-fluoro-2-vinylphenyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b1) to replace 5-(hex-5-ene-1- As described in Example 12 except ylamino)pentan-1-ol (intermediate a34) was replaced with 4-(hex-5-en-1-ylamino)butan-1-ol (intermediate a35) 1 ⁵ -Fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina -1(1,2)-Benzenacyclododecaphane 4,4-dioxide (47) was synthesized. LCMS (conditions 1): m/z 566.9 [M+H] ⁺ . 1.79 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.73 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.70 (dd, J = 7.4, 8. 6Hz, 1H), 7.44 (d, J = 8.1Hz, 1H), 7.31 (dd, J = 5.9, 8.5Hz, 1H), 7.23-7.18 (m, 1H) ), 7.17 (d, J = 7.3 Hz, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 1 H), 4.45 (t, J = 5.1Hz, 1H), 3.69-3.50 (m, 1H), 3.41 (q, J = 6.1Hz, 2H), 3.32-3.14 (m, 2H), 2.02 (d, J = 3.5Hz, 1H), 1.59-1.47 (m, 2H), 1.44 (q, J = 6.5Hz, 2H), 1.32 ( ddt, J = 8.3, 11.9, 30.0 Hz, 3H), 1.15-0.95 (m, 3H), 0.84 (dd, J = 6.7, 9.4 Hz, 1H) , 0.80-0.66 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.02 (s, 3F), -117.97 (s, 1F)

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、６－（ペンタ－４－エン－１－イルアミノ）ヘキサン－１－オール（中間体ａ３）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（６－ヒドロキシヘキシル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（４８）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６３．２［Ｍ＋Ｈ］ ^＋ 。１．８９分。 Example 48: 6-(6-Hydroxyhexyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphane 4,4-dioxide (48)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 6-(pent-4-en-1-ylamino)hexan-1-ol (intermediate a3) 6-(6-Hydroxyhexyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (48) was synthesized. LCMS (conditions 1): m/z 563.2 [M+H] ⁺ . 1.89 minutes.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、２－（２－（ペンタ－４－エン－１－イルアミノ）エトキシ）エタン－１－オール（中間体ａ４）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（２－（２－ヒドロキシエトキシ）エチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（４９）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５５１．２［Ｍ＋Ｈ］＋。１．８２分。 Example 49: 6-(2-(2-hydroxyethoxy)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-Benzenacycloundecaphane 4,4-dioxide (49)

5-(Hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was converted to 2-(2-(pent-4-en-1-ylamino)ethoxy)ethan-1-ol (intermediate 6-(2-(2-Hydroxyethoxy)ethyl)-2 ³ -(trifluoromethyl)-4-thia- using the procedure described in Example 12, except substituting with compound a4). 3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide (49) was synthesized. LCMS (conditions 1): m/z 551.2 [M+H]+. 1.82 minutes.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、５－（ブタ－３－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ５）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（５－ヒドロキシペンチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン４，４－ジオキシド（５０）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５３５．２［Ｍ＋Ｈ］＋。１．８２分。 Example 50: 6-(5-Hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclodecaphane 4,4-dioxide (50)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 5-(but-3-en-1-ylamino)pentan-1-ol (intermediate a5) 6-(5-Hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide (50) was synthesized. LCMS (conditions 1): m/z 535.2 [M+H]+. 1.82 minutes.

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、Ｎ－（５－クロロ－６－（２－ビニルフェニル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ３）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、６－（ペンタ－４－エン－１－イルアミノ）ヘキサン－１－オール（中間体ａ３）で置き換えたことを除いて、実施例１２に記載される手順を用いて、２ ^３ －クロロ－６－（６－ヒドロキシヘキシル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（５１）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５２９．２［Ｍ＋Ｈ］ ^＋ 。１．８８分。 Example 51: 2 ³ -Chloro-6-(6-hydroxyhexyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Synthesis of Decaphane 4,4-dioxide (51)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to N-(5-chloro-6 -(2-vinylphenyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b3) to replace 5-(hex-5-en-1-ylamino)pentan-1-ol ( Using the procedure described in Example 12, except that intermediate a34) was replaced with 6-(pent-4-en-1-ylamino)hexan-1-ol (intermediate a3), 2 ³ -chloro-6-(6-hydroxyhexyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4 -dioxide (51) was synthesized. LCMS (conditions 1): m/z 529.2 [M+H] ⁺ . 1.88 minutes.

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、６－フルオロ－Ｎ－（６－（５－フルオロ－２－ビニルフェニル）－５－（トリフルオロメチル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ１）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（ヘキサ－５－エン－１－イルアミノ）プロパン－１－オール（中間体ａ１７）で置き換えたことを除いて、実施例１２に記載される手順を用いて、１ ^５ －フルオロ－６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（５２）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５５３．１［Ｍ＋Ｈ］ ^＋ 。１．７９分。 Example 52: 1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-Benzenacyclododecaphane 4,4-dioxide (52)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to 6-fluoro-N-(6 -(5-fluoro-2-vinylphenyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b1) to replace 5-(hex-5-ene-1- As described in Example 12, except ylamino)pentan-1-ol (intermediate a34) was replaced with 3-(hex-5-en-1-ylamino)propan-1-ol (intermediate a17) 1 ⁵ -Fluoro-6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina -1(1,2)-Benzenacyclododecaphane 4,4-dioxide (52) was synthesized. LCMS (conditions 1): m/z 553.1 [M+H] ⁺ . 1.79 minutes.

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、６－フルオロ－Ｎ－（６－（５－フルオロ－２－ビニルフェニル）－５－（トリフルオロメチル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ１）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ペンタ－４－エン－１－イルアミノ）ブタン－１－オール（中間体ａ２９）で置き換えたことを除いて、実施例１２に記載される手順を用いて、１ ^５ －フルオロ－６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（５３）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５５３．１［Ｍ＋Ｈ］ ^＋ 。１．３８分。 Example 53: 1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-Benzenacycloundecaphane 4,4-dioxide (53)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to 6-fluoro-N-(6 -(5-fluoro-2-vinylphenyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b1) to replace 5-(hex-5-ene-1- As described in Example 12 except ylamino)pentan-1-ol (intermediate a34) was replaced with 4-(pent-4-en-1-ylamino)butan-1-ol (intermediate a29) 1 ⁵ -Fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina -1(1,2)-Benzenacycloundecaphane 4,4-dioxide (53) was synthesized. LCMS (conditions 1): m/z 553.1 [M+H] ⁺ . 1.38 minutes.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（（２－（アリルオキシ）エチル）アミノ）ブタン－１－オール（中間体ａ６）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－９－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（５４）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５５１．２［Ｍ＋Ｈ］ ^＋ 。１．７２分。 Example 54: 6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1 ,2)-Synthesis of Benzenacyclododecaphane 4,4-dioxide (54)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 4-((2-(allyloxy)ethyl)amino)butan-1-ol (intermediate a6) 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza- 2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide (54) was synthesized. LCMS (conditions 1): m/z 551.2 [M+H] ⁺ . 1.72 minutes.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ブタ－３－エン－１－イルアミノ）ブタン－１－オール（中間体ａ７）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン４，４－ジオキシド（５５）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５２１．２［Ｍ＋Ｈ］ ^＋ 。１．８５分。 Example 55: 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclodecaphane 4,4-dioxide (55)

Replacement of 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) with 4-(but-3-en-1-ylamino)butan-1-ol (intermediate a7) 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( 2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide (55) was synthesized. LCMS (conditions 1): m/z 521.2 [M+H] ⁺ . 1.85 minutes.

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、Ｎ－（５－クロロ－６－（２－ビニルフェニル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ３）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、４－（ブタ－３－エン－１－イルアミノ）ブタン－１－オール（中間体ａ７）で置き換えたことを除いて、実施例１２に記載される手順を用いて、２ ^３ －クロロ－６－（４－ヒドロキシブチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン４，４－ジオキシド（５６）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４８７．２［Ｍ＋Ｈ］ ^＋ 。１．７４分。 Example 56: 2 ³ -Chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca Synthesis of fan 4,4-dioxide (56)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to N-(5-chloro-6 -(2-vinylphenyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b3) to replace 5-(hex-5-en-1-ylamino)pentan-1-ol ( Using the procedure described in Example 12, except that intermediate a34) was replaced with 4-(but-3-en-1-ylamino)butan-1-ol (intermediate a7), 2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4- Dioxide (56) was synthesized. LCMS (conditions 1): m/z 487.2 [M+H] ⁺ . 1.74 minutes.

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、６－フルオロ－Ｎ－（６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ６）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、３－（ペンタ－４－エン－１－イルアミノ）プロパン－１－オール（中間体ａ２４）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（３－ヒドロキシプロピル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（５７）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４５３．１［Ｍ＋Ｈ］ ^＋ 。１．６６分。 Example 57: 6-(3-Hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4 - Synthesis of Dioxide (57)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to 6-fluoro-N-(6 -(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b6) to replace 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) 6-(3- Hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (57) was synthesized. LCMS (conditions 1): m/z 453.1 [M+H] ⁺ . 1.66 minutes.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、（１－（（ペンタ－４－エン－１－イルアミノ）メチル）シクロプロピル）メタノール（中間体ａ８）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（（１－（ヒドロキシメチル）シクロプロピル）メチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（５８）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５４７．３［Ｍ＋Ｈ］ ^＋ 。１．７９分。 Example 58: 6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- Synthesis of 1(1,2)-Benzenacycloundecaphane 4,4-dioxide (58)

5-(Hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was converted to (1-((pent-4-en-1-ylamino)methyl)cyclopropyl)methanol (intermediate a8 6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ³ -(trifluoromethyl)-4-thia- 3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (58) was synthesized. LCMS (conditions 1): m/z 547.3 [M+H] ⁺ . 1.79 minutes.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、（１－（（（２－（アリルオキシ）エチル）アミノ）メチル）シクロプロピル）メタノール（中間体ａ１１）で置き換えたことを除いて、実施例１２に記載される手順を用いて、６－（（１－（ヒドロキシメチル）シクロプロピル）メチル）－２ ^３ －（トリフルオロメチル）－９－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（５９）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６３．３［Ｍ＋Ｈ］ ^＋ 。１．７２分。 Example 59: 6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6 )-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide (59)

5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was converted to (1-(((2-(allyloxy)ethyl)amino)methyl)cyclopropyl)methanol (intermediate a11 6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ³ -(trifluoromethyl)-9-oxa- 4-Thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide (59) was synthesized. LCMS (conditions 1): m/z 563.3 [M+H] ⁺ . 1.72 minutes.

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、６－フルオロ－Ｎ－（６－（５－フルオロ－２－ビニルフェニル）－５－（トリフルオロメチル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ１）で置き換え、５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、２，２－ジメチル－３－（ペンタ－４－エン－１－イルアミノ）プロパン－１－オール（中間体ａ２５）で置き換えたことを除いて、実施例１２に記載される手順を用いて、１ ^５ －フルオロ－６－（３－ヒドロキシ－２，２－ジメチルプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（６０）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６７．２［Ｍ＋Ｈ］ ^＋ 。１．９８分。 Example 60: 1 ⁵ -fluoro-6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6 )-Dipyridina-1(1,2)-Benzenacycloundecaphane 4,4-dioxide (60)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to 6-fluoro-N-(6 -(5-fluoro-2-vinylphenyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b1) to replace 5-(hex-5-ene-1- ylamino)pentan-1-ol (intermediate a34) was replaced with 2,2-dimethyl-3-(pent-4-en-1-ylamino)propan-1-ol (intermediate a25) , using the procedure described in Example 12, 1 ⁵ -fluoro-6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6- Diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (60) was synthesized. LCMS (conditions 1): m/z 567.2 [M+H] ⁺ . 1.98 minutes.

５－（ヘキサ－５－エン－１－イルアミノ）ペンタン－１－オール（中間体ａ３４）を、メチルヘキサ－５－エン－１－イルグリシネート（中間体ａ１９）で置き換えたことを除いて、実施例１２に記載される手順を用いて、メチル２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）アセテート（６１）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５４９．３［Ｍ＋１］ ^＋ 、１．７４分。 Example 61: Methyl 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Synthesis of Benzenacyclododecaphan-6-yl)acetate (61)

Example 12 except 5-(hex-5-en-1-ylamino)pentan-1-ol (intermediate a34) was replaced with methylhex-5-en-1-ylglycinate (intermediate a19) Methyl 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 using the procedure described in (1,2)-Benzenacyclododecaphan-6-yl)acetate (61) was synthesized. LC-MS (conditions 1): m/z 549.3 [M+1] ⁺ , 1.74 min.

工程１．３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン－６－イル）プロパナールの合成
ＤＣＭ（６ｍＬ）中の６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）（５６ｍｇ、０．１０ｍｍｏｌ）の溶液に、デス・マーチン・ペルヨージナン（５６ｍｇ、０．１３ｍｍｏｌ）を室温で一度に加えた。混合物を２時間撹拌した。ＬＣＭＳにより、反応が完了したことが示された。飽和ＮａＨＣＯ _３ （１ｍＬ）及び飽和Ｎａ _２ Ｓ _２ Ｏ _３ （１ｍＬ）を加えた。混合物を１５分間にわたって激しく撹拌し、反応混合物を、２５０ｍＬの分液漏斗中で、１００ｍＬのＤＣＭに注ぎ、層を分離した。組み合わされた有機相を塩水で洗浄し、Ｎａ _２ ＳＯ _４ 上で乾燥させ、ろ過し、濃縮した。残渣を、ＩＳＣＯ精製（４０ｇのカラム、ＥｔＯＡｃ／ヘプタン０～１００％）に供して、表題化合物（５５ｍｇ、９８％の収率）を白色の固体として得た。ＬＣ－ＭＳ：ｍ／ｚ ５４７．２０［Ｍ＋１］ ^＋ 、１．９１分。 Example 62: 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclotridecaphan-6-yl)propanoic acid (62)

Step 1. 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Synthesis of Nacyclotridecaphan-6-yl)propanal 6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5 in DCM (6 mL) To a solution of (2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphane 4,4-dioxide (39) (56 mg, 0.10 mmol) was added Dess-Martin periodinane (56 mg, 0.13 mmol). ) was added in one portion at room temperature. The mixture was stirred for 2 hours. LCMS indicated the reaction was complete. Saturated NaHCO ₃ (1 mL) and saturated Na ₂ S ₂ O ₃ (1 mL) were added. The mixture was vigorously stirred for 15 minutes, the reaction mixture was poured into 100 mL DCM in a 250 mL separatory funnel and the layers were separated. The combined organic phases _were washed with brine, dried over _Na2SO4 , filtered and concentrated. The residue was subjected to ISCO purification (40 g column, EtOAc/heptane 0-100%) to give the title compound (55 mg, 98% yield) as a white solid. LC-MS: m/z 547.20 [M+1] ⁺ , 1.91 min.

Step 2. 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Synthesis of nacyclotridecaphan-6-yl)propanoic acid (62) 3-(4,4-dioxide-2 ³ -(trifluoromethyl) in t-BuOH (3 mL volume) and THF (3 mL volume) -a solution of 4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzonacyclotridecaphan-6-yl)propanal (54 mg, 0.10 mmol) was added 2-methyl-2-butene (0.63 mL, 5.93 mmol) followed by NaH ₂ PO ₄ (67 mg, 0.59 mmol) in water (0.5 mL) and of NaClO ₂ (71 mg, 0.59 mmol) was added. The resulting mixture was stirred at room temperature for 45 minutes. LC-MS indicated the reaction was complete. The reaction mixture was poured into 100 mL of EtOAc in a 250 mL separatory funnel and washed with water (10 mL) and brine (10 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated, then the residue was subjected to ISCO purification (40 g column, MeOH/DCM 0-10%) to give the title compound as a white solid. Obtained. LC-MS (conditions 1): m/z 563.20 [M+1] ⁺ , 1.86 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H), 11.74 (s, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.73 (dd , J = 8.7, 7.3Hz, 1H), 7.55-7.39 (m, 1H), 7.35 (td, J = 7.4, 1.5Hz, 1H), 7.30- 7.21 (m, 2H), 7.21-7.11 (m, 2H), 6.93 (d, J=8.8Hz, 1H), 3.71-3.41 (m, 4H), 2.59-2.51 (m, 2H), 2.39-2.29 (m, 1H), 2.20-1.99 (m, 1H), 1.42-1.05 (m, 6H) ), 1.05-0.92 (m, 2H), 0.91-0.76 (m, 2H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、１ ^５ －フルオロ－６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－１１－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２３）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（１ ^５ －フルオロ－４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－１１－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）ブタン酸（６３）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５６９．２［Ｍ＋１］ ^＋ 、１．７０分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１５（ｓ，１Ｈ）、１１．６７（ｓ，１Ｈ）、８．０５（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６９（ｔ，Ｊ＝７．９Ｈｚ、１Ｈ）、７．３５－７．１５（ｍ，３Ｈ）、７．１５－７．００（ｍ，２Ｈ）、６．９０（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．０５－３．７２（ｍ，３Ｈ）、３．４７－３．３５（ｍ，１Ｈ）、３．２３－３．０９（ｍ，１Ｈ）、３．０５－２．８８（ｍ，１Ｈ）、２．２６（ｔ，Ｊ＝７．１Ｈｚ、２Ｈ）、１．７９－１．５６（ｍ，３Ｈ）、１．５５－１．３４（ｍ，２Ｈ）、１．３０－１．１０（ｍ，１Ｈ）． Example 63: 4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)- Synthesis of dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)butanoic acid (63)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2, Using the procedure described in Example 62, except substituting 5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (23): 4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphan-6-yl)butanoic acid (63) was synthesized. LC-MS (conditions 1): m/z 569.2 [M+1] ⁺ , 1.70 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.15 (s, 1H), 11.67 (s, 1H), 8.05 (d, J=8.9Hz, 1H), 7.69 (t , J = 7.9Hz, 1H), 7.35-7.15 (m, 3H), 7.15-7.00 (m, 2H), 6.90 (d, J = 8.8Hz, 1H) , 4.05-3.72 (m, 3H), 3.47-3.35 (m, 1H), 3.23-3.09 (m, 1H), 3.05-2.88 (m, 1H), 2.26 (t, J=7.1 Hz, 2H), 1.79-1.56 (m, 3H), 1.55-1.34 (m, 2H), 1.30-1. 10(m, 1H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（２－（３－ヒドロキシプロポキシ）エチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１４）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）エトキシ）プロパン酸（６４）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５７９．２［Ｍ＋Ｈ］ ^＋ 、１．８４分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１６（ｓ，１Ｈ）、１１．７８（ｓ，１Ｈ）、８．０９（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６９（ｍ，１Ｈ）、７．３６（ｍ，１Ｈ）、７．２４（ｍ，４Ｈ）、７．１４（ｄ，Ｊ＝７．４Ｈｚ、１Ｈ）、６．８８（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．９３（ｍ，１Ｈ）、３．５７（ｔ，Ｊ＝６．３Ｈｚ、２Ｈ）、３．４５（ｍ，４Ｈ）、２．９１（ｍ，１Ｈ）、２．４０（ｍ，３Ｈ）、１．８９（ｍ，１Ｈ）、１．７２（ｍ，１Ｈ）、１．３３（ｍ，２Ｈ）、１．０９（ｍ，３Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．８６（ｓ）． Example 64: 3-(2-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1, 2) Synthesis of -Benzenacycloundecaphan-6-yl)ethoxy)propanoic acid (64)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(2-(3-hydroxypropoxy)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2, 6)-Dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (14) was used to prepare 3-(2) using the procedure described in Example 62. -(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundeca Phan-6-yl)ethoxy)propanoic acid (64) was synthesized. LCMS (conditions 1): m/z 579.2 [M+H] ⁺ , 1.84 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.16 (s, 1H), 11.78 (s, 1H), 8.09 (d, J=8.9Hz, 1H), 7.69 (m , 1H), 7.36 (m, 1H), 7.24 (m, 4H), 7.14 (d, J = 7.4Hz, 1H), 6.88 (d, J = 8.7Hz, 1H ), 3.93 (m, 1H), 3.57 (t, J = 6.3Hz, 2H), 3.45 (m, 4H), 2.91 (m, 1H), 2.40 (m, 3H), 1.89 (m, 1H), 1.72 (m, 1H), 1.33 (m, 2H), 1.09 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.86 (s).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（４０）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン－６－イル）ブタン酸（６５）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５７７．２［Ｍ＋１］ ^＋ 、１．８９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１４（ｓ，１Ｈ）、１１．７５（ｓ，１Ｈ）、８．１９（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７３（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．５３－７．３９（ｍ，１Ｈ）、７．３５（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．３０－７．２１（ｍ，２Ｈ）、７．２１－７．１２（ｍ，２Ｈ）、６．９５（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．７２－３．５６（ｍ，１Ｈ）、３．５６－３．４１（ｍ，１Ｈ）、３．３７－３．３４（ｍ，１Ｈ）、３．３２－３．２６（ｍ，１Ｈ）、２．４５－２．２２（ｍ，３Ｈ）、２．１７－２．０１（ｍ，１Ｈ）、１．７９－１．６２（ｍ，２Ｈ）、１．４４－１．３０（ｍ，３Ｈ）、１．２９－０．９２（ｍ，５Ｈ）、０．９０－０．７０（ｍ，２Ｈ）． Example 65: 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclotridecaphan-6-yl)butanoic acid (65)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 4-(4,4-dioxide-2 was prepared using the procedure described in Example 62, except substituting 1(1,2)-benzeneacyclotridecaphane 4,4-dioxide (40). ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphan-6-yl)butanoic acid (65 ) was synthesized. LC-MS (conditions 1): m/z 577.2 [M+1] ⁺ , 1.89 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.14 (s, 1H), 11.75 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.73 (dd , J = 8.7, 7.2 Hz, 1H), 7.53-7.39 (m, 1H), 7.35 (td, J = 7.4, 1.5Hz, 1H), 7.30- 7.21 (m, 2H), 7.21-7.12 (m, 2H), 6.95 (d, J=8.8Hz, 1H), 3.72-3.56 (m, 1H), 3.56-3.41 (m, 1H), 3.37-3.34 (m, 1H), 3.32-3.26 (m, 1H), 2.45-2.22 (m, 3H) ), 2.17-2.01 (m, 1H), 1.79-1.62 (m, 2H), 1.44-1.30 (m, 3H), 1.29-0.92 (m , 5H), 0.90-0.70 (m, 2H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロペンタデカファン４，４－ジオキシド（４２）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロペンタデカファン－６－イル）ブタン酸（６６）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ６０５．３［Ｍ＋１］ ^＋ 、１．９７分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１４（ｓ，１Ｈ）、１１．５５（ｓ，１Ｈ）、８．２２（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７５－７．５０（ｍ，２Ｈ）、７．３５（ｔｄ，Ｊ＝７．５、１．５Ｈｚ、１Ｈ）、７．２９－７．１９（ｍ，２Ｈ）、７．１８－７．０９（ｍ，２Ｈ）、６．９６（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．９３－３．５９（ｍ，１Ｈ）、３．５３－３．３４（ｍ，３Ｈ）、２．３５－２．２１（ｍ，２Ｈ）、２．２１－２．０２（ｍ，２Ｈ）、１．８２－１．６４（ｍ，２Ｈ）、１．５３－１．３７（ｍ，２Ｈ）、１．３７－０．７６（ｍ，１２Ｈ）． Example 66: 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclopentadecaphan-6-yl)butanoic acid (66)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 4-(4,4-dioxide- 2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopentadecaphan-6-yl)butanoic acid (66) was synthesized. LCMS (conditions 1): m/z 605.3 [M+1] ⁺ , 1.97 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.14 (s, 1H), 11.55 (s, 1H), 8.22 (d, J=8.9Hz, 1H), 7.75-7 .50 (m, 2H), 7.35 (td, J=7.5, 1.5Hz, 1H), 7.29-7.19 (m, 2H), 7.18-7.09 (m, 2H), 6.96 (d, J=8.8Hz, 1H), 3.93-3.59 (m, 1H), 3.53-3.34 (m, 3H), 2.35-2. 21 (m, 2H), 2.21-2.02 (m, 2H), 1.82-1.64 (m, 2H), 1.53-1.37 (m, 2H), 1.37- 0.76(m, 12H).

工程１．６－（（４－ヒドロキシブチル）（ペンタ－４－エン－１－イル）アミノ）－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミドの合成
１００ｍＬの圧力管中で、ＮＭＰ（２５ｍＬ）中の４－（ペンタ－４－エン－１－イルアミノ）ブタン－１－オール（中間体ａ２９）（４．２５ｇ、２７．００ｍｍｏｌ）、６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）（３．８１ｇ、９ｍｍｏｌ）及びＤＩＥＡ（４．７２ｍＬ、２７ｍｍｏｌ）の混合物を、１５０℃で一晩撹拌し、ＬＣ－ＭＳにより、反応がほぼ完了したことが示された。反応混合物を、１Ｌの分液漏斗中で、５００ｍＬのＥｔＯＡｃに注ぎ、１０％のクエン酸（５０ｍＬ×１）、水（５０ｍＬ×４）及び塩水（５０ｍＬ×１）で洗浄した。有機相を（Ｎａ _２ ＳＯ _４ 上で）乾燥させ、ろ過し、濃縮し、次に、残渣を、ＩＳＣＯ精製（２４０ｇのカラム、ＥｔＯＡｃ ０～１００％中のヘプタン）に供して、６－（（４－ヒドロキシブチル）（ペンタ－４－エン－１－イル）アミノ）－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミドを白色のガラス質の固体として得た。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５６１．２０、ＲＴ １．８８６分。１Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）δ １１．５３（ｓ，１Ｈ）、８．１６（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６７（ｄｄ，Ｊ＝８．０、１．２Ｈｚ、１Ｈ）、７．６１（ｄｄ，Ｊ＝８．７、７．３Ｈｚ、１Ｈ）、７．４９（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．４２（ｔｄ，Ｊ＝７．６、１．４Ｈｚ、１Ｈ）、７．３０（ｔｄ，Ｊ＝７．５、１．２Ｈｚ、１Ｈ）、７．０５（ｄ，Ｊ＝７．４Ｈｚ、１Ｈ）、７．０２（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、６．８１（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、５．９７（ｄｄ，Ｊ＝１７．５、１１．０Ｈｚ、１Ｈ）、５．７５（ｄｄｔ，Ｊ＝１６．８、１０．２、６．５Ｈｚ、１Ｈ）、５．６１（ｄ，Ｊ＝１７．４Ｈｚ、１Ｈ）、５．０４－４．８８（ｍ，３Ｈ）、４．４２（ｔ，Ｊ＝５．１Ｈｚ、１Ｈ）、３．４５－３．２０（ｍ，６Ｈ）、１．９３（ｑ，Ｊ＝７．２Ｈｚ、２Ｈ）、１．５０－１．３０（ｍ，６Ｈ）． Example 67: 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphan-6-yl)butanoic acid (67)

Step 1. 6-((4-Hydroxybutyl)(pent-4-en-1-yl)amino)-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl ) Synthesis of pyridine-2-sulfonamide In a 100 mL pressure tube, 4-(pent-4-en-1-ylamino)butan-1-ol (Intermediate a29) (4.25 g, 27.00 mmol), 6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) (3.81 g, 9 mmol) and DIEA (4.72 mL, 27 mmol) was stirred at 150° C. overnight and LC-MS indicated the reaction was nearly complete. The reaction mixture was poured into 500 mL of EtOAc in a 1 L separatory funnel and washed with 10% citric acid (50 mL x 1), water (50 mL x 4) and brine (50 mL x 1). The organic phase was dried (over Na ₂ SO ₄ ), filtered and concentrated, then the residue was subjected to ISCO purification (240 g column, heptane in EtOAc 0-100%) to 6-(( 4-hydroxybutyl)(pent-4-en-1-yl)amino)-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide was obtained as a white glassy solid. LC-MS (conditions 1): m/z 561.20, RT 1.886 min. 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.67 (dd, J = 8.0, 1.2 Hz, 1H), 7.61 (dd, J = 8.7, 7.3 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.42 (td, J = 7.6, 1 .4 Hz, 1 H), 7.30 (td, J=7.5, 1.2 Hz, 1 H), 7.05 (d, J=7.4 Hz, 1 H), 7.02 (d, J=7. 2Hz, 1H), 6.81 (d, J = 8.7Hz, 1H), 5.97 (dd, J = 17.5, 11.0Hz, 1H), 5.75 (ddt, J = 16.8 , 10.2, 6.5 Hz, 1 H), 5.61 (d, J=17.4 Hz, 1 H), 5.04-4.88 (m, 3 H), 4.42 (t, J=5. 1Hz, 1H), 3.45-3.20 (m, 6H), 1.93 (q, J = 7.2Hz, 2H), 1.50-1.30 (m, 6H).

Step 2. (E)-6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecafane-10-ene 4,4-dioxide In a 1 L flask, 6-((4-hydroxybutyl)(pent-4-en-1-yl)amino in DCE (500 mL). )-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (3.24 g, 5.78 mmol) was purged with argon. . Grubbs II (0.368 g, 0.433 mmol) catalyst was added and further purged with argon. The mixture was stirred at 65° C. for 19 hours. LC-MS indicated the reaction was complete. The mixture was concentrated and the residue was subjected to ISCO purification (330 g column, 0-100% EtOAc in hexanes) to give the trans-product (E)-6-(4-hydroxybutyl)-2 ³ -(tri fluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-10-ene 4,4-dioxide Obtained as a solid. LC-MS (conditions 1): m/z 533.20, RT 1.810 min. 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 7.70 (dd, J = 8.7, 7.2 Hz, 1H), 7.44-7.36 (m, 2H), 7.34-7.25 (m, 2H), 7.25-7.15 (m, 2H), 6.87 (d, J = 8.8Hz, 1H), 5.89 (d, J = 16.0Hz, 1H), 5.64 (dt, J = 16.0, 6.5Hz, 1H), 4.44 (t, J = 5 .1Hz, 1H), 3.62-3.45 (m, 1H), 3.43-3.34 (m, 3H), 3.28-2.98 (m, 2H), 2.11-1 .87 (m, 2H), 1.72-1.34 (m, 6H).

Step 3. 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Synthesis of nacycloundecaphane 4,4-dioxide (25) (E)-6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)- in EtOAc (72 mL) and MeOH (24.0 mL) 4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-10-ene 4,4-dioxide (2.50 g, 4. 69 mmol) and PtO ₂ (0.213 g, 0.939 mmol) was stirred under hydrogen at room temperature overnight and LC-MS indicated the reaction was complete. The mixture was filtered through a layer of celite to remove platinum and then concentrated. The residue was dissolved in EtOAc and then hexanes was added, precipitating a white solid which was filtered to afford 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia. -3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide was obtained as a white solid product. The filtrate was concentrated and the residue was subjected to ISCO purification (80 g column, 0-100% EtOAc in heptane) to give additional 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4- Thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide was obtained as a white solid. LC-MS (conditions 1): m/z 535.20, RT 1.873 min. 1H NMR (600 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.71 (dd, J = 8.7, 7.2 Hz, 1H), 7.36 (td, J = 7.5, 1.4Hz, 1H), 7.29 (dd, J = 7.9, 1.3Hz, 1H), 7.25-7.18 (m , 3 H), 7.14 (d, J = 7.6 Hz, 1 H), 6.82 (d, J = 8.7 Hz, 1 H), 4.42 (t, J = 5.1 Hz, 1 H), 4 .00-3.87 (m, 1H), 3.40 (td, J=6.3, 5.1Hz, 2H), 3.31-3.27 (m, 2H), 3.26-3. 16 (m, 1H), 2.93-2.80 (m, 1H), 2.45-2.35 (m, 1H), 1.94-1.83 (m, 1H), 1.77- 1.65 (m, 1H), 1.56-1.21 (m, 5H), 1.17-1.09 (m, 2H), 1.07-0.98 (m, 1H).

Step 4. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Synthesis of Nacycloundecaphan-6-yl)butanal (73) 6-(4-Hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza- in DCM (200 mL) To a solution of 2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (2.30 g, 4.30 mmol) was added Dess-Martin periodinane (2.30 mmol). 372 g, 5.59 mmol) was added in one portion at room temperature. The mixture was stirred for 2 hours. LC-MS indicated the reaction was complete. Saturated NaHCO ₃ (20 mL) and saturated Na ₂ S ₂ O ₃ (20 mL) were added. The mixture was stirred vigorously for 15 minutes before the layers were separated and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic phases _were washed with brine, dried over _Na2SO4 , filtered and concentrated. The residue was subjected to ISCO purification (80 g column, 0-100% EtOAc in heptane) to give 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza. -2,5(2,6)-Dipyridina-1(1,2)-Benzenacycloundecaphan-6-yl)butanal was obtained as a white solid. LC-MS (conditions 1): m/z 533.20, RT 1.940 min. 1H NMR (600MHz, DMSO-d6) δ 11.77 (s, 1H), 9.67 (t, J = 1.2Hz, 1H), 8.10 (d, J = 9.0Hz, 1H), 7 .74 (dd, J=8.7, 7.2 Hz, 1 H), 7.36 (td, J=7.5, 1.4 Hz, 1 H), 7.29 (dd, J=7.8, 1 .3Hz, 1H), 7.27-7.19 (m, 3H), 7.14 (d, J = 7.6Hz, 1H), 6.91 (d, J = 8.7Hz, 1H), 4 .00-3.86 (m, 1H), 3.31-3.25 (m, 1H), 3.25-3.17 (m, 1H), 2.93-2.82 (m, 1H) , 2.44-2.35 (m, 1H), 1.94-1.84 (m, 1H), 1.76-1.61 (m, 3H), 1.41-1.20 (m, 4H), 1.17-1.10 (m, 2H), 1.08-0.98 (m, 1H).

Step 5. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Synthesis of nacycloundecaphan-6-yl)butanoic acid 4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3 in t-BuOH (60 mL) and THF (60 mL) 2- Methyl-2-butene (8.75 mL, 83 mmol) was added followed by NaH ₂ PO ₄ (991 mg, 8.26 mmol) in water (10 mL) and NaClO ₂ (934 mg, 8.26 mmol) in water (10 mL). was added. The resulting mixture was stirred at room temperature for 45 minutes. LC-MS indicated the reaction was complete. The reaction mixture was poured into 500 mL of EtOAc in a 1 L separatory funnel and washed with water (50 mL x 1) and brine (50 mL x 1). The organic phase was _dried over _Na2SO4 , filtered and concentrated. The residue was then subjected to ISCO purification (80 g column, MeOH in DCM, 0-10%) and pure fractions were collected and concentrated. To this residue was added 24 mL of ethyl ether, which precipitated a white solid which was filtered to give 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3, 6-Diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)butanoic acid (67) was obtained as a white solid. The filtrate was concentrated to give additional 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1 ,2)-Benzenacycloundecaphan-6-yl)butanoic acid (67) was obtained as a white/slightly yellow solid. LC-MS (conditions 1): m/z 549.20, RT 1.841 min. 1H NMR (600 MHz, DMSO-d6) δ 12.14 (s, 1H), 11.77 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.72 (dd, J = 8.7, 7.2 Hz, 1H), 7.36 (td, J = 7.5, 1.4 Hz, 1H), 7.29 (dd, J = 7.8, 1.3 Hz, 1H), 7.26-7.19 (m, 3H), 7.14 (d, J = 7.6Hz, 1H), 6.91 (d, J = 8.7Hz, 1H), 4.04-3.88 (m, 1H), 3.31-3.26 (m, 1H), 3.26-3.18 (m, 1H), 2.94-2.80 (m, 1H), 2.45-2 .34 (m, 1H), 2.26 (t, J=7.1Hz, 2H), 1.97-1.82 (m, 1H), 1.76-1.58 (m, 3H), 1 .42-1.25 (m, 2H), 1.20-1.11 (m, 2H), 1.07-0.95 (m, 1H). Compound (67) is isolated as the sodium salt by adding 1.05 equivalents of NaOH to a slurry of the free acid in 95.5% IPA and 4.5% _H2O and stirring overnight. was done. Subsequent filtration gave compound (67) as the sodium salt.

