JP6868089B2 - Medicine - Google Patents

Description

The present invention relates to a medicament containing a benzoazepine derivative and a salt thereof as an active ingredient, which is useful for diagnosing, preventing and / or treating a disease involving a vasopressin receptor.

Vasopressin is an antidiuretic hormone and is known to have a function of raising blood pressure. _{Vasopressin V 1a} and vasopressin V ₂ receptors are known as subgroups of vasopressin receptors, which are involved in vasoconstriction and water reabsorption in collecting tubes, respectively.

Tolvaptan has a benzoheterocycle structure, particularly used in the treatment of various diseases as a vasopressin V ₂ receptor antagonist, primarily known to be metabolized by hepatic metabolism enzymes CYP3A4 (non-patent document 1 ~ 3). Various compounds are known as compounds having a benzoheterocyclic structure (Patent Documents 1 to 9), but the 4-position and 5-position of the benzoazepine ring as a benzoheterocycle are substituted with difluorine and hydroxy, respectively. Therefore, no compound having vasopressin antagonism of both _{vasopressin V 1a} antagonist and vasopressin V _{2 antagonist has been known so far.}

International Publication No. 2011/052519 Japanese Unexamined Patent Publication No. 10-12592 Japanese Unexamined Patent Publication No. 9-22146 International Publication No. 94/04525 International Publication No. 94/01113 Japanese Unexamined Patent Publication No. 4-321669 International Publication No. 91/05549 International Publication No. 95/354540 International Publication No. 94/08582

Shoaf S.E. et al. Br J Clin Pharmacol. 2011, 73: 579-87 Sorbera L.A. et al. Drugs of the Future. 2002, 27 (4): 350-357 Furukawa M. et al. Arch. Pharm. Res. Arch. Pharm. Res. 2014 37: 1578-87

One of the objects of the present invention is to provide a novel pharmaceutical use of a novel benzoazepine compound or a salt thereof, which has _{vasopressin V 1a} and V _{2 antagonistic activity and has good metabolic stability and absorbability.}

As a result of intensive studies, the present inventors have succeeded in developing a novel benzoazepine compound having vasopressin antagonism, good metabolic stability and absorbability, and a salt thereof. The present invention has been completed based on such findings.

［式中、
Ｒ^１は、重水素、ＯＨ、ＣＯＯＨ、置換されていてもよいＣ_１−６アルキル、置換されていてもよいＣ_１−６アルキル−Ｏ−ＣＯ−、又は置換されていてもよいＣ_２−６アルケニルを示す；
Ｌは、直接結合又は−Ｃ（＝Ｏ）−ＮＨ−を示す；
環Ａ^１は、炭化水素環又はヘテロ環を示す；
環Ａ^２は、炭化水素環又はヘテロ環を示す；
環Ａ^１及びＡ^２はそれぞれ、少なくとも１個の置換基を有していてもよい。］
で表されるベンゾアゼピン化合物又はその塩（以下、「本発明化合物」ともいう）を有効成分とする医薬組成物を提供する。 In some embodiments, the present invention describes the formula (1):

[During the ceremony,
R ¹ is good deuterium, OH, COOH, optionally substituted _{C 1-6} alkyl, optionally substituted _{C 1-6} alkyl -O-CO-, or optionally substituted _{C 2- Shows 6} alkenyl;
L indicates direct binding or -C (= O) -NH-;
Ring A ¹ represents a hydrocarbon ring or a heterocycle;
Ring A ² represents a hydrocarbon ring or a heterocycle;
Rings A ¹ and A ² may each have at least one substituent. ]
Provided is a pharmaceutical composition containing a benzoazepine compound represented by (hereinafter, also referred to as "the compound of the present invention") as an active ingredient.

_{By having vasopressin antagonistic activity of both vasopressin V 1a} antagonist and vasopressin V ₂ antagonist, the compound of the present invention may be useful for the treatment, prevention and / or diagnosis of various diseases involving vasopressin receptor. The compound of the present invention also exhibits good metabolic stability, so that the duration of the drug effect is long, and the compound can have good absorbability.

In the present specification, examples of "halo" or "halogen" include fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

In the present specification _{, examples of "C 1-6} alkyl" include linear or branched alkyl having 1 to 6 carbon atoms, and specifically, methyl, ethyl, propyl, and Examples thereof include isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl and the like.

Examples of "C _2-6 alkenyl" herein include straight or branched chain alkenyl having 2 to 6 carbon atoms and 1 to 3 double bonds. Specifically, vinyl (ethenyl), 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl- Examples thereof include 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and the like.

In the present specification, "halo C _{1-6 alkyl" is a C 1-6} alkyl substituted with the same or different 1 to 7 (preferably 1 to 3) halogens, for example, monofluoro. Methyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro-1-methylethyl, pentafluoro Ethyl, 2-trifluoromethylpropyl, 4-fluorobutyl and the like can be mentioned.

In the present specification _{, examples of "C 3-6} cycloalkyl" include saturated cyclic alkyl having 3 to 6 carbon atoms as ring atoms, and specifically, cyclopropyl, cyclobutyl, cyclopentyl, and the like. Cyclopentyl and the like can be mentioned.

Examples of "hydrocarbon rings" herein include saturated or unsaturated 3- to 15-membered monocyclic, bicyclic or tricyclic hydrocarbon rings. The "unsaturated" ring refers to an aromatic ring or a saturated ring containing a partially unsaturated bond. Examples of the "hydrocarbon ring" include (a) saturated or unsaturated 3- to 8-membered (preferably 5- or 6-membered) monocyclic hydrocarbon rings; specifically, cyclopropane, cyclobutene, cyclo. Pentan, cyclohexane, cycloheptene, cyclooctane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, benzene, etc.;
(B) Saturated or unsaturated 7 to 15 member bicyclic or tricyclic hydrocarbon rings, preferably saturated or unsaturated 7 to 12 member bicyclic hydrocarbon rings; specifically, inden, Examples thereof include dihydroindene, naphthalene, dihydronaphthalene, tetrahydronaphthalene, anthracene and phenanthrene.

In the present specification, examples of the "heterocycle" include saturation containing at least one (for example, 1 to 5) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur as ring-constituting atoms. Alternatively, unsaturated monocyclic or polycyclic heterocycles can be mentioned, including, for example, saturated or unsaturated 3- to 15-membered monocyclic, bicyclic or tricyclic heterocycles. Here, in the bicyclic or tricyclic heterocycle, any ring may contain a heteroatom, or all the rings may contain a heteroatom. The "unsaturated" ring refers to an aromatic ring or a saturated ring containing a partially unsaturated bond. Preferred heterocycles are saturated or unsaturated 5- to 10-membered monocyclic or bicyclic heterocycles containing at least one nitrogen as a ring-constituting atom. The ring atom of the heterocycle may be substituted with oxo to form an oxide. The "heterocycle" includes, for example, (a) saturated or unsaturated three-membered to eight containing at least one (for example, 1 to 4), preferably 1 or 2 nitrogen atoms as the ring-constituting heteroatom. Member, preferably 3- to 6-membered, more preferably 5- or 6-membered monocyclic heterocycle; specifically, pyrrol, imidazole, pyrazole, pyridine, tetrahydropyridine, pyrimidine, pyrazine, pyridazine, triazole, tetrazole. , Dihydrotriazine, azetidine, pyrrolidine, imidazolidine, piperidine, pyrazolidine, piperazin, azepan, 1,4-diazepan, etc .;
(B) Saturated or unsaturated 7- to 15-membered bicyclic or tricyclic heterocycles containing at least one (eg, 1-5) nitrogen atoms as ring-structured heteroatoms, preferably ring-structured heterocycles. Saturated or unsaturated 7-12 member bicyclic or tricyclic heterocycles containing 1 to 3 nitrogen atoms as atoms; specifically, indol, indoline (dihydroindole), isoindole, isoindolin (Dihydroisoindole), benzoimidazole, dihydrobenzoimidazole, indazole, indazoline (dihydroindazole), quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, dihydroisoquinolin, tetrahydroisoquinolin, benzotriazole, tetrazolopyridine, tetrazolo Pyridazine, dihydrotriazolopyridazine, imidazolepyridine, naphthylidine, tetrahydronaphthylidine, hexahydronaphthylidine, cinnoline, quinoxalin, dihydroquinoxaline, tetrahydroquinoxaline, quinazoline, dihydroquinazoline, tetrahydroquinazoline, pyrazolopyridine, tetrahydropyridindol, benzoazepine, tetra. Benzoazepine, carbazole, phenanthridin, dihydrophenanthridin, etc .;
(C) Saturated or unsaturated 3- to 8-membered (preferably 5- or 6-membered) monocyclic heterocycle containing one or two oxygen atoms as the ring-constituting heteroatom; specifically, furan. , Tetrahydropyran, tetrahydrofuran, dioxane, etc .;
(D) Saturated or unsaturated 7- to 12-membered bicyclic heterocycles containing at least one (eg, 1 to 3) oxygen atoms as ring-constituting heteroatoms; specifically, benzofurans and dihydrobenzofurans. , Chromane, benzodioxol, benzodioxan, etc .;
(E) Saturated or unsaturated 3- to 8-membered (preferably 5- or 6-membered) monocyclic heterocycle containing one or two sulfur atoms as the ring-constituting heteroatom; specifically, thiophene. , Tetrahydrothiophene, thiopyran, tetrahydrothiopyran, etc .;
(F) Saturated or unsaturated 7- to 12-membered bicyclic heterocycles containing at least one (for example, 1 to 3) sulfur atoms as ring-constituting atoms; specifically, benzothiophenes and the like;
(G) Saturated or unsaturated 3-membered to 8-membered (preferably 5-membered) containing one or two oxygen atoms and at least one (for example, 1 to 3) nitrogen atoms as the ring-constituting heteroatom. Or 6-membered) monocyclic heterocycle; specifically, oxazole, isoxazole, oxadiazole, morpholine, etc.;
(H) Saturated or unsaturated 7- to 12-membered bicyclic heterocycle containing 1 or 2 oxygen atoms and at least 1 (for example, 1 to 3) nitrogen atoms as the ring-constituting heteroatom. Specifically, benzoxazole, dihydrobenzoxazole, benzoxadiazole, benzoisoxazole, benzoxazine, dihydrobenzoxazine, flopyridine, flopirol, benzoxazepine, tetrahydrobenzoxazepine, etc.;
(I) Cyclic 3 to 8 members (preferably 5 members) of saturated or unsaturated heteroatoms containing 1 or 2 sulfur atoms and at least 1 (for example, 1 to 3) nitrogen atoms. Or 6-membered) monocyclic heterocycle; specifically, thiazole, thiazolin (dihydrothiazole), thiadiazole, isothiazole, thiazolidine, etc.;
(J) Saturated or unsaturated 7- to 12-membered bicyclic heterocycle containing one or two sulfur atoms and at least one (for example, one to three) nitrogen atoms as the ring-constituting heteroatom. Specifically; benzothiazole, dihydrobenzothiazole, benzothiadiazole, thienopyridine, imidazolethiazole, dihydroimidazolithiazole, thienopyrazine, benzothiazine, dihydrobenzothiazine, benzothiazepine, tetrahydrobenzothiazepine, etc.; and (k) ring configuration Saturated or unsaturated 7- to 12-membered bicyclic heterocycles containing one or two oxygen atoms as heteroatoms and at least one (eg, 1 to 3) sulfur atoms; specifically. , Benzoxatiin and the like.

Each group defined herein may be included as part of another group, for example -O-, -CO-, -COO-, -S-, -SO-, -SO _{2. -, - SO 2 -O -,} - O-CO -, - it may be attached to an appropriate separate group via a linker of SO 2 -NH-, and the like. For example, if C _1-6 alkyl is attached to another group via -O-, it _{is shown as C 1-6} alkyl-O-. _{The definition of C 1-6 alkyl in C 1-6} alkyl-O- in this case is synonymous with the definition of C _{1-6 alkyl alone.}

In some embodiments, R ¹ is preferably dehydrogen; OH; COOH; optionally substituted amino, _{optionally substituted C 1-6} alkyl-O−, optionally substituted C _{1 Consists of -6} alkyl-SO _2- O-, optionally substituted silyl-O-, OH, optionally substituted C _1-6 alkyl-COO-, tetrahydropyranyl-O-, and heterocycle. one to three C _1-6 alkyl optionally substituted with a group independently selected from the group; optionally substituted C _1-6 alkyl -O-CO-; or optionally substituted Good C _2-6 alkenyl,
Here, amino which may be substituted, for example may be substituted by OH C _1-6 alkyl, optionally substituted C _1-6 alkyl -SO 2 _-, a C substituted Amino that may be substituted with one or two groups independently selected from the group consisting of _{1-6 alkyl-O-CO- and benzyl-O-CO-.
C 1-6} alkyl-O- which may be _{substituted, C 1-6} alkyl-SO _2- which may be _{substituted, C 1-6} alkyl-SO _2- O- which may be substituted, substitution It is _{C 1-6} alkyl optionally -COO-, and _{C 1-6} alkyl optionally substituted in the optionally substituted _{C 1-6} alkyl -O-CO-, for example halogen, _{C 1} 1 to 3 independently selected from the group consisting of _-6 alkyl-O-, _{optionally substituted phenyl, optionally substituted phenyl-SO 2-} NH-, and naphthalenyl-SO _{2-NH- A C 1-6} alkyl optionally substituted with a number of groups, wherein the substituted phenyl is independently selected from the group consisting of _{halogen, C 1-6} alkyl, and NO _2. A phenyl that may be substituted with 1 to 3 groups.
The optionally substituted silyl-O-is, for example, the same or different 1 to 3 C _1-6 alkyl substituted silyl-O-.
The heterocycle is, for example, thiazole or pyridine and
_{The C 2-6} alkenyl which may be substituted is, for example, a _{C 2-6} alkenyl which may be substituted with 1 to 3 halogens which are the same or different.