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、１ ^５ －フルオロ－６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（４７）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（１ ^５ －フルオロ－４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）ブタン酸（６８）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５８０．９［Ｍ＋１］ ^＋ 、１．８２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１５（ｓ，１Ｈ）、１１．７４（ｓ，１Ｈ）、８．１９（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７２（ｄｄ，Ｊ＝７．３、８．７Ｈｚ、１Ｈ）、７．４４（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、７．３１（ｄｄ，Ｊ＝５．９、８．５Ｈｚ、１Ｈ）、７．２４－７．１５（ｍ，２Ｈ）、７．０７（ｄ，Ｊ＝７．７Ｈｚ、１Ｈ）、６．９４（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．５７（ｓ，１Ｈ）、３．３３（ｄｑ，Ｊ＝７．４、８．３、２３．４Ｈｚ、３Ｈ）、２．６１－２．５２（ｍ，１Ｈ）、２．２８（ｔ，Ｊ＝７．１Ｈｚ、２Ｈ）、２．０２（ｓ，１Ｈ）、１．７０（ｐ，Ｊ＝６．９Ｈｚ、２Ｈ）、１．４５－１．１６（ｍ，３Ｈ）、１．０８（ｓ，３Ｈ）、０．９４－０．６６（ｍ，２Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．０３（ｓ，３Ｆ）、－１１７．９６（ｓ，１Ｆ）． Example 68: 4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-benzeneacyclododecaphan-6-yl)butanoic acid (68)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2, 6)-Dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide (47) was used to prepare 4-(1 ⁵ ) using the procedure described in Example 62, except replacing it with 4,4-dioxide (47). -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacyclododeca Phan-6-yl)butanoic acid (68) was synthesized. LC-MS (conditions 1): m/z 580.9 [M+1] ⁺ , 1.82 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.15 (s, 1H), 11.74 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.72 (dd , J=7.3, 8.7 Hz, 1 H), 7.44 (d, J=8.7 Hz, 1 H), 7.31 (dd, J=5.9, 8.5 Hz, 1 H), 7. 24-7.15 (m, 2H), 7.07 (d, J = 7.7Hz, 1H), 6.94 (d, J = 8.8Hz, 1H), 3.57 (s, 1H), 3.33 (dq, J=7.4, 8.3, 23.4Hz, 3H), 2.61-2.52 (m, 1H), 2.28 (t, J=7.1Hz, 2H) , 2.02 (s, 1H), 1.70 (p, J = 6.9 Hz, 2H), 1.45-1.16 (m, 3H), 1.08 (s, 3H), 0.94 -0.66 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.03 (s, 3F), -117.96 (s, 1F).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロテトラデカファン４，４－ジオキシド（４３）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロテトラデカファン－６－イル）プロパン酸（６９）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５７７．２［Ｍ＋１］ ^＋ 、１．９１分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．３２（ｓ，１Ｈ）、１１．６２（ｓ，１Ｈ）、８．２０（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．６５－７．４５（ｍ，１Ｈ）、７．３５（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．２９－７．１９（ｍ，２Ｈ）、７．１９－７．１０（ｍ，２Ｈ）、６．９４（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．８３－３．６５（ｍ，１Ｈ）、３．６４－３．４８（ｍ，２Ｈ）、３．４８－３．３５（ｍ，１Ｈ）、２．５４（ｄｔ，Ｊ＝７．４、３．５Ｈｚ、２Ｈ）、２．３９－２．２４（ｍ，１Ｈ）、２．０８－１．９４（ｍ，１Ｈ）、１．４５－１．２０（ｍ，３Ｈ）、１．２０－０．８９（ｍ，７Ｈ）、０．８９－０．７６（ｍ，２Ｈ）． Example 69: 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclotetradecaphan-6-yl)propanoic acid (69)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 3-(4,4-dioxide- 2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetradecaphan-6-yl)propanoic acid (69) was synthesized. LC-MS (conditions 1): m/z 577.2 [M+1] ⁺ , 1.91 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.32 (s, 1H), 11.62 (s, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.70 (dd , J = 8.7, 7.2 Hz, 1H), 7.65-7.45 (m, 1H), 7.35 (td, J = 7.4, 1.5Hz, 1H), 7.29- 7.19 (m, 2H), 7.19-7.10 (m, 2H), 6.94 (d, J=8.8Hz, 1H), 3.83-3.65 (m, 1H), 3.64-3.48 (m, 2H), 3.48-3.35 (m, 1H), 2.54 (dt, J = 7.4, 3.5Hz, 2H), 2.39-2 .24 (m, 1H), 2.08-1.94 (m, 1H), 1.45-1.20 (m, 3H), 1.20-0.89 (m, 7H), 0.89 -0.76 (m, 2H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３）を、６－（６－ヒドロキシヘキシル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（４８）で置き換えたことを除いて、実施例６２に記載される手順を用いて、６－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）ヘキサン酸（７０）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５７７．２［Ｍ＋Ｈ］ ^＋ 、１．８５分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．９９（ｓ，１Ｈ）、１１．７７（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．６、７．３Ｈｚ、１Ｈ）、７．３６（ｔｄ，Ｊ＝７．５、１．２Ｈｚ、１Ｈ）、７．２８（ｍ，１Ｈ）、７．２２（ｍ，３Ｈ）、７．１４（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、６．８１（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．９４（ｍ，１Ｈ）、３．２６（ｍ，２Ｈ）、２．８７（ｍ，１Ｈ）、２．４０（ｍ，１Ｈ）、２．１９（ｔ，Ｊ＝７．３Ｈｚ、２Ｈ）、１．８９（ｍ，１Ｈ）、１．６９（ｍ，１Ｈ）、０．９６－１．５４（ｍ，１１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．８８（ｓ）． Example 70: 6-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphan-6-yl)hexanoic acid (70)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (3) was converted to 6-(6-hydroxyhexyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 6-(4,4-Dioxide- 2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)hexanoic acid (70) was synthesized. LCMS (conditions 1): m/z 577.2 [M+H] ⁺ , 1.85 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.99 (s, 1H), 11.77 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.71 (dd , J = 8.6, 7.3 Hz, 1H), 7.36 (td, J = 7.5, 1.2 Hz, 1H), 7.28 (m, 1H), 7.22 (m, 3H) , 7.14 (d, J=7.5 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 3.94 (m, 1H), 3.26 (m, 2H), 2 .87 (m, 1H), 2.40 (m, 1H), 2.19 (t, J = 7.3 Hz, 2H), 1.89 (m, 1H), 1.69 (m, 1H), 0.96-1.54 (m, 11H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.88 (s).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロテトラデカファン４，４－ジオキシド（４４）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロテトラデカファン－６－イル）ブタン酸（７１）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５９１．２［Ｍ＋１］ ^＋ 、１．９３分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１５（ｓ，１Ｈ）、１１．６２（ｓ，１Ｈ）、８．２１（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．８、７．２Ｈｚ、１Ｈ）、７．６２－７．４４（ｍ，１Ｈ）、７．３５（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．２９－７．１９（ｍ，２Ｈ）、７．１９－７．０８（ｍ，２Ｈ）、６．９６（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．９０－３．６６（ｍ，１Ｈ）、３．４２－３．２２（ｍ，３Ｈ）、２．４０－２．２１（ｍ，３Ｈ）、２．１０－１．９５（ｍ，１Ｈ）、１．８０－１．６７（ｍ，２Ｈ）、１．４２－１．２０（ｍ，４Ｈ）、１．２０－０．７４（ｍ，８Ｈ）． Example 71: 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclotetradecaphan-6-yl)butanoic acid (71)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 4-(4,4-dioxide- 2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetradecaphan-6-yl)butanoic acid (71) was synthesized. LC-MS (conditions 1): m/z 591.2 [M+1] ⁺ , 1.93 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.15 (s, 1H), 11.62 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.70 (dd , J = 8.8, 7.2 Hz, 1H), 7.62-7.44 (m, 1H), 7.35 (td, J = 7.4, 1.5 Hz, 1H), 7.29- 7.19 (m, 2H), 7.19-7.08 (m, 2H), 6.96 (d, J=8.7Hz, 1H), 3.90-3.66 (m, 1H), 3.42-3.22 (m, 3H), 2.40-2.21 (m, 3H), 2.10-1.95 (m, 1H), 1.80-1.67 (m, 2H) ), 1.42-1.20 (m, 4H), 1.20-0.74 (m, 8H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（４－ヒドロキシブチル）－２ ^３ －メチル－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１９）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（２ ^３ －メチル－４，４－ジオキシド－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）ブタン酸（７２）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４９５．２［Ｍ＋Ｈ］ ^＋ 、１．７２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＣＭ－ｄ _２ ＋ＭｅＯＨ－ｄ _４ ）δ ７．５７（ｄｄ，Ｊ＝７．２、１．５Ｈｚ、１Ｈ）、７．５５（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．４４－７．３７（ｍ，１Ｈ）、７．３５－７．２７（ｍ，２Ｈ）、７．２３（ｄ，Ｊ＝７．０Ｈｚ、１Ｈ）、７．１７（ｄｄ，Ｊ＝７．７、１．４Ｈｚ、１Ｈ）、７．１２（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、６．７１（ｄ，Ｊ＝８．６Ｈｚ、１Ｈ）、３．７７（ｓ，１Ｈ）、３．３０－３．２６（ｍ，２Ｈ）、３．１４（ｓ，１Ｈ）、２．５７（ｓ，１Ｈ）、２．３２（ｔ，Ｊ＝６．９Ｈｚ、２Ｈ）、２．１８（ｓ，１Ｈ）、１．９６（ｓ，３Ｈ）、１．８１（ｐ，Ｊ＝７．１Ｈｚ、２Ｈ）、１．６７－１．４２（ｍ，２Ｈ）、１．３１（ｓ，２Ｈ）、１．１２（ｍ，２Ｈ）． Example 72: 4-(2 ³ -methyl-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloun Synthesis of decafane-6-yl)butanoic acid (72)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(4-hydroxybutyl)-2 ³ -methyl-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 (1, 4-(2 ³ -methyl-4,4-dioxide using the procedure described in Example 62, except substituting 2)-benzenacycloundecaphane 4,4-dioxide (19). -4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)butanoic acid (72) was synthesized. LCMS (conditions 1): m/z 495.2 [M+H] ⁺ , 1.72 min. ¹ H NMR (400 MHz, DCM-d ₂ +MeOH-d ₄ ) δ 7.57 (dd, J=7.2, 1.5 Hz, 1 H), 7.55 (d, J=8.8 Hz, 1 H), 7.44-7.37 (m, 1H), 7.35-7.27 (m, 2H), 7.23 (d, J=7.0Hz, 1H), 7.17 (dd, J=7 .7, 1.4 Hz, 1 H), 7.12 (d, J = 8.7 Hz, 1 H), 6.71 (d, J = 8.6 Hz, 1 H), 3.77 (s, 1 H), 3 .30-3.26 (m, 2H), 3.14 (s, 1H), 2.57 (s, 1H), 2.32 (t, J = 6.9Hz, 2H), 2.18 (s , 1H), 1.96 (s, 3H), 1.81 (p, J = 7.1 Hz, 2H), 1.67-1.42 (m, 2H), 1.31 (s, 2H), 1.12(m, 2H).

実施例６７に記載されるように、４－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）ブタナール（７３）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５３３．２［Ｍ＋１］ ^＋ 、１．９４分。 ^１ Ｈ ＮＭＲ（６００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７７（ｓ，１Ｈ）、９．６７（ｔ，Ｊ＝１．２Ｈｚ、１Ｈ）、８．１０（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７４（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３６（ｔｄ，Ｊ＝７．５、１．４Ｈｚ、１Ｈ）、７．２９（ｄｄ，Ｊ＝７．８、１．３Ｈｚ、１Ｈ）、７．２７－７．１９（ｍ，３Ｈ）、７．１４（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、６．９１（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．００－３．８６（ｍ，１Ｈ）、３．３１－３．２５（ｍ，１Ｈ）、３．２５－３．１７（ｍ，１Ｈ）、２．９３－２．８２（ｍ，１Ｈ）、２．４４－２．３５（ｍ，１Ｈ）、１．９４－１．８４（ｍ，１Ｈ）、１．７６－１．６１（ｍ，３Ｈ）、１．４１－１．２０（ｍ，４Ｈ）、１．１７－１．１０（ｍ，２Ｈ）、１．０８－０．９８（ｍ，１Ｈ）． Example 73: 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphan-6-yl)butanal (73)

4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 as described in Example 67 (1,2)-Benzenacycloundecaphan-6-yl)butanal (73) was synthesized. LC-MS (conditions 1): m/z 533.2 [M+1] ⁺ , 1.94 min. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.77 (s, 1H), 9.67 (t, J = 1.2 Hz, 1H), 8.10 (d, J = 9.0 Hz, 1H) , 7.74 (dd, J=8.7, 7.2 Hz, 1H), 7.36 (td, J=7.5, 1.4 Hz, 1H), 7.29 (dd, J=7.8 , 1.3 Hz, 1 H), 7.27-7.19 (m, 3 H), 7.14 (d, J = 7.6 Hz, 1 H), 6.91 (d, J = 8.7 Hz, 1 H) , 4.00-3.86 (m, 1H), 3.31-3.25 (m, 1H), 3.25-3.17 (m, 1H), 2.93-2.82 (m, 1H), 2.44-2.35 (m, 1H), 1.94-1.84 (m, 1H), 1.76-1.61 (m, 3H), 1.41-1.20 ( m, 4H), 1.17-1.10 (m, 2H), 1.08-0.98 (m, 1H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（２－（２－ヒドロキシエトキシ）エチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（４９）で置き換えたことを除いて、実施例６２に記載される手順を用いて、２－（２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）エトキシ）酢酸（７４）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６５．２［Ｍ＋Ｈ］ ^＋ 、１．７７分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．６１（ｓ，１Ｈ）、１１．７９（ｓ，１Ｈ）、８．０９（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３６（ｔｄ，Ｊ＝７．４、１．４Ｈｚ、１Ｈ）、７．２９（ｍ，１Ｈ）、７．２２（ｍ，３Ｈ）、７．１４（ｄ，Ｊ＝７．７Ｈｚ、１Ｈ）、６．９１（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．００（ｓ，２Ｈ）、３．９６（ｍ，１Ｈ）、３．５７（ｍ，２Ｈ）、３．４８（ｍ，２Ｈ）、２．９２（ｍ，１Ｈ）、２．４０（ｍ，１Ｈ）、１．９０（ｍ，１Ｈ）、１．７２（ｍ，１Ｈ）、１．３５（ｍ，２Ｈ）、１．１５（ｍ，２Ｈ）、１．０４（ｍ，１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ６）δ－５６．８５（ｓ）． Example 74: 2-(2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1, 2) Synthesis of -Benzenacycloundecaphan-6-yl)ethoxy)acetic acid (74)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(2-(2-hydroxyethoxy)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2, 6)-Dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (49) was used to prepare 2-(2) using the procedure described in Example 62. -(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundeca Phan-6-yl)ethoxy)acetic acid (74) was synthesized. LCMS (conditions 1): m/z 565.2 [M+H] ⁺ , 1.77 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.61 (s, 1H), 11.79 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.70 (dd , J = 8.7, 7.2 Hz, 1H), 7.36 (td, J = 7.4, 1.4 Hz, 1H), 7.29 (m, 1H), 7.22 (m, 3H) , 7.14 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.00 (s, 2H), 3.96 (m, 1H), 3 .57 (m, 2H), 3.48 (m, 2H), 2.92 (m, 1H), 2.40 (m, 1H), 1.90 (m, 1H), 1.72 (m, 1H), 1.35 (m, 2H), 1.15 (m, 2H), 1.04 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -56.85 (s).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロペンタデカファン４，４－ジオキシド（４５）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロペンタデカファン－６－イル）プロパン酸（７５）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５９１．３［Ｍ＋１］ ^＋ 、１．９５分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．３３（ｓ，１Ｈ）、１１．５７（ｓ，１Ｈ）、８．１８（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．８９－７．４９（ｍ，２Ｈ）、７．３５（ｔｄ，Ｊ＝７．５、１．５Ｈｚ、１Ｈ）、７．３０－７．１９（ｍ，２Ｈ）、７．１９－７．０７（ｍ，２Ｈ）、６．９６（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．８４－３．４１（ｍ，４Ｈ）、２．６５－２．５２（ｍ，２Ｈ）、２．２２－２．０４（ｍ，２Ｈ）、１．５５－１．４１（ｍ，２Ｈ）、１．３８－１．１４（ｍ，２Ｈ）、１．１４－０．９４（ｍ，８Ｈ）、０．９４－０．８０（ｍ，２Ｈ）． Example 75: 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclopentadecaphan-6-yl)propanoic acid (75)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 3-(4,4-dioxide- 2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopentadecaphan-6-yl)propanoic acid (75) was synthesized. LC-MS (conditions 1): m/z 591.3 [M+1] ⁺ , 1.95 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.33 (s, 1H), 11.57 (s, 1H), 8.18 (d, J=8.8Hz, 1H), 7.89-7 .49 (m, 2H), 7.35 (td, J = 7.5, 1.5Hz, 1H), 7.30-7.19 (m, 2H), 7.19-7.07 (m, 2H), 6.96 (d, J=8.7Hz, 1H), 3.84-3.41 (m, 4H), 2.65-2.52 (m, 2H), 2.22-2. 04 (m, 2H), 1.55-1.41 (m, 2H), 1.38-1.14 (m, 2H), 1.14-0.94 (m, 8H), 0.94- 0.80(m, 2H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（１６）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）ブタン酸（７６）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５６３．２［Ｍ＋１］ ^＋ 、１．８８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１４（ｓ，１Ｈ）、１１．７０（ｓ，１Ｈ）、８．１６（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．４１（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、７．３４（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．２９－７．２０（ｍ，２Ｈ）、７．２０－７．１０（ｍ，２Ｈ）、６．９３（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．６９－３．４９（ｍ，１Ｈ）、３．４４－３．３５（ｍ，１Ｈ）、３．３１－３．１２（ｍ，２Ｈ）、２．６５－２．５３（ｍ，１Ｈ）、２．２７（ｔ，Ｊ＝７．１Ｈｚ、２Ｈ）、２．１１－１．９２（ｍ，１Ｈ）、１．７９－１．６０（ｍ，２Ｈ）、１．４２－１．００（ｍ，６Ｈ）、０．９４－０．６７（ｍ，２Ｈ）． Example 76: 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclododecaphan-6-yl)butanoic acid (76)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 4-(4,4-dioxide-2 was prepared using the procedure described in Example 62, except substituting 1(1,2)-benzeneacyclododecaphane 4,4-dioxide (16). ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)butanoic acid (76 ) was synthesized. LC-MS (conditions 1): m/z 563.2 [M+1] ⁺ , 1.88 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.14 (s, 1H), 11.70 (s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.71 (dd , J=8.7, 7.2 Hz, 1 H), 7.41 (d, J=8.7 Hz, 1 H), 7.34 (td, J=7.4, 1.5 Hz, 1 H), 7. 29-7.20 (m, 2H), 7.20-7.10 (m, 2H), 6.93 (d, J=8.7Hz, 1H), 3.69-3.49 (m, 1H) ), 3.44-3.35 (m, 1H), 3.31-3.12 (m, 2H), 2.65-2.53 (m, 1H), 2.27 (t, J = 7 .1Hz, 2H), 2.11-1.92 (m, 1H), 1.79-1.60 (m, 2H), 1.42-1.00 (m, 6H), 0.94-0 .67(m, 2H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（５－ヒドロキシペンチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１５）で置き換えたことを除いて、実施例６２に記載される手順を用いて、５－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）ペンタン酸（７７）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５６３．２［Ｍ＋１］ ^＋ 、１．８２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．０３（ｓ，１Ｈ）、１１．７８（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３６（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．３１－７．２６（ｍ，１Ｈ）、７．２６－７．１７（ｍ，３Ｈ）、７．１４（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、６．８３（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．０４－３．８５（ｍ，１Ｈ）、３．３１－３．１３（ｍ，１Ｈ）、２．９３－２．７８（ｍ，１Ｈ）、２．４６－２．３４（ｍ，１Ｈ）、２．２７－２．１８（ｍ，２Ｈ）、１．９６－１．８０（ｍ，１Ｈ）、１．７８－１．６２（ｍ，１Ｈ）、１．５６－１．２２（ｍ，６Ｈ）、１．２０－０．９４（ｍ，４Ｈ）． Example 77: 5-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphan-6-yl)pentanoic acid (77)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 5-(4,4-dioxide- 2 ^3- (Trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)pentanoic acid (77) was synthesized. LC-MS (conditions 1): m/z 563.2 [M+1] ⁺ , 1.82 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.03 (s, 1H), 11.78 (s, 1H), 8.10 (d, J=8.9Hz, 1H), 7.71 (dd , J = 8.7, 7.2 Hz, 1H), 7.36 (td, J = 7.4, 1.5 Hz, 1H), 7.31-7.26 (m, 1H), 7.26- 7.17 (m, 3H), 7.14 (d, J = 7.5Hz, 1H), 6.83 (d, J = 8.8Hz, 1H), 4.04-3.85 (m, 1H) ), 3.31-3.13 (m, 1H), 2.93-2.78 (m, 1H), 2.46-2.34 (m, 1H), 2.27-2.18 (m , 2H), 1.96-1.80 (m, 1H), 1.78-1.62 (m, 1H), 1.56-1.22 (m, 6H), 1.20-0.94 (m, 4H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（５－ヒドロキシペンチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（１２）で置き換えたことを除いて、実施例６２に記載される手順を用いて、５－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）ペンタン酸（７８）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５７７．２［Ｍ＋１］ ^＋ 、１．８５分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．０３（ｓ，１Ｈ）、１１．７０（ｓ，１Ｈ）、８．１６（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．６９（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．４９－７．３８（ｍ，１Ｈ）、７．３４（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．２９－７．２０（ｍ，２Ｈ）、７．２０－７．１０（ｍ，２Ｈ）、６．８６（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．６９－３．４９（ｍ，１Ｈ）、３．４７－３．３５（ｍ，１Ｈ）、３．３２－３．１０（ｍ，２Ｈ）、２．６５－２．５４（ｍ，１Ｈ）、２．２９－２．１９（ｍ，２Ｈ）、２．１０－１．９４（ｍ，１Ｈ）、１．５８－１．４３（ｍ，４Ｈ）、１．４２－０．９５（ｍ，６Ｈ）、０．９４－０．８２（ｍ，１Ｈ）、０．８２－０．６７（ｍ，１Ｈ）． Example 78: 5-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclododecaphan-6-yl)pentanoic acid (78)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 5-(4,4-dioxide-2 was prepared using the procedure described in Example 62, except substituting 1(1,2)-benzeneacyclododecaphane 4,4-dioxide (12). ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)pentanoic acid (78 ) was synthesized. LC-MS (conditions 1): m/z 577.2 [M+1] ⁺ , 1.85 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.03 (s, 1H), 11.70 (s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.69 (dd , J = 8.7, 7.2 Hz, 1H), 7.49-7.38 (m, 1H), 7.34 (td, J = 7.4, 1.5Hz, 1H), 7.29- 7.20 (m, 2H), 7.20-7.10 (m, 2H), 6.86 (d, J=8.8Hz, 1H), 3.69-3.49 (m, 1H), 3.47-3.35 (m, 1H), 3.32-3.10 (m, 2H), 2.65-2.54 (m, 1H), 2.29-2.19 (m, 2H) ), 2.10-1.94 (m, 1H), 1.58-1.43 (m, 4H), 1.42-0.95 (m, 6H), 0.94-0.82 (m , 1H), 0.82-0.67 (m, 1H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、２ ^３ －クロロ－６－（４－ヒドロキシブチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（４６）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（２ ^３ －クロロ－４，４－ジオキシド－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）ブタン酸（７９）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５１５．２［Ｍ＋Ｈ］ ^＋ 、１．７５分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１１（ｓ，１Ｈ）、１１．３１（ｓ，１Ｈ）、７．８６（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．７、７．３Ｈｚ、１Ｈ）、７．３５（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．２７（ｍ，２Ｈ）、７．１７（ｍ，３Ｈ）、６．８８（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．７７（ｍ，１Ｈ）、３．２５（ｔ，Ｊ＝７．８Ｈｚ、２Ｈ）、２．９７（ｍ，１Ｈ）、２．５２（ｍ，１Ｈ）、２．２６（ｔ，Ｊ＝７．１Ｈｚ、２Ｈ）、２．０７（ｍ，１Ｈ）、１．６６（ｓ，２Ｈ）、１．５７（ｍ，１Ｈ）、０．８７－１．３５（ｍ，５Ｈ）． Example 79: 4-(2 ³ -Chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Synthesis of Decaphan-6-yl)butanoic acid (79)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 (1, 4-(2 ³ -Chloro-4,4-dioxide using the procedure described in Example 62, except substituting 2)-Benzenacycloundecaphane 4,4-dioxide (46). -4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)butanoic acid (79) was synthesized. LCMS (conditions 1): m/z 515.2 [M+H] ⁺ , 1.75 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.11 (s, 1H), 11.31 (s, 1H), 7.86 (d, J=8.9Hz, 1H), 7.70 (dd , J = 8.7, 7.3 Hz, 1H), 7.35 (td, J = 7.4, 1.5 Hz, 1H), 7.27 (m, 2H), 7.17 (m, 3H) , 6.88 (d, J=8.7 Hz, 1H), 3.77 (m, 1H), 3.25 (t, J=7.8 Hz, 2H), 2.97 (m, 1H), 2 .52 (m, 1H), 2.26 (t, J=7.1Hz, 2H), 2.07 (m, 1H), 1.66 (s, 2H), 1.57 (m, 1H), 0.87-1.35 (m, 5H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（５－ヒドロキシペンチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン４，４－ジオキシド（５０）で置き換えたことを除いて、実施例６２に記載される手順を用いて、５－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン－６－イル）ペンタン酸（８０）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５４９．２［Ｍ＋Ｈ］ ^＋ 、１．７７分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．０１（ｓ，１Ｈ）、１１．６７（ｓ，１Ｈ）、８．１５（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．６、７．３Ｈｚ、１Ｈ）、７．３４（ｍ，２Ｈ）、７．２６（ｍ，３Ｈ）、７．１６（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、６．８１（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．９１（ｔ，Ｊ＝１１．５Ｈｚ、１Ｈ）、３．３０（ｍ，１Ｈ）、３．２２（ｍ，１Ｈ）、２．８５（ｍ，１Ｈ）、２．５４（ｍ，１Ｈ）、２．２２（ｍ，２Ｈ）、１．７４（ｍ，１Ｈ）、１．６２（ｍ，１Ｈ）、１．４８（ｍ，４Ｈ）、１．３０（ｍ，２Ｈ）、０．６７（ｍ，１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５７．００（ｓ）． Example 80: 5-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclodecaphan-6-yl)pentanoic acid (80)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 5-(4,4-dioxide-2 was prepared using the procedure described in Example 62, except substituting 1(1,2)-benzeneacyclodecaphane 4,4-dioxide (50). ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphan-6-yl)pentanoic acid (80 ) was synthesized. LCMS (conditions 1): m/z 549.2 [M+H] ⁺ , 1.77 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.01 (s, 1H), 11.67 (s, 1H), 8.15 (d, J=8.9Hz, 1H), 7.70 (dd , J = 8.6, 7.3 Hz, 1H), 7.34 (m, 2H), 7.26 (m, 3H), 7.16 (d, J = 7.2 Hz, 1H), 6.81 (d, J = 8.7Hz, 1H), 3.91 (t, J = 11.5Hz, 1H), 3.30 (m, 1H), 3.22 (m, 1H), 2.85 (m , 1H), 2.54 (m, 1H), 2.22 (m, 2H), 1.74 (m, 1H), 1.62 (m, 1H), 1.48 (m, 4H), 1 .30 (m, 2H), 0.67 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.00 (s).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、１ ^５ －フルオロ－６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－１１－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２２）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（１ ^５ －フルオロ－４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－１１－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）プロパン酸（８１）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５５５．１［Ｍ＋１］ ^＋ 、１．７０分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．３３（ｓ，１Ｈ）、１１．６５（ｓ，１Ｈ）、８．０６（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３５－７．１８（ｍ，３Ｈ）、７．１５－７．００（ｍ，２Ｈ）、６．８９（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．０５－３．９３（ｍ，１Ｈ）、３．９３－３．７２（ｍ，２Ｈ）、３．６８－３．５１（ｍ，１Ｈ）、３．４８－３．３８（ｍ，１Ｈ）、３．１１－２．９４（ｍ，１Ｈ）、２．４９－２．４０（ｍ，２Ｈ）、１．６７（ｄ，Ｊ＝６．２Ｈｚ、１Ｈ）、１．５３－１．３７（ｍ，２Ｈ）、１．３２－１．１６（ｍ，１Ｈ）． Example 81: 3-(1 ⁵ -Fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)- Synthesis of dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propanoic acid (81)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2, Using the procedure described in Example 62, except substituting 5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (22): 3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphan-6-yl)propanoic acid (81) was synthesized. LC-MS (conditions 1): m/z 555.1 [M+1] ⁺ , 1.70 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.33 (s, 1H), 11.65 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.71 (dd , J=8.7, 7.2 Hz, 1H), 7.35-7.18 (m, 3H), 7.15-7.00 (m, 2H), 6.89 (d, J=8. 8Hz, 1H), 4.05-3.93 (m, 1H), 3.93-3.72 (m, 2H), 3.68-3.51 (m, 1H), 3.48-3. 38 (m, 1H), 3.11-2.94 (m, 1H), 2.49-2.40 (m, 2H), 1.67 (d, J = 6.2Hz, 1H), 1. 53-1.37 (m, 2H), 1.32-1.16 (m, 1H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、２ ^３ －クロロ－６－（６－ヒドロキシヘキシル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（５１）で置き換えたことを除いて、実施例６２に記載される手順を用いて、６－（２ ^３ －クロロ－４，４－ジオキシド－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）ヘキサン酸（８２）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５４３．２［Ｍ＋Ｈ］ ^＋ 、１．９２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．００（ｓ，１Ｈ）、１１．２９（ｓ，１Ｈ）、７．８６（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６８（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３５（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．２７（ｍ，２Ｈ）、７．１７（ｍ，３Ｈ）、６．７８（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．７６（ｓ，１Ｈ）、３．２３（ｔ，Ｊ＝７．４Ｈｚ、２Ｈ）、２．９６（ｓ，１Ｈ）、２．５２（ｍ，１Ｈ）、２．１９（ｔ，Ｊ＝７．３Ｈｚ、２Ｈ）、２．０８（ｍ，１Ｈ）、０．８５－１．６５（ｍ，１２Ｈ）． Example 82: 6-(2 ³ -Chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Synthesis of Decaphan-6-yl)hexanoic acid (82)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 2 ³ -chloro-6-(6-hydroxyhexyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 (1, 6-(2 ³ -Chloro-4,4-dioxide using the procedure described in Example 62, except substituting 2)-Benzenacycloundecaphane 4,4-dioxide (51). -4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)hexanoic acid (82) was synthesized. LCMS (conditions 1): m/z 543.2 [M+H] ⁺ , 1.92 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.00 (s, 1H), 11.29 (s, 1H), 7.86 (d, J=8.9Hz, 1H), 7.68 (dd , J = 8.7, 7.2 Hz, 1H), 7.35 (td, J = 7.4, 1.5 Hz, 1H), 7.27 (m, 2H), 7.17 (m, 3H) , 6.78 (d, J=8.8 Hz, 1H), 3.76 (s, 1H), 3.23 (t, J=7.4 Hz, 2H), 2.96 (s, 1H), 2 .52 (m, 1H), 2.19 (t, J=7.3Hz, 2H), 2.08 (m, 1H), 0.85-1.65 (m, 12H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（４－ヒドロキシブチル）－２ ^３ －メトキシ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１７）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（２ ^３ －メトキシ－４，４－ジオキシド－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）ブタン酸（８３）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５１１．２［Ｍ＋１］ ^＋ 、１．６２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ７．９９（ｓ，１Ｈ）、７．７．７０－７．５８（ｍ，１Ｈ）、７．３９（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．２９（ｄｄｄ，Ｊ＝７．７、７．０、１．５Ｈｚ、１Ｈ）、７．２６－７．２１（ｍ，２Ｈ）、７．１９（ｄｄ，Ｊ＝７．１、１．５Ｈｚ、１Ｈ）、７．１３（ｄｄ，Ｊ＝７．５、１．５Ｈｚ、１Ｈ）、６．８７－６．７９（ｍ，１Ｈ）、３．６９（ｓ，３Ｈ）、３．５１－３．３８（ｍ，２Ｈ）、２．４１（ｔ，Ｊ＝７．３Ｈｚ、２Ｈ）、２．３３（ｔ，Ｊ＝６．９Ｈｚ、２Ｈ）、１．７７－１．７３（ｍ，２Ｈ）、１．４７－１．４２（ｍ，３Ｈ）、１．３２－１．１８（ｍ，２Ｈ）、１．１２－１．００（ｍ，２Ｈ）、０．９４－０．８３（ｍ，１Ｈ）． Example 83: 4-(2 ³ -Methoxy-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Synthesis of decafane-6-yl)butanoic acid (83)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(4-hydroxybutyl)-2 ³ -methoxy-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 (1, 4-(2 ³ -Methoxy-4,4-dioxide using the procedure described in Example 62, except substituting 2)-Benzenacycloundecaphane 4,4-dioxide (17) -4-Thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzonacycloundecaphan-6-yl)butanoic acid (83) was synthesized. LC-MS (conditions 1): m/z 511.2 [M+1] ⁺ , 1.62 min. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.99 (s, 1H), 7.7.70-7.58 (m, 1H), 7.39 (d, J=9.0Hz, 1H) , 7.29 (ddd, J=7.7, 7.0, 1.5 Hz, 1H), 7.26-7.21 (m, 2H), 7.19 (dd, J=7.1, 1 .5Hz, 1H), 7.13 (dd, J = 7.5, 1.5Hz, 1H), 6.87-6.79 (m, 1H), 3.69 (s, 3H), 3.51 -3.38 (m, 2H), 2.41 (t, J = 7.3Hz, 2H), 2.33 (t, J = 6.9Hz, 2H), 1.77-1.73 (m, 2H), 1.47-1.42 (m, 3H), 1.32-1.18 (m, 2H), 1.12-1.00 (m, 2H), 0.94-0.83 ( m, 1H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（２１）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）プロパン酸（８４）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５４９．２［Ｍ＋Ｈ］ ^＋ 、１．５５分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．３１（ｓ，１Ｈ）、１１．６８（ｓ，１Ｈ）、８．１６（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．４４（ｍ，１Ｈ）、７．３４（ｔｄ，Ｊ＝７．５、１．５Ｈｚ、１Ｈ）、７．２１（ｍ，４Ｈ）、６．９２（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．５３（ｍ，３Ｈ）、３．３８（ｍ，１Ｈ）、３．３３（ｍ，１Ｈ）、２．４７（ｍ，２Ｈ）、２．０１（ｍ，１Ｈ）、１．３５（ｍ，３Ｈ）、１．０９（ｍ，３Ｈ）、０．８０（ｍ，２Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５５．９４（ｓ）． Example 84: 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclododecaphan-6-yl)propanoic acid (84)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- Using the procedure described in Example 62, except substituting 1(1,2)-benzeneacyclododecaphane 4,4-dioxide (21), 3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)propanoic acid (84 ) was synthesized. LCMS (conditions 1): m/z 549.2 [M+H] ⁺ , 1.55 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.31 (s, 1H), 11.68 (s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.71 (dd , J = 8.7, 7.2 Hz, 1 H), 7.44 (m, 1 H), 7.34 (td, J = 7.5, 1.5 Hz, 1 H), 7.21 (m, 4 H) , 6.92 (d, J = 8.8Hz, 1H), 3.53 (m, 3H), 3.38 (m, 1H), 3.33 (m, 1H), 2.47 (m, 2H ), 2.01 (m, 1H), 1.35 (m, 3H), 1.09 (m, 3H), 0.80 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -55.94 (s).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、１ ^５ －フルオロ－６－（３－ヒドロキシプロピル）－ ^２３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（５２）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（１ ^５ －フルオロ－４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）プロパン酸（８５）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６７．１［Ｍ＋Ｈ］ ^＋ 、１．４０分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ８．０５（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６７（ｄｄ，Ｊ＝８．７、７．３Ｈｚ、１Ｈ）、７．５８（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．３２－７．２１（ｍ，２Ｈ）、７．１２－７．０１（ｍ，１Ｈ）、６．９７－６．７９（ｍ，２Ｈ）、３．８９－３．７４（ｍ，１Ｈ）、３．７３－３．５１（ｍ，２Ｈ）、３．４６－３．３３（ｍ，１Ｈ）、２．６１－２．５５（ｍ，２Ｈ）、２．５０（ｓ，１Ｈ）、２．１６－２．０２（ｍ，１Ｈ）、１．５２－１．３５（ｍ，３Ｈ）、１．２５－１．１０（ｍ，３Ｈ）、１．０２－０．９２（ｍ，２Ｈ）． Example 85: 3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-benzeneacyclododecaphan-6-yl)propanoic acid (85)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to ^{1 5} -fluoro-6-(3-hydroxypropyl)-23-(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6 3-(1 ⁵ - Fluoro-4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane -6-yl)propanoic acid (85) was synthesized. LCMS (conditions 1): m/z 567.1 [M+H] ⁺ , 1.40 min. ¹ H NMR (400 MHz, methanol- _d ) δ 8.05 (d, J=8.9 Hz, 1 H), 7.67 (dd, J=8.7, 7.3 Hz, 1 H), 7.58 ( d, J = 8.9 Hz, 1H), 7.32-7.21 (m, 2H), 7.12-7.01 (m, 1H), 6.97-6.79 (m, 2H), 3.89-3.74 (m, 1H), 3.73-3.51 (m, 2H), 3.46-3.33 (m, 1H), 2.61-2.55 (m, 2H) ), 2.50 (s, 1H), 2.16-2.02 (m, 1H), 1.52-1.35 (m, 3H), 1.25-1.10 (m, 3H), 1.02-0.92 (m, 2H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９を、１ ^５ －フルオロ－６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（５３）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（１ ^５ －フルオロ－４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）ブタン酸（８６）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６７．２［Ｍ＋Ｈ］ ^＋ 、１．７９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１４（ｓ，１Ｈ）、１１．８４（ｓ，１Ｈ）、８．１２（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７３（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３３（ｄｄ，Ｊ＝８．６、５．８Ｈｚ、１Ｈ）、７．２７－７．１６（ｍ，３Ｈ）、７．０６（ｄｄ，Ｊ＝９．４、２．７Ｈｚ、１Ｈ）、６．９１（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．０１－３．９０（ｍ，１Ｈ）、３．２９－３．１６（ｍ，２Ｈ）、２．８７（ｔ，Ｊ＝９．２Ｈｚ、１Ｈ）、２．４２－２．３４（ｍ，１Ｈ）、２．２６（ｔ，Ｊ＝７．０Ｈｚ、２Ｈ）、１．９２－１．７６（ｍ，１Ｈ）、１．７５－１．５５（ｍ，３Ｈ）、１．４２－１．２５（ｍ，２Ｈ）、１．１９－１．０６（ｍ，２Ｈ）、１．０１（ｄ，Ｊ＝６．１Ｈｚ、１Ｈ）． Example 86: 4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-benzeneacycloundecaphan-6-yl)butanoic acid (86)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39, 1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5 (2,6 )-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide (53) was substituted for 4-(1 ⁵ ) using the procedure described in Example 62. -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)butanoic acid (86) was synthesized LCMS (conditions 1): m/z 567.2 [M+H] ⁺ , 1.79 min ¹ H NMR (400 MHz, DMSO-d ₆ ) δ. 12.14 (s, 1H), 11.84 (s, 1H), 8.12 (d, J = 9.0Hz, 1H), 7.73 (dd, J = 8.7, 7.2Hz, 1H ), 7.33 (dd, J = 8.6, 5.8 Hz, 1H), 7.27-7.16 (m, 3H), 7.06 (dd, J = 9.4, 2.7 Hz, 1H), 6.91 (d, J = 8.8Hz, 1H), 4.01-3.90 (m, 1H), 3.29-3.16 (m, 2H), 2.87 (t, J = 9.2Hz, 1H), 2.42-2.34 (m, 1H), 2.26 (t, J = 7.0Hz, 2H), 1.92-1.76 (m, 1H), 1.75-1.55 (m, 3H), 1.42-1.25 (m, 2H), 1.19-1.06 (m, 2H), 1.01 (d, J=6.1Hz , 1H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（３－ヒドロキシプロピル）－ ^２３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン４，４－ジオキシド（２０）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン－６－イル）プロパン酸（８７）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５２１．２［Ｍ＋１］ ^＋ 、１．７４分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．３１（ｓ，１Ｈ）、１１．６８（ｓ，１Ｈ）、８．１４（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．７３（ｄｄ，Ｊ＝８．７、７．３Ｈｚ、１Ｈ）、７．３９－７．３０（ｍ，２Ｈ）、７．２９－７．１５（ｍ，４Ｈ）、６．８６（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．００－３．７８（ｍ，１Ｈ）、３．６２－３．４１（ｍ，２Ｈ）、３．０２－２．８５（ｍ，１Ｈ）、２．４９－２．４１（ｍ，２Ｈ）、１．８１－１．６５（ｍ，１Ｈ）、１．６８－１．５２（ｍ，１Ｈ）、１．４１－１．１１（ｍ，３Ｈ）、０．７９－０．５９（ｍ，１Ｈ）． Example 87: 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclodecaphan-6-yl)propanoic acid (87)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(3-hydroxypropyl)-23-(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- ¹ Using the procedure described in Example 62, except substituting (1,2)-benzenenacyclodecaphane 4,4-dioxide (20), 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzonacyclodecaphan-6-yl)propanoic acid (87) was synthesized. LC-MS (conditions 1): m/z 521.2 [M+1] ⁺ , 1.74 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.31 (s, 1H), 11.68 (s, 1H), 8.14 (d, J=8.8Hz, 1H), 7.73 (dd , J=8.7, 7.3 Hz, 1H), 7.39-7.30 (m, 2H), 7.29-7.15 (m, 4H), 6.86 (d, J=8. 7Hz, 1H), 4.00-3.78 (m, 1H), 3.62-3.41 (m, 2H), 3.02-2.85 (m, 1H), 2.49-2. 41 (m, 2H), 1.81-1.65 (m, 1H), 1.68-1.52 (m, 1H), 1.41-1.11 (m, 3H), 0.79- 0.59(m, 1H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－９－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（５４）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－９－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）ブタン酸（８８）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６５．２［Ｍ＋Ｈ］ ^＋ 、１．９３分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．９８（ｓ，１Ｈ）、１１．５１（ｓ，１Ｈ）、８．１３（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６０（ｍ，１Ｈ）、７．３５（ｍ，２Ｈ）、７．２０（ｍ，２Ｈ）、７．０８（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、７．０３（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、６．９５（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．７５（ｍ，１Ｈ）、３．０２－３．５３（ｍ，７Ｈ）、２．１８（ｍ，２Ｈ）、１．９５（ｍ，２Ｈ）、１．６１（ｍ，３Ｈ）、１．３４（ｍ，１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．６８（ｓ）． Example 88: 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1 , 2)-Benzenacyclododecaphan-6-yl)butanoic acid (88) synthesis

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6 )-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide (54) was used to prepare 4-(4,4) using the procedure described in Example 62. -dioxide-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane- 6-yl)butanoic acid (88) was synthesized. LCMS (conditions 1): m/z 565.2 [M+H] ⁺ , 1.93 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.98 (s, 1H), 11.51 (s, 1H), 8.13 (d, J=8.9Hz, 1H), 7.60 (m , 1H), 7.35 (m, 2H), 7.20 (m, 2H), 7.08 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H ), 6.95 (d, J = 8.8 Hz, 1H), 3.75 (m, 1H), 3.02-3.53 (m, 7H), 2.18 (m, 2H), 1. 95 (m, 2H), 1.61 (m, 3H), 1.34 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.68 (s).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、２ ^３ －クロロ－６－（３－ヒドロキシプロピル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２４）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（２ ^３ －クロロ－４，４－ジオキシド－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）プロパン酸（８９）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５０１．１［Ｍ＋１］ ^＋ 、１．７２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．３３（ｓ，１Ｈ）、１１．３１（ｓ，１Ｈ）、７．８５（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３８－７．３１（ｍ，１Ｈ）、７．３１－７．２２（ｍ，２Ｈ）、７．２２－７．１３（ｍ，３Ｈ）、６．８５（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．８７－３．６３（ｍ，１Ｈ）、３．５０（ｔ，Ｊ＝７．１Ｈｚ、２Ｈ）、３．１２－２．９１（ｍ，１Ｈ）、２．６１－２．５１（ｍ，１Ｈ）、２．４４（ｄｔ，Ｊ＝７．１、３．８Ｈｚ、２Ｈ）、２．１６－２．０１（ｍ，１Ｈ）、１．６９－１．４１（ｍ，１Ｈ）、１．３７－０．８８（ｍ，５Ｈ）． Example 89: 3-(2 ³ -Chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Synthesis of decafane-6-yl)propanoic acid (89)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 2 ³ -chloro-6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 (1, 3-(2 ³ -Chloro-4,4-dioxide using the procedure described in Example 62, except substituting 2)-Benzenacycloundecaphane 4,4-dioxide (24). -4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propanoic acid (89) was synthesized. LC-MS (conditions 1): m/z 501.1 [M+1] ⁺ , 1.72 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.33 (s, 1H), 11.31 (s, 1H), 7.85 (d, J=8.9Hz, 1H), 7.71 (dd , J = 8.7, 7.2 Hz, 1H), 7.38-7.31 (m, 1H), 7.31-7.22 (m, 2H), 7.22-7.13 (m, 3H), 6.85 (d, J = 8.7Hz, 1H), 3.87-3.63 (m, 1H), 3.50 (t, J = 7.1Hz, 2H), 3.12- 2.91 (m, 1H), 2.61-2.51 (m, 1H), 2.44 (dt, J = 7.1, 3.8Hz, 2H), 2.16-2.01 (m , 1H), 1.69-1.41 (m, 1H), 1.37-0.88 (m, 5H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（４－ヒドロキシブチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン４，４－ジオキシド（５５）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン－６－イル）ブタン酸（９０）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５３５．１［Ｍ＋Ｈ］ ^＋ 、１．７８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１０（ｓ，１Ｈ）、１１．６８（ｓ，１Ｈ）、８．１５（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７２（ｄｄ，Ｊ＝８．６、７．３Ｈｚ、１Ｈ）、７．３５（ｍ，２Ｈ）、７．２６（ｍ，３Ｈ）、７．１７（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、６．８９（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．９０（ｍ，１Ｈ）、３．３４（ｍ，２Ｈ）、２．８７（ｍ，１Ｈ）、２．５４（ｍ，１Ｈ）、２．２５（ｔ，Ｊ＝７．２Ｈｚ、２Ｈ）、１．７０（ｍ，３Ｈ）、１．２７（ｍ，３Ｈ）、０．６８（ｍ，１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５７．４２（ｓ）． Example 90: 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclodecaphan-6-yl)butanoic acid (90)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 4-(4,4-dioxide-2 was prepared using the procedure described in Example 62, except substituting 1(1,2)-benzeneacyclodecaphane 4,4-dioxide (55). ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphan-6-yl)butanoic acid (90 ) was synthesized. LCMS (conditions 1): m/z 535.1 [M+H] ⁺ , 1.78 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.10 (s, 1H), 11.68 (s, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.72 (dd , J = 8.6, 7.3 Hz, 1 H), 7.35 (m, 2 H), 7.26 (m, 3 H), 7.17 (d, J = 7.2 Hz, 1 H), 6.89 (d, J = 8.7 Hz, 1H), 3.90 (m, 1H), 3.34 (m, 2H), 2.87 (m, 1H), 2.54 (m, 1H), 2. 25 (t, J=7.2 Hz, 2H), 1.70 (m, 3H), 1.27 (m, 3H), 0.68 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -57.42 (s).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、２ ^３ －クロロ－６－（４－ヒドロキシブチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン４，４－ジオキシド（５６）で置き換えたことを除いて、実施例６２に記載される手順を用いて、４－（２ ^３ －クロロ－４，４－ジオキシド－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン－６－イル）ブタン酸（９１）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５０１．１［Ｍ＋Ｈ］ ^＋ 、１．７１分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１０（ｓ，１Ｈ）、１１．１７（ｓ，１Ｈ）、７．９１（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．７、７．３Ｈｚ、１Ｈ）、７．２８（ｍ，５Ｈ）、７．１３（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、６．８６（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．５８（ｍ，１Ｈ）、３．２４（ｍ，２Ｈ）、３．０２（ｍ，１Ｈ）、２．６１（ｍ，１Ｈ）、２．２５（ｔ，Ｊ＝７．１Ｈｚ、２Ｈ）、２．０５（ｍ，１Ｈ）、１．６６（ｐ，Ｊ＝７．３Ｈｚ、２Ｈ）、１．２８（ｍ，４Ｈ）． Example 91: 4-(2 ³ -Chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca Synthesis of phan-6-yl)butanoic acid (91)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 (1, 4-(2 ³ -Chloro-4,4-dioxide- 4-Thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzonacyclodecaphan-6-yl)butanoic acid (91) was synthesized. LCMS (conditions 1): m/z 501.1 [M+H] ⁺ , 1.71 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.10 (s, 1H), 11.17 (s, 1H), 7.91 (d, J=8.8Hz, 1H), 7.70 (dd , J = 8.7, 7.3 Hz, 1H), 7.28 (m, 5H), 7.13 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 3.58 (m, 1H), 3.24 (m, 2H), 3.02 (m, 1H), 2.61 (m, 1H), 2.25 (t, J = 7.1Hz , 2H), 2.05 (m, 1H), 1.66 (p, J=7.3 Hz, 2H), 1.28 (m, 4H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２９）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）プロパン酸（９２）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５３５．２［Ｍ＋１］ ^＋ 、１．６９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．３３（ｓ，１Ｈ）、１１．７８（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７３（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３６（ｔｄ，Ｊ＝７．５、１．５Ｈｚ、１Ｈ）、７．３１－７．１７（ｍ，４Ｈ）、７．１４（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、６．８８（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．０５－３．８２（ｍ，１Ｈ）、３．６２－３．４２（ｍ，２Ｈ）、３．００－２．８５（ｍ，１Ｈ）、２．４８－２．２８（ｍ，２Ｈ）、１．９６－１．８２（ｍ，１Ｈ）、１．７８－１．６０（ｍ，１Ｈ）、１．４４－１．２１（ｍ，３Ｈ）、１．２１－１．０８（ｍ，２Ｈ）、１．０８－０．９５（ｍ，１Ｈ）． Example 92: 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphan-6-yl)propanoic acid (92)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 3-(4,4-dioxide- 2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propanoic acid (92) was synthesized. LC-MS (conditions 1): m/z 535.2 [M+1] ⁺ , 1.69 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.33 (s, 1H), 11.78 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.73 (dd , J = 8.7, 7.2 Hz, 1H), 7.36 (td, J = 7.5, 1.5 Hz, 1H), 7.31-7.17 (m, 4H), 7.14 ( d, J = 7.5Hz, 1H), 6.88 (d, J = 8.8Hz, 1H), 4.05-3.82 (m, 1H), 3.62-3.42 (m, 2H) ), 3.00-2.85 (m, 1H), 2.48-2.28 (m, 2H), 1.96-1.82 (m, 1H), 1.78-1.60 (m , 1H), 1.44-1.21 (m, 3H), 1.21-1.08 (m, 2H), 1.08-0.95 (m, 1H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（３－ヒドロキシプロピル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（５７）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（４，４－ジオキシド－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）プロパン酸（９３）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４６７．１［Ｍ＋Ｈ］ ^＋ 、１．４２分、 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ７．７３－７．６１（ｍ，２Ｈ）、７．３８－７．３１（ｍ，１Ｈ）、７．３１－７．２３（ｍ，４Ｈ）、７．１９（ｄｄ，Ｊ＝８．５、０．８Ｈｚ、１Ｈ）、６．９２（ｄ，Ｊ＝７．４Ｈｚ、１Ｈ）、６．８１（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．６２－３．５６（ｍ，２Ｈ）、３．４４（ｔ，Ｊ＝７．２Ｈｚ、２Ｈ）、２．６７（ｄｄ，Ｊ＝８．６、６．７Ｈｚ、２Ｈ）、２．４８－２．４２（ｍ，２Ｈ）、１．４８（ｄｄ，Ｊ＝８．６、６．５Ｈｚ、２Ｈ）、１．３３（ｄ，Ｊ＝７．２Ｈｚ、２Ｈ）、１．１８－１．１４（ｍ，２Ｈ）． Example 93: 3-(4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane-6- Synthesis of yl)propanoic acid (93)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca Fan 4,4-dioxide (39) was converted to 6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene 3-(4,4-dioxide-4-thia-3,6-diaza was prepared using the procedure described in Example 62, except substituting crowndecaphane 4,4-dioxide (57). -2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propanoic acid (93) was synthesized. LCMS (conditions 1): m/z 467.1 [M+H] ⁺ , 1.42 min, ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.73-7.61 (m, 2H), 7.38. -7.31 (m, 1H), 7.31-7.23 (m, 4H), 7.19 (dd, J = 8.5, 0.8Hz, 1H), 6.92 (d, J = 7.4Hz, 1H), 6.81 (d, J = 8.7Hz, 1H), 3.62-3.56 (m, 2H), 3.44 (t, J = 7.2Hz, 2H), 2.67 (dd, J=8.6, 6.7Hz, 2H), 2.48-2.42 (m, 2H), 1.48 (dd, J=8.6, 6.5Hz, 2H) , 1.33 (d, J=7.2 Hz, 2H), 1.18-1.14 (m, 2H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（（１－（ヒドロキシメチル）シクロプロピル）メチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（５８）で置き換えたことを除いて、実施例６２に記載される手順を用いて、１－（（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）メチル）シクロプロパン－１－カルボン酸（９４）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６１．３［Ｍ＋Ｈ］ ^＋ 、１．７３分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．３６（ｓ，１Ｈ）、１１．７８（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３６（ｔｄ，Ｊ＝７．４、１．５Ｈｚ、１Ｈ）、７．２７（ｍ，２Ｈ）、７．２２（ｔｄ，Ｊ＝７．４、１．４Ｈｚ、１Ｈ）、７．１８（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．１３（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、６．９６（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．８３（ｍ，１Ｈ）、３．７４（ｄ，Ｊ＝１５．４Ｈｚ、１Ｈ）、３．６２（ｄ，Ｊ＝１５．４Ｈｚ、１Ｈ）、２．９６（ｍ，１Ｈ）、２．３７（ｍ，１Ｈ）、１．８８（ｍ，１Ｈ）、１．７３（ｍ，１Ｈ）、１．３９（ｍ，１Ｈ）、１．２５（ｍ，１Ｈ）、１．０７（ｍ，５Ｈ）、０．７７（ｍ，２Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．７５（ｓ）． Example 94: 1-((4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Synthesis of Benzenacycloundecaphan-6-yl)methyl)cyclopropane-1-carboxylic acid (94)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 ( Using the procedure described in Example 62, except replacing 2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (58), 1- ((4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundeca Phan-6-yl)methyl)cyclopropane-1-carboxylic acid (94) was synthesized. LCMS (conditions 1): m/z 561.3 [M+H] ⁺ , 1.73 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.36 (s, 1H), 11.78 (s, 1H), 8.10 (d, J=8.9Hz, 1H), 7.71 (dd , J = 8.7, 7.2 Hz, 1H), 7.36 (td, J = 7.4, 1.5 Hz, 1H), 7.27 (m, 2H), 7.22 (td, J = 7.4, 1.4 Hz, 1 H), 7.18 (d, J = 8.9 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 6.96 (d, J = 8 .8Hz, 1H), 3.83 (m, 1H), 3.74 (d, J = 15.4Hz, 1H), 3.62 (d, J = 15.4Hz, 1H), 2.96 (m , 1H), 2.37 (m, 1H), 1.88 (m, 1H), 1.73 (m, 1H), 1.39 (m, 1H), 1.25 (m, 1H), 1 .07 (m, 5H), 0.77 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.75 (s).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（（１－（ヒドロキシメチル）シクロプロピル）メチル）－２ ^３ －（トリフルオロメチル）－９－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（５９）で置き換えたことを除いて、実施例６２に記載される手順を用いて、１－（（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－９－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）メチル）シクロプロパン－１－カルボン酸（９５）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５７７．３［Ｍ＋Ｈ］ ^＋ 、１．６７分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．２７（ｓ，１Ｈ）、１１．５１（ｓ，１Ｈ）、８．１６（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、７．５５（ｍ，１Ｈ）、７．３２（ｍ，２Ｈ）、７．１９（ｍ，２Ｈ）、７．０３（ｍ，３Ｈ）、３．９０（ｍ，１Ｈ）、３．７４（ｍ，２Ｈ）、３．５３（ｍ，２Ｈ）、３．３４（ｍ，２Ｈ）、３．０２（ｍ，１Ｈ）、１．８２（ｍ，３Ｈ）、１．３２（ｍ，１Ｈ）、１．１５（ｍ，１Ｈ）、１．０３（ｍ，１Ｈ）、０．９０（ｍ，１Ｈ）、０．６７（ｍ，１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．７７（ｓ）． Example 95: 1-((4,4-dioxide-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1( Synthesis of 1,2)-benzeneacyclododecaphan-6-yl)methyl)cyclopropane-1-carboxylic acid (95)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza- Using the procedure described in Example 62, except substituting 2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide (59) , 1-((4,4-dioxide-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacyclododecaphan-6-yl)methyl)cyclopropane-1-carboxylic acid (95) was synthesized. LCMS (conditions 1): m/z 577.3 [M+H] ⁺ , 1.67 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.27 (s, 1H), 11.51 (s, 1H), 8.16 (d, J=8.8Hz, 1H), 7.55 (m , 1H), 7.32 (m, 2H), 7.19 (m, 2H), 7.03 (m, 3H), 3.90 (m, 1H), 3.74 (m, 2H), 3 .53 (m, 2H), 3.34 (m, 2H), 3.02 (m, 1H), 1.82 (m, 3H), 1.32 (m, 1H), 1.15 (m, 1H), 1.03 (m, 1H), 0.90 (m, 1H), 0.67 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.77 (s).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、１ ^５ －フルオロ－６－（３－ヒドロキシ－２，２－ジメチルプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（６０）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（１ ^５ －フルオロ－４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）－２，２－ジメチルプロパン酸（９６）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５８１．２［Ｍ＋Ｈ］ ^＋ 、１．７８分、 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ７．９６（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６４（ｄｄ，Ｊ＝８．８、７．２Ｈｚ、１Ｈ）、７．３７－７．２２（ｍ，３Ｈ）、７．１１－７．０４（ｍ，１Ｈ）、７．００（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、６．８７（ｄｄ，Ｊ＝９．４、２．８Ｈｚ、１Ｈ）、４．０６－３．９４（ｍ，１Ｈ）、３．６８－３．４８（ｍ，２Ｈ）、３．０２－２．９０（ｍ，１Ｈ）、２．４４－２．３０（ｍ，１Ｈ）、２．０５－１．９０（ｍ，１Ｈ）、１．８６－１．７２（ｍ，１Ｈ）、１．５５－１．４２（ｍ，２Ｈ）、１．３５－１．２５（ｍ，２Ｈ）、１．２０－１．１０（ｍ，７Ｈ）． Example 96: 3-(1 ⁵ -Fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-Benzenacycloundecaphan-6-yl)-2,2-dimethylpropanoic acid (96)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca Fan 4,4-dioxide (39) was converted to 1 ⁵ -fluoro-6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza- Using the procedure described in Example 62, except substituting 2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (60). 3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1, 2)-Benzenacycloundecaphan-6-yl)-2,2-dimethylpropanoic acid (96) was synthesized. LCMS (conditions 1): m/z 581.2 [M+H] ⁺ , 1.78 min, ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.96 (d, J=8.9 Hz, 1 H), 7. .64 (dd, J = 8.8, 7.2 Hz, 1H), 7.37-7.22 (m, 3H), 7.11-7.04 (m, 1H), 7.00 (d, J = 8.8Hz, 1H), 6.87 (dd, J = 9.4, 2.8Hz, 1H), 4.06-3.94 (m, 1H), 3.68-3.48 (m , 2H), 3.02-2.90 (m, 1H), 2.44-2.30 (m, 1H), 2.05-1.90 (m, 1H), 1.86-1.72 (m, 1H), 1.55-1.42 (m, 2H), 1.35-1.25 (m, 2H), 1.20-1.10 (m, 7H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、１ ^５ －フルオロ－６－（３－ヒドロキシプロピル）－ ^２３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２６）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（１ ^５ －フルオロ－４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）プロパン酸（９７）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５５３．１［Ｍ＋Ｈ］ ^＋ 、１．７９分、 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ７．９７（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６９（ｄｄ，Ｊ＝８．７、７．３Ｈｚ、１Ｈ）、７．３８－７．３１（ｍ，２Ｈ）、７．２７（ｄｄ，Ｊ＝８．６、５．６Ｈｚ、１Ｈ）、７．１３－７．０５（ｍ，１Ｈ）、６．９１－６．７９（ｍ，２Ｈ）、４．２２－４．０８（ｍ，１Ｈ）、３．６３（ｔ，Ｊ＝７．２Ｈｚ、２Ｈ）、３．０２－２．９１（ｍ，１Ｈ）、２．６０－２．４７（ｍ，２Ｈ）、２．４９－２．３４（ｍ，１Ｈ）、２．０３－１．８９（ｍ，１Ｈ）、１．８２－１．６６（ｍ，１Ｈ）、１．５３－１．３９（ｍ，２Ｈ）、１．２６－１．１５（ｍ，２Ｈ）、１．１７－１．０２（ｍ，１Ｈ）． Example 97: 3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-benzeneacycloundecaphan-6-yl)propanoic acid (97)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to ^{1 5} -fluoro-6-(3-hydroxypropyl)-23-(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6 )-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (26) was used to prepare 3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)propanoic acid (97) was synthesized. LCMS (conditions 1): m/z 553.1 [M+H] ⁺ , 1.79 min, ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.97 (d, J=8.9 Hz, 1 H), 7. .69 (dd, J=8.7, 7.3 Hz, 1 H), 7.38-7.31 (m, 2 H), 7.27 (dd, J=8.6, 5.6 Hz, 1 H), 7.13-7.05 (m, 1H), 6.91-6.79 (m, 2H), 4.22-4.08 (m, 1H), 3.63 (t, J=7.2Hz , 2H), 3.02-2.91 (m, 1H), 2.60-2.47 (m, 2H), 2.49-2.34 (m, 1H), 2.03-1.89 (m, 1H), 1.82-1.66 (m, 1H), 1.53-1.39 (m, 2H), 1.26-1.15 (m, 2H), 1.17-1 .02(m, 1H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－９－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（３０）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－９－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）プロパン酸（９８）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５５１．２［Ｍ＋Ｈ］ ^＋ 、１．５９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．１７（ｓ，１Ｈ）、１１．５４（ｓ，１Ｈ）、８．１３（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６１（ｍ，１Ｈ）、７．４１（ｍ，１Ｈ）、７．３３（ｍ，１Ｈ）、７．２１（ｍ，２Ｈ）、７．０６（ｍ，２Ｈ）、６．９７（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．８２（ｍ，１Ｈ）、３．００－３．６０（ｍ，７Ｈ）、２．４４（ｍ，１Ｈ）、２．３１（ｍ，１Ｈ）、１．９１（ｍ，２Ｈ）、１．６６（ｍ，１Ｈ）、１．３６（ｍ，１Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．６９（ｓ）． Example 98: 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1 , 2)-Benzenacyclododecaphan-6-yl)propanoic acid (98) synthesis

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6 )-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide (30) was used to convert 3-(4,4 -dioxide-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane- 6-yl)propanoic acid (98) was synthesized. LCMS (conditions 1): m/z 551.2 [M+H] ⁺ , 1.59 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.17 (s, 1H), 11.54 (s, 1H), 8.13 (d, J=8.9Hz, 1H), 7.61 (m , 1H), 7.41 (m, 1H), 7.33 (m, 1H), 7.21 (m, 2H), 7.06 (m, 2H), 6.97 (d, J=8. 7Hz, 1H), 3.82 (m, 1H), 3.00-3.60 (m, 7H), 2.44 (m, 1H), 2.31 (m, 1H), 1.91 (m , 2H), 1.66(m, 1H), 1.36(m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.69 (s).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（３－ヒドロキシ－２，２－ジメチルプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（２８）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）－２，２－ジメチルプロパン酸（９９）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５７７．２５［Ｍ＋１］ ^＋ 、１．８１分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．４４（ｓ，１Ｈ）、１１．５９（ｓ，１Ｈ）、８．１８（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６７（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．６３－７．４４（ｍ，１Ｈ）、７．３４（ｔｄ，Ｊ＝７．５、１．５Ｈｚ、１Ｈ）、７．２８－７．１９（ｍ，２Ｈ）、７．１８－７．１０（ｍ，２Ｈ）、７．０５（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．７９－３．６３（ｍ，１Ｈ）、３．６２－３．４８（ｍ，２Ｈ）、３．４５－３．３４（ｍ，２Ｈ）、２．４０－２．２３（ｍ，１Ｈ）、２．１０－１．９３（ｍ，１Ｈ）、１．４１－１．２７（ｍ，２Ｈ）、１．２７－１．１９（ｍ，１Ｈ）、１．１９－１．１１（ｍ，２Ｈ）、１．１０（ｓ，３Ｈ）、１．０７（ｓ，３Ｈ）、０．８９－０．７６（ｍ，１Ｈ）、０．７４－０．６０（ｍ，１Ｈ）． Example 99: 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclododecaphan-6-yl)-2,2-dimethylpropanoic acid (99)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2 3-(4) was prepared using the procedure described in Example 62, except substituting 4,4-dioxide (28) for 3-(4). ,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane-6- yl)-2,2-dimethylpropanoic acid (99) was synthesized. LC-MS (conditions 1): m/z 577.25 [M+1] ⁺ , 1.81 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.44 (s, 1H), 11.59 (s, 1H), 8.18 (d, J=8.9Hz, 1H), 7.67 (dd , J = 8.7, 7.2 Hz, 1H), 7.63-7.44 (m, 1H), 7.34 (td, J = 7.5, 1.5Hz, 1H), 7.28- 7.19 (m, 2H), 7.18-7.10 (m, 2H), 7.05 (d, J=8.8Hz, 1H), 3.79-3.63 (m, 1H), 3.62-3.48 (m, 2H), 3.45-3.34 (m, 2H), 2.40-2.23 (m, 1H), 2.10-1.93 (m, 1H) ), 1.41-1.27 (m, 2H), 1.27-1.19 (m, 1H), 1.19-1.11 (m, 2H), 1.10 (s, 3H), 1.07 (s, 3H), 0.89-0.76 (m, 1H), 0.74-0.60 (m, 1H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（３－ヒドロキシ－２，２－ジメチルプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（２７）で置き換えたことを除いて、実施例６２に記載される手順を用いて、３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）－２，２－ジメチルプロパン酸（１００）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５６３．３［Ｍ＋１］ ^＋ 、１．７８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．４８（ｓ，１Ｈ）、１１．７８（ｓ，１Ｈ）、８．０９（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６９（ｄｄ，Ｊ＝８．８、７．２Ｈｚ、１Ｈ）、７．３５（ｔｄ，Ｊ＝７．５、１．５Ｈｚ、１Ｈ）、７．３０－７．２５（ｍ，２Ｈ）、７．２２（ｔｄ，Ｊ＝７．４、１．３Ｈｚ、１Ｈ）、７．１８（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．１３（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、７．０８（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、３．９４－３．７３（ｍ，１Ｈ）、３．５８（ｄ，Ｊ＝１５．３Ｈｚ、１Ｈ）、３．４５（ｄ，Ｊ＝１５．２Ｈｚ、１Ｈ）、３．３８－３．３４（ｍ，１Ｈ）、２．９３－２．８０（ｍ，１Ｈ）、２．３９－２．２８（ｍ，１Ｈ）、１．９３－１．８２（ｍ，１Ｈ）、１．８１－１．６９（ｍ，１Ｈ）、１．４２－１．２０（ｍ，２Ｈ）、１．１９－１．１１（ｍ，１Ｈ）、１．１０（ｓ，３Ｈ）、１．０７（ｓ，３Ｈ）、１．０５－０．９０（ｍ，１Ｈ）． Example 100: 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphan-6-yl)-2,2-dimethylpropanoic acid (100)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2 3-( 4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane- 6-yl)-2,2-dimethylpropanoic acid (100) was synthesized. LC-MS (conditions 1): m/z 563.3 [M+1] ⁺ , 1.78 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (s, 1H), 11.78 (s, 1H), 8.09 (d, J=8.9Hz, 1H), 7.69 (dd , J = 8.8, 7.2 Hz, 1H), 7.35 (td, J = 7.5, 1.5 Hz, 1H), 7.30-7.25 (m, 2H), 7.22 ( td, J = 7.4, 1.3 Hz, 1 H), 7.18 (d, J = 8.9 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 7.08 (d , J = 8.9 Hz, 1 H), 3.94-3.73 (m, 1 H), 3.58 (d, J = 15.3 Hz, 1 H), 3.45 (d, J = 15.2 Hz, 1H), 3.38-3.34 (m, 1H), 2.93-2.80 (m, 1H), 2.39-2.28 (m, 1H), 1.93-1.82 ( m, 1H), 1.81-1.69 (m, 1H), 1.42-1.20 (m, 2H), 1.19-1.11 (m, 1H), 1.10 (s, 3H), 1.07 (s, 3H), 1.05-0.90 (m, 1H).

６－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（３９）を、６－（５－ヒドロキシペンチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン４，４－ジオキシド（４１）で置き換えたことを除いて、実施例６２に記載される手順を用いて、５－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロトリデカファン－６－イル）ペンタン酸（１０１）を合成した。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ５９１．２［Ｍ＋１］ ^＋ 、１．９３分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．０４（ｓ，１Ｈ）、１１．７３（ｓ，１Ｈ）、８．１９（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝８．６、７．４Ｈｚ、１Ｈ）、７．４６（ｄ，Ｊ＝６．６Ｈｚ、１Ｈ）、７．３５（ｍ，１Ｈ）、７．２５（ｍ，２Ｈ）、７．１７（ｍ，２Ｈ）、６．８７（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．６１（ｍ，１Ｈ）、３．４７（ｍ，１Ｈ）、３．３０（ｍ，１Ｈ）、２．３７（ｍ，１Ｈ）、２．２５（ｍ，２Ｈ）、２．０８（ｍ，１Ｈ）、１．５２（ｍ，４Ｈ）、１．３６（ｍ，２Ｈ）、１．１５（ｍ，７Ｈ）、０．８０（ｍ，２Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．７０（ｓ）． Example 101: 5-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclotridecaphan-6-yl)pentanoic acid (101)

6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca The fan 4,4-dioxide (39) was converted to 6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 5-(4,4-dioxide-2 was prepared using the procedure described in Example 62, except substituting 1(1,2)-benzeneacyclotridecaphane 4,4-dioxide (41). ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphan-6-yl)pentanoic acid (101 ) was synthesized. LC-MS (conditions 1): m/z 591.2 [M+1] ⁺ , 1.93 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.04 (s, 1H), 11.73 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.71 (dd , J = 8.6, 7.4 Hz, 1H), 7.46 (d, J = 6.6 Hz, 1H), 7.35 (m, 1H), 7.25 (m, 2H), 7.17 (m, 2H), 6.87 (d, J=8.8Hz, 1H), 3.61 (m, 1H), 3.47 (m, 1H), 3.30 (m, 1H), 2. 37 (m, 1H), 2.25 (m, 2H), 2.08 (m, 1H), 1.52 (m, 4H), 1.36 (m, 2H), 1.15 (m, 7H) ), 0.80(m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.70 (s).

工程１．ｔｅｒｔ－ブチル４－（（３－（（２－（６－（（６－フルオロピリジン）－２－スルホンアミド）－３－（トリフルオロメチル）ピリジン－２－イル）ベンジル）オキシ）プロピル）アミノ）ブタノエートの合成
Ｎ－（６－（２－（（３－アミノプロポキシ）メチル）フェニル）－５－（トリフルオロメチル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ１３）（７０ｍｇ、０．１４ｍｍｏｌ）を、アセトニトリル（２ｍＬ）に溶解させ、４－ブロモブタン酸ｔｅｒｔ－ブチル（３６ｍｇ、０．１６ｍｍｏｌ）及びＤＩＥＡ（５０μＬ、０．２９ｍｍｏｌ）を加え、反応混合物を５５℃で１６時間撹拌した。次に、それを濃縮し、シリカゲルカラムクロマトグラフィー（ＩＳＣＯ、ＥｔＯＡｃ／ヘプタン０～１００％）によって精製して、表題化合物を白色の固体として得た。（５１ｍｇ、０．０８ｍｍｏｌ、５６％の収率）。ＬＣ－ＭＳ（条件１）：ｍ／ｚ ６２７．２［Ｍ＋Ｈ］ ^＋ 、１．８０分。 Example 102: 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1 , 2)-Benzenacycloundecaphan-6-yl)butanoic acid (102) synthesis

Step 1. tert-butyl 4-((3-((2-(6-((6-fluoropyridine)-2-sulfonamido)-3-(trifluoromethyl)pyridin-2-yl)benzyl)oxy)propyl)amino ) synthesis of butanoate N-(6-(2-((3-aminopropoxy)methyl)phenyl)-5-(trifluoromethyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b13) (70 mg, 0.14 mmol) was dissolved in acetonitrile (2 mL), tert-butyl 4-bromobutanoate (36 mg, 0.16 mmol) and DIEA (50 μL, 0.29 mmol) were added and the reaction mixture was heated to 55°C. and stirred for 16 hours. It was then concentrated and purified by silica gel column chromatography (ISCO, EtOAc/heptane 0-100%) to give the title compound as a white solid. (51 mg, 0.08 mmol, 56% yield). LC-MS (conditions 1): m/z 627.2 [M+H] ⁺ , 1.80 min.

Step 2. tert-butyl 4-(4,4-dioxide-2 ^3- (trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1, 2) Synthesis of -Benzenacycloundecaphan-6-yl)butanoate tert-butyl 4-((3-((2-(6-((6-fluoropyridine)-2-sulfonamide)-3-( Trifluoromethyl)pyridin-2-yl)benzyl)oxy)propyl)amino)butanoate (50 mg, 0.08 mmol) was dissolved in NMP (2 mL) and DIEA (0.05 mL, 0.29 mmol) in a vial. was added. After flushing with _N2 , the vial was closed and stirred at 135°C for 16 hours. The reaction was cooled to room temperature, poured into water and extracted with EtOAc. The combined organic layers _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash column chromatography (ISCO, 12 g column, MeOH/DCM 0-10%, dry packed) to give the title compound (36 mg, 0.06 mmol, 75% yield) as a white solid. Obtained. LC-MS (conditions 1): m/z 607.1 [M+H] ⁺ , 1.72 min.

Step 3. 4-(4,4-dioxide-2 ^3- (trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1, 2) Synthesis of -Benzenacycloundecaphan-6-yl)butanoic acid (102) tert-butyl 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-10-oxa-4-thia- 3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)butanoate (12 mg, 0.02 mmol) in DCM (1 mL) and HCl in dioxane (6M, 100 μL, 0.6 mmol) was added. Stir at 65° C. for 16 hours in a closed vial. The reaction was then concentrated and passed through a small silica gel column using DCM/MeOH as eluent to give the title compound as a white solid. LC-MS (conditions 1): m/z 551.2 [M+H] ⁺ , 1.78 min. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.06-7.86 (m, 2H), 7.68 (dd, J=8.7, 7.3 Hz, 1H), 7.56-7. 33 (m, 2H), 7.29-7.15 (m, 2H), 6.90 (d, J = 8.7Hz, 1H), 6.59 (d, J = 8.5Hz, 1H), 4.45-4.42 (m, 4H), 4.18-3.76 (m, 3H), 3.02-3.00 (m, 1H), 2.45-2.19 (m, 2H) ), 1.82 (p, J=7.4 Hz, 1H), 1.63 (d, J=7.0 Hz, 1H), 1.50 (s, 2H).

バイアル中で、６－フルオロ－Ｎ－（２’－フルオロ－３－（トリフルオロメチル）－［２，３’－ビピリジン］－６－イル）ピリジン－２－スルホンアミド（中間体ｂ１０）（１００ｍｇ、０．２４ｍｍｏｌ）及び１，５－ペンタンジオール（２５．０ｍｇ、０．２４ｍｍｏｌ）を、ＮＭＰ（３ｍＬ）に取り込み、次に、水素化ナトリウム（２８．８ｍｇ、０．７２ｍｏｌ、６０％）を加え、反応物を、一晩、５０℃に加熱した。反応物を１ＭのＨＣｌでクエンチし、ＥｔＯＡｃ（３回）中で抽出した。次に、有機物を、水及び塩水で洗浄し、ＭｇＳＯ _４ 上で乾燥させ、減圧下で濃縮した。粗材料を、フラッシュカラムクロマトグラフィー（ＩＳＣＯ、４ｇのＲｅｄｉＳｅｐ Ｒｆ Ｇｏｌｄカラム、ＥｔＯＡｃ／ヘプタン０～６０％）によって精製して、生成物２ ^３ －（トリフルオロメチル）－６，１２－ジオキサ－４－チア－３－アザ－１（３，２），２，５（２，６）－トリピリジナシクロドデカファン４，４－ジオキシド（１０３）を白色の固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ４８１．１［Ｍ＋Ｈ］ ^＋ 、１．７６分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６９（ｓ，１Ｈ）、８．２２（ｄｄ，Ｊ＝５．３、２．０Ｈｚ、２Ｈ）、８．０２－７．８９（ｍ，１Ｈ）、７．７６（ｄ，Ｊ＝７．７Ｈｚ、１Ｈ）、７．６９（ｄ，Ｊ＝６．４Ｈｚ、１Ｈ）、７．６３－７．５２（ｍ，１Ｈ）、７．０６（ｄｄ，Ｊ＝７．３、５．０Ｈｚ、２Ｈ）、４．３０－４．２５（ｍ，１Ｈ）、４．１１（ｓ，２Ｈ）、３．９５（ｓ，１Ｈ）、１．５１（ｓ，２Ｈ）、１．４２－１．２１（ｍ，４Ｈ）． Example 103: 2 ³ -(Trifluoromethyl)-6,12-dioxa-4-thia-3-aza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4 Synthesis of ,4-dioxide (103)

6-fluoro-N-(2′-fluoro-3-(trifluoromethyl)-[2,3′-bipyridin]-6-yl)pyridine-2-sulfonamide (intermediate b10) (100 mg) in a vial , 0.24 mmol) and 1,5-pentanediol (25.0 mg, 0.24 mmol) were taken in NMP (3 mL), then sodium hydride (28.8 mg, 0.72 mol, 60%) was added. , the reaction was heated to 50° C. overnight. The reaction was quenched with 1M HCl and extracted into EtOAc (3x). The organics _were then washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The crude material is purified by flash column chromatography (ISCO, 4 g RediSep Rf Gold column, EtOAc/heptane 0-60%) to give the product 2 ^3- (trifluoromethyl)-6,12-dioxa-4- Thia-3-aza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide (103) was obtained as a white solid. LCMS (conditions 1): m/z 481.1 [M+H] ⁺ , 1.76 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.69 (s, 1H), 8.22 (dd, J=5.3, 2.0 Hz, 2H), 8.02-7.89 (m, 1H), 7.76 (d, J = 7.7Hz, 1H), 7.69 (d, J = 6.4Hz, 1H), 7.63-7.52 (m, 1H), 7.06 ( dd, J = 7.3, 5.0 Hz, 2H), 4.30-4.25 (m, 1H), 4.11 (s, 2H), 3.95 (s, 1H), 1.51 ( s, 2H), 1.42-1.21 (m, 4H).

１，５－ペンタンジオールを、シクロオクタン－１，５－ジオールで置き換えたことを除いて、実施例１０３に記載される手順を用いて、（４ ^１ ｓ，４ ^５ ｓ）－１ ^３ －（トリフルオロメチル）－３，５－ジオキサ－７－チア－８－アザ－１，６（２，６），２（３，２）－トリピリジナ－４（１，５）－シクロオクタナシクロオクタファン７，７－ジオキシド（１０４）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５２１．１［Ｍ＋Ｈ］ ^＋ 、１．８０分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７４（ｓ，１Ｈ）、８．１９（ｓ，２Ｈ）、７．８３（ｓ，１Ｈ）、７．５３－７．４８（ｍ，３Ｈ）、７．０２－６．９１（ｍ，２Ｈ）、５．１２－４．９８（ｍ，２Ｈ）、１．８５－１．０３（ｍ，１２Ｈ）． Example 104: (4 ¹ s,4 ⁵ s)-1 ³ -(trifluoromethyl)-3,5-dioxa-7-thia-8-aza-1,6(2,6),2(3, 2) Synthesis of -tripyridina-4(1,5)-cyclooctanacyclooctaphane 7,7-dioxide (104)

(4 ¹ s,4 ⁵ s)-1 ³ -( trifluoromethyl)-3,5-dioxa-7-thia-8-aza-1,6(2,6),2(3,2)-tripyridina-4(1,5)-cyclooctanacyclooctaphane A 7,7-dioxide (104) was synthesized. LCMS (conditions 1): m/z 521.1 [M+H] ⁺ , 1.80 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.74 (s, 1H), 8.19 (s, 2H), 7.83 (s, 1H), 7.53-7.48 (m, 3H) ), 7.02-6.91 (m, 2H), 5.12-4.98 (m, 2H), 1.85-1.03 (m, 12H).

マイクロ波バイアル中で、Ｎ－（２’，３－ジクロロ－［２，３’－ビピリジン］－６－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ１１）（１００ｍｇ、０．２５ｍｍｏｌ）及びペンタン－１，５－ジアミン（２５．６ｍｇ、０．２５ｍｍｏｌ）を、ＮＭＰ（３ｍＬ）に取り込み、次に、ＤＩＥＡ（０．１３ｍＬ、０．７５ｍｍｏｌ）を加え、反応物を、１時間にわたって２００℃に加熱した。反応物をろ過し、質量トリガー分取（ｍａｓｓ－ｔｒｉｇｇｅｒｅｄ ｐｒｅｐａｒａｔｏｒｙ）ＨＰＬＣ（２０～４０％のＭｅＣＮ／Ｈ _２ Ｏ＋ＴＦＡ、１００ｍＬ／分）によって精製した。画分をＧｅｎｅｖａｃによって濃縮し、残渣をＭｅＯＨに取り込み、ｉＰｒＯＨ中１ＭのＨＣｌを加え、減圧下で濃縮して、生成物２ ^３ －クロロ－４－チア－３，６，１２－トリアザ－１（３，２），２，５（２，６）－トリピリジナシクロドデカファン４，４－ジオキシド（１０５）を褐色の固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ４４５．１［Ｍ＋Ｈ］ ^＋ 、１．２５分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．３９（ｓ，１Ｈ）、８．１０－７．８２（ｍ，３Ｈ）、７．５２－７．４４（ｍ，１Ｈ）、７．３９（ｓ，１Ｈ）、７．１９－６．９５（ｍ，３Ｈ）、６．８８（ｓ，１Ｈ）、６．５８（ｄ，Ｊ＝８．５Ｈｚ、１Ｈ）、３．３９（ｓ，４Ｈ）、１．６１（ｓ，２Ｈ）、１．４１（ｓ，２Ｈ）、１．２４－１．２２（ｍ，２Ｈ）． Example 105: 2 ³ -Chloro-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide (105 ) synthesis

N-(2′,3-dichloro-[2,3′-bipyridin]-6-yl)-6-fluoropyridine-2-sulfonamide (intermediate b11) (100 mg, 0.25 mmol) in a microwave vial ) and pentane-1,5-diamine (25.6 mg, 0.25 mmol) were taken in NMP (3 mL), then DIEA (0.13 mL, 0.75 mmol) was added and the reaction was allowed to Heated to 200°C. The reaction was filtered and purified by mass-triggered preparatory HPLC (20-40% MeCN/H ₂ O+TFA, 100 mL/min). Fractions are concentrated by Genevac, the residue is taken up in MeOH, 1M HCl in iPrOH is added and concentrated under reduced pressure to give the product 2 ³ -Chloro-4-thia-3,6,12-triaza-1 ( 3,2),2,5(2,6)-Tripyridinacyclododecaphane 4,4-dioxide (105) was obtained as a brown solid. LCMS (conditions 1): m/z 445.1 [M+H] ⁺ , 1.25 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.39 (s, 1H), 8.10-7.82 (m, 3H), 7.52-7.44 (m, 1H), 7.39 (s, 1H), 7.19-6.95 (m, 3H), 6.88 (s, 1H), 6.58 (d, J=8.5Hz, 1H), 3.39 (s, 4H) ), 1.61 (s, 2H), 1.41 (s, 2H), 1.24-1.22 (m, 2H).