More preferably, R ¹ is selected independently from the group consisting of deuterium; OH; or optionally substituted amino, optionally substituted C _1-6 alkyl-O-, and OH. It is a C _1-6 alkyl optionally substituted with 3 groups.
Particularly preferably, R ¹ is a C _1-6 alkyl substituted with OH.

In formula (1), ring A ¹ is preferably selected independently of the saturated or unsaturated 3- to 8-membered monocyclic hydrocarbon ring, or the group consisting of nitrogen, oxygen and sulfur as ring-constituting atoms. A saturated or unsaturated 3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing at least one heteroatom (eg, 1-5).
More preferably, ring A ¹ is (a) a saturated or monocyclic hydrocarbon ring (preferably cyclopropane 3-8 membered unsaturated, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclobutene, cyclopentene , Cyclohexene, cycloheptene, cyclooctene or benzene, more preferably benzene),
(B) Saturated or unsaturated 5- or 6-membered monocyclic heterocycles containing at least one (eg, 1 to 4) nitrogen atoms as the ring-constituting heteroatoms (preferably pyrrol, imidazole, pyrazole, Pyridine, tetrahydropyridine, pyrimidine, pyrazine, pyridazine, triazole, tetrazole, dihydrotriazine, azetidine, pyrrolidine, imidazolidine, piperidine, pyrazolidine, piperazin, azepan or 1,4-diazepan, more preferably pyridine or pyrazine, particularly preferably pyridine. ),
(C) Saturated or unsaturated 7- to 15-membered bicyclic heterocycles containing at least one (for example, 1 to 5) nitrogen atoms as ring-constituting heteroatoms (preferably indol, indoline (dihydroindole)). ), Isoindole, Isoindolin (dihydroisoindole), benzimidazole, dihydrobenzimidazole, indazole, indazoline (dihydroindazole), quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, benzotriazole , Tetrazolopyridine, tetrazolopyridazine, dihydrotriazolopyridazine, imidazolepyridine, naphthylidine, tetrahydronaphthylidine, hexahydronaphthylidine, cinnoline, quinoline, dihydroquinoxaline, tetrahydroquinoxalin, quinazoline, dihydroquinazoline, tetrahydroquinazoline, pyrazolopyridine, tetrahydropyri Doindole, benzazepine, tetrahydrobenzoazepine, carbazole, phenanthridin or dihydrophenanthridine, more preferably tetrahydroisoquinoline),
(D) Saturated or unsaturated 5- or 6-membered monocyclic heterocycle containing 1 or 2 oxygen atoms and at least 1 (for example, 1 to 3) nitrogen atoms as the ring-constituting heteroatom. A saturated or unsaturated 5-membered ring (preferably oxazole) or (e) ring-constituting heteroatom containing one or two sulfur atoms and at least one (eg, one to three) nitrogen atoms. Alternatively, it is a 6-membered monocyclic heterocycle (preferably thiazole).
Particularly preferably, ring A ¹ is benzene or pyridine.

Ring A ¹ may have at least one or more (preferably 1 to 4, more preferably 1) substituents. The substituent is preferably _{selected independently from the group consisting of optionally substituted C 1-6} alkyl, optionally substituted C _1-6 alkyl-O-, halogen, and oxo. _{More preferred substituents are C 1-6} alkyl, which may be substituted with the same or different 1 to 3 halogens; halogens, C _1-6 alkyl-O-, and halo C _1-6 alkyl-O. _{C 1-6} alkyl-O-; halogen; or oxo, which may be substituted with 1 to 3 groups independently selected from the group consisting of −. More preferred substituents include halogen, C _1-6 alkyl, C _1-6 alkyl-O-, or C _1-6 alkyl- _{OC 1-6} alkyl-O-. More preferred substituents include halogen, C _1-6 alkyl, or C _1-6 alkyl-O-. A particularly preferred substituent is a halogen.

In some embodiments, ring A ¹ may have any one of the above substituents, benzene, pyridine, pyrazine, or tetrahydroisoquinoline (preferably benzene or pyridine) is.

In formula (1), ring A ² is preferably selected independently of the saturated or unsaturated 3- to 8-membered monocyclic hydrocarbon ring, or the group consisting of nitrogen, oxygen and sulfur as ring-constituting atoms. A saturated or unsaturated 3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing at least one heteroatom (eg, 1-5).
More preferably, ring A ² is (a) a saturated or unsaturated 3- to 8-membered monocyclic hydrocarbon ring (preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclobutene, cyclopentene). , Cyclohexene, cycloheptene, cyclooctene or benzene, more preferably benzene),
(B) Saturated or unsaturated 5- or 6-membered monocyclic heterocycles containing at least one (eg, 1 to 4) nitrogen atoms as the ring-constituting heteroatoms (preferably pyrrol, imidazole, pyrazole, Pyridine, tetrahydropyridine, pyrimidine, pyrazine, pyridazine, triazole, tetrazole, dihydrotriazine, azetidine, pyrrolidine, imidazolidine, piperidine, pyrazolidine, piperazin, azepan or 1,4-diazepan, more preferably pyridine),
(C) Saturated or unsaturated 5- or 6-membered monocyclic heterocycle containing one or two oxygen atoms as the ring-constituting heteroatom (preferably furan, tetrahydropyran, tetrahydrofuran or dioxane, more preferably. Fran),
(D) Saturated or unsaturated 7- to 12-membered bicyclic heterocycles (preferably benzofurans) containing at least one (eg, 1 to 3) oxygen atoms as the ring-constituting heteroatoms.
(E) Saturated or unsaturated 5- or 6-membered monocyclic heterocycle containing one or two sulfur atoms as the ring-constituting heteroatom (preferably thiophene, tetrahydrothiophene, tetrahydrothiopyrane, more preferably. Thiophene),
(F) Saturated or unsaturated 7- to 15-membered bicyclic heterocycles containing at least one (for example, 1 to 5) nitrogen atoms as ring-constituting heteroatoms (preferably indol, indoline (dihydroindole)). ), Isoindole, Isoindolin (dihydroisoindole), benzimidazole, dihydrobenzimidazole, indazole, indazoline (dihydroindazole), quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, benzotriazole , Tetrazolopyridine, tetrazolopyridazine, dihydrotriazolopyridazine, imidazolepyridine, naphthylidine, tetrahydronaphthylidine, hexahydronaphthylidine, cinnoline, quinoline, dihydroquinoxaline, tetrahydroquinoxaline, quinazoline, dihydroquinazoline, tetrahydroquinazoline, pyrazolopyridine, tetrahydropyry Doindole, benzazepine, tetrahydrobenzoazepine, carbazole, phenanthridin or dihydrophenanthridine, more preferably tetrahydroisoquinoline),
(G) Saturated or unsaturated 5- or 6-membered monocyclic heterocycle containing 1 or 2 oxygen atoms and at least 1 (for example, 1 to 3) nitrogen atoms as the ring-constituting heteroatom. A saturated or unsaturated 5-membered ring (preferably oxazole) or (h) ring-constituting heteroatom containing one or two sulfur atoms and at least one (eg, one to three) nitrogen atoms. Alternatively, it is a 6-membered monocyclic heterocycle (preferably thiazole).
Particularly preferably, ring A ² is benzene.

Ring A ² may have at least one or more substituents (preferably 1 to 4, more preferably 1 to 3, particularly preferably 2). The substituent is preferably a C _1-6 alkyl optionally substituted, optionally substituted C _1-6 alkyl -O- also be, optionally substituted C _3-6 cycloalkyl, halogen, It is independently selected from the group consisting of oxo, optionally substituted phenyl, and optionally substituted pyridyl. More preferred substituents are C _{1-6 alkyls which may be substituted with 1 to 3 halogens which are the same or different; C 1-} which may be substituted with 1 to 3 halogens which are the same or different. _{6 Alkyl-O-; C 3-6} cycloalkyl, which may be substituted with one to three halogens of the same or different; Halogen; Oxo; Halogen, C _1-6 Alkyl and C _1-6 Alkyl-O- Examples include phenyl, which may be substituted with 1 to 3 groups independently selected from the group consisting of; pyridyl, which may be substituted with 1 to 3 halogens of the same or different. More preferred substituents are halogen; C _1-6 alkyl optionally substituted with halogen; C _1-6 alkyl-O− optionally _{substituted with halogen; C 3-6} cycloalkyl (particularly preferably cyclo). (Propyl or cyclobutyl); _{may be substituted with halogen, C 1-6} alkyl, halo C _1-6 alkyl, C _1-6 alkyl-O-, or halo C _1-6 alkyl-O-, phenyl; and Selected independently from the group consisting of pyridils. More preferred substituents are _{independently selected from the group consisting of halogen, C 1-6} alkyl, halo C _1-6 alkyl, and phenyl optionally substituted with halogen. Particularly preferred substituents are selected independently of halogen or phenyl.
If ring A ² has multiple substituents on its ring carbon atom, these substituents together with the carbon atom form a C _3-6 cycloalkyl (preferably cyclopropyl or cyclobutyl) thereof. As a result, ring A ² may form a spiro ring.

In some embodiments, ring A ² is benzene, pyridine, furan, thiophene, or tetrahydroisoquinoline (preferably benzene), which may have any of the above substituents.

［式中、波線は結合点を示し、Ａ^１及びＡ^２は前記と同じ］ When L is -C (= O) -NH- in the formula (1), any of the following aspects is included:

[In the equation, the wavy line indicates the coupling point, and A ¹ and A ² are the same as above]

［式中、
Ｒ^１は、重水素、ＯＨ、ＣＯＯＨ、置換されていてもよいＣ_１−６アルキル、置換されていてもよいＣ_１−６アルキル−Ｏ−ＣＯ−、又は置換されていてもよいＣ_２−６アルケニルを示す；
Ｌは、直接結合又は−Ｃ（＝Ｏ）−ＮＨ−を示す；
環Ａ^１は、炭化水素環又はヘテロ環を示す；
環Ａ^２は、炭化水素環又はヘテロ環を示す；
環Ａ^１及びＡ^２はそれぞれ、少なくとも１個の置換基を有していてもよい。］
で表されるベンゾアゼピン化合物又はその塩を有効成分とする医薬組成物。 The present invention includes aspects exemplified below.
Item 1. Equation (1):

[During the ceremony,
R ¹ is good deuterium, OH, COOH, optionally substituted _{C 1-6} alkyl, optionally substituted _{C 1-6} alkyl -O-CO-, or optionally substituted _{C 2- Shows 6} alkenyl;
L indicates direct binding or -C (= O) -NH-;
Ring A ¹ represents a hydrocarbon ring or a heterocycle;
Ring A ² represents a hydrocarbon ring or a heterocycle;
Rings A ¹ and A ² may each have at least one substituent. ]
A pharmaceutical composition containing a benzoazepine compound represented by (1) or a salt thereof as an active ingredient.

Item 2. Ring A ¹ is a saturated or unsaturated 3- to 8-membered monocyclic hydrocarbon ring, or 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur as ring constituent atoms. It is a saturated or unsaturated 3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing individuals.
Ring A ² is a saturated or unsaturated 3- to 8-membered monocyclic hydrocarbon ring, or 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur as ring constituent atoms. It is a saturated or unsaturated 3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing individuals.
Rings A ¹ and A ² may each have at least one substituent.
Item 3. The pharmaceutical composition according to Item 1.

Item 3. Ring A ¹ is a saturated or unsaturated 3- to 8-membered monocyclic hydrocarbon ring, a saturated or unsaturated 5- or 6-membered ring containing 1 to 4 nitrogen atoms as a ring-constituting heteroatom. Monocyclic heterocycles, saturated or unsaturated 7- to 15-membered bicyclic heterocycles containing 1 to 5 nitrogen atoms as ring-constituting heteroatoms, 1 or 2 ring-constituting heteroatoms A saturated or unsaturated 5- or 6-membered monocyclic heterocycle containing an oxygen atom and at least one nitrogen atom, or one or two sulfur atoms and at least one nitrogen as a ring-constituting heteroatom. A saturated or unsaturated 5- or 6-membered monocyclic heterocycle containing an atom.
Ring A ² is a saturated or unsaturated 3- to 8-membered monocyclic hydrocarbon ring, a saturated or unsaturated 5- or 6-membered ring containing 1 to 4 nitrogen atoms as ring-constituting heteroatoms. Monocyclic heterocycles, saturated or unsaturated 5- or 6-membered monocyclic heteroatoms containing 1 or 2 oxygen atoms as ring-constituting heteroatoms, 1 to 3 ring-constituting heteroatoms Saturated or unsaturated 7- to 12-membered bicyclic heteroatoms containing oxygen atoms, saturated or unsaturated 5- or 6-membered monocycles containing one or two sulfur atoms as ring-constituting heteroatoms Formula hetero-ring, saturated or unsaturated 7- to 15-membered bicyclic hetero ring containing 1 to 5 nitrogen atoms as ring-constituting heteroatom, 1 or 2 oxygen atoms as ring-constituting heteroatom A saturated or unsaturated 5- or 6-membered monocyclic heteroatom containing at least one nitrogen atom, or one or two sulfur atoms and at least one nitrogen atom as a ring-constituting heteroatom. A saturated or unsaturated 5- or 6-membered monocyclic heterocycle containing
Rings A ¹ and A ² may each have at least one substituent.
Item 2. The pharmaceutical composition according to Item 1 or 2.

Item 4. Ring A ¹ is benzene, pyridine, pyrazine, or tetrahydroisoquinoline, where ring A ¹ is optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkyl-O-. It may have 1 to 4 substituents independently selected from the group consisting of, halogen, and oxo;
Ring A ² is benzene, pyridine, furan, thiophene, or tetrahydroisoquinoline, where ring A ² is optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkyl-. 1 to 4 independently selected from the group consisting of O-, optionally substituted C _3-6 cycloalkyl, halogen, oxo, optionally substituted phenyl, and optionally substituted pyridyl. It may have a plurality of substituents, and when ring A ² has a plurality of substituents on its ring carbon atom, these substituents are combined with the carbon atom to form C _3-6 cycloalkyl. May form;
Item 8. The pharmaceutical composition according to any one of Items 1 to 3.

Item 5. In ring ^{A 1,} from halogen and _{C 1-6} alkyl -O- which may be a _{C 1-6} alkyl or substituted or optionally substituted _{C 1-6} alkyl -O- the substituents are each independently 1 to 3 groups of the same or different selected from the group consisting of
In the ring A ^2, the same optionally substituted C _1-6 alkyl or optionally substituted C _1-6 alkyl -O- substituents independently or different in one to three halogen Yes, the substituents of C _3-6 cycloalkyl which may be substituted are 1 to 3 halogens which are the same or different, and the substituents of phenyl which may be substituted are halogens, C _1-6 alkyl, 1 to 3 halogens independently selected from the group consisting of C _1-6 alkyl-O- and 1 to 3 halogens having the same or different substituents on the pyridyl which may be substituted. Item 4. The pharmaceutical composition according to Item 4.

Item 6. R ¹ is deuterium; OH; COOH; optionally substituted amino, _{optionally substituted C 1-6} alkyl-O-, optionally substituted C _1-6 alkyl-SO _2- O. -Independently selected from the group consisting of optionally substituted silyl-O-, OH, optionally substituted C _1-6 alkyl-COO-, tetrahydropyranyl-O-, thiazolyl, and pyridyl. in or optionally substituted _{C 2-6} alkenyl; one to three optionally substituted with _{C 1-6} alkyl; optionally substituted _{C 1-6} alkyl -O-CO- Yes,
Here, the amino that may be substituted is C _1-6 alkyl _{which may be substituted with OH, C 1-6} alkyl-SO ₂ − which may be substituted, and C _{1 which may be substituted. An} amino that may be substituted with one or two groups independently selected from the group consisting of -6 alkyl-O-CO- and benzyl-O-CO-.
_{C 1-6} alkyl-O- which may be _{substituted, C 1-6} alkyl-SO _2- which may be _{substituted, C 1-6} alkyl-SO _2- O- which may be substituted, substitution which may _{C 1-6} alkyl -COO-, and _{C 1-6} alkyl optionally substituted in the optionally substituted _{C 1-6} alkyl -O-CO- is _{halogen, C 1-} 1 to 3 independently selected from the group consisting of ₆ alkyl-O-, _{optionally substituted phenyl, optionally substituted phenyl-SO 2-} NH-, and naphthalenyl-SO _2-NH- C _1-6 alkyl optionally substituted with, where the substituted phenyl is independently selected from the group consisting of _{halogen, C 1-6} alkyl, and NO _2. A phenyl that may be substituted with 1 to 3 groups.
The optionally substituted silyl-O-is a silyl-O- that may be substituted with one to three C _1-6 alkyls that are the same or different.
Good C _2-6 alkenyl optionally substituted are the same or different one to three good C _2-6 alkenyl optionally substituted with halogen, pharmaceutical composition according to any one of Items 1 to 5 Stuff.

Item 7. R ¹ is deuterium; OH; or an optionally substituted amino, optionally substituted C _1-6 alkyl-O- or optionally substituted C _1-6 alkyl.
Here, the amino that may be substituted is an amino that may be substituted with C _1-6 alkyl which may be substituted with OH.
Optionally substituted _{C 1-6} alkyl -O- is the same or different one to three halogen a _{C 1-6} optionally substituted by alkyl -O-, any of items 1-6 The pharmaceutical composition according to.

Item 8. Item 6. The pharmaceutical composition according to any one of Items 1 to 7, wherein R ¹ is a C _{1-6 alkyl substituted with OH.}

Item 9. Ring A ¹ is halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkyl-O-, halo C _1-6 alkyl-O-, C _1-6 alkyl- _{OC 1- 6} Alkyl-O-, Halo C _1-6 Alkyl- _{OC 1-6} Alkyl-O-, C _1-6 Alkyl-O-Halogen C _1-6 Alkyl-O-, or Halogen C _1-6 Alkyl- O-Halo C _1-6 Alkyl-O-, benzene; halogen-substituted pyridine; pyrazine; or oxo-substituted tetrahydroisoquinoline;
Ring A ² is substituted with halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkyl-O-, halo C _1-6 alkyl-O-, C _{3-6 cycloalkyl.} Phenyl may be substituted with 1 to 3 groups independently selected from the group consisting of phenyl and pyridyl, benzene (where the phenyl optionally substituted is halogen, _{C1- 6} alkyl, halo C _1-6 alkyl, C _1-6 alkyl-O-, or halo C _1-6 alkyl-O-may be substituted, phenyl); C _1-6 alkyl, halo C _1-6 optionally substituted by alkyl or phenyl, pyridine; C _1-6 alkyl furan optionally substituted by; C _1-6 optionally thiophene optionally substituted with alkyl; or halogen, C _{1 Tetrahydroisoquinoline, optionally substituted with one to three groups independently selected from the group consisting of -6alkyl} , and oxo, wherein a plurality of Cs are present on the ring carbon atom of the tetrahydroisoquinoline. _{If they have 1-6} alkyl, these C _1-6 alkyl may be combined with the carbon atom to form _{C 3-6 cycloalkyl.}
Item 8. The pharmaceutical composition according to any one of Items 1 to 8.

Item 10. R ¹ is a C _1-6 alkyl substituted with OH,
Ring A ¹ may be substituted with halogen, C _1-6 alkyl, C _1-6 alkyl-O-, or C _1-6 alkyl- _{OC 1-6} alkyl-O-, benzene; or A pyridine that may be substituted with a halogen,
Ring A ² is substituted with halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkyl-O-, halo C _1-6 alkyl-O-, C _{3-6 cycloalkyl.} Phenyl may be substituted with 1 to 3 groups independently selected from the group consisting of phenyl and pyridyl (where the phenyl optionally substituted is halogen, C). _It may be substituted with 1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkyl-O-, or halo C _1-6 alkyl-O-),
Item 8. The pharmaceutical composition according to any one of Items 1 to 9.

Item 11. R ¹ is a C _1-6 alkyl substituted with OH,
Ring A ¹ is benzene, optionally substituted with halogen, C _1-6 alkyl, or C _{1-6 alkyl-O-.}
Ring A ² is substituted with 1 to 3 groups independently selected from the group consisting of halogen, C _1-6 alkyl, halo C _{1-6 alkyl, and phenyl optionally substituted with halogen.} May be benzene,
Item 8. The pharmaceutical composition according to any one of Items 1 to 10.

Item 12. R ¹ is a C _1-6 alkyl substituted with OH,
Ring A ¹ is benzene or halogen-substituted benzene.
Ring A ² is a benzene substituted with 1 to 3 groups independently selected from the group consisting of halogen and phenyl.
Item 8. The pharmaceutical composition according to any one of Items 1 to 11.

Item 13. R ¹ is a C _1-6 alkyl substituted with OH,
Ring A ¹ is pyridine and
Ring A ² is substituted with 1 to 3 groups independently selected from the group consisting of halogen, C _1-6 alkyl, halo C _{1-6 alkyl, and phenyl optionally substituted with halogen.} May be benzene,
Item 8. The pharmaceutical composition according to any one of Items 1 to 10.

Item 14. R ¹ is a C _1-6 alkyl substituted with OH,
Ring A ¹ may be substituted with halogen, C _1-6 alkyl-O- or halo-C _1-6 alkyl-O-, benzene; or pyridine.
Ring A ² is substituted with 1 to 3 groups independently selected from the group consisting of halogen, C _1-6 alkyl, halo C _{1-6 alkyl, and phenyl optionally substituted with halogen.} May be benzene; _{optionally substituted with phenyl or halo C 1-6} alkyl; or substituted with 1 to 3 groups independently selected from the group consisting of halogen and oxo. Is also a good tetrahydroisoquinoline,
Item 8. The pharmaceutical composition according to any one of Items 1 to 9.

Item 15. Item 6. The pharmaceutical composition according to any one of Items 1 to 14, wherein L is -C (= O) -NH-.

Item 16. A pharmaceutical composition containing a compound selected from the following compound group or a salt thereof as an active ingredient.

Item 17. Item 8. The pharmaceutical composition according to any one of Items 1 to 16, which is a vasopressin receptor antagonist.

Item 18. Meniere's disease, hypertension, edema, ascites, heart failure, acute or chronic renal dysfunction, acute or chronic renal failure, polycystic kidney disease, vasopressin dyssecretion syndrome, liver cirrhosis, hyponatremia, hypopotassium, diabetes, Item 6. The pharmaceutical composition according to any one of Items 1 to 16, which is used for treating, preventing and / or diagnosing a disease selected from the group consisting of circulatory failure, agitation, water metabolism disorder, and ischemic disease.

Item 19. Meniere's disease, hypertension, edema, ascites, heart failure, acute or chronic renal dysfunction, acute or chronic renal failure, characterized in that the pharmaceutical composition according to any one of Items 1 to 16 is administered to a subject. Treatment and prevention of diseases selected from the group consisting of polycystic kidney disease, vasopressin dyssecretion syndrome, liver cirrhosis, hyponatremia, hypopotassium, diabetes, circulatory failure, agitation, water metabolism disorders, and ischemic diseases. And / or diagnostic method.

Item 20. Meniere's disease, hypertension, edema, ascites, heart failure, acute or chronic renal dysfunction, acute or chronic renal failure, polycystic kidney disease, vasopressin dyssecretion syndrome, liver cirrhosis, hyponatremia, hypopotassium, diabetes, Item 8. The pharmaceutical composition according to any one of Items 1 to 16 in the manufacture of a medicament for treating, preventing and / or diagnosing a disease selected from the group consisting of circulatory failure, sway disease, water metabolism disorder, and ischemic disease. Use of.

Item 21. Item 2. The pharmaceutical composition according to any one of Items 1 to 16, and the pharmaceutical composition can be used for Meniere's disease, hypertension, edema, ascites, heart failure, acute or chronic renal dysfunction, acute or chronic renal failure, polycystic kidney disease, and the like. For the treatment, prevention and / or diagnosis of diseases selected from the group consisting of vasopressin dyssecretion syndrome, liver cirrhosis, hyponatremia, hypopotassium, diabetes, circulatory failure, agitation, water metabolism disorders, and ischemic diseases. A kit that includes an attachment stating that it can be used.

The present invention also includes, as long as there is no contradiction, any combination of preferred embodiments or options for different elements or features herein, in addition to the embodiments exemplified above.

[General manufacturing method]
The compound of the present invention can be produced, for example, based on the general production method shown below, but the production method of the compound of the present invention is not limited thereto.
As the raw material compound, a commercially available compound may be used, or may be produced according to a method known per se or a method similar thereto.
The solvent, acid, base, protecting group and leaving group appropriately used in the production of the compound of the present invention are not particularly limited as long as they are usually used in the field of synthetic organic chemistry.
In the production of the compound of the present invention, the product can be used as a reaction solution as it is or as a crude product in the next reaction, but it can also be isolated from the reaction mixture according to a conventional method, and easily purified by ordinary separation means. You can also do it. Conventional separation means include, for example, filtration, extraction, concentration, distillation, crystallization, recrystallization, distillation, chromatography, and optical resolution.
When the alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction, etherification reaction, oxidation reaction, reduction reaction and the like are carried out in the production of the compound of the present invention, these reactions are carried out by methods known per se. Can be done according to.
These commonly used reagents and methods are described, for example, in the second edition of ORGANIC FUNCTIONAL GROUP PREPARATIONS, published by ACADEMIC PRESS, INC. In 1989; Comprehensive Organic. Transformations (Comprehensive Organic Transformations) VCH Publishers Inc., 1989, PGM Wuts; TW Greene, "Greene's Protective Groups in Organic Synthesis" (4th edition, 2006); John Wiley & It is described in Sons; New York, 1991, P.309, etc.

[式中、Ｒ^１、Ａ^１、Ａ^２及びＬは、前記と同じ]
本発明化合物は、化合物（２）と化合物（３）をアミド化して得ることができる。具体的には、化合物（１）は、化合物（２）又はそのカルボキシ基における反応性誘導体及び化合物（３）又はそのイミノ基における反応性誘導体を反応させることにより製造することができる。 Reaction equation-1

[In the formula, R ¹ , A ¹ , A ² and L are the same as above]
The compound of the present invention can be obtained by amidating compound (2) and compound (3). Specifically, compound (1) can be produced by reacting compound (2) or its carboxy group-reactive derivative and compound (3) or its imino group-reactive derivative.

Suitable reactive derivatives for the carboxy group of compound (2) include, for example, acid halides, acid azides, acid anhydrides, activated amides, activated esters and the like. More preferred reactive derivatives include acidifieds; acid azide; substituted phosphates (eg, dialkyl phosphate, phenyl phosphate, diphenyl phosphate, dibenzyl phosphate, halogenated phosphate, etc.), dialkyl fluorinated acid, etc. Sulfuric acid, thiosulfate, sulfuric acid, sulfonic acid (eg methanesulfonic acid, etc.), aliphatic carboxylic acid (eg acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc. ), Or mixed acid anhydrides with acids such as aromatic carboxylic acids (eg benzoic acid, etc.); symmetric acid anhydrides; imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole activated amides; activation Esters (eg, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, etc.) ; Or an ester with an N-hydroxy compound (for example, N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, HOBt, etc.). These reactive derivatives can be arbitrarily selected from them according to the type of compound (2) to be used.