Ｎ－（２’，３－ジクロロ－［２，３’－ビピリジン］－６－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ１１）を、Ｎ－（２’，３－ジクロロ－４’－メチル－［２，３’－ビピリジン］－６－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ１２）で置き換えたことを除いて、実施例１０６に記載される手順を用いて、２ ^３ －クロロ－１ ^４ －メチル－４－チア－３，６，１２－トリアザ－１（３，２），２，５（２，６）－トリピリジナシクロドデカファン４，４－ジオキシド（１０６）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４５９．１［Ｍ＋Ｈ］ ^＋ 、１．４４分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ７．８６（ｄ，Ｊ＝５．４Ｈｚ、１Ｈ）、７．８１（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．５３（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．４７（ｄｄ，Ｊ＝８．５、７．１Ｈｚ、１Ｈ）、７．１７（ｄｄ，Ｊ＝７．２、０．７Ｈｚ、１Ｈ）、６．５７（ｄｄ，Ｊ＝８．５、０．８Ｈｚ、１Ｈ）、６．５３（ｄ，Ｊ＝５．４Ｈｚ、１Ｈ）、３．８４（ｓ，１Ｈ）、３．５８（ｄｄ，Ｊ＝１１．７、７．３Ｈｚ、１Ｈ）、３．１２－３．０２（ｍ，１Ｈ）、２．９９－２．９３（ｍ，１Ｈ）、１．９５（ｓ，３Ｈ）、１．６５－１．６３（ｍ，２Ｈ）、１．４７－１．３７（ｍ，２Ｈ）、１．２９－１．１８（ｍ，２Ｈ）． Example 106: 2 ³ -Chloro-1 ⁴ -methyl-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4, Synthesis of 4-dioxide (106)

N-(2′,3-dichloro-[2,3′-bipyridin]-6-yl)-6-fluoropyridine-2-sulfonamide (intermediate b11) was converted to N-(2′,3-dichloro- The procedure described in Example 106 was followed except that 4′-methyl-[2,3′-bipyridin]-6-yl)-6-fluoropyridine-2-sulfonamide (intermediate b12) was substituted. 2 ³ -Chloro-1 ⁴ -methyl-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4 - Dioxide (106) was synthesized. LCMS (conditions 1): m/z 459.1 [M+H] ⁺ , 1.44 min. ¹ H NMR (400 MHz, methanol- _d ) δ 7.86 (d, J = 5.4 Hz, 1 H), 7.81 (d, J = 8.9 Hz, 1 H), 7.53 (d, J = 8.9Hz, 1H), 7.47 (dd, J = 8.5, 7.1Hz, 1H), 7.17 (dd, J = 7.2, 0.7Hz, 1H), 6.57 (dd , J=8.5, 0.8 Hz, 1 H), 6.53 (d, J=5.4 Hz, 1 H), 3.84 (s, 1 H), 3.58 (dd, J=11.7, 7.3 Hz, 1H), 3.12-3.02 (m, 1H), 2.99-2.93 (m, 1H), 1.95 (s, 3H), 1.65-1.63 ( m, 2H), 1.47-1.37 (m, 2H), 1.29-1.18 (m, 2H).

工程１．Ｎ－（２’，３－ジクロロ－［２，３’－ビピリジン］－６－イル）－６－（（５－ヒドロキシペンチル）アミノ）ピリジン－２－スルホンアミドの合成
マイクロ波バイアル中で、Ｎ－（２’，３－ジクロロ－［２，３’－ビピリジン］－６－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ１１）（１００ｍｇ、０．２５ｍｍｏｌ）及び５－アミノ－１－ペンタノール（５１．７ｍｇ、０．２５ｍｍｏｌ、５０％）を、ＮＭＰ（３ｍＬ）に取り込み、次に、ＤＩＥＡ（０．１３ｍＬ、０．７５ｍｍｏｌ）を加え、反応物を、マイクロ波中で、１時間にわたって２００℃に加熱した。反応物を、１ＭのＨＣｌでクエンチし、ＥｔＯＡｃ（３回）中で抽出した。次に、有機物を、水及び塩水で洗浄し、ＭｇＳＯ _４ 上で乾燥させ、減圧下で濃縮した。粗材料を、フラッシュカラムクロマトグラフィー（ＩＳＣＯ、４ｇのＲｅｄｉＳｅｐ Ｒｆ Ｇｏｌｄカラム、０～８０％のＥｔＯＡｃ／ヘプタン）によって精製して、表題化合物（８６ｍｇ、０．１８ｍｍｏｌ、７２％の収率）をオフホワイトの固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ４８２．０［Ｍ＋Ｈ］ ^＋ 、１．４７分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ８．４３（ｄｄ，Ｊ＝４．９、１．９Ｈｚ、１Ｈ）、７．８４（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７１（ｄｄ，Ｊ＝７．６、１．９Ｈｚ、１Ｈ）、７．５６（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．５０－７．４１（ｍ，２Ｈ）、７．０９（ｄｄ，Ｊ＝７．２、０．６Ｈｚ、１Ｈ）、６．５９（ｄｄ，Ｊ＝８．５、０．７Ｈｚ、１Ｈ）、３．５２（ｔ，Ｊ＝６．６Ｈｚ、２Ｈ）、３．１４（ｔ，Ｊ＝７．０Ｈｚ、２Ｈ）、１．５７－１．４１（ｍ，４Ｈ）、１．４１－１．２９（ｍ，２Ｈ）． Example 107: 2 ³ -Chloro-12-oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide Synthesis of (107)

Step 1. Synthesis of N-(2′,3-dichloro-[2,3′-bipyridin]-6-yl)-6-((5-hydroxypentyl)amino)pyridine-2-sulfonamide In a microwave vial, N -(2′,3-dichloro-[2,3′-bipyridin]-6-yl)-6-fluoropyridine-2-sulfonamide (intermediate b11) (100 mg, 0.25 mmol) and 5-amino-1 -Pentanol (51.7 mg, 0.25 mmol, 50%) was taken up in NMP (3 mL), followed by DIEA (0.13 mL, 0.75 mmol) and the reaction was stirred in the microwave for 1 Heated to 200° C. for hours. The reaction was quenched with 1M HCl and extracted into EtOAc (3x). The organics _were then washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by flash column chromatography (ISCO, 4 g RediSep Rf Gold column, 0-80% EtOAc/heptane) to give the title compound (86 mg, 0.18 mmol, 72% yield) as an off-white obtained as a solid. LCMS (conditions 1): m/z 482.0 [M+H] ⁺ , 1.47 min. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.43 (dd, J=4.9, 1.9 Hz, 1 H), 7.84 (d, J=8.9 Hz, 1 H), 7.71 ( dd, J = 7.6, 1.9 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.50-7.41 (m, 2H), 7.09 (dd, J = 7.2, 0.6Hz, 1H), 6.59 (dd, J = 8.5, 0.7Hz, 1H), 3.52 (t, J = 6.6Hz, 2H), 3.14 ( t, J=7.0 Hz, 2H), 1.57-1.41 (m, 4H), 1.41-1.29 (m, 2H).

Step 2.2 ³ -Chloro-12-oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide vial in N-(2′,3-dichloro-[2,3′-bipyridin]-6-yl)-6-((5-hydroxypentyl)amino)pyridine-2-sulfonamide (86 mg, 0.18 mmol ) was taken in NMP (3 mL), then sodium hydride (22 mg, 0.54 mmol, 60%) was added and the reaction was heated to 50° C. overnight. The reaction was quenched with 1M HCl and extracted into EtOAc (3x). The organics _were then washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by flash column chromatography (ISCO, 4g RediSep Rf Gold column, EtOAc/heptane 0-80%) to afford the title compound (107) as a white solid. LCMS (conditions 1): m/z 446.1 [M+H] ⁺ , 1.77 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.94 (s, 1H), 8.21 (dd, J=5.0, 1.9 Hz, 1H), 7.91 (d, J=8. 9Hz, 1H), 7.67 (dd, J = 7.2, 1.7Hz, 1H), 7.58 (d, J = 8.9Hz, 1H), 7.51 (dd, J = 8.5 , 7.2 Hz, 1 H), 7.06 (dd, J = 7.2, 5.0 Hz, 2 H), 7.00 (d, J = 7.1 Hz, 1 H), 6.60 (d, J = 8.5 Hz, 1H), 4.24-4.22 (m, 2H), 3.06 (s, 2H), 1.55 (s, 2H), 1.24-1.19 (m, 2H) , 1.10(s, 2H).

Ｎ－（２’，３－ジクロロ－［２，３’－ビピリジン］－６－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ１１）を、６－フルオロ－Ｎ－（２’－フルオロ－３－（トリフルオロメチル）－［２，３’－ビピリジン］－６－イル）ピリジン－２－スルホンアミド（中間体ｂ１０）で置き換えたことを除いて、実施例１０７に記載される手順を用いて、２ ^３ －（トリフルオロメチル）－１ ^２ －オキサ－４－チア－３，６－ジアザ－１（３，２），２，５（２，６）－トリピリジナシクロドデカファン４，４－ジオキシド（１０８）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４８０．１［Ｍ＋Ｈ］ ^＋ 、１．８２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．３９（ｓ，１Ｈ）、８．２８－８．１０（ｍ，２Ｈ）、７．７０（ｄｄ，Ｊ＝１５．７、８．１Ｈｚ、２Ｈ）、７．５３（ｄｄ，Ｊ＝８．５、７．２Ｈｚ、１Ｈ）、７．１２（ｓ，１Ｈ）、７．０８－６．９８（ｍ，２Ｈ）、６．６３（ｄ，Ｊ＝８．５Ｈｚ、１Ｈ）、４．２８－４．１０（ｍ，２Ｈ）、３．０８－３．０３（ｍ，２Ｈ）、１．５３－１．４５（ｍ，２Ｈ）、１．１９－１．１４（ｍ，４Ｈ）． Example 108: 2 ³ -(Trifluoromethyl)-1 ² -oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane Synthesis of 4,4-dioxide (108)

N-(2′,3-dichloro-[2,3′-bipyridin]-6-yl)-6-fluoropyridine-2-sulfonamide (intermediate b11) was converted to 6-fluoro-N-(2′- Procedure as described in Example 107, except substituting fluoro-3-(trifluoromethyl)-[2,3′-bipyridin]-6-yl)pyridine-2-sulfonamide (intermediate b10) using 2 ³ -(trifluoromethyl)-1 ² -oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane A 4,4-dioxide (108) was synthesized. LCMS (conditions 1): m/z 480.1 [M+H] ⁺ , 1.82 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.39 (s, 1H), 8.28-8.10 (m, 2H), 7.70 (dd, J = 15.7, 8.1 Hz, 2H), 7.53 (dd, J = 8.5, 7.2 Hz, 1H), 7.12 (s, 1H), 7.08-6.98 (m, 2H), 6.63 (d, J=8.5 Hz, 1H), 4.28-4.10 (m, 2H), 3.08-3.03 (m, 2H), 1.53-1.45 (m, 2H), 1. 19-1.14 (m, 4H).

工程１．ｔｅｒｔ－ブチルジメチル（ペンタ－４－エン－１－イルオキシ）シランの合成
０℃でＤＣＭ（２００ｍＬ）中のペンタ－４－エン－１－オール（３．００ｇ、３４．８ｍｍｏｌ）の溶液に、ｔｅｒｔ－ブチルジメチルシリルクロリド（１１．６ｇ、７６．７ｍｍｏｌ）及びイミダゾール（５．７０ｇ、８３．７ｍｍｏｌ）を加えた。反応混合物を０℃で２０分間撹拌し、次に、室温に温め、１．５時間撹拌した。次に、反応物を水でクエンチした。層を分離し、水性層をジクロロメタン（２回）で抽出し、塩水で洗浄した。組み合わされた有機抽出物をＮａ _２ ＳＯ _４ 上で乾燥させ、濃縮して、表題化合物（７．１０ｇ、３４．７ｍｍｏｌ、１００％の収率）を油として得た。粗生成物を、さらに精製せずに次の工程に利用した。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、クロロホルム－ｄ）δ ５．８２（ｄｄｔ，Ｊ＝６．６、１０．２、１６．９Ｈｚ、１Ｈ）、５．０２（ｄｑ，Ｊ＝１．７、１７．１Ｈｚ、１Ｈ）、４．９５（ｄｄｔ，Ｊ＝１．２、２．２、１０．２Ｈｚ、１Ｈ）、３．６２（ｔ，Ｊ＝６．５Ｈｚ、２Ｈ）、２．０９（ｍ，２Ｈ）、１．６１（ｄｑ，Ｊ＝６．５、８．３Ｈｚ、２Ｈ）、０．８９（ｓ，９Ｈ）、０．０５（ｓ，６Ｈ）． Example 109: 7-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphane 4,4-dioxide (109) Synthesis

Step 1. Synthesis of tert-butyldimethyl(pent-4-en-1-yloxy)silane To a solution of pent-4-en-1-ol (3.00 g, 34.8 mmol) in DCM (200 mL) at 0° C. was added tert -Butyldimethylsilyl chloride (11.6 g, 76.7 mmol) and imidazole (5.70 g, 83.7 mmol) were added. The reaction mixture was stirred at 0° C. for 20 minutes, then warmed to room temperature and stirred for 1.5 hours. The reaction was then quenched with water. The layers were separated and the aqueous layer was extracted with dichloromethane (2x) and washed with brine. The combined organic extracts were dried over Na ₂ SO ₄ and concentrated to give the title compound (7.10 g, 34.7 mmol, 100% yield) as an oil. The crude product was taken on to the next step without further purification. ¹ H NMR (400 MHz, chloroform-d) δ 5.82 (ddt, J=6.6, 10.2, 16.9 Hz, 1 H), 5.02 (dq, J=1.7, 17.1 Hz, 1H), 4.95 (ddt, J = 1.2, 2.2, 10.2 Hz, 1H), 3.62 (t, J = 6.5 Hz, 2H), 2.09 (m, 2H), 1.61 (dq, J=6.5, 8.3 Hz, 2H), 0.89 (s, 9H), 0.05 (s, 6H).

Step 2. Synthesis of tert-butyldimethyl(3-(oxiran-2-yl)propoxy)silane m-CPBA (5.87 g, 26.2 mmol) (77% w/w in H ₂ O) was added to DCM (100 mL) at 0 °C. was added to a solution of tert-butyldimethyl(pent-4-en-1-yloxy)silane (3.50 g, 17.5 mmol) in ). The reaction mixture was stirred at 0° C. for 20 minutes, then warmed to room temperature and stirred overnight before adding saturated aqueous Na ₂ CO ₃ and NaHSO ₃ (1:1) solutions. The layers were separated and the aqueous layer was further extracted with DCM. The combined organic layers _were dried, washed with saturated _NaHCO3 solution, dried over _Na2SO4 and concentrated. Purification by ISCO silica gel column (EtOAc/heptane 5%) gave the title compound (1.84 g, 49% yield) as a colorless oil. ¹ H NMR (400 MHz, chloroform-d) δ 3.64 (m, 2H), 2.95 (m, 1H), 2.75 (dd, J = 4.1, 4.9 Hz, 1H),2. 48 (dd, J=2.7, 5.0 Hz, 1H), 1.64 (m, 4H), 0.89 (s, 9H), 0.05 (s, 6H).

Step 3. Synthesis of 1-((tert-Butyldimethylsilyl)oxy)oct-7-en-4-ol A flask was charged with copper(I) iodide (0.317 g, 1.66 mmol) and dried under reduced pressure. was gently heated at , then cooled slowly under a stream of nitrogen. Dry ether (50 mL) was added, the resulting suspension was cooled to −78° C., stirred and allylmagnesium bromide (1M in diethyl ether, 15 ml, 15 mmol) was added. A solution of tert-butyldimethyl(3-(oxiran-2-yl)propoxy)silane (1.69 g, 6.54 mmol) in dry ether (10 mL) was added to the above mixture and stirred at −78° C. for 4 hours. did. The reaction was quenched with saturated aqueous NH4Cl, extracted with EA _{( x3} ), washed with brine and dried over _Na2SO4 . Purification on an ISCO silica gel column (EtOAc/heptane 0-15%) gave the title compound (1.69 g, 79% yield) as an oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.81 (ddt, J=6.6, 10.2, 16.9 Hz, 1H), 4.99 (m, 1H), 4.92 (ddt, J = 1.2, 2.3, 10.2Hz, 1H), 4.35 (d, J = 5.5Hz, 1H), 3.56 (t, J = 6.4Hz, 2H), 3.38 (m, 1H), 2.06 (m, 2H), 1.39 (m, 6H), 0.86 (s, 9H), 0.02 (s, 6H).

Step 4. 6-((1-((tert-Butyldimethylsilyl)oxy)oct-7-en-4-yl)oxy)-N-(5-(trifluoromethyl)-6-(2-vinylphenyl) )pyridin-2-yl)pyridin-2-sulfonamide 6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl) in DMF (5 mL) To a solution of pyridine-2-sulfonamide (intermediate b2) (200 mg, 0.47 mmol) and 1-((tert-butyldimethylsilyl)oxy)oct-7-en-4-ol (610 mg, 2.36 mmol) , NaH (189 mg, 4.7 mmol) was added under a nitrogen atmosphere. The mixture was stirred at room temperature for 45 minutes, quenched with water, acidified with a 10% solution of citric acid and extracted with EtOAc. The combined layers were washed with water, _NaHCO3 , brine ₍ x2) and dried over _Na2SO4 . Purification on an ISCO silica gel column (EtOAc/heptane 0-100%) gave the title compound (185 mg, 0.165 mmol, 59% yield) as an oil. Conditions 1, LCMS: m/z 662.3 [M+H] ⁺ , 2.06 min.

Step 5. 6-((1-Hydroxyoct-7-en-4-yl)oxy)-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine- Synthesis of 2-sulfonamides 6-((1-((tert-butyldimethylsilyl)oxy)oct-7-en-4-yl)oxy)-N-(5-(trifluoromethyl )-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (185 mg, 0.28 mmol) was added TBAF (1 M in THF, 2 mL, 2 mmol) under nitrogen atmosphere. . The mixture was stirred at room temperature for 45 minutes. Water was added and extracted with EtOAc. The combined extracts _were washed with brine and dried over _Na2SO4 . Purification on an ISCO silica gel column (EtOAc/heptane 0-100%) gave the title compound (101 mg, 66% yield) as an oil: LCMS (conditions 1): m/z 548.3 [M+H] ⁺ . , 1.69 min. ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -56.97 (s).

Step 6. (E)-7-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphan-10-ene 4,4-dioxide Synthesis of 6-((1-hydroxyoct-7-en-4-yl)oxy)-N-(5- A 100 mL flask containing a solution of (trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (101 mg, 0.184 mmol) was purged with argon. Grubbs II catalyst (16 mg, 0.018 mmol) was added and purged with argon again. The flask was capped and the reaction mixture was stirred at 45° C. for 40 hours. The reaction mixture was loaded directly onto silica and purified on an ISCO silica gel column (EtOAc/heptane 0-50%) to give the title compound (93 mg, 95% yield) as white crystals. LCMS (conditions 1): m/z 520.2 [M+H] ⁺ , 1.65 min. ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 57.16 (s), 57.51 (s). Diastereomers, 55:45 ratio.

Step 7. 7-(3-Hydroxypropyl)-2 ³ -(trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2) - Synthesis of Benzenacycloundecaphane 4,4-dioxide (109) (E)-7-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-6-oxa-4 in EtOAc (10 mL) - thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-10-ene 4,4-dioxide (95 mg, 0.183 mmol). , hydrogenated over PtO _dihydrate (10 mg, 0.044 mmol) with a hydrogen balloon at room temperature overnight. The slurry was filtered to remove the catalyst and the filtrate was concentrated. Purification on an ISCO silica gel column (EtOAc/heptane 0-50%) gave the title compound as white crystals. LCMS (conditions 1): m/z 522.2 [M+H] ⁺ , 1.68 min. ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.83 (s), -57.56 (s). Diastereomers, 42:58 ratio.

工程１．３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－６－オキサ－４－チア－３－アザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－７－イル）プロパナールの合成
ＤＣＭ（２ｍＬ）中の７－（３－ヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－６－オキサ－４－チア－３－アザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１０９）（６６ｍｇ、０．１２７ｍｍｏｌ）の溶液に、デス・マーチン・ペルヨージナン（７０ｍｇ、０．１７ｍｍｏｌ）を０℃で一度に加えた。混合物を、ゆっくりと室温に温め、４時間撹拌した。飽和ＮａＨＣＯ _３ 水溶液（１ｍＬ）及び飽和Ｎａ _２ Ｓ _２ Ｏ _３ 水溶液（１ｍＬ）を加えた。混合物を１５分間にわたって激しく撹拌してから、層を分離した。水性層をＤＣＭ（３回）で抽出し、組み合わされた有機層を塩水で洗浄し、Ｎａ _２ ＳＯ _４ 上で乾燥させ、ろ過し、濃縮した。残渣を、ＩＳＣＯシリカゲルカラム（ＥｔＯＡｃ／ヘプタン０～６０％）によって精製して、表題化合物（５９ｍｇ、０．１１３ｍｍｏｌ、８９％の収率）を白色の固体として得た。条件１、ＬＣＭＳ：ｍ／ｚ ５２０．２［Ｍ＋Ｈ］ ^＋ 、１．７３分。 Example 110: 3-(4,4-dioxide-2 ^3- (trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphan-7-yl)propanoic acid (110)

Step 1. 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2) -Synthesis of Benzenacycloundecaphan-7-yl)propanal 7-(3-Hydroxypropyl)-2 ^3- (trifluoromethyl)-6-oxa-4-thia-3- in DCM (2 mL) To a solution of aza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide (109) (66 mg, 0.127 mmol) was added Dess-Martin periodinane. (70 mg, 0.17 mmol) was added in one portion at 0°C. The mixture was slowly warmed to room temperature and stirred for 4 hours. A saturated aqueous NaHCO ₃ solution (1 mL) and a saturated aqueous Na ₂ S ₂ O ₃ solution (1 mL) were added. The mixture was vigorously stirred for 15 minutes and then the layers were separated. The aqueous layer was extracted with DCM (3x) and the combined organic layers _were washed with brine, dried over _Na2SO4 , filtered and concentrated. The residue was purified by ISCO silica gel column (EtOAc/heptane 0-60%) to give the title compound (59 mg, 0.113 mmol, 89% yield) as a white solid. Conditions 1, LCMS: m/z 520.2 [M+H] ⁺ , 1.73 min.

Step 2. 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2) - Synthesis of Benzenacycloundecaphan-7-yl)propanoic acid (110) 3-(4,4-dioxide-2 ³ -(trifluoromethyl)- in THF (2 mL) and t-BuOH (2 mL) 6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzonacycloundecaphan-7-yl)propanal (52 mg, 0.10 mmol) 2-methyl-2-butene (0.5 mL, 4.7 mmol) followed by NaH ₂ PO ₄ (72 mg, 0.6 mmol) in water (0.25 mL) and water (0.25 mL) of NaClO ₂ (68 mg, 0.6 mmol) was added. The solution was stirred at room temperature for 3 hours. Water was added, extracted with DCM (3x), the combined organic layers _were washed with brine, dried over _Na2SO4 , filtered and concentrated. The residue was purified by ISCO silica gel column (EtOAc/heptane 0-100%) to give the title compound as a white solid. LCMS (conditions 1): m/z 536.2 [M+H] ⁺ , 1.65 min, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.08 (s, 1.6H), 11.53 (s , 0.4H), 8.28 (d, J = 9.0Hz, 0.4H), 8.08 (d, J = 8.9Hz, 0.6H), 7.97 (m, 1H), 7 .83 (m, 0.4H), 7.75 (d, J = 7.0Hz, 0.6H), 7.55 (d, J = 7.2Hz, 0.4H), 7.29 (m, 3.6H), 7.15 (m, 1H), 7.03 (m, 1H), 5.42 (m, 0.6H), 4.34 (m, 0.4H), 2.24 (m , 3.4H), 1.86 (m, 0.6H), 0.9-1.8 (m, 8H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.74 (s, 0.4 F), -57.52 (s, 0.6 F). Diastereomers, 2:3 ratio.

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、Ｎ－（５－クロロ－６－（２－ビニルフェニル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ３）で置き換え、１－（（ｔｅｒｔ－ブチルジメチルシリル）オキシ）オクタ－７－エン－４－オールを、ヘキサ－５－エン－１－オールで置き換えたことを除いて、実施例１０９に記載される手順を用いて、２ ^３ －クロロ－６－オキサ－４－チア－３－アザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（１１１）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４４４．１［Ｍ＋Ｈ］ ^＋ 、１．７９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．５１（ｓ，１Ｈ）、７．９５（ｍ，２Ｈ）、７．６１（ｄ，Ｊ＝７．３Ｈｚ、１Ｈ）、７．３８（ｄ，Ｊ＝８．５Ｈｚ、１Ｈ）、７．３２（ｍ，１Ｈ）、７．２６（ｍ，２Ｈ）、７．１９（ｍ，１Ｈ）、７．０５（ｄ，Ｊ＝８．３Ｈｚ、１Ｈ）、４．２４（ｓ，２Ｈ）、２．５５（ｍ，１Ｈ）、２．１７（ｍ，１Ｈ）、１．３８（ｓ，２Ｈ）、１．０９（ｍ，６Ｈ）． Example 111: 2 ³ -Chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide ( 111) synthesis

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to N-(5-chloro-6 -(2-vinylphenyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b3) to replace 1-((tert-butyldimethylsilyl)oxy)oct-7-ene-4 2 ³ -chloro-6-oxa-4-thia-3-aza- was prepared using the procedure described in Example 109, except that -ol was replaced with hex-5-en-1-ol. 2,5(2,6)-Dipyridina-1(1,2)-Benzenacyclododecaphane 4,4-dioxide (111) was synthesized. LCMS (conditions 1): m/z 444.1 [M+H] ⁺ , 1.79 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.51 (s, 1H), 7.95 (m, 2H), 7.61 (d, J = 7.3 Hz, 1H), 7.38 (d , J = 8.5Hz, 1H), 7.32 (m, 1H), 7.26 (m, 2H), 7.19 (m, 1H), 7.05 (d, J = 8.3Hz, 1H ), 4.24 (s, 2H), 2.55 (m, 1H), 2.17 (m, 1H), 1.38 (s, 2H), 1.09 (m, 6H).

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、Ｎ－（５－クロロ－６－（２－ビニルフェニル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ３）で置き換え、１－（（ｔｅｒｔ－ブチルジメチルシリル）オキシ）オクタ－７－エン－４－オールを、ブタ－３－エン－１－オールで置き換えたことを除いて、実施例１０９に記載される手順を用いて、２ ^３ －クロロ－６－オキサ－４－チア－３－アザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン４，４－ジオキシド（１１２）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４１６．１［Ｍ＋Ｈ］ ^＋ 、１．６９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．２５（ｓ，１Ｈ）、７．９５（ｍ，２Ｈ）、７．６１（ｄ，Ｊ＝７．３Ｈｚ、１Ｈ）、７．３５（ｍ，３Ｈ）、７．２８（ｔｄ，Ｊ＝１．８、７．２Ｈｚ、１Ｈ）、７．２１（ｄｄ，Ｊ＝１．１、７．５Ｈｚ、１Ｈ）、７．０２（ｄ，Ｊ＝８．３Ｈｚ、１Ｈ）、４．１０（ｓ，２Ｈ）、２．６５（ｍ，１Ｈ）、２．０４（ｍ，１Ｈ）、１．４８（ｍ，４Ｈ）． Example 112: 2 ³ -Chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide ( 112) synthesis

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to N-(5-chloro-6 -(2-vinylphenyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b3) to replace 1-((tert-butyldimethylsilyl)oxy)oct-7-ene-4 2 ³ -chloro-6-oxa-4-thia-3-aza- was prepared using the procedure described in Example 109, except that but-3-en-1-ol was substituted for but-3-en-1-ol. 2,5(2,6)-Dipyridina-1(1,2)-Benzenacyclodecaphane 4,4-dioxide (112) was synthesized. LCMS (conditions 1): m/z 416.1 [M+H] ⁺ , 1.69 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.25 (s, 1H), 7.95 (m, 2H), 7.61 (d, J = 7.3 Hz, 1H), 7.35 (m , 3H), 7.28 (td, J = 1.8, 7.2 Hz, 1H), 7.21 (dd, J = 1.1, 7.5 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 4.10 (s, 2H), 2.65 (m, 1H), 2.04 (m, 1H), 1.48 (m, 4H).

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、Ｎ－（５－クロロ－６－（２－ビニルフェニル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ３）で置き換え、１－（（ｔｅｒｔ－ブチルジメチルシリル）オキシ）オクタ－７－エン－４－オールを、ペンタ－４－エン－１－オールで置き換えたことを除いて、実施例１０９に記載される手順を用いて、２ ^３ －クロロ－６－オキサ－４－チア－３－アザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１１３）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４３０．２［Ｍ＋Ｈ］ ^＋ 、１．７５分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．３２（ｓ，１Ｈ）、７．９５（ｍ，２Ｈ）、７．６２（ｄ，Ｊ＝７．３Ｈｚ、１Ｈ）、７．４４（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．３４（ｔｄ，Ｊ＝１．４、７．４Ｈｚ、１Ｈ）、７．２７（ｍ，２Ｈ）、７．１３（ｍ，１Ｈ）、７．０３（ｄ，Ｊ＝８．４Ｈｚ、１Ｈ）、４．１１（ｍ，１Ｈ）、３．８３（ｍ，１Ｈ）、２．３７（ｍ，１Ｈ）、２．２４（ｍ，１Ｈ）、１．３３（ｍ，６Ｈ）． Example 113: 2 ³ -Chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide Synthesis of (113)

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to N-(5-chloro-6 -(2-vinylphenyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b3) to replace 1-((tert-butyldimethylsilyl)oxy)oct-7-ene-4 2 ³ -chloro-6-oxa-4-thia-3-aza- was prepared using the procedure described in Example 109, except that pent-4-en-1-ol was substituted for 2 3 -ol. 2,5(2,6)-Dipyridina-1(1,2)-Benzenacycloundecaphane 4,4-dioxide (113) was synthesized. LCMS (conditions 1): m/z 430.2 [M+H] ⁺ , 1.75 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.32 (s, 1H), 7.95 (m, 2H), 7.62 (d, J = 7.3 Hz, 1H), 7.44 (d , J = 8.9 Hz, 1H), 7.34 (td, J = 1.4, 7.4 Hz, 1H), 7.27 (m, 2H), 7.13 (m, 1H), 7.03 (d, J=8.4 Hz, 1 H), 4.11 (m, 1 H), 3.83 (m, 1 H), 2.37 (m, 1 H), 2.24 (m, 1 H), 1. 33(m, 6H).

６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）を、Ｎ－（５－クロロ－６－（２－ビニルフェニル）ピリジン－２－イル）－６－フルオロピリジン－２－スルホンアミド（中間体ｂ３）で置き換え、１－（（ｔｅｒｔ－ブチルジメチルシリル）オキシ）オクタ－７－エン－４－オールを、プロパ－２－エン－１－オールで置き換えたことを除いて、実施例１０９に記載される手順を用いて、２ ^３ －クロロ－６－オキサ－４－チア－３－アザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロノナファン４，４－ジオキシド（１１４）を、合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４０２．１［Ｍ＋Ｈ］ ^＋ 、１．６２分、 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １０．９７（ｓ，１Ｈ）、８．０６（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、７．９３（ｄｄ，Ｊ＝７．４、８．３Ｈｚ、１Ｈ）、７．６０（ｍ，１Ｈ）、７．４６（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、７．３６（ｍ，２Ｈ）、７．３０（ｍ，１Ｈ）、７．２３（ｍ，１Ｈ）、７．０１（ｄｄ，Ｊ＝０．５、８．４Ｈｚ、１Ｈ）、３．９６（ｍ，２Ｈ）、１．３－２．５（ｍ，４Ｈ）． Example 114: 2 ³ -Chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenacyclononaphane 4,4-dioxide ( 114).

6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) was converted to N-(5-chloro-6 -(2-vinylphenyl)pyridin-2-yl)-6-fluoropyridine-2-sulfonamide (intermediate b3) to replace 1-((tert-butyldimethylsilyl)oxy)oct-7-ene-4 2 ³ -Chloro-6-oxa-4-thia-3-aza- was prepared using the procedure described in Example 109, except that -ol was replaced with prop-2-en-1-ol. 2,5(2,6)-Dipyridina-1(1,2)-Benzenacyclononaphane 4,4-dioxide (114) was synthesized. LCMS (conditions 1): m/z 402.1 [M+H] ⁺ , 1.62 min, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 8.06 (d, J = 8.7Hz, 1H), 7.93 (dd, J = 7.4, 8.3Hz, 1H), 7.60 (m, 1H), 7.46 (d, J = 8.7Hz, 1H) , 7.36 (m, 2H), 7.30 (m, 1H), 7.23 (m, 1H), 7.01 (dd, J = 0.5, 8.4Hz, 1H), 3.96 (m, 2H), 1.3-2.5 (m, 4H).

工程１．６－（ブタ－３－エン－１－イル（２－ヒドロキシエチル）アミノ）－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミドの合成
ジオキサン（４ｍＬ）中の６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）（６０ｍｇ、０．１４ｍｍｏｌ）及びブタ－３－エン－１－アミン（５０ｍｇ、０．７１ｍｍｏｌ）の混合物を、１２０℃で一晩加熱した。混合物をＥｔＯＡｃと水とに分け、１ＮのＨＣｌ水溶液（２ｍＬ）を用いて酸性化した。有機層を収集し、ＭｇＳＯ _４ 上で乾燥させ、ろ過し、濃縮した。残渣を、ＩＳＣＯ（ＥｔＯＡｃ／ヘプタン０～１００％）によって精製して、表題化合物（５０ｍｇ、０．１０５ｍｍｏｌ、７４％の収率）を白色の固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ４７５．２［Ｍ＋Ｈ］ ^＋ 、１．６９分。 Example 115: 2 ³ -(Trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4- Synthesis of Dioxide (115)

Step 1. 6-(But-3-en-1-yl(2-hydroxyethyl)amino)-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine 6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate A mixture of body b2) (60 mg, 0.14 mmol) and but-3-en-1-amine (50 mg, 0.71 mmol) was heated at 120° C. overnight. The mixture was partitioned between EtOAc and water and acidified with 1N aqueous HCl (2 mL). The organic layer was collected, dried over _MgSO4 , filtered and concentrated. The residue was purified by ISCO (EtOAc/heptane 0-100%) to give the title compound (50 mg, 0.105 mmol, 74% yield) as a white solid. LCMS (conditions 1): m/z 475.2 [M+H] ⁺ , 1.69 min.

Step 2.2 ^3- (Trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphan-9-ene 4 Synthesis of ,4-dioxide 6-(But-3-en-1-yl(2-hydroxyethyl)amino)-N-(5-(trifluoromethyl)-6-(2-vinyl) in DCM (50 mL) A solution of phenyl)pyridin-2-yl)pyridine-2-sulfonamide) (50 mg, 0.105 mmol) was purged with nitrogen. Grubbs II catalyst (9 mg, 11 μmol) was added and the mixture was purged with nitrogen again. The flask was sealed and heated at 45° C. overnight. LCMS indicated the reaction was not complete. An additional 15 mg of Grubbs II catalyst was added and the mixture continued to heat at 45° C. for 3 days. The reaction mixture was concentrated under reduced pressure and the residue was purified on an ISCO column (EtOAc/heptane 0-25%) to give the title compound (45 mg, 0.096 mmol, 91% yield) in a 3:1 Obtained as a mixture of E/Z isomers in ratios. LCMS (conditions 1): m/z 447.2 [M+H] ⁺ , 1.6 min.

Step 3.2 ^3- (Trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide Synthesis of (115) 2 ^3- (Trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacin in EtOAc (10 mL) A solution of clodecaphan-9-ene 4,4-dioxide (45 mg, 0.096 mmol) was hydrogenated overnight at room temperature over PtO _dihydrate (50 mg, 0.22 mmol). The mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by ISCO (EtOAc/heptane 0-25%) to give the title compound as a white solid. LCMS (conditions 1): m/z 449.2 [M+H] ⁺ , 1.65 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.50 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.56 (dd, J = 8.4, 7.50). 2Hz, 1H), 7.43-7.32 (m, 2H), 7.32-7.19 (m, 3H), 7.14 (t, J = 5.9Hz, 1H), 7.10 ( d, J = 7.1Hz, 1H), 6.61 (d, J = 8.4Hz, 1H), 2.89-2.75 (m, 1H), 2.63-2.55 (m, 1H) ), 1.83 (m, 1H), 1.58 (m, 1H), 1.42-1.31 (m, 1H), 1.31-1.20 (m, 2H), 0.98- 0.89(m, 1H).

ブタ－３－エン－１－アミンを、２－（ブタ－３－エン－１－イルアミノ）エタン－１－オール（購入した）で置き換えたことを除いて、実施例１１５に記載される手順を用いて、６－（２－ヒドロキシエチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロデカファン４，４－ジオキシド（１１６）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４９３．２［Ｍ＋Ｈ］ ^＋ 、１．６１分； ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６９（ｓ，１Ｈ）、８．１６（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．７、７．３Ｈｚ、１Ｈ）、７．３９－７．３１（ｍ，２Ｈ）、７．３０－７．２２（ｍ，３Ｈ）、７．１７（ｄ，Ｊ＝７．２Ｈｚ、１Ｈ）、６．８８（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．７６（ｔ，Ｊ＝５．４Ｈｚ、１Ｈ）、３．９４（ｔ，Ｊ＝１０．３Ｈｚ、１Ｈ）、３．５０（ｑ，Ｊ＝５．８Ｈｚ、２Ｈ）、３．４５－３．３４（ｍ，１Ｈ）、２．９４－２．８７（ｍ，１Ｈ）、２．６０－２．５４（ｍ，１Ｈ）、１．７５（ｔ，Ｊ＝１０．９Ｈｚ、１Ｈ）、１．６７－１．６０（ｍ，１Ｈ）、１．４０－１．２１（ｍ，２Ｈ）、０．８９－０．８３（ｍ，１Ｈ）、０．６８（ｓ，１Ｈ）． Example 116: 6-(2-Hydroxyethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclodecaphane 4,4-dioxide (116)

The procedure described in Example 115 was followed except that but-3-en-1-amine was replaced with 2-(but-3-en-1-ylamino)ethan-1-ol (purchased). 6-(2-hydroxyethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Nacyclodecaphane 4,4-dioxide (116) was synthesized. LCMS (conditions 1): m/z 493.2 [M+H] ⁺ , 1.61 min; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.69 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.70 (dd, J = 8.7, 7.3 Hz, 1H), 7.39-7.31 (m, 2H), 7.30-7.22 (m, 3 H), 7.17 (d, J=7.2 Hz, 1 H), 6.88 (d, J=8.7 Hz, 1 H), 4.76 (t, J=5.4 Hz, 1 H), 3. 94 (t, J = 10.3Hz, 1H), 3.50 (q, J = 5.8Hz, 2H), 3.45-3.34 (m, 1H), 2.94-2.87 (m , 1H), 2.60-2.54 (m, 1H), 1.75 (t, J = 10.9 Hz, 1H), 1.67-1.60 (m, 1H), 1.40-1 .21 (m, 2H), 0.89-0.83 (m, 1H), 0.68 (s, 1H).