When compound (2) is used in the form of a free acid or a salt thereof in Reaction Scheme-1, the reaction may be carried out in the presence of a condensing agent. As the condensing agent, those known in this field can be widely used, for example, DCC; N-cyclohexyl-N'-morpholinoethyl carbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl) carbodiimide; N, N'. -Diethylcarbodiimide; N, N'-diisopropylcarbodiimide; WSC or an HCl salt thereof; N, N'-carbonylbis (2-methylimidazole); pentamethyleneketen-N-cyclohexylimine; diphenylketen-N-cyclohexylimine; ethoxy Acetylene, 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphoryl azide; thionyl chloride; oxalyl chloride; for example, chlorogi Alkyl halogiates such as ethyl acid and isopropyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisooxazolium salt; 2-ethyl-5- (m-sulfophenyl) isooxazolium hydroxide within the molecule Salts; benzotriazole hexafluorophosphate-1-yloxy-tris (dimethylamino) phosphonium; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; DMF and thionyl chloride, phosgen, trichloromethyl chlorophosphate , So-called Billsmeyer reagent prepared by reaction with phosphorus oxychloride and the like. Further, the reaction may be carried out in the presence of the above condensing agent in the presence of an active esterifying agent such as N-hydroxysuccinimide, N-hydroxyphthalimide and HOBt.

Suitable reactive derivatives of the imino group of compound (3) include Schiff base imino produced by reaction of compound (3) with a carbonyl compound such as aldehyde, ketone and the like, or an enamine homomorphic form thereof; A silyl derivative produced by reacting compound (3) with a silyl compound such as bis (trimethylsilyl) acetamido, mono (trimethylsilyl) acetamido, bis (trimethylsilyl) urea; Examples thereof include derivatives produced by the reaction.

Equation-1 is usually carried out in a conventional solvent that does not adversely affect the reaction. Examples of the solvent include water; alcohol solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; THF, dioxane, Et ₂ O, diisopropyl ether and jigglime. Ether-based solvents such as: AcOMe, AcOEt and other ester-based solvents; Aprotonic polar solvents such as MeCN, DMF, DMSO; N-pentane, n-hexane, n-heptane, cyclohexane and other hydrocarbon-based solvents; DCM, A halogenated hydrocarbon solvent such as ethylene chloride; or another organic solvent; or a mixed solvent thereof and the like can be mentioned.

Reaction equation-1 may be carried out in the presence of a base. As the base, known inorganic bases and organic bases can be widely used. Examples of the inorganic base include alkali metals (eg, sodium, potassium, etc.), alkali metals hydrogen carbonate (eg, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (eg, LiOH, NaOH). , KOH, etc.), alkali metal carbonates (eg, Li ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO _3, etc.), alkali metal lower alkoxides (eg, sodium methoxydo, sodium ethoxydo, etc.), Alkali metal hydrides (eg, NaH, KH, etc.) can be mentioned. Examples of the organic base include trialkylamine (eg, trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO. , DBU and the like. When these bases are liquids, they can also be used as a solvent. These bases are used alone or in admixture of two or more. The amount of the base used is usually 0.1 to 10 mol, preferably 0.1 to 3 mol, per 1 mol of compound (2).

The ratio of compound (2) to compound (3) used in Reaction Scheme-1 is usually at least 1 mol, preferably about 1 to 5 mol, of the former with respect to 1 mol of the latter.
The reaction temperature is not particularly limited, and the reaction usually proceeds under cooling, at room temperature, or under heating. Preferably, the reaction is preferably carried out under temperature conditions of room temperature to 100 ° C. for 30 minutes to 30 hours, preferably 30 minutes to 5 hours.

［式中、Ａ^１、Ａ^２及びＬは前記と同じであり、Ｒ^１’は、ＯＨが保護基で保護されたヒドロキシアルキルであり、Ｒ^１ａは、ＯＨで置換されたＣ_１−６アルキルを示す］
反応式−２は、化合物（３）のＲ^１がＯＨが保護基で保護されたヒドロキシアルキルである場合の本発明化合物の製法である。化合物（１ａ）は、無溶媒又は不活性溶媒中、化合物（４）のＲ^１’におけるＯＨ保護基の脱保護を行うことにより得ることができる。
ＯＨ保護基としては、有機合成化学の分野で使用されるヒドロキシの保護基であれば特に限定されないが、例えば、アルキル基類（例、メチル、エチル、イソプロピル、ｔｅｒｔ−ブチル、トリフルオロメチル、ヒドロキシメチル、２−ヒドロキシエチル、アセチルメチル）；アルキル（アルケニル）カルボニル基類（例、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ピバロイル、バレリル、イソバレリル、クロロアセチル、ジクロロアセチル、トリクロロアセチル、トリフルオロアセチル、メトキシアセチル、アクリロイル、プロピオロイル、メタクリロイル、クロトノイル、イソクロトノイル、（Ｅ）−２−メチル−２−ブテノイル）；アリールカルボニル基類（例、ベンゾイル、α−ナフトイル、β−ナフトイル、２−ブロモベンゾイル、４−ブロモベンゾイル、４−クロロベンゾイル、２，４，６−トリメチルベンゾイル、４−トルオイル、４−アニソイル、４−ニトロベンゾイル、２−ニトロベンゾイル、２−（メトキシカルボニル）ベンゾイル、４−フェニルベンゾイル）；テトラヒドロ（チオ）ピラニル（フラニル）基類（例、テトラヒドロピラン−２−イル、３−ブロモテトラヒドロピラン−２−イル）；シリル基類（例、トリメチルシリル、トリエチルシリル、イソプロピルジメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、メチルジイソプロピルシリル、メチルジｔｅｒｔ−ブチルシリル、トリイソプロピルシリル、ジフェニルメチルシリル、ジフェニルブチルシリル、ジフェニルイソプロピルシリル、フェニルジイソプロピルシリル）；アルコキシメチル基類（例、メトキシメチル、１，１−ジメチル−１−メトキシメチル、エトキシメチル、プロポキシメチル、イソプロポキシメチル、ブトキシメチル、ｔｅｒｔ−ブトキシメチル、２−メトキシエトキシメチル、２，２，２−トリクロロエトキシメチル、ビス（２−クロロエトキシ）メチル）；アラルキル基類（例、ベンジル、α−ナフチルメチル、β−ナフチルメチル、ジフェニルメチル、トリフェニルメチル、α−ナフチルジフェニルメチル、９−アンスリルメチル、４−メチルベンジル、２，４，６−トリメチルベンジル、３，４，５−トリメチルベンジル、４−メトキシベンジル、４−メトキシフェニルジフェニルメチル、２−ニトロベンジル、４−ニトロベンジル、４−クロロベンジル、４−ブロモベンジル、４−シアノベンジル）等が挙げられる。脱保護は、当業者が通常用いうる脱保護化を採用することができる。
不活性溶媒としては、例えば水；ジオキサン、テトラヒドロフラン、ジエチルエーテル、１，２−ジメトキシエタン、ジエチレングリコールジメチルエーテル、エチレングリコールジメチルエーテル等のエーテル系溶媒；塩化メチレン、クロロホルム、１，２−ジクロロエタン、四塩化炭素等のハロゲン化炭化水素系溶媒；ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶媒；メタノール、エタノール、イソプロパノール等の低級アルコール系溶媒；ＤＭＦ、ＤＭＳＯ、ヘキサメチルリン酸トリアミド、アセトニトリル等の極性溶剤を挙げることができる。これらの不活性溶媒は、１種単独で又は２種以上混合して使用される。 Reaction equation-2

^Wherein, A 1, ^{A 2} and L are as defined above, R ^{1 'is,} OH is a protected hydroxy alkyl protecting ^{group, R 1a} is, _{C 1-6} alkyl substituted with OH Show]
The reaction formula-2 is ^{a method for producing the compound of the present invention when R 1} of the compound (3) is a hydroxyalkyl in which OH is protected by a protecting group. Compound (1a) is, without solvent or in an inert solvent, can be obtained by deprotection of the OH protecting group in R ^{1 'of} compound (4).
The OH protective group is not particularly limited as long as it is a hydroxy protective group used in the field of synthetic organic chemistry, but for example, alkyl groups (eg, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy). Methyl, 2-hydroxyethyl, acetylmethyl); alkyl (alkenyl) carbonyl groups (eg, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, Methoxyacetyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E) -2-methyl-2-butenoyl); arylcarbonyl groups (eg, benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4- Bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoil, 4-anisoyle, 4-nitrobenzoyl, 2-nitrobenzoyl, 2- (methoxycarbonyl) benzoyl, 4-phenylbenzoyl); tetrahydro (Thio) pyranyl (franyl) groups (eg, tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl); silyl groups (eg, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl) , Methyldiisopropylsilyl, methylditert-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl); alkoxymethyl groups (eg, methoxymethyl, 1,1-dimethyl-1-methoxy). Methyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl); aralkyl groups ( Examples, benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4 , 5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl , 4-Cyanobenzyl) and the like. For deprotection, deprotection that can be usually used by those skilled in the art can be adopted.
Examples of the inert solvent include water; ether solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether; methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like. Halogenized hydrocarbon solvent; aromatic hydrocarbon solvent such as benzene, toluene, xylene; lower alcohol solvent such as methanol, ethanol, isopropanol; polar solvent such as DMF, DMSO, hexamethylphosphate triamide, acetonitrile Can be mentioned. These inert solvents are used alone or in admixture of two or more.

Equation-2 is carried out according to conventional methods such as hydrolysis or reduction.
Hydrolysis is preferably carried out in the presence of an acid containing a base or Lewis acid. Examples of the base include alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (eg, magnesium hydroxide, calcium hydroxide), alkali metal carbonates (eg, sodium carbonate). , Potassium carbonate), alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate), alkali metal hydrogen carbonates (eg sodium hydrogencarbonate, potassium hydrogencarbonate); and trialkylamines (eg, potassium hydrogencarbonate). Includes organic bases such as trimethylamine, triethylamine), picolin, DBN, DABCO and DBU. Acids include organic acids (eg formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid). Deprotection with trihaloacetic acid (eg, trichloroacetic acid, trifluoroacetic acid) may be performed in the presence of cation scavengers (eg, anisole, phenol). When these bases or acids are liquids, they can also be used as a solvent.
The hydrolysis reaction is not particularly limited and is usually carried out under cooling, at room temperature or under heating.

Examples of the reduction reaction include chemical reduction and catalytic reduction.
Reducing agents used in chemical reduction include, for example, metals (eg, tin, zinc, iron) or metal compounds (eg, chromium chloride, chromium acetate) and organic or inorganic acids (eg, formic acid, acetic acid, propionic acid, tri). Fluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid) can be mentioned.
Examples of the catalyst used in the catalytic reduction include platinum catalysts (eg, platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire), palladium catalysts (eg, palladium sponge, palladium black, palladium oxide, etc.). Palladium-carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate), nickel catalysts (eg reduced nickel, nickel oxide, lane nickel), cobalt catalysts (eg reduced cobalt, lane cobalt), iron catalysts (eg) Conventional ones such as reduced iron, Rane iron) and copper catalysts (eg reduced copper, Rane copper, Ulman copper) can be mentioned.
The reduction reaction is carried out in a conventional solvent that does not adversely affect the reaction, such as water; alcohols such as methanol, ethanol, trifluoroethanol and ethylene glycol; ethers such as acetone, diethyl ether, dioxane and tetrahydrofuran; chloroform, methylene chloride, etc. Halogenated hydrocarbons such as ethylene chloride; esters such as methyl acetate and ethyl acetate; aproton polar solvents such as acetonitrile, N, N-dimethylformamide; basic solvents such as pyridine; or other organic solvents; or It is carried out with a mixed solvent thereof or the like. The reduction reaction is usually carried out under temperature conditions of room temperature to 200 ° C., preferably room temperature to 150 ° C., for about 1 to 30 hours.

［式中、Ｒ^１は前記と同じであり、Ｐ^Ｎはアミノの保護基である］
化合物（３）は、化合物（５）を、アミノの保護基の脱離反応により製造することができる。アミノの保護基の脱離反応は、反応式−２の加水分解、又は水素化分解等の慣用の方法に従って行ってもよい。
アミノの保護基としては、例えばアルコキシカルボニル、アルカノイル、アリール置換アルキル等が挙げられる。
アルコキシカルボニルとしては、例えばメトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ブトキシカルボニル、ｔｅｒｔ−ブトキシカルボニル、ペンチルオキシカルボニル、ヘキシルオキシカルボニル等を挙げることができる。
アルカノイルとしては、例えばホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ｔｅｒｔ−ブチルカルボニル、ヘキサノイル等が挙げられる。
アリール置換アルキルとしては、例えばベンジル、２−フェニルエチル、１−フェニルエチル、３−フェニルプロピル、４−フェニルブチル、５−フェニルペンチル、６−フェニルヘキシル、ジフェニルメチル、トリチル、及び同一又は異なる１個〜３個の置換基で置換されていてもよいフェニルで置換されたＣ_１−６アルキル等が挙げられる。フェニル基上の置換基としては、例えば、ハロゲン、Ｃ_１−６アルキル、ハロＣ_１−６アルキル、Ｃ_１−６アルキル−Ｏ−、ハロＣ_１−６アルキル−Ｏ−、ヒドロキシＣ_１−６アルキル、ヒドロキシハロＣ_１−６アルキル、ヒドロキシＣ_１−６アルキル−Ｏ−、ヒドロキシハロＣ_１−６アルキル−Ｏ−、Ｃ_３−６シクロアルキル等を例示できる。フェニル基上の置換基が２個以上の場合、これらの置換基は、それぞれ独立して同一又は異なってもよい。 Reaction equation-3

[In the formula, R ¹ is the same as above and ^PN is an amino protecting group]
Compound (3) can be produced by subjecting compound (5) to an elimination reaction of an amino protecting group. The elimination reaction of the amino protecting group may be carried out according to a conventional method such as hydrolysis or hydrogenation of Reaction Scheme-2.
Examples of the amino-protecting group include alkoxycarbonyl, alkanoyl, aryl-substituted alkyl and the like.
Examples of the alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
Examples of alkanoyl include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl and the like.
Examples of the aryl-substituted alkyl include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, diphenylmethyl, trityl, and the same or different one. Examples thereof include _{C 1-6} alkyl substituted with phenyl, which may be substituted with ~ 3 substituents. Examples of the substituent on the phenyl group include halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkyl-O-, halo C _1-6 alkyl-O-, and hydroxy C _1-6. Examples thereof include alkyl, hydroxyhalo C _1-6 alkyl, hydroxy C _1-6 alkyl-O-, hydroxyhalo C _1-6 alkyl-O-, and C _{3-6 cycloalkyl.} When there are two or more substituents on the phenyl group, these substituents may be independently the same or different.