ブタ－３－エン－１－アミンを、２－（ペンタ－４－エン－１－イルアミノ）エタン－１－オール（中間体ａ４２）で置き換えたことを除いて、実施例１１５に記載される手順を用いて、６－（２－ヒドロキシエチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１１７）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５０７．２［Ｍ＋Ｈ］ ^＋ 、１．６４分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７９（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７０（ｄｄ，Ｊ＝８．７、７．２Ｈｚ、１Ｈ）、７．３９－７．３５（ｍ，１Ｈ）、７．２９（ｄ，Ｊ＝６．９Ｈｚ、１Ｈ）、７．２６－７．１２（ｍ，４Ｈ）、６．９０（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、４．７７（ｔ，Ｊ＝５．４Ｈｚ、１Ｈ）、４．０２－３．９１（ｍ，１Ｈ）、３．５１（ｑ，Ｊ＝６．１Ｈｚ、２Ｈ）、３．４６－３．３５（ｍ，２Ｈ）、２．９７－２．８７（ｍ，１Ｈ）、２．４５－２．３６（ｍ，１Ｈ）、１．９７－１．８４（ｍ，１Ｈ）、１．８２－１．６７（ｍ，１Ｈ）、１．４５－１．２６（ｍ，２Ｈ）、１．２１－０．９９（ｍ，３Ｈ）． Example 117: 6-(2-Hydroxyethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphane 4,4-dioxide (117)

Procedure as described in Example 115 except but-3-en-1-amine was replaced with 2-(pent-4-en-1-ylamino)ethan-1-ol (intermediate a42) 6-(2-Hydroxyethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphane 4,4-dioxide (117) was synthesized. LCMS (conditions 1): m/z 507.2 [M+H] ⁺ , 1.64 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.79 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.70 (dd, J = 8.7, 7. 2Hz, 1H), 7.39-7.35 (m, 1H), 7.29 (d, J = 6.9Hz, 1H), 7.26-7.12 (m, 4H), 6.90 ( d, J = 8.8Hz, 1H), 4.77 (t, J = 5.4Hz, 1H), 4.02-3.91 (m, 1H), 3.51 (q, J = 6.1Hz , 2H), 3.46-3.35 (m, 2H), 2.97-2.87 (m, 1H), 2.45-2.36 (m, 1H), 1.97-1.84 (m, 1H), 1.82-1.67 (m, 1H), 1.45-1.26 (m, 2H), 1.21-0.99 (m, 3H).

ブタ－３－エン－１－アミンを、ペンタ－４－エン－１－アミンで置き換えたことを除いて、実施例１１５に記載される手順を用いて、２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１１８）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４６３．２［Ｍ＋Ｈ］ ^＋ 、１．６９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６０（ｓ，１Ｈ）、８．１３（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．５５（ｄｄ，Ｊ＝８．５、７．２Ｈｚ、１Ｈ）、７．３９－７．２６（ｍ，３Ｈ）、７．２５－７．２１（ｍ，１Ｈ）、７．１４（ｄ，Ｊ＝７．２Ｈｚ、２Ｈ）、７．１０－７．０３（ｍ，１Ｈ）、６．６２（ｄ，Ｊ＝８．４Ｈｚ、１Ｈ）、３．４１（ｍ，１Ｈ）、２．８１（ｍ，１Ｈ）、２．４１－２．３１（ｍ，１Ｈ）、２．０５－１．９３（ｍ，１Ｈ）、１．５９（ｍ，１Ｈ）、１．３６（ｍ，１Ｈ）、１．３０－１．１３（ｍ，４Ｈ）． Example 118: 2 ³ -(Trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4 - Synthesis of Dioxide (118)

2 ³ -(Trifluoromethyl)-4 was prepared using the procedure described in Example 115 except that but-3-en-1-amine was replaced with pent-4-en-1-amine. -thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide (118) was synthesized. LCMS (conditions 1): m/z 463.2 [M+H] ⁺ , 1.69 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.60 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 7.55 (dd, J = 8.5, 7.5). 2Hz, 1H), 7.39-7.26 (m, 3H), 7.25-7.21 (m, 1H), 7.14 (d, J = 7.2Hz, 2H), 7.10- 7.03 (m, 1H), 6.62 (d, J = 8.4Hz, 1H), 3.41 (m, 1H), 2.81 (m, 1H), 2.41-2.31 ( m, 1H), 2.05-1.93 (m, 1H), 1.59 (m, 1H), 1.36 (m, 1H), 1.30-1.13 (m, 4H).

ブタ－３－エン－１－アミンを、２－（アリルオキシ）エタン－１－アミンで置き換えたことを除いて、実施例１１５に記載される手順を用いて、２ ^３ －（トリフルオロメチル）－９－オキサ－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン４，４－ジオキシド（１１９）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ４７９．２［Ｍ＋Ｈ］ ^＋ 、１．５７分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６２（ｓ，１Ｈ）、８．１５（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．５５（ｄｄ，Ｊ＝８．４、７．３Ｈｚ、１Ｈ）、７．４０－７．３１（ｍ，２Ｈ）、７．２８－７．２０（ｍ，２Ｈ）、７．１５（ｄ，Ｊ＝６．９Ｈｚ、１Ｈ）、７．０９－７．０１（ｍ，２Ｈ）、６．６８（ｄ，Ｊ＝８．５Ｈｚ、１Ｈ）、３．３３－３．２４（ｍ，４Ｈ）、３．２１－３．１４（ｍ，２Ｈ）、２．４０－２．２９（ｍ，１Ｈ）、２．１１－１．９８（ｍ，１Ｈ）、１．５８－１．４７（ｍ，１Ｈ）、１．４０－１．２８（ｍ，１Ｈ）． Example 119: 2 ^3- (Trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane Synthesis of 4,4-dioxide (119)

Using the procedure described in Example 115, except replacing but-3-en-1-amine with 2-(allyloxy)ethan-1-amine, 2 ³ -(trifluoromethyl)- 9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide (119) was synthesized. LCMS (conditions 1): m/z 479.2 [M+H] ⁺ , 1.57 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.62 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.55 (dd, J = 8.4, 7.5). 3Hz, 1H), 7.40-7.31 (m, 2H), 7.28-7.20 (m, 2H), 7.15 (d, J = 6.9Hz, 1H), 7.09- 7.01 (m, 2H), 6.68 (d, J=8.5Hz, 1H), 3.33-3.24 (m, 4H), 3.21-3.14 (m, 2H), 2.40-2.29 (m, 1H), 2.11-1.98 (m, 1H), 1.58-1.47 (m, 1H), 1.40-1.28 (m, 1H) ).

メチル２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）アセテート（６１）（８０ｍｇ、０．１５ｍｍｏｌ）、ＬｉＯＨ（１５０ｍｇ、６．２６ｍｍｏｌ）、ジオキサン（３ｍＬ）及び水（３．００ｍＬ）の混合物を室温で一晩撹拌した。ＬＣＭＳにより、反応が完了したことが示された。反応物を、１０％のクエン酸を用いて酸性化し、水性後処理（ａｑｕｅｏｕｓ ｗｏｒｋ－ｕｐ）、続いてＩＳＣＯ精製（ＭｅＯＨ／ＤＣＭ ０～１０％）により、生成物２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロドデカファン－６－イル）酢酸（１２０）を白色の固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ５３５．２［Ｍ＋１］ ^＋ 、１．８０分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １２．７９（ｓ，１Ｈ）、１１．７７（ｓ，１Ｈ）、８．２９－７．９７（ｍ，１Ｈ）、７．７９－７．６２（ｍ，１Ｈ）、７．５０－７．３０（ｍ，３Ｈ）、７．３０－７．１９（ｍ，２Ｈ）、７．１９－７．０８（ｍ，１Ｈ）、６．８９－６．５１（ｍ，１Ｈ）、４．０９（ｓ，２Ｈ）、３．８０－３．５４（ｍ，１Ｈ）、３．５２－３．３３（ｍ，２Ｈ）、２．１２－１．９４（ｍ，１Ｈ）、１．４５－１．１７（ｍ，３Ｈ）、１．１７－０．９９（ｍ，３Ｈ）、０．９９－０．６０（ｍ，２Ｈ）． Example 120: 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacyclododecaphan-6-yl)acetic acid (120)

Methyl 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclo A mixture of dodecaphan-6-yl)acetate (61) (80 mg, 0.15 mmol), LiOH (150 mg, 6.26 mmol), dioxane (3 mL) and water (3.00 mL) was stirred at room temperature overnight. LCMS indicated the reaction was complete. The reaction was acidified with 10% citric acid and aqueous work-up followed by ISCO purification (MeOH/DCM 0-10%) gave the product 2-(4,4-dioxide -2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)acetic acid ( 120) was obtained as a white solid. LCMS (conditions 1): m/z 535.2 [M+1] ⁺ , 1.80 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.79 (s, 1H), 11.77 (s, 1H), 8.29-7.97 (m, 1H), 7.79-7.62 (m, 1H), 7.50-7.30 (m, 3H), 7.30-7.19 (m, 2H), 7.19-7.08 (m, 1H), 6.89-6 .51 (m, 1H), 4.09 (s, 2H), 3.80-3.54 (m, 1H), 3.52-3.33 (m, 2H), 2.12-1.94 (m, 1H), 1.45-1.17 (m, 3H), 1.17-0.99 (m, 3H), 0.99-0.60 (m, 2H).

工程１．２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）アセトアルデヒドの合成
ＣＨ _２ Ｃｌ _２ （１０ｍＬ）中の６－（２－ヒドロキシエチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１１７）（３２０ｍｇ、０．６３２ｍｍｏｌ）の溶液に、デス・マーチン・ペルヨージナン（３４８ｍｇ、０．８２１ｍｍｏｌ）を０℃で一度に加えた。混合物を、一晩、ゆっくりと室温に温めた。ＬＣＭＳにより、反応が完了したことが示された。次に、飽和ＮａＨＣＯ _３ 水溶液（２．５ｍＬ）及び飽和Ｎａ _２ Ｓ _２ Ｏ _３ 水溶液（２．５ｍＬ）を加えた。混合物を１５分間にわたって激しく撹拌してから、層を分離した。水性層をＤＣＭで抽出した。組み合わされた有機層をＭｇＳＯ _４ 上で乾燥させ、ろ過し、濃縮した。残渣を、ＩＳＣＯカラム（ＥｔＯＡｃ／ヘプタン０～１００％）を用いて精製して、表題化合物（２２０ｍｇ、０．４３６ｍｍｏｌ、６９％の収率）を淡褐色の固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ５０５．２［Ｍ＋Ｈ］ ^＋ 、１．６３分。 Example 121: 6-(2-(piperazin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 Synthesis of (1,2)-Benzenacycloundecaphane 4,4-dioxide (121)

Step 1. 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Synthesis of Nacycloundecaphan-6-yl)acetaldehyde 6-(2-Hydroxyethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza- in CH ₂ Cl ₂ (10 mL) Dess-Martin periodinane (348 mg , 0.821 mmol) was added in one portion at 0°C. The mixture was slowly warmed to room temperature overnight. LCMS indicated the reaction was complete. Then saturated aqueous NaHCO ₃ (2.5 mL) and saturated aqueous Na ₂ S ₂ O ₃ (2.5 mL) were added. The mixture was vigorously stirred for 15 minutes and then the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers _were dried over MgSO4, filtered and concentrated. The residue was purified using an ISCO column (EtOAc/heptane 0-100%) to give the title compound (220 mg, 0.436 mmol, 69% yield) as a light brown solid. LCMS (conditions 1): m/z 505.2 [M+H] ⁺ , 1.63 min.

Step 2. tert-butyl 4-(2-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphan-6-yl)ethyl)piperazine-1-carboxylate 2-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia in DCE (3 mL) tert- Butyl piperazine-1-carboxylate (11 mg, 0.06 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. Then SiliCycle BH ₃ CN (40 mg, 0.04 mmol) was added in one portion and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a syringe filter and rinsed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified via ISCO column (EtOAc/heptane 0-100%) to give the title compound (20 mg, 0.03 mmol, 75% yield). LCMS (conditions 1): m/z 675.4 [M+H] ⁺ , 1.62 min.

Step 3. 6-(2-(Piperazin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( Synthesis of 1,2)-Benzenacycloundecaphane 4,4-dioxide (121) tert-butyl 4-(2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3 ,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)ethyl)piperazine-1-carboxylate (20 mg, 0.03 mmol). , 4N HCl in dioxane (2 mL) was added and the mixture was stirred for 2 h. The mixture was then diluted with ether and allowed to stand overnight. The resulting precipitate was collected and the solid was washed with ether and dried under high vacuum to give the title compound as HCl salt. LCMS (conditions 1): m/z 575.3 [M+H] ⁺ , 1.46 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.81 (s, 1H), 9.32 (s, 2H), 8.12 (d, J = 9.0 Hz, 1H), 7.81-7 .72 (m, 1H), 7.39-7.35 (m, 1H), 7.32-7.29 (m, 2H), 7.26-7.22 (m, 2H), 7.15 (d, J = 7.6Hz, 1H), 7.08 (s, 1H), 3.91-3.85 (m, 1H), 3.84-3.61 (m, 3H), 3.32 -3.12 (m, 9H), 3.06-2.95 (m, 1H), 2.43-2.35 (m, 1H), 1.92-1.83 (m, 1H), 1 .72-1.63 (m, 1H), 1.42-1.31 (m, 2H), 1.26-1.03 (m, 3H).

ｔｅｒｔ－ブチルピペラジン－１－カルボキシレートを、ｔｅｒｔ－ブチルピロリジン－１－カルボキシレートで置き換えたことを除いて、実施例１２１に記載される手順を用いて、６－（２－（ピロリジン－１－イル）エチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１２２）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６０．３［Ｍ＋Ｈ］ ^＋ 、１．５１分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ７．９４（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６８－７．５５（ｍ，１Ｈ）、７．３１－７．２５（ｍ，１Ｈ）、７．２０（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、７．１８－７．１２（ｍ，２Ｈ）、７．０７（ｔ，Ｊ＝８．３Ｈｚ、２Ｈ）、６．７５（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．８６－３．７５（ｍ，１Ｈ）、３．４１－３．３５（ｍ，３Ｈ）、２．９３－２．８３（ｍ，１Ｈ）、２．７０－２．５１（ｍ，５Ｈ）、２．３７－２．２７（ｍ，１Ｈ）、１．９０－１．７７（ｍ，１Ｈ）、１．７１－１．５３（ｍ，５Ｈ）、１．３３－１．２１（ｍ，２Ｈ）、１．１５－０．８８（ｍ，３Ｈ）． Example 122: 6-(2-(pyrrolidin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 Synthesis of (1,2)-Benzenacycloundecaphane 4,4-dioxide (122)

Using the procedure described in Example 121, except replacing tert-butylpiperazine-1-carboxylate with tert-butylpyrrolidine-1-carboxylate, 6-(2-(pyrrolidine-1- yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-Dioxide (122) was synthesized. LCMS (conditions 1): m/z 560.3 [M+H] ⁺ , 1.51 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.94 (d, J = 8.9 Hz, 1H), 7.68-7.55 (m, 1H), 7.31-7.25 (m, 1H), 7.20 (d, J = 7.6Hz, 1H), 7.18-7.12 (m, 2H), 7.07 (t, J = 8.3Hz, 2H), 6.75 ( d, J = 8.7 Hz, 1H), 3.86-3.75 (m, 1H), 3.41-3.35 (m, 3H), 2.93-2.83 (m, 1H), 2.70-2.51 (m, 5H), 2.37-2.27 (m, 1H), 1.90-1.77 (m, 1H), 1.71-1.53 (m, 5H) ), 1.33-1.21 (m, 2H), 1.15-0.88 (m, 3H).

ｔｅｒｔ－ブチルピペラジン－１－カルボキシレートを、ｔｅｒｔ－ブチル（３Ｓ，４Ｓ）－３，４－ジヒドロキシピロリジン－１－カルボキシレートで置き換えたことを除いて、実施例１２１に記載される手順を用いて、６－（２－（（３Ｓ，４Ｓ）－３，４－ジヒドロキシピロリジン－１－イル）エチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１２３）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５９２．３［Ｍ＋Ｈ］ ^＋ 、１．４０分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）１１．６５（ｓ，１Ｈ）、８．０５（ｄ，Ｊ＝８．０Ｈｚ、１Ｈ）、７．７１（ｔ，Ｊ＝７．８Ｈｚ、１Ｈ）、７．３５（ｍ，１Ｈ）、７．２８（ｄ，Ｊ＝７．４Ｈｚ、１Ｈ）、７．１９（ｍ，４Ｈ）、６．８１（ｄ，Ｊ＝８．５Ｈｚ、１Ｈ）、４．９６（ｍ，２Ｈ）、３．８８（ｍ，３Ｈ）、３．４０（ｍ，１Ｈ）、２．９２（ｍ，３Ｈ）、２．３０－２．７０（ｍ，５Ｈ）、２．４０、１．８９（ｍ，１Ｈ）、１．６９（ｍ，１Ｈ）、０．９６－１．４２（ｍ，６Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．７７（ｓ）． Example 123: 6-(2-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2 ,5(2,6)-Dipyridina-1(1,2)-Benzenacycloundecaphane 4,4-dioxide (123)

Using the procedure described in Example 121, except replacing tert-butyl piperazine-1-carboxylate with tert-butyl (3S,4S)-3,4-dihydroxypyrrolidine-1-carboxylate. , 6-(2-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5( 2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (123) was synthesized. LCMS (conditions 1): m/z 592.3 [M+H] ⁺ , 1.40 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) 11.65 (s, 1H), 8.05 (d, J=8.0 Hz, 1 H), 7.71 (t, J=7.8 Hz, 1 H), 7.35 (m, 1H), 7.28 (d, J=7.4Hz, 1H), 7.19 (m, 4H), 6.81 (d, J=8.5Hz, 1H), 4. 96 (m, 2H), 3.88 (m, 3H), 3.40 (m, 1H), 2.92 (m, 3H), 2.30-2.70 (m, 5H), 2.40 , 1.89 (m, 1H), 1.69 (m, 1H), 0.96-1.42 (m, 6H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.77 (s).

ｔｅｒｔ－ブチルピペラジン－１－カルボキシレートを、ｔｅｒｔ－ブチル３－ヒドロキシアゼチジン－１－カルボキシレートで置き換えたことを除いて、実施例１２１に記載される手順を用いて、６－（２－（３－ヒドロキシアゼチジン－１－イル）エチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１２４）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６２．３［Ｍ＋Ｈ］ ^＋ 、１．４３分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）１１．６７（ｓ，１Ｈ）、８．００（ｍ，１Ｈ）、７．６８（ｍ，１Ｈ）、７．３４（ｔｄ，Ｊ＝７．５、１．５Ｈｚ、１Ｈ）、７．２７（ｍ，１Ｈ）、７．１９（ｍ，４Ｈ）、６．７８（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、５．３６（ｓ，１Ｈ）、４．１７（ｍ，１Ｈ）、３．８３（ｍ，１Ｈ）、３．６０（ｍ，２Ｈ）、３．２０（ｍ，２Ｈ）、２．８８（ｍ，３Ｈ）、２．５８（ｍ，２Ｈ）、２．３９（ｍ，１Ｈ）、１．９０（ｍ，１Ｈ）、１．６５（ｍ，１Ｈ）、１．３２（ｍ，２Ｈ）、１．１３（ｍ，２Ｈ）、１．０１（ｍ，１Ｈ）． Example 124: 6-(2-(3-Hydroxyazetidin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6) -Synthesis of Dipyridina-1(1,2)-Benzenacycloundecaphane 4,4-dioxide (124)

6-(2-( 3-hydroxyazetidin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphane 4,4-dioxide (124) was synthesized. LCMS (conditions 1): m/z 562.3 [M+H] ⁺ , 1.43 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) 11.67 (s, 1H), 8.00 (m, 1H), 7.68 (m, 1H), 7.34 (td, J = 7.5, 1.5Hz, 1H), 7.27 (m, 1H), 7.19 (m, 4H), 6.78 (d, J = 8.7Hz, 1H), 5.36 (s, 1H), 4 .17 (m, 1H), 3.83 (m, 1H), 3.60 (m, 2H), 3.20 (m, 2H), 2.88 (m, 3H), 2.58 (m, 2H), 2.39 (m, 1H), 1.90 (m, 1H), 1.65 (m, 1H), 1.32 (m, 2H), 1.13 (m, 2H), 1. 01(m, 1H).

ｔｅｒｔ－ブチルピペラジン－１－カルボキシレートを、１－メチルピペラジンで置き換えたことを除いて、実施例１２１に記載される手順を用いて、６－（２－（４－メチルピペラジン－１－イル）エチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１２５）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５８９．３［Ｍ＋Ｈ］ ^＋ 、１．４９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．６３（ｂｒｓ、１ｈ）、８．０５－７．９６（ｍ，１Ｈ）、７．７０（ｄｄ，Ｊ＝８．６、７．３Ｈｚ、１Ｈ）、７．３９－７．３２（ｍ，１Ｈ）、７．３０－７．２６（ｍ，１Ｈ）、７．２６－７．１９（ｍ，２Ｈ）、７．１６－ ７．１２（ｍ，２Ｈ）、６．７９（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、３．９５－３．８４（ｍ，１Ｈ）、２．９４－２．８３（ｍ，１Ｈ）、２．４５－２．２０（ｍ，９Ｈ）、２．１９（ｓ，１Ｈ）、２．１７（ｓ，３Ｈ）、１．９７－１．８８（ｍ，１Ｈ）、１．７７－１．６５（ｍ，１Ｈ）、１．４２－１．２９（ｍ，２Ｈ）、１．２２－０．９７（ｍ，３Ｈ）． Example 125: 6-(2-(4-methylpiperazin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)- Synthesis of dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (125)

6-(2-(4-methylpiperazin-1-yl) was prepared using the procedure described in Example 121, except replacing tert-butylpiperazine-1-carboxylate with 1-methylpiperazine. Ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-4,4- Dioxide (125) was synthesized. LCMS (conditions 1): m/z 589.3 [M+H] ⁺ , 1.49 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.63 (brs, 1 h), 8.05-7.96 (m, 1 H), 7.70 (dd, J = 8.6, 7.3 Hz, 1H), 7.39-7.32 (m, 1H), 7.30-7.26 (m, 1H), 7.26-7.19 (m, 2H), 7.16-7.12 ( m, 2H), 6.79 (d, J = 8.7Hz, 1H), 3.95-3.84 (m, 1H), 2.94-2.83 (m, 1H), 2.45- 2.20 (m, 9H), 2.19 (s, 1H), 2.17 (s, 3H), 1.97-1.88 (m, 1H), 1.77-1.65 (m, 1H), 1.42-1.29 (m, 2H), 1.22-0.97 (m, 3H).

ｔｅｒｔ－ブチルピペラジン－１－カルボキシレートを、２－アミノ酢酸メチル（購入した）で置き換えたことを除いて、実施例１２１に記載される手順を用いて、メチル（２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）エチル）グリシネート（１２６）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５７８．３［Ｍ＋Ｈ］ ^＋ 、１．４９分。 Example 126: Methyl (2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphan-6-yl)ethyl)glycinate (126) 1

Methyl (2-(4,4-dioxide) was prepared using the procedure described in Example 121, except replacing tert-butylpiperazine-1-carboxylate with methyl 2-aminoacetate (purchased). -2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)ethyl ) synthesized glycinate (126). LCMS (conditions 1): m/z 578.3 [M+H] ⁺ , 1.49 min.

ＭｅＯＨ（３ｍＬ）及び水（１ｍＬ）中のメチル（２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）エチル）グリシネート（１２６）（１５ｍｇ、０．０２６ｍｍｏｌ）及びＬｉＯＨ（３．２ｍｇ、０．１３ｍｍｏｌ）の混合物。混合物を室温で９０分間撹拌した。反応物の体積を、減圧下で減少させて、ＭｅＯＨを除去した。次に、混合物を、１ＮのＨＣｌを用いて酸性化し、次に、ＤＣＭ（５～１０％のＭｅＯＨと混合される）で抽出した。有機層を収集し、ＭｇＳＯ _４ 上で乾燥させ、ろ過し、濃縮し、１時間にわたって７０℃で加熱しながら、高真空下で乾燥させて、（２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）エチル）グリシン（１２７）を白色の粉末として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ５６４．２［Ｍ＋Ｈ］ ^＋ 、１．４４分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ８．１１（ｄ，Ｊ＝９．０Ｈｚ、１Ｈ）、７．７９（ｄｄ，Ｊ＝８．７、７．３Ｈｚ、１Ｈ）、７．４０－７．３５（ｍ，１Ｈ）、７．３３－７．２８（ｍ，２Ｈ）、７．２６－７．１９（ｍ，２Ｈ）、７．１５（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、６．９８（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、４．０３－３．９２（ｍ，１Ｈ）、３．６１－３．４６（ｍ，２Ｈ）、３．００－２．８５（ｍ，３Ｈ）、２．４６－２．３４（ｍ，１Ｈ）、１．９５－１．８３（ｍ，１Ｈ）、１．７９－１．６４（ｍ，１Ｈ）、１．４４－１．２７（ｍ，２Ｈ）、１．２１－０．９６（ｍ，３Ｈ）． Example 127: 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphan-6-yl)ethyl)glycine (127)

Methyl (2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)- in MeOH (3 mL) and water (1 mL) A mixture of dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)ethyl)glycinate (126) (15 mg, 0.026 mmol) and LiOH (3.2 mg, 0.13 mmol). The mixture was stirred at room temperature for 90 minutes. The volume of the reaction was reduced under reduced pressure to remove MeOH. The mixture was then acidified with 1N HCl and then extracted with DCM (mixed with 5-10% MeOH). The organic layer was collected, dried over MgSO ₄ , filtered, concentrated and dried under high vacuum with heating at 70° C. for 1 hour to give (2-(4,4-dioxide-2 ³ - (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)ethyl)glycine (127 ) as a white powder. LCMS (conditions 1): m/z 564.2 [M+H] ⁺ , 1.44 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (d, J=9.0 Hz, 1 H), 7.79 (dd, J=8.7, 7.3 Hz, 1 H), 7.40- 7.35 (m, 1H), 7.33-7.28 (m, 2H), 7.26-7.19 (m, 2H), 7.15 (d, J = 7.6Hz, 1H), 6.98 (d, J=8.7Hz, 1H), 4.03-3.92 (m, 1H), 3.61-3.46 (m, 2H), 3.00-2.85 (m , 3H), 2.46-2.34 (m, 1H), 1.95-1.83 (m, 1H), 1.79-1.64 (m, 1H), 1.44-1.27 (m, 2H), 1.21-0.96 (m, 3H).

ＭｅＯＨ（２ｍＬ）及びＴＨＦ（１ｍＬ）中の６－（（２，２－ジメチル－１，３－ジオキソラン－４－イル）メチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（３７）（３４ｍｇ、０．０５９ｍｍｏｌ）の溶液に、１ＮのＨＣｌ（１ｍＬ、１ｍｍｏｌ）を加え、次に、反応物を室温で３時間撹拌した。溶液を濃縮し、飽和ＮａＨＣＯ _３ 溶液を加えた。得られた混合物をＥｔＯＡｃ（３回）で抽出し、組み合わされた抽出物をＮａ _２ ＳＯ _４ 上で乾燥させ、ろ過し、濃縮した。次に、残渣を、ＩＳＣＯシリカゲルカラム（ＥｔＯＡｃ／ヘプタン０～１００％）上で精製して、６－（２，３－ジヒドロキシプロピル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１２８）を白色の結晶として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ５３７．３［Ｍ＋Ｈ］ ^＋ 、１．５２分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、メタノール－ｄ _４ ）δ ７．９５（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．６５（ｄｄ，Ｊ＝７．５、８．５Ｈｚ、１Ｈ）、７．３１（ｍ，４Ｈ）、７．２０（ｔｄ，Ｊ＝１．１、７．５Ｈｚ、１Ｈ）、７．１１（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、６．９３（ｍ，１Ｈ）、４．１４（ｍ，１Ｈ）、３．８１（ｍ，１Ｈ）、３．２３－３．５５（ｍ，４Ｈ）、３．０３（ｍ，１Ｈ）、２．４３（ｄｄｄ，Ｊ＝５．４、９．９、１３．５Ｈｚ、１Ｈ）、２．０３（ｍ，１Ｈ）、１．８１（ｍ，１Ｈ）、１．５１（ｍ，２Ｈ）、１．２４（ｍ，３Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、メタノール－ｄ _４ ）δ－５９．５７（ｓ）、－５９．６２（ｓ）．ジアステレオマー，１：１の比率． Example 128: 6-(2,3-dihydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphane 4,4-dioxide (128)

6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ³ -(trifluoromethyl)-4-thia-3,6 in MeOH (2 mL) and THF (1 mL) -diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide (37) (34 mg, 0.059 mmol) was added to a solution of 1N HCl ( 1 mL, 1 mmol) was added, then the reaction was stirred at room temperature for 3 hours. The solution was concentrated and saturated _NaHCO3 solution was added. The resulting mixture was extracted with EtOAc (3x) and the combined extracts _were dried over _Na2SO4 , filtered and concentrated. The residue is then purified on an ISCO silica gel column (EtOAc/heptane 0-100%) to give 6-(2,3-dihydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3, 6-Diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (128) was obtained as white crystals. LCMS (conditions 1): m/z 537.3 [M+H] ⁺ , 1.52 min. ¹ H NMR (400 MHz, methanol- _d ) δ 7.95 (d, J=8.9 Hz, 1 H), 7.65 (dd, J=7.5, 8.5 Hz, 1 H), 7.31 ( m, 4H), 7.20 (td, J = 1.1, 7.5Hz, 1H), 7.11 (d, J = 7.5Hz, 1H), 6.93 (m, 1H), 4. 14 (m, 1H), 3.81 (m, 1H), 3.23-3.55 (m, 4H), 3.03 (m, 1H), 2.43 (ddd, J = 5.4, 9.9, 13.5 Hz, 1H), 2.03 (m, 1H), 1.81 (m, 1H), 1.51 (m, 2H), 1.24 (m, 3H). ¹⁹ F NMR (376 MHz, methanol-d ₄ ) δ -59.57 (s), -59.62 (s). Diastereomers, 1:1 ratio.

６－（（２，２－ジメチル－１，３－ジオキソラン－４－イル）メチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（３７）を、６－（（（４Ｓ，５Ｓ）－５－（ヒドロキシメチル）－２，２－ジメチル－１，３－ジオキソラン－４－イル）メチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（３４）で置き換えたことを除いて、実施例１２８に記載される手順を用いて、２ ^３ －（トリフルオロメチル）－６－（（２Ｓ，３Ｓ）－２，３，４－トリヒドロキシブチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１２９）を合成した。ＬＣＭＳ（条件１）：ｍ／ｚ ５６７．３［Ｍ＋Ｈ］ ^＋ 、１．４９分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．８０（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．７０（ｍ，１Ｈ）、７．３６（ｍ，１Ｈ）、７．２９（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、７．２３（ｍ，２Ｈ）、７．１９（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．１４（ｄ，Ｊ＝７．４Ｈｚ、１Ｈ）、６．９１（ｍ，１Ｈ）、４．６５（ｍ，１Ｈ）、４．５８（ｍ，１Ｈ）、４．４７（ｍ，１Ｈ）、３．９８（ｍ，１Ｈ）、３．６９（ｍ，１Ｈ）、３．１７－３．４８（ｍ，５Ｈ）、２．９５（ｍ，１Ｈ）、２．３９（ｍ，１Ｈ）、１．９１（ｍ，１Ｈ）、１．７６（ｍ，１Ｈ）、１．３５（ｍ，２Ｈ）、１．１０（ｍ，３Ｈ）． ^１９ Ｆ ＮＭＲ（３７６ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ－５６．７８（ｓ）、－５６．８１（ｓ）．ジアステレオマー，１：１の比率． Example 129: 2 ³ -(Trifluoromethyl)-6-((2S,3S)-2,3,4-trihydroxybutyl)-4-thia-3,6-diaza-2,5(2,6 )-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (129)

6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6) -dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (37) with 6-(((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene 2 ³ -(trifluoromethyl)-6-((2S,3S) was prepared using the procedure described in Example 128, except substituting nacycloundecaphane 4,4-dioxide (34). -2,3,4-trihydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4- Dioxide (129) was synthesized. LCMS (conditions 1): m/z 567.3 [M+H] ⁺ , 1.49 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.80 (s, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.70 (m, 1H), 7.36 (m , 1H), 7.29 (d, J = 7.5Hz, 1H), 7.23 (m, 2H), 7.19 (d, J = 8.9Hz, 1H), 7.14 (d, J = 7.4Hz, 1H), 6.91(m, 1H), 4.65(m, 1H), 4.58(m, 1H), 4.47(m, 1H), 3.98(m, 1H), 3.69 (m, 1H), 3.17-3.48 (m, 5H), 2.95 (m, 1H), 2.39 (m, 1H), 1.91 (m, 1H) ), 1.76 (m, 1H), 1.35 (m, 2H), 1.10 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.78 (s), -56.81 (s). Diastereomers, 1:1 ratio.

工程１．
ジオキサン（３ｍＬ）中の６－フルオロ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ２）（１００ｍｇ、０．２３６ｍｍｏｌ）及びｔｅｒｔ－ブチル（２－（ブタ－３－エン－１－イルアミノ）エチル）カルバメート（中間体ａ４３）（９３ｍｇ、０．２８３ｍｍｏｌ）（ＴＦＡ塩）及びＤＩＥＡ（２０６μＬ、１．２ｍｍｏｌ）の溶液を１１０℃で一晩加熱した。その後、さらなる２００ｍｇのアミン及び８００μＬのＤＩＥＡを加えた。混合物を、さらに２日間にわたって撹拌し続けた。次に、粗反応混合物に、Ｂｏｃ _２ Ｏ（１００ｍｇ）を加え、３０分間撹拌した。混合物をＥｔＯＡｃで抽出し、組み合わされた抽出物を、水及び１ＮのＨＣｌで洗浄した。有機層を収集し、ＭｇＳＯ _４ 上で乾燥させ、ろ過し、濃縮した。残渣を、ＩＳＣＯカラム（ＥｔＯＡｃ／ヘプタン０～１００％）を用いて精製して、２つの生成物の混合物を得た。ＬＣＭＳ（条件１）：ｍ／ｚ ６１８．３［Ｍ＋Ｈ］ ^＋ 、１．８３分。 Example 130: 6-(2-Aminoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphane 4,4-dioxide (130) and 2 ^3- (trifluoromethyl)-4-thia-3,6,9-triaza-2,5(2,6)-dipyridina-1 (1, 2) Synthesis of -Benzenacyclotridecaphane 4,4-dioxide (131)

Step 1.
6-fluoro-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b2) (100 mg, 0 .236 mmol) and tert-butyl (2-(but-3-en-1-ylamino)ethyl)carbamate (intermediate a43) (93 mg, 0.283 mmol) (TFA salt) and DIEA (206 μL, 1.2 mmol). The solution was heated at 110° C. overnight. An additional 200 mg of amine and 800 μL of DIEA were then added. The mixture was kept stirring for two more days. Boc ₂ O (100 mg) was then added to the crude reaction mixture and stirred for 30 minutes. The mixture was extracted with EtOAc and the combined extracts were washed with water and 1N HCl. The organic layer was collected, dried over _MgSO4 , filtered and concentrated. The residue was purified using an ISCO column (EtOAc/heptane 0-100%) to give a mixture of two products. LCMS (conditions 1): m/z 618.3 [M+H] ⁺ , 1.83 min.

Step 2.
To a mixture of starting material (130 mg, 0.21 mmol) in DCM (100 mL) was added Grubbs II catalyst (50 mg, 0.059 mmol) under a nitrogen atmosphere, then heated in a 55° C. oil bath overnight. did. The mixture was concentrated under reduced pressure and the residue was purified by ISCO column (EtOAc/heptane 0-100%) to give a mixture of cyclized products as a brown solid. LCMS (conditions 1): m/z 590.3 [M+H] ⁺ , 1.77 min.

Step 3.
A mixture of starting material (100 mg, 0.17 mmol) in EtOAc (15 mL) was hydrogenated over PtO _dihydrate (50 mg, 0.220 mmol) at room temperature for 2 days. The mixture was filtered through Celite, rinsed with EtOAc, then the filtrate was concentrated. The residue was purified on an ISCO column (EtOAc/Hexane 0-100%) to give tert-butyl (2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6- Diaza-2,5(2,6)-dipyridina-1(1,2)-benzonacyclodecaphan-6-yl)ethyl)carbamate (35 mg, 0.059 mmol, 35% yield) (Peak 1) as a white solid and tert-butyl 2 ^3- (trifluoromethyl)-4-thia-3,6,9-triaza-2,5(2,6)dipyridina-1(1,2)-benzenacin Clotridecaphane-9-carboxylate 4,4-dioxide (35 mg, 0.059 mmol, 35% yield) (peak 2) was obtained as a white solid. The structure is tentatively specified. Peak 1: LCMS (conditions 1): m/z 592.3 [M+H] ⁺ , 1.80 min; Peak 2: LCMS (conditions 1): m/z 592.3 [M+H] ⁺ , 1.76 min.

Step 4. 6-(2-Aminoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Synthesis of nacyclodecaphane 4,4-dioxide (130) To peak 1 (35 mg, 0.059 mmol) was added 4M HCl in dioxane (2 mL, 8.00 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was precipitated by the addition of ether and stirred overnight. The solids are filtered and dried under high vacuum to give 6-(2-aminoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)- Dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide (130) was obtained as a white solid (HCl salt). LCMS (conditions 1): m/z 492.2 [M+H] ⁺ , 1.41 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.71 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.94-7.87 (m, 3H), 7 .79 (dd, J = 8.6, 7.4 Hz, 1H), 7.39-7.33 (m, 2H), 7.30-7.20 (m, 4H), 7.00 (d, J=8.7 Hz, 1H), 3.92 (brs, 1H), 3.45-3.25 (m, 1H), 3.06-2.86 (m, 3H), 2.55-2. 45 (m, 2H), 1.75 (t, J=10.8Hz, 1H), 1.61-1.56 (m, 1H), 1.42-1.20 (m, 2H), 0. 72(s, 1H).

Step 4.2 ^3- (Trifluoromethyl)-4-thia-3,6,9-triaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphane 4,4 - Synthesis of Dioxide (131) To peak 2 (35.0 mg, 0.059 mmol) was added 4M HCl in dioxane (2 mL, 8.00 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was precipitated by the addition of ether and stirred overnight. The solid is filtered and dried under high vacuum to give 2 ^3- (trifluoromethyl)-4-thia-3,6,9-triaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacyclotridecaphane 4,4-dioxide (131) was obtained as a white solid (HCl salt). LCMS (conditions 1): m/z 492.2 [M+H] ⁺ , 1.35 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.65 (s, 1H), 8.57-8.47 (m, 1H), 8.38-8.28 (m, 1H), 8.18 (d, J=9.0 Hz, 1H), 7.70 (dd, J=8.5, 7.2 Hz, 1H), 7.46-7.35 (m, 2H), 7.36-7. 22 (m, 4H), 7.17 (d, J = 7.5Hz, 1H), 6.79 (d, J = 8.5Hz, 1H), 3.95-3.80 (m, 1H), 3.37-3.26 (m, 1H), 3.12-3.02 (m, 1H), 2.98-2.86 (m, 1H), 2.71-2.60 (m, 2H) ), 2.45-2.39 (m, 1H), 1.96-1.87 (m, 1H), 1.63-1.52 (m, 1H), 1.45-1.28 (m , 3H).