As used herein, the compounds of the present invention, raw material compounds and intermediate compounds include chemically acceptable geometric isomers, stereoisomers, optical isomers and tautomers. Various isomers can be separated by a general optical resolution method, or can be produced from the corresponding optically active raw material compound.

In the present specification, the compound of the present invention, the raw material compound and the intermediate compound may also be in the form of a salt, and the target compound obtained in each reaction may also form a salt. When the compound obtained in each reaction is a free compound, it can be converted to the target salt by a method known per se, and when the compound is a salt, the free compound can be converted by a method known per se. Alternatively, it can be converted to another salt of interest. Examples of such salts include the salts exemplified below.

Examples of the salt in the present specification include pharmaceutically acceptable acid-added salts or base-added salts. Examples of the acid in the acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitrate, sulfuric acid and phosphoric acid; formic acid, propionic acid, oxalic acid, carbonic acid, picric acid, methanesulfonic acid and ethane. Organic acids such as sulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, lactic acid; and amino acids such as lysine, arginine, aspartic acid, glutamic acid, etc. Can be mentioned. Examples of the base in the base addition salt include metals such as alkali metals (for example, sodium, potassium, etc.) and alkaline earth metals (for example, calcium, magnesium, etc.); alkali metals carbonate (for example, lithium carbonate, potassium carbonate, sodium carbonate, carbonate). Cesium, etc.), alkali metals hydrogen carbonate (eg, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, water) Inorganic bases such as cesium oxide); and methylamine, diethylamine, trimethylamine, triethylamine, N-ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, dicyclohexylamine, N, N Included are organic bases such as'-dibenzylethylenediamine, guanidine, pyridine, quinoline, piperidine, imidazole, dimethylaminopyridine, dimethylaniline, picolin, choline, N-methylmorpholin, DBN, DBU, DABCO; and ammonium salts.

The compound of the present invention also includes various hydrates, solvates and polymorphic substances of the compound represented by the formula (1) and salts thereof.
^{In addition to the compound of formula (1) in which R 1} is deuterium, the compound of the present invention includes a compound in which any one or more atoms of formula (1) are replaced with one or more isotope atoms. included. Examples of isotope atoms include deuterium ( ² H), tritium ( ³ H), ¹³ C, ¹⁴ N, ¹⁸ O and the like.

The compounds of the present invention also include pharmaceutically acceptable co-crystals or co-crystal salts. Here, the co-crystal or co-crystal salt means a crystalline substance composed of two or more molecules at room temperature, each of which has different physical properties (for example, structure, melting point, heat of fusion, etc.). To do. The co-crystal and the co-crystal salt can be produced by applying a known co-crystallization method.

The compounds of the present invention also include pharmaceutically acceptable prodrugs. Examples of the prodrug include compounds in which any substituent of the compound of the formula (1) is modified with a reactive functional group such as OH, COOH, or amino.

Basically, the vasopressin V _1a receptor is thought to be present in blood vessels and myocardium and can cause vasoconstriction, and the vasopressin V ₂ receptor is thought to be present in renal tubules and endothelium and can cause water retention. Considering such an action of the vasopressin receptor, the compound of the present invention has _{a vasopressin antagonistic action of both a vasopressin V 1a} antagonist and a vasopressin V ₂ antagonist, for example, a vasopressin action, a blood pressure lowering action, a hepatic glucose release inhibitory action, and mesangium. Cell proliferation inhibitory effect, aliquot action, platelet aggregation inhibitory effect, vomiting inhibitory effect, urea excretion promoting effect, factor VIII secretion inhibitory effect, cardiac function enhancing effect, mesangium cell contraction inhibitory effect, hepatic glycosylation inhibitory effect, aldosterone secretion inhibitory effect It may have an action, an endothelin production inhibitory action, a renin secretion regulating action, a memory regulating action, a body temperature regulating action, or a prostaglandin production regulating action.

The compound of the present invention can also be useful as an active ingredient of, for example, a vasodilator, an antihypertensive agent, a water diuretic agent, a platelet aggregation inhibitor, a urea excretion promoter, an anti-heart failure agent or an anti-renal failure agent, and is a vasopressin receptor. Various diseases associated with, such as Meniere's disease, hypertension, edema, ascites, heart failure, renal dysfunction, renal failure, polycystic kidney disease (PKD), vasopressin dyssecretion syndrome (SIDH), liver cirrhosis, hyponatremia, low It may be useful for the diagnosis, prevention and / or treatment of heart failure, renal failure or PKD, more preferably PKD, such as potassiumemia, diabetes, circulatory failure, agitation, water metabolism disorders, various ischemic diseases and the like. In the sense of the present invention, the term renal dysfunction or renal failure refers to both acute and chronic signs of renal dysfunction, as well as potential or related renal diseases such as renal hypoperfusion, dialysis hypotension, obstructive urine. Road disease, glomerulopathy, glomerular nephritis, acute glomerular nephritis, glomerulosclerosis, tubulointerstitial disease, nephropathy, such as primary and congenital renal disease, nephritis, immunological renal disease For example, renal transplant rejection, immune complex-induced renal disease, toxic substance-induced nephropathy, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, nephritis, renal cyst, nephrosclerosis, etc. Includes hypertensive nephropathy and nephropathy syndrome, which include, for example, abnormal reduction of creatinine and / or water excretion, abnormal increase in blood levels of urea, nitrogen, potassium and / or creatinine, urinary molar osmotic concentration or urine volume. It can be diagnostically characterized by changes, increased microalbuminuria, overt albuminuria, glomerular and arterial lesions, tubule dilation, hyperphosphatemia and / or the need for dialysis.

The compound of the present invention also exhibits better metabolic stability than drugs such as tolvaptan, which are known to be metabolized mainly by the hepatic metabolizing enzyme CYP3A4, and thus may have a long drug efficacy duration. The compounds of the present invention may also be highly tolerated and safe with few side effects.

Next, a medical preparation containing the compound of the present invention as an active ingredient (hereinafter, also referred to as “pharmaceutical composition”) will be described.

The medical preparation is a formulation of the compound of the present invention in the form of a conventional medical preparation, and is prepared by using the compound of the present invention and a pharmaceutically acceptable carrier. Examples of the carrier include commonly used fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, diluents such as lubricants, and excipients.

Such medical preparations can be selected from various forms according to the purpose of treatment, for example, tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquids, suspensions, etc.) and the like.

As the carrier used when molding into the form of tablets, known ones can be widely used, for example, excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorption of sodium lauryl sulfate and the like. Accelerators; moisturizers such as glycerin and starch; adsorbents such as colloidal silicic acid; lubricants such as polyethylene glycol and the like.

Further, the tablet can be a tablet with a normal lock skin, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet, or a multi-layer tablet, if necessary.

As the carrier used when molding into the form of pills, known ones can be widely used, and examples thereof include excipients such as glucose; binders such as gum arabic powder; and disintegrants such as laminarin.

As the carrier used when molding into the form of a suppository, known ones can be widely used, and examples thereof include cacao fat and the like.

When prepared as an injectable, liquids, emulsions and suspensions are preferably sterilized and isotonic with blood. As the diluent used when molding into the form of these liquids, emulsions and suspensions, known ones can be widely used, and examples thereof include water. In this case, a sufficient amount of salt or the like for preparing an isotonic solution may be contained in the medical preparation, and ordinary solubilizing agents, buffers, soothing agents and the like are further required. Colorants, preservatives, flavors, flavors, sweeteners and the like and other pharmaceuticals may be included depending on the circumstances.

The amount of the compound of the present invention contained in the medical preparation is not particularly limited and can be appropriately selected from a wide range, but usually, the compound of the present invention is contained in the medical preparation in an amount of 0.1 to 70% by weight. Is preferable.

The administration method of the above medical preparation is not particularly limited, and may be administered by a method according to various preparation forms, the age, sex, disease state, and other conditions of the patient. For example, in the case of tablets, pills, liquids, suspensions, emulsions, granules and capsules, they may be orally administered. In the case of an injection, it may be administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acid, or if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. Can be administered. In the case of suppositories, they may be administered intrarectally.

The dose of the above medical preparation may be appropriately selected according to the usage, age, sex, degree of disease, and other conditions of the patient, and is usually 0.01 to 100 mg of the compound of the present invention per 1 kg of body weight per day. , Preferably 0.1 to 50 mg may be administered in 1 to several divided doses. Since the dose varies depending on various conditions, a dose smaller than the above range may be sufficient, or a dose exceeding the above range may be required.

The present invention will be further described in detail with reference to the following Reference Examples, Examples and Test Examples, but these do not limit the present invention and may be changed without departing from the scope of the present invention.
The following abbreviations may be used herein.
REX: Reference example number
EX: Example number
STR: Structural formula (in the formula, the structure indicated by "Chiral" indicates absolute configuration)
RProp: Manufacturing method (The number indicates that the product was manufactured using the corresponding raw material in the same manner as in the method described in the reference example using the number as the reference example number).
Prop: Manufacturing method (the number indicates that the product was manufactured using the corresponding raw material in the same manner as in the method described in the example in which the number is used as the example number).
Data: physical data (NMR1: δ (ppm in ¹ H-NMR in dimethylsulfoxide _{-d 6); NMR2: δ (} ppm in ¹ H-NMR in CDCl _3); NMR3: ¹ in CD ₃ OD H- Δ (ppm) in NMR; NMR4: δ (ppm) in ¹ H-NMR in a mixed solvent of _{CDCl 3} and dimethyl sulfoxide-d ₆₎
AcOEt: Ethyl acetate AcOH: AcOME acetate: Methyl acetate AcONa: Sodium acetate 9-BBN: 9-Borabicyclo [3.3.1] Nonan BBr ₃ : Boron tribromide Boc ₂ O: Di-t-butyl dicarbonate n-BuLi : N-Butyl Lithium CDI: 1,1'-carbonyldiimidazole Cs ₂ CO ₃ : Cesium carbonate DCE: 1,2-dichloroethane DCM: Hexane DEAD: Diethylazodicarboxylate DHP: 3,4-dihydro-2H-pyran DIBAL: Diisobutylaluminum hydride DIPEA: Diisopropylethylamine DMA: N, N-dimethylacetamide DMAP: 4- (dimethylamino) pyridine DME: Dimethoxyethane DMEDA: N, N'-dimethyl-1,2-ethylenediamine DMF: N, N -Dimethylformamide DMSO: Dimethylsulfoxide DPPA: Diphenylphosphate Azide DPPP: 1,3-Diphenylphosphinopropane Et ₂ O: Diethyl ether EtOH: Ethanol HATU: O- (7-azabenzotriazole-1-yl) -N, N, N', N'-Tetramethyluronium Hexafluorophosphate HCl: Hydrochloride HCO ₂ Na: Sodium formate Hexane: n-Hexane HOBt: 1-Hydroxybenzotriazole IBX: 2-iodoxybenzoate Im: Imidazole IPA: 2- Propanol IPE: diisopropyl ether K ₂ CO ₃ : potassium carbonate KHCO ₃ : potassium hydrogen carbonate KottBu: potassium t-butoxide KOH: potassium hydroxide K ₃ PO ₄ : tripotassium phosphate LAH: aluminum hydride Lithium LDA: lithium diisopropylamide LHMDS : Lithium hexamethyldisilazide LiOH: Lithium hydroxide MCPBA: m-chloroperbenzoic acid MeCN: acetonitrile MEK: 2-butanone MeOH: methanol NaBH ₄ : sodium boron hydride NaH: sodium hydride NaHCO ₃ : sodium hydrogen carbonate NaOH : Sodium hydroxide NaOtBu: Sodium t-butoxide Na ₂ SO ₄ : Sodium sulfate NCS: N-chlorosuccinimide NH ₄ Cl: Ammonium chloride NMO: N-methylmorpholine NMP: N-methylpyrrolidone Pd / C: Palladium-bearing carbon Pd _{2 (Dba) 3} : Tris (dibenziliden ace) Tons) Dipalladium (0)
Ph: Phenyl PPTS: Pyridinium p-toluenesulfonate Pyr: Pyridine TBAF: Tetra-n-butylammonium fluoride TBDMSCl: t-butyldimethylsilyl chloride TEA: Triethylamine TFA: Trifluoroacetate THF: tetrahydrofuranTMPDA: N, N, N' , N'-tetramethyl-1,3-propanediamine TMSCl: chlorotrimethylsilane TsCl: p-toluenesulfonyl chloride WSC: 3-ethyl-1- (3-dimethylaminopropyl) carbodiimide xanthphos: 4,5-bis (diphenyl) Phosphino) -9,9-Dimethylxanthene ZCl: Benzyl Chloroate In the present specification, "room temperature" usually indicates about 10 ° C to about 35 ° C. The ratio shown in the mixed solvent indicates a volume ratio (v / v) unless otherwise specified. % Indicates a weight% (% (w / w)) unless otherwise specified.
¹ H-NMR (proton nuclear magnetic resonance spectrum) is any of Fourier transform type NMR (Bruker AVANCE 300 (300MHz), Bruker AVANCE 500 (500MHz), Bruker AVANCE III 400 (400MHz) and Bruker AVANCE III 500 (500MHz) at room temperature. Or).
When described as basic in silica gel column chromatography, aminopropylsilane-bonded silica gel was used.
The absolute configuration of the compound is determined by a known X-ray crystal structure analysis method (for example, Shigeru Oba and Shigenobu Yano, "Basic Lecture for Chemists 12 X-ray Crystal Structure Analysis" (1st edition, 1999)). , Or the rule of thumb of historical asymmetric epoxidation (Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and Cong-Gui Zhao: Tetrahedron: Asymmetry 1998, 9, 397-401. Yuanming Zhu, Yong Tu, Hongwu Yu , Yian Shi: Tetrahedron Lett. 1988, 29, 2437-2440).

[Reference example]
Reference example 1
Methyl 6- (benzylamino) -2-chloro-5-fluoropyridin-3-carboxylate (5 g) and 10% HCl- in a THF (80 mL) suspension of Pd / C (NX type; 500 mg) MeOH (80 mL) was added and the mixture was stirred for 3 hours. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated to give methyl 6-amino-2-chloro-5-fluoropyridine-3-carboxylate (3.83 g).

Reference example 2
Methyl 6-amino-2-chloro-5-fluoropyridin-3-carboxylate (2.837 g) was added to a THF (50 mL) suspension of TEA (3.87 mL) and Pd (OH) _{2 (280 mg).} The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere of 1 atm. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated, a saturated _{aqueous solution of acrylamide 3} and AcOEt were added to the obtained residue, the AcOEt layer was separated, and the mixture was dried over _{anhydrous Na 2} SO _4. After filtering the mixture, the filtrate was concentrated to give methyl 6-amino-5-fluoropyridine-3-carboxylate (2.03 g).

Reference example 3
_{(COCl) 2} (1.543 mL) and DMF (14 μL) were added to a DCM solution of 2-chloro-5-fluorobenzoic acid (1.026 g) at 0 ° C., and the mixture was stirred for 1 hour and concentrated. The resulting residue was dissolved in DCM (2.0 mL) and added to a solution of methyl 6-amino-5-fluoropyridine-3-carboxylate (1 g) and Pyr (15 mL) in DCM (10 mL). After stirring overnight at room temperature, water was added and the precipitated crystals were collected by filtration and washed with water to obtain methyl 6- (2-chloro-5-fluorobenzamide) -5-fluoropyridine-3-carboxylate (1.25 g). ..

Reference example 4
Add 5N NaOH aqueous solution (1.148 mL) to a solution of methyl 6- (2-chloro-5-fluorobenzamide) -5-fluoropyridine-3-carboxylate (1.25 g) in MeOH (10 mL) and stir overnight at room temperature. did. The reaction mixture was acidified with HCl, the precipitated solid was _{collected by filtration, washed with water and Et 2} O, and 6- (2-chloro-5-fluorobenzamide) -5-fluoropyridine-3-carboxylic acid (678.3 mg). ) Was obtained.

Reference example 5
A DCM (600 mL) suspension of 5-bromo-1-indane oxime (108 g) is ice-cooled and TEA (80 mL) and p-TsCl (109 g) are added. The temperature was returned to room temperature and the mixture was stirred overnight. After distilling off about half of the solvent under reduced pressure, water was added to the reaction solution and the mixture was stirred. The precipitate was collected by filtration and washed with Hexane / AcOEt = 1/1 to obtain a white solid. The aqueous layer was re-extracted with DCM. The combined organic layers were washed with water and saturated brine, and dried over anhydrous Na ₂ SO ₄ . After filtering the mixture, the filtrate is concentrated and the precipitate is collected by filtration. Washed with Hexane: AcOEt = 1: 1. The solids were combined to give [(1E) -5-bromo-2,3-dihydro-1H-indene-1-iriden] amino 4-methylbenzene-1-sulfonate (166.37 g).

Reference example 6
[(1E) -5-Bromo-2,3-dihydro-1H-Inden-1-Ilidene] A suspension of amino 4-methylbenzene-1-sulfonate (4.77 g) in TFA (24 mL) at 60 ° C. 2 Stirred for hours. After distilling off TFA under reduced pressure, the mixture _{was neutralized with a saturated aqueous solution of LVDS 3} and extracted with DCM. The DCM layer was washed with water and saturated brine and dried over anhydrous DDL ₄ . After filtering the mixture, the filtrate was concentrated under reduced pressure. The obtained black oil was purified by medium pressure column chromatography (Hexane / AcOEt). The fraction was concentrated, the solid was collected by filtration and washed with a mixed solvent of Hexane / AcOEt = 1: 1 to give 6-bromo-1,2,3,4-tetrahydroisoquinoline-1-one (1.14 g). ..

Reference example 7
_{Toluene (20 mL), (COCl) 2} (2.268 mL) and a drop of DMF were added to 2- (difluoromethyl) benzoic acid (2.238 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain acid chloride. Methyl 6-aminonicotinate (2.374 g) was suspended in Pyr (20 mL) and a solution of acid chloride in MeCN (10 mL) was added under ice cooling. After stirring at room temperature for 1 hour, water was added and the precipitated crystals were collected by filtration. It was washed with water and air-dried to obtain methyl 6- [2- (difluoromethyl) benzamide] pyridine-3-carboxylate (3.60 g).

Reference example 8
THF (18 mL) and 2N LiOH aqueous solution (17.63 mL) were added to methyl 6- [2- (difluoromethyl) benzamide] pyridine-3-carboxylate (3.60 g). After stirring at room temperature for 2 hours, THF was distilled off under reduced pressure, and water (30 mL) and concentrated HCl (5 mL) were added. Precipitated crystals were collected by filtration and washed with water. It was dried with warm air to obtain 6- [2- (difluoromethyl) benzamide] pyridine-3-carboxylic acid (3.19 g).

Reference example 9
Methyl 5-chloropyrazine-2-carboxylate (0.703 g), 2-chlorobenzamide (0.962 g), Cs ₂ CO ₃ (1.67 g), xantphos (0.225 g) and Pd ₂ (dba) ₃ (0.12 g) The dioxane (20 mL) suspension was stirred at 80 ° C. for 9 hours under an argon atmosphere. After cooling, AcOEt and water were added and stirred. Unnecessary substances were filtered off from Celite. The filtrate was separated and the organic layer was washed with water and saturated brine. The residue was dried, filtered, and the solvent was distilled off with anhydrous EDTA ₄ , and the obtained residue was purified by column chromatography (Hexane / AcOEt) to obtain methyl 5- (2-chlorobenzamide) pyrazine-2-carboxylate (1.05 g). It was.

Reference example 10
MeOH (4.7 mL) was added to methyl 5- (2-chlorobenzamide) pyrazine-2-carboxylate (469 mg), and a 5N NaOH aqueous solution (1.3 mL) was added under ice-cooling. After stirring at room temperature for 2 hours, 1N HCl (6.5 mL) was added under ice-cooling to adjust the pH to 7. The precipitate was collected by filtration and dried at 60 ° C. 5- (2-Chlorobenzamide) pyrazine-2-carboxylic acid (89 mg) was obtained. The filtrate was further concentrated, 1N HCl was added to the aqueous layer to adjust the pH to 4, and the precipitated crystals were collected by filtration. Drying at 60 ° C. gave 5- (2-chlorobenzamide) pyrazine-2-carboxylic acid (330 mg).

Reference example 11
_{DMF (50 μL) and (COCl) 2} (1.7 mL) were added to a solution of 2-chloro-6-methylbenzoic acid (1.08 g) in DCM (25 mL) under ice-cooling. After stirring at room temperature for 1.5 hours, the solvent was distilled off to dissolve in DCM (10 mL) and added to a solution of methyl 6-aminonicotinate (0.965 g) and DIPEA (5.5 mL) in DCM (10 mL). .. The mixture was stirred at room temperature for 37 hours. The solvent was distilled off, AcOEt and water were added to separate the liquids, and the organic layer was washed with water and saturated brine. The _{residue obtained by drying, filtering and distilling off the solvent with anhydrous DDL 4} was purified by column chromatography (Hexane / AcOEt) to obtain an ethyl ester product. EtOH (12 mL) was added to the ester, 5N NaOH aqueous solution (3.8 mL) was added under ice-cooling, and the mixture was stirred under reflux for 7 hours. 5N HCl (3.8 mL) was added under ice-cooling. The precipitate was collected by filtration and dried at 60 ° C. to obtain 6- (2-chloro-6-methylbenzamide) pyridine-3-carboxylic acid (0.686 g).

Reference example 12
Methyl 5-chloropyrazine-2-carboxylate (879 mg), 2-trifluoromethylbenzamide (1.05 g), Cs ₂ CO ₃ (2.31 g), xantphos (0.268 g) and Pd ₂ (dba) ₃ (0.141 g) ) Was stirred in dioxane (25.5 mL) at 80 ° C. for 6 hours under an argon atmosphere. After cooling, AcOEt and water were added, and the mixture was stirred, and unnecessary substances were removed by filtration through Celite. The filtrate was separated and the organic layer was washed with water and saturated brine. After drying with anhydrous Na ₂ SO ₄ and distilling off the solvent, the obtained residue was purified by column chromatography (Hexane / AcOEt). Methyl 5-[(2- (trifluoromethyl) benzamide] pyrazine-2-carboxylate (1.69 g) was ^{confirmed by 1} H-NMR (CDCl ₃ ), to which MeOH (16.5 mL) was added. Then, 5N NaOH aqueous solution (4.1 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. 5N HCl (4.1 mL) was added to make pH = 4, and the precipitate was collected by filtration and dried at 60 ° C. 5- [2- (trifluoromethyl) benzamide] pyrazine-2-carboxylic acid (1.56 g) was obtained.

Reference example 13
2-Methylfuran-3-carboxylic acid (2.87 g) was dissolved in DMA (30 mL), ice-cooled, and _{SOCL 2} (1.963 mL) was added. After stirring for 30 minutes, methyl 4-amino-3-methoxybenzoate (3.75 g) was added. Then, the mixture was stirred at room temperature for 1 hour, water was added, and the precipitated crystals were collected by filtration. The obtained solid was dissolved in THF (30 mL) and a 2N LiOH aqueous solution (31.0 mL) was added. The mixture was stirred at 60 ° C. for 1 hour. 1N HCl (90 mL) was added, and the mixture was stirred under ice-cooling for 30 minutes, and the precipitated crystals were collected by filtration. After washing with water, it was dried with warm air to obtain 3-methoxy-4- (2-methylfuran-3-amide) benzoic acid (4.81 g).

Reference example 14
Under a nitrogen atmosphere, 2- (trifluoromethyl) benzoyl chloride (1.7 mL) was added to a solution of methyl 4-amino-3-methoxybenzoate (2.0 g) in Pyr (27 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, the precipitate was collected by filtration, and washed with water. MeOH (30 mL) and 5N NaOH aqueous solution (4.4 mL) were added to the obtained solid, and the mixture was stirred at room temperature for 1 hour. 5N Hydrochloric acid and water were added to the reaction solution for neutralization. The precipitate was collected by filtration, washed with water and dried to obtain 3-methoxy-4- (2- (trifluoromethyl) benzamide) benzoic acid (3.2 g).

Reference example 15
A 1N aqueous NaOH solution (22.11 mL) was added to MeOH (50 mL) of methyl 3-fluoro-4- [2- (trifluoromethyl) benzamide] benzoate (5.03 g) at room temperature, and the mixture was stirred overnight. After adding 1N HCl until the mixture became acidic, the mixture was stirred for 2 hours. Precipitated crystals were collected by filtration and washed with water. The mixture was air-dried at 60 ° C. to obtain 3-fluoro-4- [2- (trifluoromethyl) benzamide] benzoic acid (4.70 g).

Reference example 16
2-Chlorobenzoyl chloride (6.99 mL) was added to a solution of methyl 4-amino-3- (methoxymethoxy) benzoate (10.6 g) in Pyr (100 mL), and the mixture was stirred overnight at room temperature. After confirming the disappearance of the raw materials, the mixture was poured into water, the powder was collected by filtration, washed with water, and dried to obtain methyl 4- (2-chlorobenzamide) -3- (methoxymethoxy) benzoate (quantitative).

Reference example 17
5N NaOH (20 mL) was added to a suspension of methyl 4- (2-chlorobenzamide) -3- (methoxymethoxy) benzoate (17.5 g) in MeOH (200 mL), and the mixture was stirred at 60 ° C. for 4.5 hours. After concentration, 5N HCl (20 mL) was added, and the resulting powder was collected by filtration, washed with water, and dried to obtain 4- (2-chlorobenzamide) -3- (methoxymethoxy) benzoic acid (15.2 g).

Reference example 18
2- (Trifluoromethyl) benzoyl chloride (7.67 mL) was added to Pyr (50 mL) of methyl 4-amino-3- (methoxymethoxy) benzoate (10 g), and the mixture was stirred overnight at room temperature. The formation of an ester was confirmed by LCMS, water was added to the reaction solution, and the mixture was extracted with AcOEt. The organic layer was concentrated. MeOH was added to the residue to make a solution, 5N aqueous NaOH solution (20 mL) was added, and the mixture was stirred at 60 ° C. After stirring for 8 hours and cooling, the mixture was concentrated, and the powder produced by adding 5N HCl (20 mL) was collected by filtration. After washing with water and drying, 3- (methoxymethoxy) -4- [2- (trifluoromethyl) benzamide] benzoic acid (16.5 g) was obtained.

Reference example 19
4-Amino-3-methoxybenzoic acid (1.253 g) was added to a DMA (10 mL) solution of 2-chloro-4-fluorobenzoyl chloride (1.0 mL), and the mixture was stirred at room temperature for 1 hour, and then water was added and stirred. The precipitated powder was collected by filtration, washed with water and dried to obtain 4- (2-chloro-4-fluorobenzamide) -3-methoxybenzoic acid (2.4 g).

Reference example 21
2-Chloro-5-fluorobenzoic acid (5.63 g) was dissolved in DMA (50 mL) and SOCL ₂ (2.82 mL) was added. After stirring at room temperature for 1.5 hours, 4-amino-3-fluorobenzoic acid (5 g) is added, and the mixture is stirred at room temperature for 1 hour, water is added, the precipitated solid is collected by filtration, washed with water, and dried at 60 ° C. Then, 4- (2-chloro-5-fluorobenzamide) -3-fluorobenzoic acid (9.59 g) was obtained.