ＭｅＯＨ（１５ｍＬ）中のベンジル（Ｅ）－（２－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－１０－エン－６－イル）エチル）カルバメート（８０ｍｇ、０．１２５ｍｍｏｌ）の溶液を、５時間にわたって室温で、Ｐｄ／Ｃ（１０重量％）（１００ｍｇ、０．０９ｍｍｏｌ）上で水素化した。混合物をセライトに通してろ過し、ＭｅＯＨですすぎ、ろ液を濃縮した。残渣を、ＩＳＣＯ逆相カラム（Ｃ１８カラム、Ｈ _２ Ｏ／ＡＣＮ勾配）を用いて精製して、６－（２－アミノエチル）－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン４，４－ジオキシド（１３２）を白色の固体として得た。ＬＣＭＳ（条件１）：ｍ／ｚ ５０６．３［Ｍ＋Ｈ］ ^＋ 、１．３８分。 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ ８．９１（ｂｒｓ、１Ｈ）、７．６０－７．５３（ｍ，２Ｈ）、７．３２（ｓ，１Ｈ）、７．３０－７．２１（ｍ，２Ｈ）、７．１３－７．０８（ｍ，１Ｈ）、７．０４－７．００（ｍ，１Ｈ）、６．７７（ｄ，Ｊ＝７．５Ｈｚ、１Ｈ）、６．７２（ｄ，Ｊ＝８．７Ｈｚ、１Ｈ）、６．６４（ｄ，Ｊ＝８．３Ｈｚ、１Ｈ）、３．４５－３．２５（ｍ，２Ｈ）、２．９５－２．８８（ｍ，１Ｈ）、２．８５－２．６３（ｍ，３Ｈ）、２．５５－２．４５（ｍ，１Ｈ）、２．１５－２．０４（ｍ，１Ｈ）、１．７１－１．６０（ｍ，１Ｈ）、１．４６－１．３５（ｍ，１Ｈ）、１．３０－１．１９（ｍ，３Ｈ）、１．１６－１．０３（ｍ，２Ｈ）． Example 131: 6-(2-Aminoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Synthesis of Benzenacycloundecaphane 4,4-dioxide (132)

Benzyl (E)-(2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina in MeOH (15 mL) -1(1,2)-Benzenacycloundecafane-10-en-6-yl)ethyl)carbamate (80 mg, 0.125 mmol) was added over 5 h at room temperature to Pd/C (10 wt. ) (100 mg, 0.09 mmol). The mixture was filtered through celite, rinsed with MeOH, and the filtrate was concentrated. The residue was purified using an ISCO reverse phase column (C18 column, H ₂ O/ACN gradient) to give 6-(2-aminoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6 -diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide (132) was obtained as a white solid. LCMS (conditions 1): m/z 506.3 [M+H] ⁺ , 1.38 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (brs, 1H), 7.60-7.53 (m, 2H), 7.32 (s, 1H), 7.30-7.21 (m, 2H), 7.13-7.08 (m, 1H), 7.04-7.00 (m, 1H), 6.77 (d, J = 7.5Hz, 1H), 6.72 (d, J = 8.7Hz, 1H), 6.64 (d, J = 8.3Hz, 1H), 3.45-3.25 (m, 2H), 2.95-2.88 (m, 1H), 2.85-2.63 (m, 3H), 2.55-2.45 (m, 1H), 2.15-2.04 (m, 1H), 1.71-1.60 ( m, 1H), 1.46-1.35 (m, 1H), 1.30-1.19 (m, 3H), 1.16-1.03 (m, 2H).

ＥｔＯＡｃ（１０ｍＬ）中の（Ｅ）－２－（３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－１０－エン－６－イル）プロピル）イソインドリン－１，３－ジオン（１０２ｍｇ、０．１５７ｍｍｏｌ）の溶液を、室温で水素バルーンを用いてＰｔＯ _２ 水和物（１０ｍｇ、０．０４ｍｍｏｌ）上で一晩水素化した。触媒をろ過して取り出し、ろ液を濃縮した。ＩＳＣＯシリカゲルカラム（ＥｔＯＡｃ／ヘプタン０～４５％）における残渣の精製により、２つの生成物：２－（３－（４，４－ジオキシド－２ ^３ －（トリフルオロメチル）－４－チア－３，６－ジアザ－２，５（２，６）－ジピリジナ－１（１，２）－ベンゼナシクロウンデカファン－６－イル）プロピル）イソインドリン－１，３－ジオン（１３３）が白色の結晶として得られた。条件１、ＬＣＭＳ：ｍ／ｚ ６５０．２［Ｍ＋Ｈ］ ^＋ 、１．８２分、 ^１ Ｈ ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ _６ ）δ １１．７８（ｓ，１Ｈ）、８．１０（ｄ，Ｊ＝８．９Ｈｚ、１Ｈ）、７．８５（ｍ，４Ｈ）、７．７２（ｄｄ，Ｊ＝８．７、７．３Ｈｚ、１Ｈ）、７．３６（ｔｄ，Ｊ＝７．５、１．５Ｈｚ、１Ｈ）、７．２９（ｍ，１Ｈ）、７．２２（ｍ，３Ｈ）、７．１４（ｄ，Ｊ＝７．６Ｈｚ、１Ｈ）、６．８８（ｄ，Ｊ＝８．８Ｈｚ、１Ｈ）、３．９６（ｍ，１Ｈ）、３．６２（ｔ，Ｊ＝７．１Ｈｚ、２Ｈ）、３．３６（ｍ，２Ｈ）、２．９０（ｍ，１Ｈ）、２．３９（ｍ，１Ｈ）、１．８０（ｍ，４Ｈ）、１．３１（ｍ，２Ｈ）、１．１４（ｄ，Ｊ＝１０．１Ｈｚ、２Ｈ）、１．０１（ｍ，１Ｈ）． Example 132: 2-(3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1, 2)-Benzenacycloundecaphan-6-yl)propyl)isoindoline-1,3-dione (133) and 2-(3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4 - Thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)propyl)hexahydro-1H-isoindole-1,3 Synthesis of (2H)-dione (134)

(E)-2-(3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)- in EtOAc (10 mL) A solution of dipyridina-1(1,2)-benzeneacycloundecaphan-10-en-6-yl)propyl)isoindoline-1,3-dione (102 mg, 0.157 mmol) was added at room temperature through a hydrogen balloon. hydrogenation over PtO _dihydrate (10 mg, 0.04 mmol) overnight using . The catalyst was filtered off and the filtrate was concentrated. Purification of the residue on an ISCO silica gel column (EtOAc/heptane 0-45%) gave two products: 2-(3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3, 6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propyl)isoindoline-1,3-dione (133) is white crystals obtained as Condition 1, LCMS: m/z 650.2 [M+H] ⁺ , 1.82 min, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.78 (s, 1H), 8.10 (d, J= 8.9Hz, 1H), 7.85 (m, 4H), 7.72 (dd, J = 8.7, 7.3Hz, 1H), 7.36 (td, J = 7.5, 1.5Hz , 1H), 7.29 (m, 1H), 7.22 (m, 3H), 7.14 (d, J = 7.6Hz, 1H), 6.88 (d, J = 8.8Hz, 1H ), 3.96 (m, 1H), 3.62 (t, J = 7.1Hz, 2H), 3.36 (m, 2H), 2.90 (m, 1H), 2.39 (m, 1H), 1.80 (m, 4H), 1.31 (m, 2H), 1.14 (d, J = 10.1 Hz, 2H), 1.01 (m, 1H).

2-(3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1) as a white solid ,2)-Benzenacycloundecaphan-6-yl)propyl)hexahydro-1H-isoindole-1,3(2H)-dione (134). Condition 1, LCMS: m/z 656.2 [M+H] ⁺ , 1.95 min, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.79 (s, 1H), 8.09 (d, J= 8.9Hz, 1H), 7.73 (dd, J = 8.7, 7.2Hz, 1H), 7.36 (td, J = 7.5, 1.5Hz, 1H), 7.29 (m , 1H), 7.22 (m, 3H), 7.14 (d, J = 7.6Hz, 1H), 6.82 (d, J = 8.8Hz, 1H), 3.95 (m, 1H ), 3.40 (t, J = 7.1 Hz, 2H), 3.24 (m, 2H), 2.91 (m, 3H), 2.39 (m, 1H), 1.88 (m, 1H), 1.70 (m, 5H), 1.55 (m, 2H), 1.38 (m, 4H), 1.25 (m, 2H), 1.12 (m, 2H), 1. 01(m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -56.90 (s).

工程１．トルエン（２ｍＬ）中の６－ブロモ－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミド（中間体ｂ１４）（１０２ｍｇ、０．２１１ｍｍｏｌ）、（Ｒ）－５－（ブタ－３－エン－１－イル）ピロリジン－２－オン（中間体ａ４４）（４４．０ｍｇ、０．３１６ｍｍｏｌ）、Ｎ１，Ｎ２－ジメチルエタン－１，２－ジアミン（ＤＭＥＤＡ）（５．５７ｍｇ、０．０６３ｍｍｏｌ）、ヨウ化銅（Ｉ）（１．８０５ｍｇ、９．４８μｍｏｌ）及び炭酸カリウム（５８．２ｍｇ、０．４２１ｍｍｏｌ）の混合物を脱気し、次に、１２０℃で３８時間撹拌した。次に、反応混合物をＥｔＯＡｃ（５０ｍＬ）で希釈し、水（２×５ｍＬ）、次に塩水（５ｍＬ）で洗浄し、次に、抽出した。水性相をＥｔＯＡｃ（２０ｍＬ）で逆抽出し、ＥｔＯＡｃ相を組み合わせて、Ｎａ _２ ＳＯ _４ 上で乾燥させ、蒸発させた。残渣を、フラッシュクロマトグラフィー（ＥｔＯＡｃ：ｈｅｘ／０～５０％）によって精製して、（Ｒ）－６－（２－（ブタ－３－エン－１－イル）－５－オキソピロリジン－１－イル）－Ｎ－（５－（トリフルオロメチル）－６－（２－ビニルフェニル）ピリジン－２－イル）ピリジン－２－スルホンアミドを得た：ＭＳ ５４３．１［Ｍ＋Ｈ］＋、ｒｔ＝１．４９分。 Example 133: (R)-3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1 , 2)-Benzenacycloundecaphan-7-yl)propanoic acid (135) synthesis

Step 1. 6-bromo-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (intermediate b14) (102 mg, 0 .211 mmol), (R)-5-(but-3-en-1-yl)pyrrolidin-2-one (intermediate a44) (44.0 mg, 0.316 mmol), N1,N2-dimethylethane-1, A mixture of 2-diamine (DMEDA) (5.57 mg, 0.063 mmol), copper(I) iodide (1.805 mg, 9.48 μmol) and potassium carbonate (58.2 mg, 0.421 mmol) is degassed, Next, it was stirred at 120° C. for 38 hours. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (2 x 5 mL), then brine (5 mL), then extracted. The aqueous phase was back extracted with EtOAc (20 mL) and the EtOAc phases _were combined, dried over _Na2SO4 and evaporated. The residue is purified by flash chromatography (EtOAc:hex/0-50%) to give (R)-6-(2-(but-3-en-1-yl)-5-oxopyrrolidin-1-yl )-N-(5-(trifluoromethyl)-6-(2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide was obtained: MS 543.1 [M+H]+, rt=1. 49 minutes.

Step 2. (S)-6-(2-(but-3-en-1-yl)-5-oxopyrrolidin-1-yl)-N-(5-(trifluoromethyl)-6- in dichloroethane (15 mL) A solution of (2-vinylphenyl)pyridin-2-yl)pyridine-2-sulfonamide (89 mg, 0.164 mmol) and Grubbs II (13.93 mg, 0.016 mmol) was purged with argon. The mixture is then stirred at 80° C. for 18 hours, then the solvent is evaporated and the residue is purified by flash chromatography (EtOAC:hex/0-30%) to give (R,E)-5 ⁵ -(trifluoromethyl)-3-thia-4-aza-2,5(2,6)-dipyridina-1(1,2)-pyrrolidina-6(1,2)-benzeneacyclodecaphane-7- En-15-one 3,3-dioxide was obtained as a white solid: MS 515.1 [M+H]+, rt=1.39 min.

Step 3. (R,E)-5 ^5- (trifluoromethyl)-3-thia-4-aza-2,5(2,6)-dipyridina-1(1,2)-pyrrolidina-6 in EtOAc (2 mL) (1,2)-Benzenacyclodecaphan-7-en-15-one 3,3-dioxide (66 mg, 0.128 mmol), suspension of platinum (IV) oxide (5.83 mg, 0.026 mmol) was stirred under hydrogen (1 atmosphere) at room temperature overnight. The reaction mixture was then filtered through a syringe filter and the filtrate was evaporated. The resulting residue was purified by flash chromatography (12 g silica gel column, EtOAc:hex/20-50%) to give (R)-5 ^5- (trifluoromethyl)-3-thia-4-aza- 2,5(2,6)-dipyridina-1(1,2)-pyrrolidina-6(1,2)-benzenecyclodecaphan-15-one 3,3-dioxide was obtained as a white solid. LCMS: m/z 517.1 [M+H]+, 1.43 min; 1H NMR (400 MHz, methylene chloride-d ₂ ) δ 8.57 (dd, J=8.5, 0.8 Hz, 1H), 8. .01 (d, J = 8.8 Hz, 1 H), 7.89 (dd, J = 8.5, 7.5 Hz, 1 H), 7.75 (dd, J = 7.5, 0.9 Hz, 1 H ), 7.66 (dd, J = 7.9, 1.2 Hz, 1H), 7.59 (s, 1H), 7.49-7.41 (m, 1H), 7.31 (td, J = 7.5, 1.3Hz, 1H), 7.11 (d, J = 7.7Hz, 1H), 6.12 (dd, J = 17.4, 11.0Hz, 1H), 5.77 ( ddt, J = 16.9, 10.2, 6.6 Hz, 1 H), 5.61 (dd, J = 17.4, 1.0 Hz, 1 H), 5.06 (dd, J = 11.0, 1.0Hz, 1H), 5.02-4.89 (m, 2H), 4.57 (s, 1H), 2.71 (ddd, J = 17.7, 10.2, 9.4Hz, 1H ), 2.49 (ddd, J = 17.7, 9.7, 3.2 Hz, 1H), 2.22-2.06 (m, 1H), 2.06-1.94 (m, 3H) , 1.87 (dtd, J=16.1, 8.3, 7.6, 2.8 Hz, 2H), 1.50 (dq, J=14.2, 7.6 Hz, 1H).
LCMS: m/z 517.1 [M+H] ⁺ , 1.43 min; 1H NMR (400 MHz, methanol-d4) δ 8.43 (dd, J=7.1, 2.3 Hz) and 8.32 (d , J = 8.4 Hz, 1 H), 8.15-7.98 (m, 2 H), 7.93 (d, J = 8.9 Hz) and 7.81 (d, J = 7.6 Hz, 1 H) , 7.35 (td, J = 7.5, 1.5 Hz, 1H), 7.27 (dd, J = 7.7, 1.3 Hz, 1H), 7.25-7.13 (m, 2H ), 7.11 (d, J = 7.6 Hz, 1H), 4.67-4.49 (m, 1H), 2.74-2.58 (m, 1H), 2.58-2.43 (m, 1H), 2.40-2.01 (m, 3H), 1.99-1.83 (m, 2H), 1.84-1.70 (m, 1H), 1.70-1 .53 (m, 1H), 1.48-1.27 (m, 2H), 1.19 (br s, 1H); 19F NMR (376 MHz, methanol-d4) δ -58.61 (small atropisomer ), −59.54 (larger atropisomer).

Step 4. (R)-5 ^5- (trifluoromethyl)-3-thia-4-aza-2,5(2,6)-dipyridina-1(1,2)- in NaOH solution (1N, 1.2 mL) A solution of pyrrolidina-6(1,2)-benzeneacyclodecaphan-15-one 3,3-dioxide (30 mg, 0.058 mmol) was stirred at 80° C. for 12 hours, then treated with 1N HCl. acidified to pH ˜5 and extracted with EtOAc (4×50 mL). The EtOAc phase was _dried over _Na2SO4 and then evaporated. The resulting residue is purified by flash chromatography (EtOAc:heptane/30-50%) to give (R)-3-(4,4-dioxide-23-(trifluoromethyl)-4-thia-3 ,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-7-yl)propanoic acid (135) was obtained as a white solid. MS: 535.2 [M+H]+, 1.41 min; 1H NMR (400 MHz, methylene chloride-d ₂ +CD ₃ OD) (major atropisomer) δ 7.87 (d, J=8.9 Hz, 1H). , 7.46 (dd, J = 8.5, 7.2 Hz, 1H), 7.42-7.34 (m, 2H), 7.31-7.26 (m, 2H), 7.23 ( td, J=7.4, 1.3 Hz, 1 H), 7.11 (d, J=7.6 Hz, 1 H), 6.51 (dd, J=8.5, 0.8 Hz, 1 H), 4 .34 (tt, J = 9.4, 4.5 Hz, 1H), 2.44-2.24 (m, 3H), 1.95-1.75 (m, 2H), 1.69 (m, 1H), 1.58 (m, 1H), 1.43 (dq, J = 9.4, 4.5Hz, 2H), 1.37-1.21 (m, 2H), 1.15 (m, 1H). 19F NMR (376 MHz, methylene chloride-d ₂ +CD ₃ OD) δ -58.69, -59.41

Administration and Pharmaceutical Compositions For therapeutic use of the compounds of the present invention, such compounds are administered alone or as part of a pharmaceutical composition. Accordingly, in another aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers such as those described herein. Pharmaceutical compositions may be formulated for particular routes of administration such as oral administration, parenteral administration (eg, by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration can also involve inhalation or intranasal administration. In certain embodiments, pharmaceutical compositions comprising a compound of the invention may be formulated for intramuscular, intravenous, subcutaneous, oral, intrapulmonary, intrathecal, topical or intranasal administration.

Pharmaceutical compositions of the present invention may be in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including but not limited to solutions, suspensions or emulsions). ). Tablets may be film coated or enteric coated according to methods known in the art.

Typically, the pharmaceutical composition comprises
a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;
b) lubricants such as silica, talcum, stearic acid, its magnesium or calcium salts and/or polyethylene glycol;
c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone;
d) disintegrants such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) tablets or gelatin capsules containing the active ingredient together with absorbents, colorants, flavors and sweeteners. is an agent.

Compositions suitable for oral administration contain a compound of the invention in the form of tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. include. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions provide a pharmaceutically pleasing and palatable formulation. To do so, it may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as maize starch or alginic acid; binding agents such as starch. , gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. Tablets are either uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use are presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules, in which The active ingredient can be presented as a water or oil vehicle (mixed with, for example, peanut oil, liquid paraffin or olive oil).

Parenteral compositions (eg, intravenous (IV) formulations) are aqueous isotonic solutions or suspensions. Parenteral compositions may be sterile and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts to adjust the osmotic pressure and/or buffers. can contain In addition, they can also contain other therapeutically valuable substances. Compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or about 1-50% active ingredient.

A compound of the invention or a pharmaceutical composition thereof for use in a subject (e.g., a human) will typically be at about 100 mg/kg, 75 mg/kg, 50 mg/kg, 25 mg/kg, 10 mg/kg, 7.5 mg. /kg, 5.0 mg/kg, 3.0 mg/kg, 1.0 mg/kg, 0.5 mg/kg, 0.05 mg/kg or 0.01 mg/kg or less, but preferably about 0.0001 mg /kg or higher, administered orally or parenterally. When administered intravenously by infusion, the dosage may depend on the infusion rate at which the intravenous (iv) formulation is administered. Generally, the therapeutically effective dosage of a compound, pharmaceutical composition, or combination thereof, will depend on the species of the subject, the body weight, age and individual condition, the disorder or disease being treated or the severity thereof. A physician, pharmacist, clinician or veterinarian of ordinary skill will readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of the disorder or disease. be able to.

The above dosage characteristics are advantageously demonstrable in in vitro or in vivo tests using mammals such as mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the invention can be administered in vitro, in the form of solutions, e.g., aqueous solutions, and in vivo, e.g., as suspensions or in aqueous solutions, enterally, parenterally, advantageously intravenously. can be applied. Dosages in vitro may range from about 10 ⁻³ molar and 10 ⁻⁹ molar. A therapeutically effective amount in vivo may range from about 0.1-500 mg/kg, or from about 1-100 mg/kg, depending on the route of administration.

Certain aspects and examples of pharmaceutical compositions of the invention are provided in the following list of enumerated embodiments. It will be appreciated that features defined in each embodiment can be combined with other defined features to provide further embodiments of the invention.

Embodiment 120. A pharmaceutical composition comprising a compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

Embodiment 121. A pharmaceutical composition comprising a compound according to any one of embodiments 118-119, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

Embodiment 122. A pharmaceutical composition according to embodiment 120 or 121, comprising one or more additional pharmaceutical agents.

Embodiment 123. 123. The pharmaceutical composition according to embodiment 122, wherein the additional pharmaceutical agent is selected from mucolytics, aerosolized hypertonic saline, bronchodilators, antibiotics, anti-infectives, CFTR modulators, and anti-inflammatory agents.

Embodiment 124 The pharmaceutical composition of embodiment 122, wherein the one or more additional pharmaceutical agents is a CFTR modulator.

Embodiment 125. A pharmaceutical composition according to embodiment 122, wherein the one or more additional pharmaceutical agents is a CFTR collector.

Embodiment 126. The pharmaceutical composition of embodiment 122, wherein the one or more additional pharmaceutical agents is a CFTR potentiator.

Embodiment 127. The pharmaceutical composition of embodiment 122, wherein the one or more additional pharmaceutical agents is a CFTR modulator and a CFTR potentiator.

Embodiment 128 The pharmaceutical composition according to embodiment 122, wherein the one or more additional pharmaceutical agents are CFTR collectors and CFTR potentiators.

Pharmacology and Utility Compounds of the invention have been found to modulate CFTR activity, cystic fibrosis and additional diseases not directly caused by mutations in CFTR, such as secretory diseases and CFTR mediated. It may be useful in treating other protein folding diseases. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjögren's syndrome.

COPD is characterized by airflow limitation that is progressive and not fully reversible. Airflow limitation results from mucus hypersecretion, emphysema, and bronchiolitis. Activators of mutant or wild-type CFTR offer potential treatments for mucus hypersecretion and impaired mucociliary clearance common in COPD. Specifically, increasing anion secretion across CFTR may enhance fluid transport to airway surface fluids to lubricate the mucosa and optimize interciliary fluid viscosity. This can lead to improved mucociliary clearance and reduced symptoms associated with COPD.

Dry eye disease is characterized by decreased tear production and abnormal tear film lipid, protein and mucin profiles. There are many causes of dry eye, some of which include aging, LASIK eye surgery, arthritis, drugs, chemical/burns, allergies, and diseases such as cystic fibrosis and Sjögren's syndrome. Increasing anion secretion via CFTR may facilitate fluid transport from corneal endothelial cells and secretory glands around the eye to increase corneal hydration. This can help alleviate symptoms associated with dry eye disease.

Sjögren's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eyes, mouth, skin, respiratory tissues, liver, vagina, and digestive tract. Symptoms include dry eyes, mouth, and vagina, and lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and polymyositis/dermatomyositis. Defective protein trafficking is thought to cause diseases with limited therapeutic options. Enhancers or inducers of CFTR activity can hydrate various organs affected by the disease and help improve associated symptoms.

The compounds of the invention, in free form or in pharmaceutically acceptable salt form, exhibit beneficial pharmacological properties, such as CFTR modulating properties as demonstrated by the in vitro studies presented herein, and are therefore indicated for therapy. or used as a research chemical, for example as a tool compound.

The compounds of the present invention are useful for male infertility due to cystic fibrosis, chronic bronchitis, recurrent bronchitis, acute bronchitis, congenital bilateral deferens duct defect (CBAVD), congenital uterine-vaginal defect (CAUV) female infertility, chronic rhinosinusitis, primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, diabetes, dry eye, constipation, allergic bronchopulmonary aspergillosis (ABPA), bone diseases (e.g., osteoporosis), Asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis or associated dyspnea, recurrent bronchitis, acute bronchitis, rhinosinusitis, constipation, pancreatitis (idiopathic chronic pancreatitis (ICP), idiopathic relapsing pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency), male infertility due to congenital bilateral deferens duct defect (CBAVD), mild lung disease, idiopathic pancreatitis, liver disease , emphysema, hereditary emphysema, gallstones, gastroesophageal reflux disease, gastrointestinal malignancies, inflammatory bowel disease, constipation, diabetes, arthritis, osteoporosis, osteopenia, dry eye disease, and Sjögren's syndrome obtain.

The compounds of the invention may be useful in the treatment of pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency.

Accordingly, as a further aspect the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in therapy. In further embodiments, the therapy is selected from diseases that can be treated by modulation of CFTR activity. In another embodiment, the disease is selected from the list above, preferably cystic fibrosis, asthma, COPD, chronic bronchitis and emphysema, more preferably cystic fibrosis, asthma, COPD and chronic bronchitis. , more preferably cystic fibrosis, COPD and emphysema, even more preferably cystic fibrosis.

Accordingly, in a further aspect the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in therapy. In further embodiments, the therapy is selected from diseases that can be treated by modulation of CFTR activity. In another embodiment, the disease is selected from the list above, preferably cystic fibrosis, asthma, COPD, chronic bronchitis and emphysema, more preferably cystic fibrosis, asthma, COPD and chronic bronchitis. , more preferably cystic fibrosis, COPD and emphysema, even more preferably cystic fibrosis.

Thus, in a further aspect, the present invention provides a method for the treatment of pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency. Use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in therapy is provided.

In another aspect, the invention provides a method of treating a disease treated by modulation of CFTR, comprising administering a therapeutically acceptable amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. I will provide a. In a further embodiment, the disease is selected from the list above, preferably cystic fibrosis, asthma, COPD, chronic bronchitis and emphysema, more preferably cystic fibrosis, asthma, COPD and chronic bronchitis, More preferably, it is selected from cystic fibrosis, COPD and emphysema, even more preferably cystic fibrosis.

In another aspect, the invention is a method of treating pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency. Thus, methods are provided comprising administering a therapeutically acceptable amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

Accordingly, as a further aspect the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. In a further embodiment, the medicament is for treatment of a disease treatable by modulation of CFTR. In another embodiment, the disease is selected from the list above, preferably cystic fibrosis, asthma, COPD, chronic bronchitis and emphysema, more preferably cystic fibrosis, asthma, COPD and chronic bronchitis. , more preferably cystic fibrosis, COPD and emphysema, even more preferably cystic fibrosis.

Thus, in a further aspect, the present invention provides a method for the treatment of pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency. A use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament is provided.

In one embodiment of the present invention, 4-(4,4-dioxide-2 ³ -(trifluoromethyl) for use in treating cystic fibrosis, asthma, COPD, chronic bronchitis, pancreatitis and emphysema. -4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacyclodecaphan-6-yl)butanoic acid is provided.

In one embodiment of the present invention, 4-(4,4-dioxide-2 ³ -(trifluoromethyl) for use in treating cystic fibrosis, asthma, COPD, chronic bronchitis, pancreatitis and emphysema. -4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)butanoic acid is provided.

In one embodiment of the present invention, 4-(4,4-dioxide-2 ³ -(trifluoromethyl) for use in treating cystic fibrosis, asthma, COPD, chronic bronchitis, pancreatitis and emphysema. -4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)butanoic acid is provided.

In one embodiment of the present invention, 4-(4,4-dioxide-2 ³ -(trifluoromethyl) for use in treating cystic fibrosis, asthma, COPD, chronic bronchitis, pancreatitis and emphysema. -4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphan-6-yl)butanoic acid is provided.

In one embodiment of the present invention, 4-(4,4-dioxide-2 ³ -(trifluoromethyl) for use in treating cystic fibrosis, asthma, COPD, chronic bronchitis, pancreatitis and emphysema. -4-Thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetradecaphan-6-yl)butanoic acid is provided.

In one embodiment of the present invention, 4-(4,4-dioxide-2 ³ -(trifluoromethyl) for use in treating cystic fibrosis, asthma, COPD, chronic bronchitis, pancreatitis and emphysema. -4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopentadecan-6-yl)butanoic acid is provided.

In one embodiment of the present invention, for use in the treatment of pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency. , 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclo Decaphan-6-yl)butanoic acid is provided.

In one embodiment of the present invention, for use in the treatment of pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency. , 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenenacyclo Ndecaphan-6-yl)butanoic acid is provided.

In one embodiment of the present invention, for use in the treatment of pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency. , 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclo Dodecaphan-6-yl)butanoic acid is provided.

In one embodiment of the present invention, for use in the treatment of pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency. , 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotri Decaphan-6-yl)butanoic acid is provided.

In one embodiment of the present invention, for use in the treatment of pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency. , 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclo Tetradecaphan-6-yl)butanoic acid is provided.

In one embodiment of the present invention, for use in the treatment of pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency. , 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclo Pentadecaphan-6-yl)butanoic acid is provided.

Another aspect of the invention is a method for treating or lessening the severity of a disease, disorder, or condition associated with modulation of CFTR in a subject, comprising: a compound of the invention, or a pharmaceutically acceptable salt thereof to a subject.

In certain embodiments, the invention is a method of treating a condition, disease, or disorder involving defective CFTR activity, comprising administering a compound of the invention to a subject in need thereof. provide a way. In certain embodiments, the invention is a method of treating a condition, disease, or disorder involving a deficiency in CFTR activity, comprising administering a composition comprising a compound of the invention to a subject in need thereof. providing a method comprising:

In a specific embodiment, the invention provides a method of treating diseases associated with decreased CFTR function due to mutations in the gene encoding CFTR or environmental factors (e.g., smoking), wherein the compounds of the invention are Methods are provided comprising administering to a subject in need of treatment. In certain embodiments, the invention provides a method of treating diseases associated with decreased CFTR function due to mutations in the gene encoding CFTR or environmental factors (e.g., smoking), comprising a composition comprising a compound of the invention A method is provided comprising administering the product to a subject in need of treatment thereof. Diseases associated with decreased CFTR function due to mutations in genes encoding CFTR or environmental factors (e.g., smoking) include cystic fibrosis, chronic bronchitis, recurrent bronchitis, acute bronchitis, congenital bilateral deferens. Male infertility due to CBAVD, female infertility due to congenital uterine-vaginal defect (CAUV), idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic nasal sinuses inflammation, primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, diabetes, dry eye, constipation, allergic bronchopulmonary aspergillosis (ABPA), bone diseases (eg, osteoporosis), and asthma.

In certain embodiments, the invention provides a method for treating a disease associated with normal CFTR function comprising administering a compound of the invention to a subject in need of such treatment. do. In certain embodiments, the invention provides a method for treating a disease associated with normal CFTR function, comprising administering a composition comprising a compound of the invention to a subject in need thereof. to provide a method comprising Diseases associated with normal CFTR function include chronic obstructive pulmonary disease (COPD), chronic bronchitis or associated dyspnea, recurrent bronchitis, acute bronchitis, rhinosinusitis, constipation, pancreatitis (chronic pancreatitis). , recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency), male infertility due to congenital bilateral deferens duct defect (CBAVD), mild lung disease, idiopathic pancreatitis, liver disease, emphysema, hereditary emphysema, gallstones , gastroesophageal reflux disease, gastrointestinal malignancies, inflammatory bowel disease, constipation, diabetes, arthritis, osteoporosis, and osteopenia.

According to an alternative preferred embodiment, the present invention provides a method of treating cystic fibrosis comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment. A method is provided comprising administering According to an alternative preferred embodiment, the present invention provides a method of treating cystic fibrosis comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment. A method is provided comprising administering a composition comprising

According to an alternative preferred embodiment, the invention provides a method of treating chronic obstructive pulmonary disease (COPD), comprising administering to a subject in need of such treatment a compound of the invention, or a pharmaceutical agent thereof. A method is provided comprising administering an acceptable salt to the According to an alternative preferred embodiment, the invention provides a method of treating chronic obstructive pulmonary disease (COPD), comprising administering to a subject in need of such treatment a compound of the invention, or a pharmaceutical agent thereof. A method is provided comprising administering a composition comprising an acceptable salt to the

According to alternative preferred embodiments, the present invention provides pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency. A method of treatment is provided comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment. According to alternative preferred embodiments, the present invention provides pancreatitis, including idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic pancreatitis, recurrent pancreatitis, acute pancreatitis and pancreatic insufficiency. A method of treatment is provided comprising administering to a subject in need of such treatment a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof.

According to the present invention, an "effective dose" or "effective amount" of a compound or pharmaceutical composition is effective to treat or reduce the severity of one or more of the diseases, disorders or conditions listed above. quantity.

The compounds and compositions according to the methods of the present invention may be administered using any amount and any route of administration effective to treat or lessen the severity of one or more of the diseases, disorders or conditions listed above. can be administered.

In certain embodiments, the invention relates to the above method, wherein said compound is administered parenterally.

In a specific embodiment, the present invention provides the above compound, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, intrapulmonarily, intrathecally, topically or intranasally. concerning the method of

In certain embodiments, the invention relates to the above method, wherein said compound is administered systemically.

In certain embodiments, the invention relates to the above method, wherein said subject is a mammal.

In certain embodiments, the invention relates to the above method, wherein said subject is a primate.

In certain embodiments, the invention relates to the above method, wherein said subject is human.

Certain aspects and examples of the use of the compounds of the invention and pharmaceutical compositions of the invention are provided in the following list of enumerated embodiments. It will be appreciated that features defined in each embodiment can be combined with other defined features to provide further embodiments of the invention.

Embodiment 129. A compound according to any one of embodiments 1-119, or a pharmaceutical formulation thereof, for use in the treatment of a CFTR-mediated disease selected from cystic fibrosis, asthma, COPD, chronic bronchitis and emphysema. acceptable salt.

Embodiment 130. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable compound thereof, for use in treating a CFTR-mediated disease selected from cystic fibrosis, asthma, COPD and chronic bronchitis salt.

Embodiment 131. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, for use in the treatment of a CFTR-mediated disease selected from cystic fibrosis, COPD and emphysema.

Embodiment 132. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, for use in the treatment of a CFTR-mediated disease that is cystic fibrosis.

Embodiment 133. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, for use in treating pancreatitis.

Embodiment 134. A method of treating a CFTR-mediated disease in a subject comprising administering to the subject a compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, or embodiments 120-128 A method comprising administering a pharmaceutical composition according to any one of

Embodiment 135. A method of treating a CFTR-mediated disease in a subject, comprising: administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof A method comprising administering a pharmaceutical composition according to any one of Forms 120-128.

Embodiment 136. 136. The method of embodiment 134 or 135, wherein the CFTR-mediated disease is selected from cystic fibrosis, asthma, COPD and chronic bronchitis.

Embodiment 137. 136. The method of embodiment 134 or 135, wherein the CFTR-mediated disease is selected from cystic fibrosis, COPD and emphysema.

Embodiment 138. 136. The method of embodiment 134 or 135, wherein the CFTR-mediated disease is cystic fibrosis.

Embodiment 139. A method of treating pancreatitis in a subject comprising administering to the subject a compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, or any of embodiments 120-128 A method comprising administering a pharmaceutical composition according to one.

Embodiment 140. One or more additional The method of any one of embodiments 134-139, further comprising administering a pharmaceutical agent to the subject.

Embodiment 141. 141. The method of embodiment 140, wherein the additional pharmaceutical agent is selected from mucolytics, nebulized hypertonic saline, bronchodilators, antibiotics, anti-infectives, CFTR modulators, and anti-inflammatory agents.

Embodiment 142. 141. The method of embodiment 140, wherein the additional pharmaceutical agent is selected from CFTR modulators.

Embodiment 143. 141. The method of embodiment 140, wherein the additional pharmaceutical agent is selected from CFTR potentiators.

Embodiment 144. 141. The method of embodiment 140, wherein the additional pharmaceutical agent is selected from CFTR modulators and CFTR potentiators.

Embodiment 145. 141. The method of embodiment 140, wherein the additional pharmaceutical agent is selected from CFTR collectors.

Embodiment 146. 141. The method of embodiment 140, wherein the additional pharmaceutical agent is selected from CFTR collectors and CFTR potentiators.

Embodiment 147. Use of a compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in which CFTR modulation contributes to the pathology and/or symptoms of the disease.

Embodiment 148. Use of a compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating pancreatitis.

Combination Therapy In some cases, it may be advantageous to administer a compound of the invention in combination with one or more additional therapeutic agents, or before or after one or more other therapeutic agents. The compounds of the invention can be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other therapeutic agent. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid that has therapeutic activity or that enhances therapeutic activity when administered to a patient in combination with a compound of the invention.

In one embodiment, the invention provides a product comprising a compound of the invention and at least one other therapeutic agent as a combined formulation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is treatment of a CFTR-mediated disease or condition. Products provided as combination formulations include the compound of the invention and the other therapeutic agent together in the same pharmaceutical composition, or the compound of the invention and the other therapeutic agent in separate forms, e.g., kit form. including compositions comprising agents.

In one embodiment, the invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. Optionally, the pharmaceutical composition may contain a pharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides kits comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention. In one embodiment, the kit includes a means for keeping said compositions separate, such as containers, divided bottles, divided foil packets and the like. An example of such a kit is a blister pack, as typically used for packaging tablets, capsules and the like.

The kits of the invention are used to administer different dosage forms (eg, oral and parenteral), to administer separate compositions at different dosing intervals, or to titrate separate compositions against each other. obtain. To aid compliance, the kits of the invention typically include directions for administration.

In the combination therapy of the invention, the compounds of the invention and the other therapeutic agent can be manufactured and/or formulated by the same or different manufacturers. Additionally, the compounds of this invention and other therapeutic agents may be combined into a combination therapy: (i) prior to release of the combination product to physicians (e.g., a kit containing a compound of this invention and other therapeutic agents); (ii) by the physician himself (or under the guidance of a physician) immediately prior to administration; (iii) by the patient himself (eg, during sequential administration of a compound of the invention and other therapeutic agents).

Accordingly, the invention provides the use of a compound of the invention to treat a disease or condition mediated by CFTR, wherein the medicament is formulated for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating diseases or conditions mediated by CFTR, wherein the agent is administered with a compound of the invention .

The invention also provides a compound of the invention for use in a method of treating a disease or condition mediated by CFTR, wherein the compound of the invention is formulated for administration with another therapeutic agent. . The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by CFTR, wherein the other therapeutic agent is prepared for administration with a compound of the invention. . The invention also provides a compound of the invention for use in a method of treating a disease or condition mediated by CFTR, wherein the compound of the invention is administered with another therapeutic agent. The invention also provides additional therapeutic agents for use in methods of treating diseases or conditions mediated by CFTR, wherein the other therapeutic agent is administered with a compound of the invention.

The invention also provides the use of a compound of the invention to treat a disease or condition mediated by CFTR, wherein the patient has been previously (eg, within 24 hours) treated with another therapeutic agent. there is The invention also provides the use of another therapeutic agent to treat a disease or condition mediated by CFTR, wherein the patient has been previously (eg, within 24 hours) treated with a compound of the invention. there is

In one embodiment, the other therapeutic agent is selected from osmotic agents, ion channel modulators, mucolytic agents, bronchodilators, antihistamines, antibiotics, anti-inflammatory agents and CFTR modulators.

In another embodiment, the other therapeutic agent is an osmotic agent such as nebulized hypertonic saline, dextran, mannitol or xylitol.

In another embodiment, the other therapeutic agent is a mucolytic agent, eg, Pulmozyme™.

In another embodiment, the other therapeutic agent is a bronchodilator, such as albuterol, metaproterenol sulfate, pirbuterol acetate, salmeterol, indacaterol, or terbutaline sulfate; Also included are agonists and antimuscarinic agents, especially ipratropium bromide, oxitropium bromide, glycopyrronium salts or tiotropium salts.

In another embodiment, the other therapeutic agent is an antihistamine such as cetirizine hydrochloride, clemastine fumarate, promethazine, loratadine, desloratadine, diphenylhydramine fexofenadine hydrochloride, acrivastine, astemizole, azelastine, ebastine, epinastine , mizolastine or terfenadine.

In another embodiment, the other therapeutic agent is an antibiotic, such as tobramycin (including tobramycin inhalation powder), azithromycin, cayston, aztreonam (including aerosolized forms of aztreonam), amikacin (including liposomal formulations thereof). ), ciprofloxacin (including formulations thereof suitable for administration by inhalation), levofloxacin (including aerosolized formulations thereof) and combinations of two antibiotics such as fosfomycin and tobramycin.

In another embodiment, the other therapeutic agent is an anti-inflammatory drug such as ibuprofen, docosahexaenoic acid, sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine or simvastatin; a steroid such as a glucocorticosteroid such as budesonide, dipropion. beclomethasone acid, fluticasone propionate, ciclesonide or mometasone furoate; LTD4 antagonists such as montelukast or zafirlukast; PDE4 inhibitors such as enprophylline, theophylline, roflumilast, Aliflo (cilomilast), tofimilast, pumafentrine, lilimilast, Apremilast, Allophylline, Atizorame, Oglemilast, or Tetomilast.

In another embodiment, the other therapeutic agent is a CFTR modulator. In another embodiment, the other therapeutic agent is a CFTR potentiator. In another embodiment, the other therapeutic agent is a CFTR collector. Exemplary CFTR modulators include N-(2-(5-chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl)-benzamide (Corr-4a ), N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide (Ivacaftor), N-[2-(1,1-dimethyl ethyl)-4-[1,1-di(methyl-d3)ethyl-2,2,2 _- d3]-5-hydroxyphenyl]-1,4-dihydro-4-oxo- ₃ -quinolinecarboxamide ( CTP-656), (((3-((3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)carbamoyl )-1H-pyrazol-1-yl)methoxy)methyl)phosphonic acid (GLPG1833), 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl) Cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid (Lumakaftol), N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno [2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1- [(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide (VX-661), 4-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide)-7-(difluoromethoxy)chroman -2-yl)benzoic acid (GLPG2222), 4-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide)isoquinoline-1 -yl)benzoic acid, N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl) -1,4-dihydroquinoline-3-carboxamide, 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid (Atarlen), 5,7-dihydric Droxy-3-(4-hydroxyphenyl)chromen-4-one (genistein), N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d ₃ )propan-2-yl -1,1,1,3,3,3-d ₆ )phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (CTP-656), N-(3-carbamoyl-5,5, 7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide (GLPG1837), 3-chloro-4-(6- Hydroxyquinolin-2-yl)benzoic acid (N-91115) and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5 -(trifluoromethyl)picolinamide.

In one embodiment of the invention there is provided a product comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a CFTR modulator as a combined formulation for simultaneous, separate or sequential use in therapy. . In another embodiment, a product is provided comprising a compound of the invention and a CFTR potentiator as a combined formulation for simultaneous, separate or sequential use in therapy. In another embodiment, a product is provided comprising a compound of the invention, a CFTR potentiator and a CFTR collector as a combined formulation for simultaneous, separate or sequential use in therapy.

Specific aspects and examples of combinations and combination therapies of the invention are provided in the following list of further enumerated embodiments. It will be appreciated that features defined in each embodiment can be combined with other defined features to provide further embodiments of the invention.

Embodiment 149. a compound of any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, and (S)-3- as a combination formulation for simultaneous, separate or sequential use in therapy A product containing amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 150. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy- A product containing N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 151. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy - A product containing N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 152. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy- A product containing N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 153. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy- A product containing N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 154. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-Dipyridina-1(1,2)-Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy - A product containing N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 155. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-Dipyridina-1(1,2)-Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy - A product containing N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 156. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, and N-(2,4) as a combination formulation for simultaneous, separate or sequential use in therapy -di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 157. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl -5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 158. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert- A product containing butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 159. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl -5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 160. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl -5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 161. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzeneacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert- A product containing butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 162. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzeneacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert- A product containing butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 163. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, N-(2,4- di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2, 2-Difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof.

Embodiment 164. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl- 5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1, A product containing 3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof.

Embodiment 165. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl -5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof.

Embodiment 166. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl- 5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1, A product containing 3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof.

Embodiment 167. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl- 5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1, A product containing 3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof.

Embodiment 168. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-Dipyridina-1(1,2)-Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl -5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof.

Embodiment 169. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-Dipyridina-1(1,2)-Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl -5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof.

Embodiment 170. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, N-(2,4- Di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3- Benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indole -5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 171. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl- 5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxole-5 -yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]- A product comprising cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 172. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl -5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxole- 5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl] - A product containing cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 173. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl- 5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxole-5 -yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]- A product comprising cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 174. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl- 5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxole-5 -yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]- A product comprising cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 175. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-Dipyridina-1(1,2)-Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl -5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxole- 5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl] - A product containing cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 176. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-Dipyridina-1(1,2)-Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl -5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxole- 5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl] - A product containing cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 177. A pharmaceutical composition comprising a compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, a CFTR modulator and a pharmaceutically acceptable carrier.

Embodiment 178. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a CFTR potentiator and a pharmaceutically acceptable carrier.

Embodiment 179. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a CFTR collector and a pharmaceutically acceptable carrier.

Embodiment 180. a compound of any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2 - hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 181.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy -2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 182.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- A pharmaceutical composition comprising hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 183.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy -2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 184.4-(4,4-dioxide ^- 2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy -2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 185.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- A pharmaceutical composition comprising hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 186.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- A pharmaceutical composition comprising hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 187. a compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro- A pharmaceutical composition comprising 4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 188.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- A pharmaceutical composition comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 189.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4 - A pharmaceutical composition comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 190.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- A pharmaceutical composition comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 191.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- A pharmaceutical composition comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 192.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4 - A pharmaceutical composition comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 193. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4 - A pharmaceutical composition comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 194. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4 - oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl ]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 195. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl } amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 196. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl] A pharmaceutical composition comprising carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 197. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl } amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 198. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl } amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 199. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl] A pharmaceutical composition comprising carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 200. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl] A pharmaceutical composition comprising carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 201. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4 - oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R) -2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

Embodiment 202.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2 ,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof, and pharmaceuticals A pharmaceutical composition comprising a legally acceptable carrier.

Embodiment 203. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)- 2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof, and A pharmaceutical composition comprising a pharmaceutically acceptable carrier.

Embodiment 204.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2 ,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof, and pharmaceuticals A pharmaceutical composition comprising a legally acceptable carrier.

Embodiment 205. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2 ,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof, and pharmaceuticals A pharmaceutical composition comprising a legally acceptable carrier.

Embodiment 20 6. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)- 2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof, and A pharmaceutical composition comprising a pharmaceutically acceptable carrier.

Embodiment 207. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)- 2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof, and A pharmaceutical composition comprising a pharmaceutically acceptable carrier.

Embodiment 208. a compound of any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2 -Hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 209. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy -2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 210. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- A combination comprising hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 211. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy -2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 212. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy -2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 213. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- A combination comprising hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 214. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2- A combination comprising hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 215. a compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro- A combination comprising 4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 216. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- A combination comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 217. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4 - a combination comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, in fixed or non-fixed combinations.

Embodiment 218. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- A combination comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 219. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- A combination comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 220.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4 - a combination comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, in fixed or non-fixed combinations.

Embodiment 221.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4 - a combination comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, in fixed or non-fixed combinations.

Embodiment 222. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4 - oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl ]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 223. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl }amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 224.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl] A combination comprising carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 225. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl }amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 226. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl }amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 227. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl] A combination comprising carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 228. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl] A combination comprising carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 229. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4 - oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R) -2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof A combination comprising a combination that is a constant combination or a non-constant combination.

Embodiment 230. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2 ,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof. A combination that is a fixed combination or a non-constant combination.

Embodiment 231.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)- 2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof A combination that is a fixed combination or a non-constant combination.

Embodiment 232. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2 ,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof. A combination that is a fixed combination or a non-constant combination.

Embodiment 233. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2 ,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof. is a fixed combination or a non-constant combination.

Embodiment 234.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)- 2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof A combination that is a fixed combination or a non-constant combination.

Embodiment 235. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)- 2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof A combination that is a fixed combination or a non-constant combination.

Embodiment 236. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, 6-(piperazine-1- yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino- A product containing 6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 237. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-( 6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N- A product containing (3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 238. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N- (6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N - (3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 239. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-( 6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N- A product containing (3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 240. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-( 6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N- A product containing (3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 241. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-Dipyridina-1(1,2)-Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N- (6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N - (3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 242. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N- (6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N - (3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof.

Embodiment 243. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, 6-(piperazine-1- yl)-N-(6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di -tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 244. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-( 6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5 -hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 245. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N- (6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl- 5-Hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 246. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-( 6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5 -hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 247. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-( 6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5 -hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 248. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-Dipyridina-1(1,2)-Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N- (6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl- 5-Hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 249. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5 as a combination formulation for simultaneous, separate or sequential use in therapy (2,6)-dipyridina-1(1,2)-benzonacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N- (6-(o-tolyl)-5-(trifluoromethyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl- 5-Hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof.

Embodiment 250. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a CFTR modulator and a pharmaceutically acceptable carrier.

Embodiment 251. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a CFTR potentiator and a pharmaceutically acceptable carrier.

Embodiment 252. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a CFTR collector and a pharmaceutically acceptable carrier.

Embodiment 253. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoro Methyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy -2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 254.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2 -methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 255.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl ) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy- A pharmaceutical composition comprising 2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 256. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2 -methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 257.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2 -methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 258.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl ) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy- A pharmaceutical composition comprising 2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 259.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl ) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy- A pharmaceutical composition comprising 2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Embodiment 260. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoro Methyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- A pharmaceutical composition comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 261.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) Pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline - A pharmaceutical composition comprising 3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 262.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl )pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo A pharmaceutical composition comprising quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 263.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) Pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline - A pharmaceutical composition comprising 3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 264.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) Pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline - A pharmaceutical composition comprising 3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 265. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl )pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo A pharmaceutical composition comprising quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 266. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl )pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo A pharmaceutical composition comprising quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 267. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoro Methyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy -2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 268. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2 -methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 269. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl ) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy- A combination comprising 2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 270.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2 -methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 27 1.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2 -methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 272.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl ) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy- A combination comprising 2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 273.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl ) pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy- A combination comprising 2-methylpropyl)-5-(trifluoromethyl)picolinamide or a pharmaceutically acceptable salt thereof, in fixed or non-definite combinations.

Embodiment 274. A compound according to any one of embodiments 1-119, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoro Methyl)pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- A combination comprising oxoquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 275.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclodecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) Pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline - A combination comprising a 3-carboxamide, or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 276.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl )pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo A combination comprising quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 277.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) Pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline - A combination comprising a 3-carboxamide, or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 278. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotridecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl) Pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline - A combination comprising a 3-carboxamide, or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 279. 4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclotetradecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl )pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo A combination comprising quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 280.4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclopentadecaphan-6-yl)butanoic acid, or a pharmaceutically acceptable salt thereof, 6-(piperazin-1-yl)-N-(6-(o-tolyl)-5-(trifluoromethyl )pyridin-2-yl)pyridine-2-sulfonamide or a pharmaceutically acceptable salt thereof and N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxo A combination comprising quinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof, which is a fixed combination or a non-fixed combination.

Embodiment 236. A product according to any one of embodiments 149-176 or embodiments 236-249 for use in treating a disease, disorder, or condition associated with modulation of CFTR.

Embodiment 237. A product according to any one of embodiments 149-176 or embodiments 236-249 for use in the treatment of cystic fibrosis, asthma, COPD, chronic bronchitis, pancreatitis or emphysema.

Embodiment 238. A product according to any one of embodiments 149-176 or embodiments 236-249 for use in treating pancreatitis.

Embodiment 236. A pharmaceutical composition according to any one of embodiments 177-207 or embodiments 250-266 for use in treating a disease, disorder, or condition associated with modulation of CFTR.

Embodiment 237. A pharmaceutical composition according to any one of embodiments 177-207 or embodiments 250-266 for use in treating cystic fibrosis, asthma, COPD, chronic bronchitis, pancreatitis or emphysema.

Embodiment 238. A pharmaceutical composition according to any one of embodiments 177-207 or embodiments 250-266 for use in treating pancreatitis.

Embodiment 236. A combination according to any one of embodiments 208-235 or embodiments 267-280 for use in treating a disease, disorder, or condition associated with modulation of CFTR.

Embodiment 237. A combination according to any one of embodiments 208-235 or embodiments 267-280 for use in the treatment of cystic fibrosis, asthma, COPD, chronic bronchitis, pancreatitis or emphysema.

Embodiment 238. A combination according to any one of embodiments 208-235 or embodiments 267-280 for use in treating pancreatitis.

Biological Assay Determination of delF508-CFTR-HRP Surface Expression in CFBE41o- Cells This assay quantifies cell surface expression of mutant CFTR channels using an extracellular HRP tag.

A cellular assay was developed to measure the surface expression of horseradish peroxidase (HRP)-tagged delF508-CFTR in the human bronchial epithelial immortalized CFBE41o- cell line (Phuan, P.W., et al, (2014) Molecular Pharmacology 86:42-51). Specifically, the HRP sequence was inserted into the fourth extracellular loop of delF508-CFTR and stably expressed in CFBE41o- cells. Cells were seeded in 384-well plates at a density of 5000 cells/well and added to medium (Gibco MEM #11095, 10% FBS, 10 mM HEPES, 200 mM L-glutamine, 200 μg/mL G418, 3 μg/well). mL puromycin) for 12-24 hours at 37°C. delF508-CFTR-HRP expression was induced in the medium with 500 ng/mL doxycycline (Sigma D-9891, dissolved in H ₂ O, sterile filtered) and cells were incubated at 37° C. for 48 hours. . Old medium was removed and new medium was added containing 500 ng/mL doxycycline and unknown test compound at the required test concentration in DMSO not exceeding a final DMSO concentration of 0.5%. The highest concentration tested was 10 μM in a 10-point concentration-response curve using 3-fold dilutions. After compound addition, cells were incubated at 37° C. for 24 hours. On the final day, cells were washed _four times in PBS containing ₁ mM MgCl2 and 0.1 mM CaCl2. 20 μl/well of HRP substrate (SuperSignal ELISA Pico, Fisher #37069) was added and the luminescence signal was measured (Viewlux, Perkin Elmer). Light was emitted after addition of exogenous HRP substrate only when delF508-CFTR-HRP reached the cell surface and the HRP tag reached the HRP substrate (Note: HRP substrate traverses the lipid bilayer to Intracellularly misfielded delF508-CFTR-HRP cannot be reached).

を用いて、測定された用量反応データ点に対してロジスティック回帰を行うことによって、各化合物についての半数効果濃度値（ｅｆｆｅｃｔｉｖｅ ｈａｌｆ ｍａｘｉｍａｌ ｖａｌｕｅ）（ＥＣ _５０ ）を計算し、式中、「Ｙ」は、観察される活性であり、「ボトム」は、観察される最低値であり、「トップ」は、観察される最高値であり、「ヒル係数」は、傾きの最大絶対値を示す。曲線当てはめを、Ｍａｔｌａｂ（Ｍａｔｈｗｏｒｋｓ）を用いてＧＮＦで実施される曲線当てはめプログラムによって行う。 The median activity value for the lowest concentration of compound in each assay plate was calculated and this value was used to normalize the signal for each well in each plate. Three replicates at each concentration for all compounds were tested to determine one _EC50 . Median values were determined and used to calculate compound activity as described below. The following formula:

Calculate the effective _half maximal value (EC50) for each compound by performing logistic regression on the measured dose-response data points using , is the observed activity, 'bottom' is the lowest observed value, 'top' is the highest observed value, and 'Hill coefficient' indicates the maximum absolute value of the slope. Curve fitting is performed by a curve fitting program implemented in GNF using Matlab (Mathworks).

を用いて、倍率変化（ＦＣ）を計算した。 Also, using the dose-response curve, the following formula:

was used to calculate the fold change (FC).

を用いて決定した。 Control compound 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-3-methylpyridin-2-yl)benzoic acid The compound efficacy compared to is expressed by the following formula:

was determined using

Determination of delF508-CFTR Functional Activity in Primary Human Bronchial Epithelial Cells (HBEC) Using the Multi-Transepithelial Clamp Circuit (MTECC-24) Assay This assay uses forskolin activation to and the CFTR channel (chloride ion transport) functional activity in patient-derived primary human bronchial epithelial cells in the presence of a CFTR collector/potentiator combination.

Primary human delF508-CFTR bronchial epithelial cells were cultured according to previously established methods (Neuberger, T. et, al., Methods in Molecular Biology, 2011, 741, pp 39-54). Briefly, T25 flasks were coated with 2 mL of 3T3 conditioned medium (MTI-GlobalStem, Cat# GSM9100) for at least 12 hours in a 37° C. CO ₂ incubator prior to thawing the HBEC cells. 1.7×10 ⁵ cells were added (Lonza, Cat# CC-3170) in 1 T25 flask containing BEBM Medium was changed daily until cells reached 100% confluence Cells were plated 4.95× in 15 mL HBE growth medium 10 ⁵ cells/T75 flask were seeded into T75 flasks (pre-coated with 5 mL of 3T3 conditioned medium over 12 hours) Flasks were fed daily with fresh HBE growth medium until cells reached confluence. 24-well transwell plates (Corning, Cat# 3378) were coated with 3T3 conditioned medium (70 μL on top of filter, 350 μL on bottom of wells) overnight in a 37° C. CO ₂ incubator. Cells were plated in precoated 24-well transwell plates at 1.7×10 ⁵ cells/well containing 700 μL growth medium on the bottom of the well and 200 μL growth medium on the top of the filter. After 24 hours, cells were plated in HBE differentiation medium (2% Ultroser G (Pall, Cat# 15950-017), 2% Fetal Clone II (Hyclone, Cat# SH30066.03), 0.25% bovine brain extract (Lonza, Cat# CC-4098), 1% PSA, 2.5 μg/mL of insulin (Sigma, Cat# I9278), 20 nM hydrocortisone (Sigma, Cat# H0888), 500 nM triiodothyronine (Sigma, Cat# T6397), 2.5 μg/mL transferrin (Sigma, Cat# T8158), DMEM/F12 supplemented with 250 nM ethanolamine (Sigma, Cat# E0135), 1.5 μM epinephrine (Sigma, Cat# E4250), 250 nM phosphoethanolamine (Sigma, Cat# P0503), 10 nM retinoic acid. Gibco, Cat# 11330-032))) Cells were fed in differentiation medium every other day. rice field. After 4 days, cells were exposed to the air/liquid interface. Cells were then fed every other day for 4 weeks before being fully differentiated.

Cells were washed with 70 ul/well, 3 mM DTT in PBS for 30 minutes at 37° C. 6 days prior to assay. Three days prior to assay, cells were washed again with PBS at 70 ul/well for 30 minutes at 37°C. Cells were then treated with compound for 24 hours prior to assay.

After 24 hours of treatment with compounds, cells were plated with 750 ul assay medium on the basolateral side and 250 ul on the apical side (assay medium: F-12 Coon modified, 20 mM HEPES (pH 7.4 with TRIS base)). , no FCS or bicarbonate). The plate was then transferred to the heated plate compartment of the TECC24 system (basolateral buffer temperature in the heating block is approximately 36.5° C.) for 45 minutes prior to measurement.

Modulators were added sequentially as follows while a TECC24 instrument recorded the equivalent short circuit current (Ieq).

Stocks were as follows before dilution in assay medium:
Benzamil stock: 10 mM in DMSO
Forskolin stock: 50 mM in DMSO
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide: 50 mM in DMSO
(S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide: 50 mM in 100% DMSO stock bumetanide stock: 20 mM in EtOH.

を用いて行い、式中、「Ｙ」は、観察される活性であり、「ボトム」は、観察される最低値であり、「トップ」は、観察される最高値であり、「ヒル係数」は、傾きの最大絶対値を示す。曲線当てはめを、Ｍａｔｌａｂ（Ｍａｔｈｗｏｒｋｓ）を用いてＧＮＦで実施される曲線当てはめプログラムによって行う。 Data were normalized using the median signal from wells treated with 0.1% DMSO as baseline. Curve fitting and _EC50 calculation were performed using the following formula:

where 'Y' is the observed activity, 'bottom' is the lowest observed value, 'top' is the highest observed value, and the 'Hill coefficient' indicates the maximum absolute value of the slope. Curve fitting is performed by a curve fitting program implemented in GNF using Matlab (Mathworks).

At least two replicates for all compounds were tested and the _EC50 reported in the table is the average value.

を用いて倍率変化（ＦＣ）を計算した。 Also, using the dose-response curve, the following formula:

was used to calculate the fold change (FC).

を用いて行い、ここで、試験化合物（アッセイの２４時間前に加えられる）は、アッセイの時点でポテンシエータ（Ｓ）－３－アミノ－６－メトキシ－Ｎ－（３，３，３－トリフルオロ－２－ヒドロキシ－２－メチルプロピル）－５－（トリフルオロメチル）ピコリンアミドの存在下にあった。対照化合物は、アッセイの２４時間前に加えられる２μＭの３－（６－（１－（２，２－ジフルオロベンゾ［ｄ］［１，３］ジオキソール－５－イル）シクロプロパン－１－カルボキサミド）－３－メチルピリジン－２－イル）安息香酸と、アッセイの時点で加えられる０．５μＭのＮ－（２，４－ジ－ｔｅｒｔ－ブチル－５－ヒドロキシフェニル）－４－オキソ－１，４－ジヒドロキノリン－３－カルボキサミドとの組合せであった。 Calculation of %Amax is performed using the following formula:

where the test compound (added 24 hours prior to the assay) was potentiated by the potentiator (S)-3-amino-6-methoxy-N-(3,3,3-tri In the presence of fluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide. The control compound is 2 μM 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamide) added 24 hours prior to assay. -3-methylpyridin-2-yl)benzoic acid and 0.5 μM N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4 added at the time of assay. -dihydroquinoline-3-carboxamide.

The present invention includes the following embodiments.
[Claim 1]
Formula (I)

(in the formula:
A. ₁ , A ₂ and A ₃ are each independently selected from optionally substituted arylene and optionally substituted heteroarylene;
L. ₁ is a sulfonamide, amide, carbonyl or urea;
L. ₂ is optionally substituted alkylene, optionally substituted alkoxylen, optionally substituted polyalkylene oxide, optionally substituted alkylene oxide, optionally substituted amino alkylene or optionally substituted C _{3 to 8} is cycloalkylene;
X _A. is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-)
or a pharmaceutically acceptable salt thereof.
[Claim 2]
Formula (I)
(in the formula:
A. ₁ is arylene or heteroarylene, where A ₁ are unsubstituted or H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} substituted with 1 to 2 groups independently selected from alkoxy;
A. ₂ is arylene or heteroarylene, where A ₂ are unsubstituted or H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} substituted with 1 to 2 groups independently selected from alkoxy;
A. ₃ is arylene or heteroarylene, where A ₃ are unsubstituted or H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} substituted with 1 to 2 groups independently selected from alkoxy;
L. ₁ but -NR ^A. S(O) _0-2 - ^* , -S(O) _0-2 NR ^A. - ^* , -NR ^A. C(=O)- ^* , -C(=O)NR ^A. - ^* , -C (= O) -, or -NR ^A. C(=O)NR ^A. - where said ^* but A ₂ indicates the point of attachment to
L. ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene or C _{3 to 8} is cycloalkylene, wherein L2 said alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene and C _{3 to 8} The cycloalkylene is unsubstituted or C ₁ ～C ₆ Alkyl, —OH, —(CH ₂ ) _m C(=O) OR ^A. , C ₁ ～C ₆ Alkoxy, C substituted with 1-6 hydroxyl groups ₁ ～C ₆ Alkyl, deuterium, deuterium-substituted C ₁ ～C ₆ alkyl, and spiro-bonded C ₃ ～C ₈ substituted with 1 to 3 groups independently selected from cycloalkyl;
X _A. is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-;
R. ^A. is H or C ₁ ～C ₆ is an alkyl,
m is 1, 2, 3, 4, 5, or 6)
The compound of claim 1, or a pharmaceutically acceptable salt thereof, of
[Claim 3]
Formula (I)
(in the formula:
A. ₁ is arylene or heteroarylene, where A ₁ are unsubstituted or H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} substituted with 1 to 2 groups independently selected from alkoxy;
A. ₂ is arylene or heteroarylene, where A ₂ are unsubstituted or H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} substituted with 1 to 2 groups independently selected from alkoxy;
A. ₃ is arylene or heteroarylene, where A ₃ are unsubstituted or H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} substituted with 1 to 2 groups independently selected from alkoxy;
L. ₁ but -NR ^A. S(O) _0-2 - ^* or -S (O) _0-2 NR ^A. - ^* where ^* but A ₂ indicates the point of attachment to
L. ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene or C _{3 to 8} is cycloalkylene, wherein L2 said alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene and C _{3 to 8} The cycloalkylene is unsubstituted or C ₁ ～C ₆ alkyl, —OH, deuterium, —(CH ₂ ) _m C(=O) OR ^A. , C ₁ ～C ₆ Alkoxy, C substituted with 1-6 hydroxyl groups ₁ ～C ₆ alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, and spiro-bonded C ₃ ～C ₈ substituted with 1 to 3 groups independently selected from cycloalkyl;
X _A. is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-;
R. ^A. is H or C ₁ ～C ₆ is an alkyl,
m is 1, 2, 3, 4, 5, or 6)
or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2.
[Claim 4]
Formula (I)
(in the formula:
A. ₁ is phenylene or pyridylene, where A ₁ is unsubstituted or H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} substituted with 1 to 2 groups independently selected from alkoxy;
A. ₂ is phenylene or pyridylene, where A ₂ is unsubstituted or H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} substituted with 1 to 2 groups independently selected from alkoxy;
A. ₃ is phenylene or pyridylene, where A ₃ is unsubstituted or H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} substituted with 1 to 2 groups independently selected from alkoxy;
L. ₁ but -NR ^A. S(O) _0-2 - ^* or -S (O) _0-2 NR ^A. - ^* where ^* but A ₂ indicates the point of attachment to
L. ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene or C _{3 to 8} cycloalkylene, wherein L ₂ the alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene and C _{3 to 8} The cycloalkylene is unsubstituted or C ₁ ～C ₆ alkyl, —OH, deuterium, —(CH ₂ ) _m C(=O) OR ^A. , C ₁ ～C ₆ Alkoxy, C substituted with 1-6 hydroxyl groups ₁ ～C ₆ alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, and spiro-bonded C ₃ ～C ₈ substituted with 1 to 3 groups independently selected from cycloalkyl;
X _A. is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-;
R. ^A. is H or C ₁ ～C ₆ is an alkyl,
m is 1, 2, 3, 4, 5, or 6)
, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3.
[Claim 5]
Formula (I)
(in the formula:
A. ₁ is pyridylene, where A ₁ is H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} substituted with 1 to 2 groups independently selected from alkoxy;
A. ₂ is pyridylene, where A ₂ the pyridylene of is unsubstituted;
A. ₃ is phenylene or pyridylene, where A ₃ is unsubstituted or H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} substituted with 1 to 2 groups independently selected from alkoxy;
L. ₁ but -NR ^A. S(O) _0-2 - ^* or -S (O) _0-2 NR ^A. - ^* where ^* but A ₂ indicates the point of attachment to
L. ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene or C _{3 to 8} cycloalkylene, wherein L ₂ the alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene and C _{3 to 8} The cycloalkylene is unsubstituted or C ₁ ～C ₆ alkyl, —OH, deuterium, —(CH ₂ ) _m C(=O) OR ^A. , C ₁ ～C ₆ Alkoxy, C substituted with 1-6 hydroxyl groups ₁ ～C ₆ alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, and spiro-bonded C ₃ ～C ₈ substituted with 1 to 3 groups independently selected from cycloalkyl;
X _A. is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-;
R. ^A. is H or C ₁ ～C ₆ is an alkyl,
m is 1, 2, 3, 4, 5, or 6)
, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4.
[Claim 6]
Formula (Ia)

(in the formula:
X _1a , X _1b , X _1c and X _1d are independently CR ¹ or N, where X _1a , X _1b , X _1c and X _1d can be N and the others are CR ¹ is;
X _2a , X _2b , X _2c and X _2d are independently CR ¹ or N, where X _2a , X _2b , X _2c and X _2d can be N and the others are CR ¹ is;
X _3a , X _3b , X _3c and X _3d are independently CR ² or N, where X _3a , X _3b , X _3c and X _3d can be N and the others are CR ² is;
X ₄ but,

or -O-, where ^* but L ₂ indicates the point of attachment to
L. ₂ but -(CR ⁴ R. ⁵ ) _n -,
-O(CR ⁴ R. ⁵ ) _n - ^** ,
-NR ⁷ (CR ⁴ R. ⁵ ) _n - ^** ,
-(CR ⁴ R. ⁵ ) _n O(CR ⁶ R. ¹⁰ ) _p - ^** ,
-(CR ⁴ R. ⁵ ) _n (CR ⁶ R. ¹⁸ )- ^** ,
-(CR ⁴ R. ⁵ ) _n (CR ⁸ R. ⁹ ) _p (CR ⁴ R. ⁵ ) _m -,
-(CR ⁴ R. ⁵ ) _p NR ⁷ (CR ⁶ R. ¹⁰ ) _n - ^** ,
-(CR ⁴ R. ⁵ ) _n O) _t (CR ⁶ R. ¹⁰ ) _p - ^** ,
or
-O-C ₃ ～C ₈ Cycloalkylene- ^** and
here, ^** but X ₄ indicates the point of attachment to
Each R ¹ is independently H, halo, halo-substituted C ₁ ～C ₆ alkyl, C ₁ ～C ₆ alkyl, deuterium-substituted C ₁ ～C ₆ alkyl, nitrile, hydroxyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} selected from alkoxy;
Each R ² is independently H, halo, nitrile, hydroxyl, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, deuterium-substituted C ₁ ～C ₆ Alkyl, hydroxy substituted C ₁ ～C ₆ alkyl, C _{1 to 6} alkoxy and halo substituted C _{1 to 6} selected from alkoxy;
R. ³ but H,
-C _{1 to 6} alkyl,
-(CR ¹¹ R. ¹² ) _y R. ¹⁶ ,
-(CR ¹¹ R. ¹² ) _y C(=O) OR ¹³ ,
-((CR ¹¹ R. ¹² ) _y O(CR ¹⁴ R. ¹⁵ ) _z C(=O) OR ¹³ ,
-((CR ¹¹ R. ¹² ) _y O(CR ¹⁴ R. ¹⁵ ) _z OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y C(=O)R ¹³ ,
-(CR ¹¹ R. ¹² ) _y OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y (CR ⁸ R. ⁹ ) _z C(=O) OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y (CR ⁸ R. ⁹ ) _z OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y (CR ⁸ R. ⁹ ) _z (CR ¹⁴ R. ¹⁵ ) _q OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y NR ¹⁰ (CR ¹⁴ R. ¹⁵ ) _q C(=O) OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y NR ¹³ R. ¹⁴ ,
-(CR ¹¹ R. ¹² ) _y R. ²⁰ ,
-((CR ¹¹ R. ¹² ) _y O) _q (CR ¹⁴ R. ¹⁵ ) _z C(=O) OR ¹³ ,
-((CR ¹¹ R. ¹² ) _y O) _q (CR ¹⁴ R. ¹⁵ ) _z OR ¹³ ,

is;
Each R ⁴ are independently H, D, deuterated C ₁ ～C ₆ alkyl and C _{1 to 6} selected from alkyl;
Each R ⁵ is independently H, D deuterated C ₁ ～C ₆ alkyl and C _{1 to 6} selected from alkyl;
Each R ⁶ is independently H, D deuterated C ₁ ～C ₆ alkyl and C _{1 to 6} selected from alkyl;
Each R ⁷ but independently H and C _{1 to 6} selected from alkyl;
Each R ⁸ and R ⁹ are independently H, D, deuterated C ₁ ～C ₆ alkyl, C _{1 to 6} selected from alkyl, or -OH;
or R ⁸ and R ⁹ is CR ⁸ R. ⁹ Together with the carbon inside, C _{3 to 8} forming a cycloalkyl;
Each R ¹⁰ are independently H, D and C _{1 to 6} selected from alkyl;
Each R ¹¹ are independently H, D and C _{1 to 6} selected from alkyl;
Each R ¹² are independently H, D, deuterated C ₁ ～C ₆ alkyl and C _{1 to 6} selected from alkyl;
Each R ¹³ but independently H and C _{1 to 6} selected from alkyl;
Each R ¹⁴ are independently H, D, deuterated C ₁ ～C ₆ alkyl and C _{1 to 6} selected from alkyl;
Each R ¹⁵ are independently H, D, deuterated C ₁ ～C ₆ alkyl and C _{1 to 6} selected from alkyl;
R. ¹⁶ is a 4-6 membered heterocycloalkyl having 1-2 ring members independently selected from N, O and S, wherein said 4-6 membered heterocycloalkyl is unsubstituted , or 1-2 R ¹⁷ substituted with a group;
Each R ¹⁷ is independently C _{1 to 6} selected from alkyl and hydroxyl;
R. ¹⁸ but H, C _{1 to 6} alkyl, —C(R ⁴ R. ⁵ ) _m OR ¹⁹ , or -(CH ₂ ) _m C(=O) OR ¹⁹ is;
Each R ¹⁹ but independently H and C _{1 to 6} selected from alkyl;
R. ²⁰ but,

is;
each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each p is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each w is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each y is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each z is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each q is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10)
or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, which has the structure of
[Claim 7]
Formula (Ib)

or a pharmaceutically acceptable salt thereof, according to claim 6, having the structure of the formula:
[Claim 8]
Formula (Ic) or Formula (Id)

(in the formula:
X _1a is CH or N;
X _2a is CH or N;
X _3a is CH or N)
or a pharmaceutically acceptable salt thereof, according to claim 7, having the structure:
[Claim 9]
Formula (Ie), Formula (If), Formula (Ig) or Formula (Ih):