Reference example 22
_{SOCl 2} (0.844 mL) and DMF (45 μL) were added to a solution of 4'-fluoro- [1,1'-biphenyl] -2-carboxylic acid (2.5 g) in anhydrous DCM (40 mL) at room temperature, and the temperature was 40 ° C. Was stirred for 3 hours. The reaction was concentrated and a solution of acid chloride in anhydrous DCM (20 mL) was added dropwise to a solution of methyl 6-aminonicotinate (1.759 g) and Pyr (1.870 mL) in anhydrous DCM (50 mL) at 0 ° C. After stirring overnight, 1N HCl was added, and the mixture was extracted twice with AcOEt / Hexane (10/1). The combined organic layers were washed with LVDS ₃ aqueous solution. After drying over anhydrous DDL ₄ , the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and then crystallized with _{acetone-Et 2 O.} The filtrate was further concentrated and then purified by silica gel column chromatography (Hexane / AcOEt). Crystallized with Et ₂ On-hexane and collected by filtration. Together, methyl 6- {4'-fluoro- [1,1'-biphenyl] -2-amide} pyridine-3-carboxylate (3.36 g) was obtained.

Reference example 23
1N NaOH aqueous solution (16.48) in MeOH-THF (50 mL-40 mL) solution of methyl 6- {4'-fluoro- [1,1'-biphenyl] -2-amide} pyridine-3-carboxylate (3.85 g) mL) was added at room temperature and stirred overnight. It was acidified with 1N HCl and extracted with AcOEt. Further, the aqueous layer was extracted with AcOEt, and the combined organic layer was washed with saturated brine. The organic layer was dried over anhydrous DDL ₄ , filtered, and the filtrate was concentrated under reduced pressure. The obtained white powder was collected by filtration, washed with Hexane, and air-dried to obtain 6- {4'-fluoro- [1,1'-biphenyl] -2-amide} pyridine-3-carboxylic acid (3.26 g). It was.

Reference example 25
DMF (50 mL), MeOH (10 mL) and TEA (10 mL) were added to 2-bromo-1- (difluoromethyl) -4-fluorobenzene (4.95 g). Pd (OAc) ₂ (0.494 g) and DPPP (0.907 g) were added, and the mixture was stirred at 70 ° C. for 24 hours under a carbon monoxide atmosphere at 1 atm, water and AcOEt were added, and the insoluble material was filtered off. Water was added to the filtrate and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give methyl 2- (difluoromethyl) -5-fluorobenzoate (2.08 g).

Reference example 26
MeOH (15 mL) and 5N NaOH aqueous solution (4.06 mL) were added to methyl 2- (difluoromethyl) -5-fluorobenzoate (2.07 g), and the mixture was stirred at room temperature for 3 hours. Water and 1N HCl were added and extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give 2- (difluoromethyl) -5-fluorobenzoic acid (1.83 g).

Reference example 27
In a nitrogen atmosphere, o-toluyl chloride (0.74 mL) was added dropwise to a DMA (8.0 mL) solution of 4-amino-3-methoxybenzoic acid (1.0 g) under ice-cooling, and the mixture was stirred at room temperature for 1 day. Water was added, and the precipitate was collected by filtration and washed with water to obtain 3-methoxy-4- (2-methylbenzamide) benzoic acid (1.6 g).

Reference example 30
_{SOCl 2} (0.36 mL) was added dropwise to a DMA (6.0 mL) solution of 2-chloro-5-methylbenzoic acid (0.83 g) under a nitrogen atmosphere at room temperature, and the mixture was stirred for 2 hours. 4-Amino-3-methoxybenzoic acid (1.0 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 day. Water was added, and the precipitate was collected by filtration and washed with water to obtain 3-methoxy-4- (2-chloro-5-methylbenzamide) benzoic acid (1.4 g).

Reference example 31
_{Under a nitrogen atmosphere, (COCl) 2} (0.51 mL) and DMF (19 μL) were added to a DCM (3 mL) solution of 2-chloro-5-methylbenzoic acid (0.83 g), and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentration was added dropwise to a solution of methyl 6-aminonicotinate (0.74 g) in Pyr (4.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction solution, the precipitate was collected by filtration, and washed with water. MeOH (12 mL) and 5N NaOH aqueous solution (4.9 mL) were added to the obtained solid, and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, 5N HCl (4.9 mL) and water were added to the reaction solution to neutralize, and the precipitate was collected by filtration, washed with water, and 6- (2-chloro-5-methylbenzamide) pyridine-3-carboxylic acid. (1.03 g) was obtained.

Reference example 32
Methyl 5-chloropyrazine-2-carboxylate (4.44 g), 2-chloro-5-fluorobenzamide (6.70 g), Cs ₂ CO ₃ (10.9 g), Pd ₂ dba ₃ (0.754 g) and xantphos (1.4 g) ) Was suspended in dioxane (150 mL) and stirred at 80 ° C. for 5 hours under an argon atmosphere. After diluting with AcOEt, water was added and the insoluble matter was filtered off. The filtrate was extracted with AcOEt, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (AcOEt / Hexane). After concentration, it was vacuum dried to obtain methyl 5- (2-chloro-5-fluorobenzamide) pyrazine-2-carboxylate (9.6 g).

Reference example 33
Methyl 5- (2-chloro-5-fluorobenzamide) pyrazine-2-carboxylate (9.6 g) was dissolved in MeOH (100 mL), 5N aqueous NaOH solution (18.60 mL) was added, and the mixture was stirred at room temperature for 4 hours. 5N HCl was added to pH <4, and the solid formed after dilution with water was collected by filtration. The mixture was washed with water and AcOEt and dried at 60 ° C. to obtain 5- (2-chloro-5-fluorobenzamide) pyrazine-2-carboxylic acid (6.2 g).

Reference example 35
Under nitrogen atmosphere, 1,2,3,4-tetrahydroisoquinoline-1-one (1.0 g), 1,4-dioxane (10.0 mL), methyl 6-chloronicotinate (1.39 g), Pd ₂ (dba) ₃ A mixture of (0.124 g), xantphos (0.197 g), and Cs ₂ CO ₃ (2.88 g) was stirred under heating reflux for 1 day. After cooling to room temperature, water was added to the reaction solution and the mixture was extracted with AcOEt. The organic layer was _{dried over anhydrous Na 2} SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt) to give methyl 6- (1-oxo-1,2,3,4-tetrahydroisoquinoline-2-yl) pyridine-3-carboxylate (1.76 g). It was.

Reference example 37
Methyl 6- (1-oxo-1,2,3,4-tetrahydroisoquinoline-2-yl) pyridine-3-carboxylate (1.76 g) was added with MeOH (10.0 mL) and 5N NaOH aqueous solution (6.23 mL). The mixture was stirred at room temperature for 3 hours. Under ice-cooling, 5N HCl was added to the reaction solution to make it acidic, the precipitate was collected by filtration, washed with water, and 6- (1-oxo-1,2,3,4-tetrahydroisoquinoline-2-yl) pyridine-3-carboxylic acid. Acid (1.63 g) was obtained.

Reference example 39
Under nitrogen atmosphere, 1,2,3,4-tetrahydroisoquinoline-1-one (0.509 g), 4-iodo-3-methoxymethyl benzoate (1.01 g), CuI (66.0 mg), DMEDA (74.0 μL), A mixture of K ₃ PO ₄ (1.47 g) and toluene (5.0 mL) was stirred at 90 ° C. for 1 day. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Haxane / AcOEt) to obtain methyl 3-methoxy-4- (1-oxo-1,2,3,4-tetrahydroisoquinoline-2-yl) benzoate (1.08 g). It was.

Reference example 41
_{SOCl 2} (1.379 mL) was added to a DMA (50 mL) solution of 4-fluoro-2-methylbenzoic acid (2.77 g) under a nitrogen atmosphere, and after stirring at room temperature for 1 hour, 4-amino-3-methoxybenzoic acid was added. Acid (3 g) was added. After stirring at room temperature for 3 hours, water was added. Precipitated crystals were collected by filtration and washed with water to obtain 4- (4-fluoro-2-methylbenzamide) -3-methoxybenzoic acid (5.20 g).

Reference example 44
_{In a nitrogen atmosphere, add (COCl) 2} (0.556 mL) and DMF (1 drop) to a solution of 2- (difluoromethyl) pyridine-3-carboxylic acid (1.0 g) in DCM (3 mL) for 2 hours at room temperature. The mixture was stirred at 50 ° C. for 30 minutes. The residue was added dropwise to a solution of methyl 6-aminonicotinate (1.06 g) in Pyr (8.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with AcOEt. The organic layer was washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and recrystallization (Hexane / AcOEt) to give methyl 6- [2- (difluoromethyl) pyridine-3-amide] pyridine-3-carboxylate (732 mg). Obtained.

Reference example 45
A mixture of methyl 6- [2- (difluoromethyl) pyridine-3-amide] pyridine-3-carboxylate (732 mg), THF (4.0 mL) and 2N LiOH aqueous solution (3.57 mL) was stirred at room temperature for 2 hours. .. Under ice-cooling, 5N HCl was added to the reaction solution to neutralize it, and the precipitate was collected by filtration, washed with water, and 6- [2- (difluoromethyl) pyridine-3-amide] pyridine-3-carboxylic acid (603 mg). ) Was obtained.

Reference example 48
Methyl 5-chloropyrazine-2-carboxylate (1.0 g), [1,1'-biphenyl] -2-carboxamide (1.257 g), Cs ₂ CO ₃ (2.454 g), Pd ₂ dba ₃ (0.170 g) and xantphos (0.315 g) was suspended in dioxane (30 mL) and stirred overnight at 80 ° C. under an argon atmosphere. After diluting with AcOEt, water was added and the insoluble matter was filtered off. The filtrate was extracted with AcOEt, washed with saturated brine, and dried over anhydrous Na ₂ SO ₄ . After filtration and concentration under reduced pressure, the obtained residue was purified by column chromatography (Hexane / AcOEt). After concentration, it was vacuum dried. Methyl 5-{[1,1'-biphenyl] -2-amide} pyrazine-2-carboxylate (1.49 g) was obtained.

Reference example 49
Methyl 5-{[1,1'-biphenyl] -2-amide} pyrazine-2-carboxylate (1.49 g) is dissolved in MeOH (30 mL), 5N NaOH aqueous solution (1.788 mL) is added, and the mixture is stirred at room temperature for 24 hours. did. 5N HCl was added to adjust the pH to 5-6, water was added, and the precipitated crystals were collected by filtration. The mixture was washed with water and AcOEt and dried at 60 ° C. to obtain 5-{[1,1'-biphenyl] -2-amide} pyrazine-2-carboxylic acid (1.3 g).

Reference example 53
Methyl 5-chloropyrazine-2-carboxylate (692 mg), 4-fluoro- [1,1'-biphenyl] -2-carboxamide (948.7 mg), Cs ₂ CO ₃ (1697 mg), Pd ₂ dba ₃ ( 183 mg) and xantphos (348 mg) were suspended in dioxane (25 mL) and stirred at 80 ° C. for 2 days under an argon atmosphere. After diluting with AcOEt, water was added, the mixture was extracted with AcOEt, the organic layer was washed with saturated brine, and dried over anhydrous Na ₂ SO ₄ . The residue obtained by filtering and concentrating under reduced pressure was purified by column chromatography (Hexane / AcOEt). After concentration, the resulting solid was dispersed and washed with AcOEt / Hexane, collected by filtration, and dried at 60 ° C. Methyl 5- {4-fluoro- [1,1'-biphenyl] -2-amide} pyrazine-2-carboxylate (1.1 g) was obtained.

Reference example 54
Methyl 5- {4-fluoro- [1,1'-biphenyl] -2-amide} pyrazine-2-carboxylate (1.1 g) was suspended in MeOH (18 mL), and 5N NaOH aqueous solution (1.879 mL) was added. The mixture was stirred at room temperature for 4 days. 5N HCl was added to pH = 5-6. Water was added and the mixture was stirred under ice-cooling, and the resulting precipitated crystals were collected by filtration and dried at 60 ° C. 5- {4-Fluoro- [1,1'-biphenyl] -2-amide} pyrazine-2-carboxylic acid (620.8 mg) was obtained.

Reference example 55
4-Fluoro- [1,1'-biphenyl] -2-carboxylic acid (1.0 g) is suspended in toluene (10 mL), and ice-cooled (COCl) ₂ (0.442 mL) and DMF (16 μL) are added. The temperature was raised to room temperature and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure, and a MeCN solution (10 mL) of the obtained acid chloride was added dropwise to a suspension of methyl 6-aminonicotinate (0.640 g) in Pyr (20 mL) under ice-cooling, and the mixture was stirred for 1 hour. Water was added and the precipitated solid was collected by filtration. The solid was suspended in MeOH (20 mL), 5N NaOH (2.102 mL) was added and stirred overnight at room temperature. 5N HCl was added to adjust the pH to 5, water was added, and the precipitated solid was collected by filtration and dried at 60 ° C. 6-{4-Fluoro- [1,1'-biphenyl] -2-amide} pyridine-3-carboxylic acid (1.00 g) was obtained.

Reference example 58
2-Phenyl-3-pyridinecarboxylic acid (1.00 g) was suspended in toluene (10 mL), ice-cooled (COCl) ₂ (0.479 mL) and DMF (35 μL) were added, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. .. Concentrate under reduced pressure, suspend the obtained acid chloride in MeCN (5 mL), add methyl 6-aminonicotinate (0.694 g) and Pyr (20 mL) under ice-cooling, stir for 1 hour, and then add water. The resulting solid was collected by filtration. The solid was suspended in MeOH (20 mL), 5N aqueous NaOH solution (1.825 mL) was added, and the mixture was stirred overnight at room temperature. 5N HCl was added to adjust the pH to 5, water was added and the resulting solid was collected by filtration and dried at 60 ° C. to obtain 6- (2-phenylpyridine-3-amide) pyridine-3-carboxylic acid (849.3 mg). ..