(in the formula:
X _1a is CH or N;
X _2a is CH or N)
or a pharmaceutically acceptable salt thereof, according to any one of claims 6 to 8, having the structure of
[Claim 10]
Formula (Ii), Formula (Ij), Formula (Ik) or Formula (Il):

or a pharmaceutically acceptable salt thereof, according to any one of claims 6 to 9, having the structure of
[Claim 11]
Formula (Im), Formula (In), Formula (Io) or Formula (Ip):

or a pharmaceutically acceptable salt thereof, according to any one of claims 6 to 9, having the structure of
[Claim 12]
Formula (Iq)

or a pharmaceutically acceptable salt thereof, according to claim 6 or claim 7, having the structure of the formula:
[Claim 13]
X ₄ but,

or -O-, where ^* but L ₂ indicates the point of attachment to
L. ₂ but -(CR ⁴ R. ⁵ ) _n -,
-O(CR ⁴ R. ⁵ ) _n - ^** ,
-NR ⁷ (CR ⁴ R. ⁵ ) _n - ^** ,
-(CR ⁴ R. ⁵ ) _n O(CR ⁶ R. ¹⁰ ) _p - ^** ,
-(CR ⁴ R. ⁵ ) _n (CR ⁶ R. ¹⁸ )- ^** ,
-(CR ⁴ R. ⁵ ) _n (CR ⁸ R. ⁹ ) _p (CR ⁴ R. ⁵ ) _m -,
-(CR ⁴ R. ⁵ ) _p NR ⁷ (CR ⁶ R. ¹⁰ ) _n - ^** ,
or
-O-C _{3 to 8} Cycloalkylene- ^** and where ^** but X ₄ indicates the point of attachment to
R. ¹ is H, halo, halo-substituted C _{1 to 6} alkyl, C _{1 to 6} alkyl, or C _{1 to 6} is alkoxy;
R. ² is H or halo;
R. ³ but H,
-C _{1 to 6} alkyl,
-(CR ¹¹ R. ¹² ) _y R. ¹⁶ ,
-(CR ¹¹ R. ¹² ) _y C(=O) OR ¹³ ,
-((CR ¹¹ R. ¹² ) _y O(CR ¹⁴ R. ¹⁵ ) _z C(=O) OR ¹³ ,
-((CR ¹¹ R. ¹² ) _y O(CR ¹⁴ R. ¹⁵ ) _z OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y C(=O)R ¹³ ,
-(CR ¹¹ R. ¹² ) _y OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y (CR ⁸ R. ⁹ ) _z C(=O) OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y (CR ⁸ R. ⁹ ) _z OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y (CR ⁸ R. ⁹ ) _z (CR ¹⁴ R. ¹⁵ ) _q OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y NR ¹⁰ (CR ¹⁴ R. ¹⁵ ) _q C(=O) OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y NR ¹³ R. ¹⁴ ,
-(CR ¹¹ R. ¹² ) _y R. ²⁰ ,

is;
Each R ⁴ is H;
Each R ⁵ is H;
Each R ⁶ is H;
Each R ⁷ but independently H and C _{1 to 6} selected from alkyl;
Each R ⁸ and R ⁹ is independently H, C _{1 to 6} selected from alkyl, or -OH;
or R ⁸ and R ⁹ is CR ⁸ R. ⁹ Together with the carbon inside, C _{3 to 8} forming a cycloalkyl;
Each R ¹⁰ is H;
Each R ¹¹ is H;
Each R ¹² is H;
Each R ¹³ but independently H and C _{1 to 6} selected from alkyl;
Each R ¹⁴ is H;
Each R ¹⁵ is H;
R. ¹⁶ is a 4-6 membered heterocycloalkyl having 1-2 ring members independently selected from N or O, wherein said 4-6 membered heterocycloalkyl is unsubstituted or 1 to 2 R ¹⁷ substituted with a group;
Each R ¹⁷ is independently C _{1 to 6} selected from alkyl and hydroxyl;
R. ¹⁸ is -C(R ⁴ R. ⁵ ) _m OR ¹⁹ , or -(CH ₂ ) _m C(=O) OR ¹⁹ is;
Each R ¹⁹ is H;
R. ²⁰ but,

is;
each m is independently selected from 1, 2 and 3;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;
each p is independently selected from 1, 2 and 3;
each w is independently selected from 1 and 2;
each y is independently selected from 1, 2, 3, 4 and 5;
each z is independently selected from 1, 2 and 3;
13. The compound of any one of claims 6-12, or a pharmaceutically acceptable salt thereof, wherein each q is independently selected from 1 and 2.
[Claim 14]
X ₄ but,

or -O-, where ^* but L ₂ indicates the point of attachment to
L. ₂ but -(CR ⁴ R. ⁵ ) _n -,
-O(CR ⁴ R. ⁵ ) _n - ^** ,
or
-(CR ⁴ R. ⁵ ) _n O(CR ⁶ R. ¹⁰ ) _p - ^** and where ^** but X ₄ indicates the point of attachment to
R. ¹ is halo or halo-substituted C _{1 to 6} is alkyl;
R. ² is H, or halo (F;
R. ³ but -(CR ¹¹ R. ¹² ) _y C(=O) OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y OR ¹³ ,
-(CR ¹¹ R. ¹² ) _y (CR ⁸ R. ⁹ ) _z C(=O) OR ¹³ ,
or
-(CR ¹¹ R. ¹² ) _y (CR ⁸ R. ⁹ ) _z (CR ¹⁴ R. ¹⁵ ) _q OR ¹³ and
Each R ⁴ is H;
Each R ⁵ is H;
Each R ⁶ is H;
Each R ⁸ and R ⁹ is independently H or C _{1 to 6} selected from alkyl;
or R ⁸ and R ⁹ is CR ⁸ R. ⁹ Together with the carbon inside, C _{3 to 8} forming a cycloalkyl;
Each R ¹⁰ is H;
Each R ¹¹ is H;
Each R ¹² is H;
Each R ¹³ but independently H and C _{1 to 6} selected from alkyl;
Each R ¹⁴ is H;
Each R ¹⁵ is H;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;
each p is independently selected from 1, 2 and 3;
each y is independently selected from 1, 2, 3, 4 and 5;
each z is independently selected from 1, 2 and 3;
14. The compound of any one of claims 6-13, or a pharmaceutically acceptable salt thereof, wherein each q is independently selected from 1 and 2.
[Claim 15]
X ₄ but,

or -O-, where ^* but L ₂ indicates the point of attachment to
L. ₂ but -(CR ⁴ R. ⁵ ) _n -,
-O(CR ⁴ R. ⁵ ) _n - ^** ,
or
-(CR ⁴ R. ⁵ ) _n O(CR ⁶ R. ¹⁰ ) _p - ^** and where ^** but X ₄ indicates the point of attachment to
R. ¹ is Cl, F or CF ₃ is;
R. ² is H or F;
R. ³ but -(CR ¹¹ R. ¹² ) _y C(=O) OR ¹³ , -(CR ¹¹ R. ¹² ) _y OR ¹³ , -(CR ¹¹ R. ¹² ) _y (CR ⁸ R. ⁹ ) _z C(=O) OR ¹³ , or -(CR ¹¹ R. ¹² ) _y (CR ⁸ R. ⁹ ) _z (CR ¹⁴ R. ¹⁵ ) _q OR ¹³ and
Each R ⁴ is H;
Each R ⁵ is H;
Each R ⁶ is H;
Each R ⁸ and R ⁹ is independently selected from H or methyl;
or R ⁸ and R ⁹ is CR ⁸ R. ⁹ with the carbon in to form cyclopropyl;
Each R ¹⁰ is H;
Each R ¹¹ is H;
Each R ¹² is H;
Each R ¹³ is independently selected from H, methyl and ethyl;
Each R ¹⁴ is H;
Each R ¹⁵ is H;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;
each p is independently selected from 1, 2 and 3;
each y is independently selected from 1, 2, 3, 4 and 5;
z is 1;
15. The compound according to any one of claims 6 to 14, or a pharmaceutically acceptable salt thereof, wherein q is 1.
[Claim 16]
X ₄ but,

and where ^* but L ₂ indicates the point of attachment to
L. ₂ is-(CR ⁴ R. ⁵ ) _n - is;
R. ¹ is CF ₃ is;
R. ² is H;
R. ³ is-(CR ¹¹ R. ¹² ) _y C(=O) OR ¹³ is;
Each R ⁴ is H;
Each R ⁵ is H;
Each R ¹¹ is H;
Each R ¹² is H;
Each R ¹³ is H;
n is 1, 2, 3, 4, 5, 6, 7, 8, or 9;
16. The compound according to any one of claims 6 to 15, or a pharmaceutically acceptable salt thereof, wherein y is 2, 3 or 4.
[Claim 17]
6-(2-morpholinoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
2 ³ -(Trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide ;
2-(4,4-dioxide-2 ³ -(trifluoromethyl)-1 ¹ -oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)acetic acid;
2 ³ -(trifluoromethyl)-4-thia-3,6,1 ¹ -triaza-1(3,2),2,5(2,6)-tripyridinacycloundecaphane 4,4-dioxide;
2 ³ -(trifluoromethyl)-1 ² -oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl) butanoic acid;
3-(2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)ethoxy)propanoic acid ;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphan-6-yl)butanoic acid;
2 ³ -(Trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide ;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopentadecaphan-6-yl)butanoic acid;
6-(2-(3-hydroxypropoxy)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)butanoic acid;
4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)butanoic acid;
3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetradecaphan-6-yl)propanoic acid;
6-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)hexanoic acid;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetradecaphan-6-yl)butanoic acid;
3-(4,4-dioxide ^- 2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphan-6-yl)propanoic acid;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl) butanoic acid;
4-(2 ³ -methyl-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)butanoic acid ;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)butanal;
2-(2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)ethoxy)acetic acid;
3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopentadecaphan-6-yl)propanoic acid;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)butanoic acid;
5-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)pentanoic acid;
5-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)pentanoic acid;
4-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)butanoic acid ;
5-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphan-6-yl)pentanoic acid;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl) propanoic acid;
6-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)hexanoic acid ;
4-(2 ³ -Methoxy-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)butanoic acid ;
6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)propanoic acid;
6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ³ -methoxy-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide;
6-ethyl-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ³ -methyl-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)propanoic acid;
4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)butanoic acid;
6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide;
3-(2 ³ -(difluoromethyl)-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacyclodecaphan-6-yl) propanoic acid;
6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)butane acid;
3-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)propanoic acid ;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphan-6-yl)butanoic acid;
1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ³ -(Trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide ;
4-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphan-6-yl)butanoic acid;
1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ³ -(Trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide ;
3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propanoic acid;
2 ³ -chloro-6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4- dioxide;
2 ³ -(trifluoromethyl)-6,12-dioxa-4-thia-3-aza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
2 ³ -chloro-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propanoic acid ;
1-((4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)methyl)cyclopropane -1-carboxylic acid;
1-((4,4-dioxide-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)methyl ) cyclopropane-1-carboxylic acid;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)-2,2 - dimethylpropanoic acid;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propanoic acid;
6-(2-hydroxyethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide;
6-(2-hydroxyethyl)-2 ³ -(Trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide ;
3-(4,4-dioxide-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)propane acid;
2 ³ -chloro-14-methyl-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
2 ³ -(trifluoromethyl)-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
2 ³ -(trifluoromethyl)-4-thia-3,6,13-triaza-1(3,2),2,5(2,6)-tripyridinacyclotridecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)-2,2- dimethylpropanoic acid;
1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl)-2,2 - dimethylpropanoic acid;
6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
6,13-dimethyl-2 ³ -(trifluoromethyl)-4-thia-3,6,13-triaza-1(3,2),2,5(2,6)-tripyridinacyclotridecaphane 4,4-dioxide;
2 ³ -chloro-12-oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
6-(2-hydroxyethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ³ -(trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-7-yl)propanoic acid ;
6,10-dimethyl-2 ³ -(trifluoromethyl)-4-thia-3,6,10-triaza-1(3,2),2,5(2,6)-tripyridinacyclodecaphane 4,4-dioxide;
(4 ¹ s, 4 ⁵ s)-1 ³ -(trifluoromethyl)-3,5-dioxa-7-thia-8-aza-1,6(2,6),2(3,2)-tripyridina-4(1,5)-cyclooctanacyclo octaphane 7,7-dioxide;
6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
1 ⁵ -Fluoro-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
2 ³ -(trifluoromethyl)-4-thia-3,6,10-triaza-1(3,2),2,5(2,6)-tripyridinacyclodecaphane 4,4-dioxide;
7-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
Ethyl 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)-2,2- dimethyl propanoate;
2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide;
2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)acetic acid;
2 ³ -(trifluoromethyl)-6-((2S,3S)-2,3,4-trihydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
8-hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide;
6-(2-(piperazin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(2-(4-methylpiperazin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
(2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)ethyl)glycine;
6-(2-(3-hydroxyazetidin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
²³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
6-(2-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenenacyclodecaphane 4,4-dioxide;
6-methyl-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
Ethyl 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphan-6-yl) acetate;
6-(2,3-dihydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(2-(pyrrolidin-1-yl)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
methyl (2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)ethyl)glycinate;
6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide;
6-(2-aminoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide;
2 ³ -(trifluoromethyl)-4-thia-3,6,9-triaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenacyclononaphane 4,4-dioxide;
8-hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(2-aminoethyl)-2 ³ -(difluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
2-(3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propyl)isoindoline -1,3-dione;
2-(3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propyl)hexahydro- 1H-isoindole-1,3(2H)-dione;
methyl 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)acetate 6-(4 -hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphane 4,4-dioxide;
6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopentadecaphane 4,4-dioxide;
6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetradecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetradecaphane 4,4-dioxide;
6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopentadecaphane 4,4-dioxide;
2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4- dioxide;
1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
6-(6-hydroxyhexyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(2-(2-hydroxyethoxy)ethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(5-hydroxypentyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide;
2 ³ -chloro-6-(6-hydroxyhexyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4- dioxide;
1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide;
2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacyclodecaphane 4,4-dioxide ;
6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
1 ⁵ -fluoro-6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphan-6-yl)propanoic acid;
5-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphan-6-yl)pentanoic acid;
6-(2-aminoethyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide, and
(R)-3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-7-yl)propanoic acid
7. The compound of claim 6, selected from
[Claim 18]
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetradecaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopentadecan-6-yl)butanoic acid, and
6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide
7. The compound of claim 6, selected from
[Claim 19]
A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
[Claim 20]
20. The pharmaceutical composition of Claim 19, further comprising one or more additional pharmaceutical agents.
[Claim 21]
21. The pharmaceutical composition of claim 20, wherein said additional pharmaceutical agent is selected from mucolytics, aerosolized hypertonic saline, bronchodilators, antibiotics, anti-infectives, CFTR modulators, and anti-inflammatory agents.
[Claim 22]
21. A pharmaceutical composition according to claim 20, wherein said further pharmaceutical agent is a CFTR collector.
[Claim 23]
21. A pharmaceutical composition according to claim 20, wherein said additional pharmaceutical agent is a CFTR potentiator.
[Claim 24]
21. The pharmaceutical composition according to claim 20, wherein said additional pharmaceutical agents are CFTR collectors and CFTR potentiators.
[Claim 25]
A method for treating a CFTR-mediated disease in a subject, comprising a compound according to any one of claims 1-18 or a pharmaceutically acceptable salt thereof, or any one of claims 19-24. A method comprising administering the described pharmaceutical composition to said subject.
[Claim 26]
26. The method of claim 25, wherein said CFTR-mediated disease is selected from cystic fibrosis, asthma, COPD, and chronic bronchitis.
[Claim 27]
27. The method of claim 25 or 26, wherein the CFTR-mediated disease is cystic fibrosis, COPD, or emphysema.
[Claim 28]
27. The method of claim 25 or 26, wherein said CFTR-mediated disease is cystic fibrosis.
[Claim 29]
one or more additional pharmaceutical agents prior to, simultaneously with, or after the compound according to any one of claims 1-18 or the pharmaceutical composition according to any one of claims 19-24. 29. The method of any one of claims 25-28, further comprising administering to said subject.
[Claim 30]
30. The method of claim 29, wherein said additional pharmaceutical agent is selected from mucolytics, nebulized hypertonic saline, bronchodilators, antibiotics, anti-infectives, CFTR modulators, and anti-inflammatory agents.
[Claim 31]
30. The method of claim 29, wherein said additional pharmaceutical agent is a CFTR collector.
[Claim 32]
30. The method of claim 29, wherein said additional pharmaceutical agent is a CFTR potentiator.
[Claim 33]
30. The method of claim 29, wherein said additional pharmaceutical agents are CFTR collectors and CFTR potentiators.
[Claim 34]
Use of a compound according to any one of claims 1-18 in the manufacture of a medicament for treating CFTR-mediated diseases.
[Claim 35]
35. Use according to claim 34, wherein said medicament further comprises one or more additional pharmaceutical agents.
[Claim 36]
36. Use according to claim 35, wherein said additional pharmaceutical agent is selected from mucolytics, nebulized hypertonic saline, bronchodilators, antibiotics, anti-infectives, CFTR modulators and anti-inflammatory agents.
[Claim 37]
36. Use according to claim 35, wherein said further pharmaceutical agent is a CFTR collector.
[Claim 38]
36. Use according to claim 35, wherein said further pharmaceutical agent is a CFTR potentiator.
[Claim 39]
36. Use according to claim 35, wherein said further pharmaceutical agents are CFTR collectors and CFTR potentiators.
[Claim 40]
A method for treating pancreatitis in a subject, comprising a compound according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, or according to any one of claims 19-24. administering to said subject a pharmaceutical composition of
[Claim 41]
one or more additional pharmaceutical agents prior to, simultaneously with, or after the compound according to any one of claims 1-18 or the pharmaceutical composition according to any one of claims 19-24. 41. The method of claim 40, further comprising administering to said subject.
[Claim 42]
42. The method of claim 41, wherein said additional pharmaceutical agent is selected from mucolytics, nebulized hypertonic saline, bronchodilators, antibiotics, anti-infectives, CFTR modulators, and anti-inflammatory agents.
[Claim 43]
42. The method of claim 41, wherein said additional pharmaceutical agent is a CFTR collector.
[Claim 44]
42. The method of claim 41, wherein said additional pharmaceutical agent is a CFTR potentiator.
[Claim 45]
42. The method of claim 41, wherein said additional pharmaceutical agents are CFTR collectors and CFTR potentiators.
[Claim 46]
A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or any one of claims 19 to 24, for use in treating a CFTR-mediated disease. Pharmaceutical composition as described.
[Claim 47]
47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, or the medicament of claim 46, wherein said CFTR-mediated disease is selected from cystic fibrosis, asthma, COPD, and chronic bronchitis. Composition.
[Claim 48]
47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 46, wherein said CFTR-mediated disease is cystic fibrosis, COPD, or emphysema.
[Claim 49]
47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 46, wherein said CFTR-mediated disease is cystic fibrosis.
[Claim 50]
A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a medicament according to any one of claims 19 to 24, for use in treating pancreatitis Composition.

Claims (17)

Formula (I)

(in the formula:
A ₁ , A ₂ and A ₃ are each independently selected from optionally substituted arylene and optionally substituted heteroarylene;
L ₁ is sulfonamide, amide, carbonyl or urea;
L ₂ is optionally substituted alkylene, optionally substituted alkoxylen, optionally substituted polyalkylene oxide, optionally substituted alkylene oxide, optionally substituted is an aminoalkylene or an optionally substituted C _3-8 cycloalkylene;
X _A is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-)
or a pharmaceutically acceptable salt thereof. Formula (I)
(in the formula:
A ₁ is arylene or heteroarylene, wherein said arylene and heteroarylene of A ₁ are unsubstituted or H, halo, halo-substituted C _1-6 alkyl, C _1-6 alkyl, heavy substituted with _1-2 groups independently selected from hydrogen-substituted C _1-6 alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy;
A ₂ is arylene or heteroarylene, wherein said arylene and heteroarylene of A ₂ are unsubstituted or H, halo, halo-substituted C _1-6 alkyl, C _1-6 alkyl, heavy substituted with _1-2 groups independently selected from hydrogen-substituted C _1-6 alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy;
A ₃ is arylene or heteroarylene, wherein said arylene and heteroarylene of A ₃ are unsubstituted or H, halo, halo-substituted C _1-6 alkyl, C _1-6 alkyl, heavy substituted with _1-2 groups independently selected from hydrogen-substituted C _1-6 alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy;
L ₁ is -NR ^A S(O) _0-2 - ^* , -S(O) _0-2 NR ^A - ^* , -NR ^A C(=O)- ^* , -C(=O)NR ^A - ^* , -C(=O)-, or -NR ^A C(=O)NR ^A -, wherein said ^* indicates the point of attachment to A ₂ ;
L ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene or C _3-8 cycloalkylene, wherein said alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene and C _3-8 cycloalkylene is unsubstituted or C ₁ -C ₆ alkyl, —OH, —(CH ₂ ) _m C(=O)OR ^A , C ₁ -C ₆ alkoxy, 1-6 hydroxyl C ₁ -C ₆ alkyl substituted with groups, deuterium, deuterium-substituted C ₁ -C ₆ alkyl, and spiro-bonded C ₃ -C ₈ cycloalkyl substituted with 1 to 3 groups ;
X _A is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-;
R ^A is H or C ₁ -C ₆ alkyl;
m is 1, 2, 3, 4, 5, or 6)
The compound of claim 1, or a pharmaceutically acceptable salt thereof, of Formula (I)
(in the formula:
A ₁ is phenylene or pyridylene, wherein said phenylene or pyridylene of A ₁ is unsubstituted or H, halo, halo-substituted C _1-6 alkyl, C _1-6 alkyl, deuterium-substituted substituted with _1-2 groups independently selected from C _1-6 alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy;
A ₂ is phenylene or pyridylene, wherein said phenylene or pyridylene of A ₂ is unsubstituted or H, halo, halo-substituted C _1-6 alkyl, C _1-6 alkyl, deuterium-substituted substituted with _1-2 groups independently selected from C _1-6 alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy;
A ₃ is phenylene or pyridylene, wherein said phenylene or pyridylene of A ₃ is unsubstituted or H, halo, halo-substituted C _1-6 alkyl, C _1-6 alkyl, deuterated substituted with _1-2 groups independently selected from C _1-6 alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo-substituted C _1-6 alkoxy;
L ₁ is -NR ^A S(O) _0-2 - ^* or -S(O) _0-2 NR ^A - ^* , wherein said ^* indicates the point of attachment to A ₂ ;
L ₂ is alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene or C _3-8 cycloalkylene, wherein L ₂ said alkylene, alkoxylen, alkylene oxide, polyalkylene oxide, aminoalkylene and C _3-8 cycloalkylene is unsubstituted or C ₁ -C ₆ alkyl, —OH, deuterium, —(CH ₂ ) _m C(=O)OR ^A , C ₁ -C ₆ alkoxy, 1 substituted with 1 to 3 groups independently selected from C ₁ -C ₆ alkyl substituted with up to 6 hydroxyl groups, deuterium-substituted C ₁ -C ₆ alkyl, and spiro-bonded C ₃ -C ₈ cycloalkyl; be;
X _A is optionally substituted divalent amino, optionally substituted divalent amide, optionally substituted heterocycloalkylene or -O-;
R ^A is H or C ₁ -C ₆ alkyl;
m is 1, 2, 3, 4, 5, or 6)
or a pharmaceutically acceptable salt thereof, according to claim 2 . Formula (Ia)

(in the formula:
X _1a , X _1b , X _1c and X _1d are each independently selected from CR ¹ or N, wherein only one or two of X _1a , X _1b , X _1c and X _1d are N, the others being CR ¹ ;
X _2a , X _2b , X _2c and X _2d are each independently selected from CR ¹ or N, wherein only one or two of X _2a , X _2b , X _2c and X _2d are N, the others being CR ¹ ;
X _3a , X _3b , X _3c and X _3d are each independently selected from CR ² or N, wherein only one or two of X _3a , X _3b , X _3c and X _3d are ^N , the others being CR2;
_X4 is

or -O-, where ^* indicates the point of attachment to _L2 ;
L ₂ is —(CR ⁴ R ⁵ ) _n —,
-O ^{( CR4R5} ) _n - ^** ,
^{-NR7 ( CR4R5} ) _n - ^** ,
-( ^CR4R5 ) _{nO (} ^{CR6R10 ) p} - ^** ,
-( ^CR4R5 ) _n ^{( CR6R18 )-** ,}
- ^{( CR4R5} ) _n ^{( CR8R9} ) _p ^{( CR4R5} ) _m- ,
-( ^CR4R5 ) _{pNR7 (} ^{CR6R10 ) n} - ^{** ,}
-( ^CR4R5 ) _nO ) _t ( ^CR6R10 _)p ^{- ** ,}
or —O—C ₃ -C ₈ cycloalkylene- ^** ,
where ^** indicates the point of attachment to _X4 ;
Each R ¹ is independently H, halo, halo-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, deuterium-substituted C ₁ -C ₆ alkyl, nitrile, hydroxyl, C _1-6 alkoxy and halo selected from substituted C _1-6 alkoxy;
each R ² is independently H, halo, nitrile, hydroxyl, halo-substituted C _1-6 alkyl, C _1-6 alkyl, deuterium-substituted C _1-6 alkyl, hydroxy _{-substituted C 1-6 alkyl ,} selected from C _1-6 alkoxy and halo-substituted C _1-6 alkoxy;
R ³ is H,
—C _1-6 alkyl,
-( ^CR11R12 ₎ ^{yR16 ,}
-(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ ,
-(( ^CR11R12 ) _yO ^{( CR14R15} ) ^{zC (} =O) _OR13 ,
—((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z OR ¹³ ,
—(CR ¹¹ R ¹² ) _y C(=O)R ¹³ ,
-(CR ¹¹ R ¹² ) _y OR ¹³ ,
-(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O)OR ¹³ ,
—(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z OR ¹³ ,
—(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ ,
- ^{( CR11R12} ) _yNR10 ^{( CR14R15} ) ^{qC (} =O) _OR13 ,
—(CR ¹¹ R ¹² ) _y NR ¹³ R ¹⁴ ,
- ^{( CR11R12} _)yR20 ^,
-(( ^CR11R12 ) _yO ) _q ^{( CR14R15} ) ^{zC (} =O) _OR13 ,
—((CR ¹¹ R ¹² ) _y O) _q (CR ¹⁴ R ¹⁵ ) _z OR ¹³ ,

is;
each R ⁴ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl and C _1-6 alkyl;
each R ⁵ is independently selected from H, D deuterated C ₁ -C ₆ alkyl and C _1-6 alkyl;
each R ⁶ is independently selected from H, D deuterated C ₁ -C ₆ alkyl and C _1-6 alkyl;
each R ⁷ is independently selected from H and C _1-6 alkyl;
each R ⁸ and R ⁹ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl, C _1-6 alkyl, or —OH;
or R ⁸ and R ⁹ together with the carbon in CR ⁸ R ⁹ form C _3-8 cycloalkyl;
each R ¹⁰ is independently selected from H, D and C _1-6 alkyl;
each R ¹¹ is independently selected from H, D and C _1-6 alkyl;
each R ¹² is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl and C _1-6 alkyl;
each R ¹³ is independently selected from H and C _1-6 alkyl;
each R ¹⁴ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl and C _1-6 alkyl;
each R ¹⁵ is independently selected from H, D, deuterium-substituted C ₁ -C ₆ alkyl and C _1-6 alkyl;
R ¹⁶ is a 4-6 membered heterocycloalkyl having 1-2 ring members independently selected from N, O and S, wherein said 4-6 membered heterocycloalkyl is unsubstituted is or is substituted with 1-2 R ¹⁷ groups;
each R ¹⁷ is independently selected from C _1-6 alkyl and hydroxyl;
R ¹⁸ is H, C _1-6 alkyl, —C(R ⁴ R ⁵ ) _m OR ¹⁹ , or —(CH ₂ ) _m C(=O)OR ¹⁹ ;
each R ¹⁹ is independently selected from H and C _1-6 alkyl;
^R20 is

is;
each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each p is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each w is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each y is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each z is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
each q is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10)
or a pharmaceutically acceptable salt thereof, according to claim 1 , having the structure: Formula (Ib)

or a pharmaceutically acceptable salt thereof, according to claim 4 , having the structure of the formula: i) structure of formula (Ic) or formula (Id):

(in the formula:
X _1a is CH or N;
X _2a is CH or N;
X _3a is CH or N)
ii) structures of formula (Ie), formula (If), formula (Ig) or formula (Ih):

(in the formula:
X _1a is CH or N;
X _2a is CH or N)
iii) structures of formula (Ii), formula (Ij), formula (Ik) or formula (Il):

iv) structures of formula (Im), formula (In), formula (Io) or formula (Ip):

or
v) structure of formula (Iq):

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, comprising: _X4 is

or -O-, where ^* indicates the point of attachment to _L2 ;
L ₂ is —(CR ⁴ R ⁵ ) _n —,
-O ^{( CR4R5} ) _n - ^** ,
^{-NR7 ( CR4R5} ) _n - ^** ,
-( ^CR4R5 ) _{nO (} ^{CR6R10 ) p} - ^** ,
-( ^CR4R5 ) _n ^{( CR6R18 )-** ,}
- ^{( CR4R5} ) _n ^{( CR8R9} ) _p ^{( CR4R5} ) _m- ,
-( ^CR4R5 ) _{pNR7 (} ^{CR6R10 ) n} - ^{** ,}
or —O—C _3-8 cycloalkylene- ^** , where ^** indicates the point of attachment to X ₄ ;
R ¹ is H, halo, halo-substituted C _1-6 alkyl, C _1-6 alkyl, or C _1-6 alkoxy;
R ² is H or halo;
R ³ is H,
—C _1-6 alkyl,
-( ^CR11R12 ₎ ^{yR16 ,}
-(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ ,
-(( ^CR11R12 ) _yO ^{( CR14R15} ) ^{zC (} =O) _OR13 ,
—((CR ¹¹ R ¹² ) _y O(CR ¹⁴ R ¹⁵ ) _z OR ¹³ ,
—(CR ¹¹ R ¹² ) _y C(=O)R ¹³ ,
-(CR ¹¹ R ¹² ) _y OR ¹³ ,
-(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O)OR ¹³ ,
—(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z OR ¹³ ,
—(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ ,
- ^{( CR11R12} ) _yNR10 ^{( CR14R15} ) ^{qC (} =O) _OR13 ,
—(CR ¹¹ R ¹² ) _y NR ¹³ R ¹⁴ ,
- ^{( CR11R12} _)yR20 ^,

is;
each R ⁴ is H;
each R ⁵ is H;
each R ⁶ is H;
each R ⁷ is independently selected from H and C _1-6 alkyl;
each R ⁸ and R ⁹ is independently selected from H, C _1-6 alkyl, or —OH;
or R ⁸ and R ⁹ together with the carbon in CR ⁸ R ⁹ form C _3-8 cycloalkyl;
each R ¹⁰ is H;
each R ¹¹ is H;
each R ¹² is H;
each R ¹³ is independently selected from H and C _1-6 alkyl;
each R ¹⁴ is H;
each R ¹⁵ is H;
R ¹⁶ is a 4-6 membered heterocycloalkyl having 1-2 ring members independently selected from N or O, wherein said 4-6 membered heterocycloalkyl is unsubstituted; , or substituted with 1-2 R ¹⁷ groups;
each R ¹⁷ is independently selected from C _1-6 alkyl and hydroxyl;
R ¹⁸ is —C(R ⁴ R ⁵ ) _m OR ¹⁹ or —(CH ₂ ) _m C(=O)OR ¹⁹ ;
each R ¹⁹ is H;
^R20 is

is;
each m is independently selected from 1, 2 and 3;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;
each p is independently selected from 1, 2 and 3;
each w is independently selected from 1 and 2;
each y is independently selected from 1, 2, 3, 4 and 5;
each z is independently selected from 1, 2 and 3;
7. The compound of claim 5 or 6 , or a pharmaceutically acceptable salt thereof, wherein each q is independently selected from 1 and 2. _X4 is

or -O-, where ^* indicates the point of attachment to _L2 ;
L ₂ is —(CR ⁴ R ⁵ ) _n —,
-O ^{( CR4R5} ) _n - ^** ,
or -(CR ⁴ R ⁵ ) _n O(CR ⁶ R ¹⁰ ) _p - ^** , where ^** indicates the point of attachment to X ₄ ;
R ¹ is halo or halo-substituted C _1-6 alkyl;
R ² is H or halo (F;
R ³ is -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ ,
-(CR ¹¹ R ¹² ) _y OR ¹³ ,
-(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O)OR ¹³ ,
or -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ ;
each R ⁴ is H;
each R ⁵ is H;
each R ⁶ is H;
each R ⁸ and R ⁹ is independently selected from H or C _1-6 alkyl;
or R ⁸ and R ⁹ together with the carbon in CR ⁸ R ⁹ form C _3-8 cycloalkyl;
each R ¹⁰ is H;
each R ¹¹ is H;
each R ¹² is H;
each R ¹³ is independently selected from H and C _1-6 alkyl;
each R ¹⁴ is H;
each R ¹⁵ is H;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;
each p is independently selected from 1, 2 and 3;
each y is independently selected from 1, 2, 3, 4 and 5;
each z is independently selected from 1, 2 and 3;
8. A compound according to any one of claims 5 to 7 , or a pharmaceutically acceptable salt thereof, wherein each q is independently selected from 1 and 2. _X4 is

or -O-, where ^* indicates the point of attachment to _L2 ;
L ₂ is —(CR ⁴ R ⁵ ) _n —,
-O ^{( CR4R5} ) _n - ^** ,
or -(CR ⁴ R ⁵ ) _n O(CR ⁶ R ¹⁰ ) _p - ^** , where ^** indicates the point of attachment to X ₄ ;
R ¹ is Cl, F or _CF3 ;
R ² is H or F;
R ³ is -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ , -(CR ¹¹ R ¹² ) _y OR ¹³ , -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z C(=O )OR ¹³ , or -(CR ¹¹ R ¹² ) _y (CR ⁸ R ⁹ ) _z (CR ¹⁴ R ¹⁵ ) _q OR ¹³ ,
each R ⁴ is H;
each R ⁵ is H;
each R ⁶ is H;
each R ⁸ and R ⁹ is independently selected from H or methyl;
or R ⁸ and R ⁹ together with the carbon in CR ⁸ R ⁹ form cyclopropyl;
each R ¹⁰ is H;
each R ¹¹ is H;
each R ¹² is H;
each R ¹³ is independently selected from H, methyl and ethyl;
each R ¹⁴ is H;
each R ¹⁵ is H;
each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9;
each p is independently selected from 1, 2 and 3;
each y is independently selected from 1, 2, 3, 4 and 5;
z is 1;
9. The compound according to any one of claims 5 to 8 , wherein q is 1, or a pharmaceutically acceptable salt thereof. _X4 is

where ^* indicates the point of attachment to _L2 ;
L ₂ is -(CR ⁴ R ⁵ ) _n -;
R ¹ is CF ₃ ;
R ² is H;
R ³ is -(CR ¹¹ R ¹² ) _y C(=O)OR ¹³ ;
each R ⁴ is H;
each R ⁵ is H;
each R ¹¹ is H;
each R ¹² is H;
each R ¹³ is H;
n is 1, 2, 3, 4, 5, 6, 7, 8, or 9;
10. The compound according to any one of claims 5 to 9 , or a pharmaceutically acceptable salt thereof, wherein y is 2, 3 or 4. 6-(2-morpholinoethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
2 ^3- (Trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4 - a dioxide;
2-(4,4-dioxide-2 ³ -(trifluoromethyl)-1 ¹ -oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphan-6-yl)acetic acid;
2 ^3- (trifluoromethyl)-4-thia-3,6,1 ¹ -triaza-1(3,2),2,5(2,6)-tripyridinacycloundecaphane 4,4-dioxide ;
2 ³ -(trifluoromethyl)-1 ² -oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4- dioxide;
4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphan-6-yl)butanoic acid;
3-(2-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Nacycloundecaphan-6-yl)ethoxy)propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca phan-6-yl)butanoic acid;
2 ^3- (Trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4 - a dioxide;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphan-6-yl)butanoic acid;
6-(2-(3-hydroxypropoxy)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphane 4,4-dioxide;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)butanoic acid;
4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzeneacyclododecaphan-6-yl)butanoic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphan-6-yl)propanoic acid;
6-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)hexanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphan-6-yl)butanoic acid;
3-(4,4-dioxide ^- 2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca phan-6-yl)propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-10-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphan-6-yl)butanoic acid;
4-(2 ³ -methyl-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-6 - yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)butanal;
2-(2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Nacycloundecaphan-6-yl)ethoxy)acetic acid;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphan-6-yl)propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)butanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)pentanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)pentanoic acid;
4-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-6 - yl)butanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca phan-6-yl)pentanoic acid;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphan-6-yl)propanoic acid;
6-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-6 - yl) hexanoic acid;
4-(2 ³ -methoxy-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-6 - yl)butanoic acid;
6-(5-hydroxypentyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
6-(5-hydroxypentyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca fan 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)propanoic acid;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca fan 4,4-dioxide;
6-(4-hydroxybutyl)-2 ³ -methoxy-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
6-ethyl-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphane4,4 - a dioxide;
6-(4-hydroxybutyl)-2 ³ -methyl-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzeneacyclododecaphan-6-yl)propanoic acid;
4-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphan-6-yl)butanoic acid;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca fan 4,4-dioxide;
3-(2 ^3- (difluoromethyl)-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane -6-yl)propanoic acid;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca fan 4,4-dioxide;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)butanoic acid;
3-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane-6 - yl) propanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca phan-6-yl)butanoic acid;
1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphane 4,4-dioxide;
4-(2 ³ -chloro-4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane-6- yl)butanoic acid;
1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)propanoic acid;
2 ³ -chloro-6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
2 ^3- (trifluoromethyl)-6,12-dioxa-4-thia-3-aza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide ;
2 ³ -chloro-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
3-(4,4-dioxide-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundecaphan-6-yl)propanoic acid ;
1-((4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenenacyclo ndecafane-6-yl)methyl)cyclopropane-1-carboxylic acid;
1-((4,4-dioxide-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzeneacyclododecaphan-6-yl)methyl)cyclopropane-1-carboxylic acid;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzeneacycloundecaphan-6-yl)-2,2-dimethylpropanoic acid;
3-(1 ⁵ -fluoro-4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - benzenacycloundecaphan-6-yl)propanoic acid;
6-(2-hydroxyethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca fan 4,4-dioxide;
6-(2-hydroxyethyl)-2 ^3- (trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphan-6-yl)propanoic acid;
2 ³ -chloro-14-methyl-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6,12-triaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6,13-triaza-1(3,2),2,5(2,6)-tripyridinacyclotridecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)-2,2-dimethylpropanoic acid;
1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphane 4,4-dioxide;
6-(3-hydroxy-2,2-dimethylpropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)-2,2-dimethylpropanoic acid;
6-(3-hydroxy-2,2-dimethylpropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacyclododecaphane 4,4-dioxide;
6,13-dimethyl-2 ^3- (trifluoromethyl)-4-thia-3,6,13-triaza-1(3,2),2,5(2,6)-tripyridinacyclotridecaphane 4,4-dioxide;
2 ³ -chloro-12-oxa-4-thia-3,6-diaza-1(3,2),2,5(2,6)-tripyridinacyclododecaphane 4,4-dioxide;
6-(2-hydroxyethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenacin crowndecaphan-7-yl)propanoic acid;
6,10-dimethyl-2 ^3- (trifluoromethyl)-4-thia-3,6,10-triaza-1(3,2),2,5(2,6)-tripyridinacyclodecaphane 4 , 4-dioxide;
(4 ¹ s,4 ⁵ s)-1 ³ -(trifluoromethyl)-3,5-dioxa-7-thia-8-aza-1,6(2,6),2(3,2)-tripyridina -4(1,5)-cyclooctanacyclooctaphane 7,7-dioxide;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphane 4,4-dioxide;
1 ⁵ -fluoro-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6,10-triaza-1(3,2),2,5(2,6)-tripyridinacyclodecaphane 4,4-dioxide;
7-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenacin crownedecaphane 4,4-dioxide;
Ethyl 3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclo dodecaphan-6-yl)-2,2-dimethylpropanoate;
2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide;
2-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)acetic acid;
2 ^3- (trifluoromethyl)-6-((2S,3S)-2,3,4-trihydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 1(1,2)-Benzenacycloundecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
8-hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4- dioxide;
6-(2-(piperazin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphane 4,4-dioxide;
6-(2-(4-methylpiperazin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 ( 1,2)-Benzenacycloundecaphane 4,4-dioxide;
(2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenenacyclo ndecafane-6-yl)ethyl)glycine;
6-(2-(3-hydroxyazetidin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1 (1,2)-Benzenacycloundecaphane 4,4-dioxide;
^23- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide ;
6-(2-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2 ,6)-dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide;
6-(((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ^3- (trifluoromethyl)-4-thia-3 ,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4-dioxide;
6-methyl-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4- dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide;
Ethyl 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-11-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphan-6-yl)acetate;
6-(2,3-dihydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacin crownedecaphane 4,4-dioxide;
6-(2-(pyrrolidin-1-yl)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2 )-Benzenacycloundecaphane 4,4-dioxide;
Methyl (2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacin Crown Decaphan-6-yl)ethyl)glycinate;
6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6) - dipyridina-1(1,2)-benzeneacycloundecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-(2-aminoethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca fan 4,4-dioxide;
2 ^3- (trifluoromethyl)-4-thia-3,6,9-triaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotridecaphane 4,4-dioxide;
2 ³ -chloro-6-oxa-4-thia-3-aza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclononaphane 4,4-dioxide;
8-Hydroxy-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4 - a dioxide;
6-(2-aminoethyl)-2 ^3- (difluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacycloundeca fan 4,4-dioxide;
2-(3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene Nacycloundecaphan-6-yl)propyl)isoindoline-1,3-dione;
2-(3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzene nacycloundecaphan-6-yl)propyl)hexahydro-1H-isoindole-1,3(2H)-dione;
Methyl 2-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclo dodecaphan-6-yl)acetate 6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1 , 2)-Benzenacyclotridecaphane 4,4-dioxide;
6-(5-hydroxypentyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca fan 4,4-dioxide;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphane 4,4-dioxide;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphane 4,4-dioxide;
6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphane 4,4-dioxide;
2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacyclododecaphane 4,4-dioxide;
6-(6-hydroxyhexyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide;
6-(2-(2-hydroxyethoxy)ethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphane 4,4-dioxide;
6-(5-hydroxypentyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca fan 4,4-dioxide;
2 ³ -chloro-6-(6-hydroxyhexyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4, 4-dioxide;
1 ⁵ -fluoro-6-(3-hydroxypropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacyclododecaphane 4,4-dioxide;
1 ⁵ -fluoro-6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2) - Benzenacycloundecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)- Benzenacyclododecaphane 4,4-dioxide;
6-(4-hydroxybutyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca fan 4,4-dioxide;
2 ³ -chloro-6-(4-hydroxybutyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodecaphane 4,4 - a dioxide;
6-(3-hydroxypropyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloundecaphane 4,4-dioxide;
6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1, 2)-Benzenacycloundecaphane 4,4-dioxide;
6-((1-(hydroxymethyl)cyclopropyl)methyl)-2 ³ -(trifluoromethyl)-9-oxa-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 1(1,2)-Benzenacyclododecaphane 4,4-dioxide;
1 ⁵ -fluoro-6-(3-hydroxy-2,2-dimethylpropyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina- 1(1,2)-Benzenacycloundecaphane 4,4-dioxide;
3-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca phan-6-yl)propanoic acid;
5-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca phan-6-yl)pentanoic acid;
6-(2-aminoethyl)-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphane 4,4-dioxide and (R)-3-(4,4-dioxide-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)- 7. A compound according to claim 6, selected from dipyridina-1(1,2)-benzeneacycloundecaphan-7-yl)propanoic acid. 4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclodeca phan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzenacycloun Decaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclododeca phan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotrideca phan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclotetra Decaphan-6-yl)butanoic acid;
4-(4,4-dioxide-2 ^3- (trifluoromethyl)-4-thia-3,6-diaza-2,5(2,6)-dipyridina-1(1,2)-benzeneacyclopenta Decaphan-6-yl)butanoic acid and 6-(3-hydroxy-2,2-dimethylpropyl)-2 ³ -(trifluoromethyl)-4-thia-3,6-diaza-2,5(2 ,6)-dipyridina-1(1,2)-benzeneacyclododecaphane 4,4-dioxide. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. further comprising one or more additional pharmaceutical agents ;
14. The pharmaceutical composition according to claim 13 , wherein said additional pharmaceutical agent is selected from mucolytics, nebulized hypertonic saline, bronchodilators, antibiotics, anti-infectives, CFTR modulators and anti-inflammatory agents . Use of a compound according to any one of claims 1-12 in the manufacture of a medicament for treating CFTR-mediated diseases. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a medicament according to claims 13 or 14 , for use in treating a CFTR-mediated disease. A pharmaceutical composition , wherein the CFTR-mediated disease is selected from cystic fibrosis, asthma, COPD, emphysema, and chronic bronchitis . A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claims 13 or 14 , for use in treating pancreatitis.