Reference example 59
Methyl 5-chloropyrazine-2-carboxylate (459 mg), 2-phenylpyridine-3-carboxamide (580.3 mg), Cs ₂ CO ₃ (1127 mg), Pd ₂ dba ₃ (122 mg) and xantphos (231 mg) ) Was suspended in dioxane (15 mL) and stirred at 80 ° C. for 60 hours under an argon atmosphere. After diluting with AcOEt, water was added, the mixture was extracted with AcOEt, the organic layer was washed with saturated brine, and dried over _{anhydrous Na 2} SO _4. After filtration and concentration under reduced pressure, the obtained residue was purified by column chromatography (Hexane / AcOEt). After concentration, the mixture was vacuum dried to obtain methyl 5- (2-phenylpyridine-3-amide) pyrazine-2-carboxylate (417.2 mg).

Reference example 61
_{(COCl) 2} (5.14 mL) and DMF (91 μL) were added to a DCM (50 mL) suspension of 5-fluoro-2-methylbenzoic acid (3.99 g) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. .. The reaction mixture was concentrated and then azeotropically boiled twice with DCM. A solution of the residue in DCM was added to DCM (30 mL) -Pyr (9.51 mL) of methyl 6-amino-5-fluoropyridine-3-carboxylate (2 g) and stirred overnight. A saturated _{aqueous solution of LVDS 3} was added, and the mixture was extracted with AcOEt. The organic layer was washed with 1N HCl and saturated brine, and dried over _{anhydrous Na 2} SO _4. MeOH (50 mL) and 5N NaOH aqueous solution (5.17 mL) were added to the obtained residue after filtration and concentration, and the mixture was stirred overnight at room temperature. HCl was added to neutralize, and the precipitated solid was collected by filtration and dried. 5-Fluoro-6- (5-fluoro-2-methylbenzamide) pyridine-3-carboxylic acid (2.54 g) was obtained.

Reference example 62
6-Bromo-1,2,3,4-tetrahydroisoquinoline-1-one (1.0 g), 1-chloro-4-fluoro-2-iodobenzene (1.134 g), DMEDA (0.094 mL) and K ₃ PO ₄ CuI (0.084 g) was added to a suspension of (1.878 g) in toluene (10 mL) under a nitrogen stream, and the mixture was stirred overnight at 90 ° C. under a nitrogen atmosphere. At room temperature, 1-chloro-4-fluoro-2-iodobenzene (0.3 g) was added, and the mixture was stirred overnight at 90 ° C. under a nitrogen atmosphere. After cooling, the crude product obtained by concentration is purified by medium pressure column chromatography (Hexane / AcOEt) to 6-bromo-2- (2-chloro-5-fluorophenyl) -1,2,3, 4-Tetrahydroisoquinoline-1-one (0.75 g) was obtained.

Reference example 69
Tert-Butyl acrylate (0.929 mL) in DMA (7.5 mL) solution of 6-bromo-2- (2-chloro-5-fluorophenyl) -1,2,3,4-tetrahydroisoquinoline-1-one (0.75 g) ), LiCl (0.090 g) and TEA (1.474 mL) were added, PdCl ₂ (PPh ₃ ) ₂ (0.074 g) was added under a nitrogen stream, and the mixture was stirred at 150 ° C. under a nitrogen atmosphere. After stirring for 5 hours, water was added at room temperature, and the mixture was extracted with AcOEt. After concentrating the organic layer, the obtained crude product is purified by medium pressure column chromatography (Hexane / AcOEt) to tert-butyl (2E) -3- [2- (2-chloro-5-fluorophenyl). -1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl] propa-2-enoate (0.85 g) was obtained.

Reference example 70
tert-butyl (2E) -3- [2- (2-chloro-5-fluorophenyl) -1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl] propa-2-enoate (0.85 g) _{), NaIO 4} (2.262 g) and OsO ₄ (immobilized cat; 0.230 g) were added to THF: H ₂ O (3: 2, 10 mL), and the mixture was stirred at 50 ° C. for 2.5 hours. After cooling, the mixture was filtered through Celite, water was added to the filtrate, and the mixture was extracted with AcOEt. The organic layer was _{dried, filtered and concentrated in anhydrous EDTA 4} , 2- (2-chloro-5-fluorophenyl) -1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde (0.7 g crude). ) Was obtained. _{DCM / t-BuOH / H 2} O (1/1) of 2- (2-chloro-5-fluorophenyl) -1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde (0.7 g) / 1; 6 mL) 2-Methyl-2-butene (1.221 mL), NaClO ₂ (1.042 g) and NaH ₂ PO ₄ (1.383 g) were added to the solution, and the mixture was stirred overnight at room temperature. Water was added, the mixture was extracted with AcOEt, and washed with saturated brine. The organic layer was _{dried, filtered and concentrated on anhydrous DDL 4} and 2- (2-chloro-5-fluorophenyl) -1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (0.67 g). Got

Reference example 79
_{SOCl 2} (0.933 mL) was added to a DMA (20 mL) solution of 5-fluoro-2- (trifluoromethyl) benzoic acid (2.54 g), and the mixture was stirred at room temperature for 2.5 hours. As a result of confirming LC-MS, the raw material remained, so SOCl ₂ (0.170 mL) was further added and the mixture was stirred for 1 hour. 4-Amino-m-toluic acid (1.757 g) was added thereto, and the mixture was stirred overnight at room temperature. After adding 5N NaOH aqueous solution (20 mL) and water to make a uniform solution, the aqueous layer was washed with AcOEt. After adding 5N HCl to the aqueous layer to make it acidic, iPr ₂ O was added and the mixture was stirred for a while. The precipitated solid was filtered and dried at 60 ° C. to obtain 4- [5-fluoro-2- (trifluoromethyl) benzamide] -3-methylbenzoic acid (2.874 g).

Reference example 81
4,4'-Difluoro- [1,1'-biphenyl] -2-carboxylic acid (1.75 g) was dissolved in DMA (10 mL), SOCl ₂ (0.709 mL) was added, and the mixture was stirred at room temperature for 2 hours. .. 4-Aminobenzoic acid (1.025 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. The disappearance of raw materials was confirmed by LCMS. Water was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water, air-dried at 60 ° C., and dried under reduced pressure at 60 ° C. 4- {4,4'-difluoro- [1,1'-biphenyl] -2-amide} benzoic acid (2.58 g) was obtained.

Reference example 95
_{Under a nitrogen atmosphere, add (COCl) 2} (1.495 mL) and DMF (50 μL) to a DCM (50 mL) solution of 4,2'-difluoro-1,1'-biphenyl-2-carboxylic acid (2.00 g). The mixture was stirred at room temperature for 2 hours. After concentration, the residue was dissolved in DCM (50 mL), methyl 6-aminonicotinate (1.364 g) and Pyr (2.072 mL) were added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, dissolved in THF (15 mL) and MeOH (15 mL), 5N NaOH aqueous solution (5.12 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, add 5N hydrochloric acid and water to the reaction solution to neutralize, filter out the precipitate, wash with water, and 6- {2', 4-difluoro- [1,1'-biphenyl] -2-amide. } Pyridine-3-carboxylic acid (2.60 g) was obtained.

Reference example 97
4-Fluoro-2'-methoxy- [1,1'-biphenyl] -2-carboxylic acid (2.5 g) is dissolved in DMA (100 mL), and DMF (10 μL) and SOCl ₂ (0.963 mL) are added. The mixture was stirred at room temperature for 2 hours. 4-Aminobenzoic acid (1.420 g) was added and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration, air-dried at 60 ° C., and 4-{4-fluoro-2'-methoxy- [1,1'-biphenyl] -2-amide} benzoic acid (3.8). g) was obtained.

Reference example 98
4-Fluoro-2'-methoxy- [1,1'-biphenyl] -2-carboxylic acid (2.5 g) is dissolved in DMA (20 mL), SOCl ₂ (0.963 mL) is added, and the mixture is stirred at room temperature for 2 hours. did. 4-Amino-3-fluorobenzoic acid (1.606 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated. The resulting residue was crystallized from DCM. The solid was dispersed and washed with AcOEt / Hexane = 1/3, collected by filtration, air-dried, and 3-fluoro-4- {4-fluoro-2'-methoxy- [1,1'-biphenyl] -2-amide}. Benzoic acid (3.32 g) was obtained.

Reference example 99
4-Fluoro-2'-methoxy- [1,1'-biphenyl] -2-carboxylic acid (2.5 g) was dissolved in DCM / DMA = 2/1 (120 mL) and (COCl) ₂ (10.15 mL). And Pyr (1.642 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, DCM (50 mL) and DMA (30 mL) were added, methyl 6-aminonicotinate (1.576 g) and Pyr (1.642 mL) were sequentially added, and the mixture was stirred at room temperature for 15 hours. Although the disappearance of the raw material was confirmed by LC-MS, about 10% of the diacyl compound was confirmed. The reaction solution was concentrated. The residue was dissolved in MeOH / THF = 1/1 (60 mL), 1N NaOH (30 mL) was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, washed with a small amount of AcOEt, and the aqueous layer was separated. 5N HCl (7 mL) was added to the obtained aqueous layer, and 1N HCl was further added to adjust the pH to 3-4. The precipitated solid was collected by filtration and air-dried at 60 ° C. to 6- {4-fluoro. -2'-Methoxy- [1,1'-biphenyl] -2-amide} pyridine-3-carboxylic acid (2.26 g) was obtained.

Reference example 109
_{Under a nitrogen atmosphere, add (COCl) 2} (1.495 mL) and DMF (51 μL) to a DCM (30 mL) solution of 4,3'-difluoro-1,1'-biphenyl-2-carboxylic acid (2.0 g). It was stirred at room temperature for 1.5 hours. The residue was added dropwise to a solution of methyl 6-aminonicotinate (1.364 g) in Pyr (15 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, the precipitate was collected by filtration, and washed with water. MeOH (20 mL), THF (20 mL) and 5N NaOH aqueous solution (5.12 mL) were added to the obtained solid, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, add 5N hydrochloric acid and water to the reaction solution to neutralize, filter out the precipitate, wash with IPE, and 6- {3', 4-difluoro- [1,1'-biphenyl] -2-amide. } Pyridine-3-carboxylic acid (2.38 g) was obtained.

Reference example 116
7-Methyl-1,2,3,4-tetrahydroisoquinoline-1-one (3 g), methyl 4-iodobenzoate (4.88 g), CuI (0.354 g), DMEDA (0.396 mL) and K ₃ PO ₄ (7.90 g) was mixed in 1,4-dioxane (50 mL) and stirred at 90 ° C. overnight. After filtration through Celite, the filtrate was washed with water and saturated brine. The organic layer was _{dried over anhydrous Na 2} SO ₄ and the solvent was distilled off. The crude crystals were _{washed with Et 2} O and air-dried at 60 ° C. Methyl 4- (7-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-2-yl) benzoate (4.42 g) was obtained.

Reference example 121
A solution of methyl 4- (7-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-2-yl) benzoate (4.42 g) in EtOH (90 mL) was ice-cooled, and a 5N NaOH aqueous solution (14.97) was cooled. mL) and water were added. The mixture was stirred at room temperature for 3 hours. After distilling off the solvent, the pH was adjusted to pH = 1 with 5N HCl. The crystals were collected by filtration and air-dried at 60 ° C. 4- (7-Methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-2-yl) benzoic acid (2.45 g) was obtained.

Reference example 137
4-Amino-3-methoxybenzoic acid (300 mg) was added to a solution of 2-chlorobenzoyl chloride (0.227 mL) in DMA (8 mL), and the mixture was stirred overnight at room temperature. Water was added, and after stirring for 30 minutes, the precipitate was collected by filtration _{, washed with water and Et 2} O, and air-dried at 60 ° C. to obtain 4- (2-chlorobenzamide) -3-methoxybenzoic acid (470 mg). ..

Reference example 138
_{Add (COCl) 2} (13.41 mL) and DMF (0.119 mL) to a DCM (200 mL) suspension of 2- (trifluoromethyl) pyridine-3-carboxylic acid (9.76 g) at 0 ° C. After stirring at 30-40 ° C for 1 hour, the mixture was stirred at 30-40 ° C for 2 hours. The reaction mixture was concentrated, diluted with DCM, and added to a suspension of methyl 6-aminonicotinate (7.77 g) in Pyr (20.65 mL) and DCM (200 mL). After stirring at room temperature for 2 hours, the DCM was distilled off under reduced pressure. Water was added and the mixture was extracted with AcOEt. The organic layer was _{dried over anhydrous Na 2} SO ₄ , filtered, and concentrated. The obtained residue was dissolved in MeOH-THF (4: 1; 200 mL), 5N NaOH aqueous solution (20.43 mL) was added, and the temperature was 60 ° C. Was stirred for 2 hours. The reaction mixture was concentrated, MeOH was distilled off, diluted with water, adjusted to pH (4-5) with HClaq., The precipitated solid was collected by filtration, washed with water, and 6- [2- (trifluoromethyl) pyridine-3. -Amid] A pyridine-3-carboxylic acid (11.21 g) was obtained.

Reference example 139
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] Octanebis (tetrafluoroborate) (Selectfluor; 379 g) in MeCN (950 mL) solution with N-[(5Z) -7-Chloro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-iriden] Butane-1-amine (197g) every 40 minutes 5 It was added in batches and stirred at room temperature for 3 days. Add concentrated HCl (203 mL) and ice water, stir, filter out the precipitate, wash with water, 7-chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4, 5-Tetrahydro-1H-1-benzoazepine-5-one (187 g) was obtained.

Reference example 140
7-Chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-one (240 g) in concentrated sulfuric acid (265 mL) ) Was added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was added to a solution of 50% aqueous NaOH solution (796 g) and ice (3 L), the precipitate was collected by filtration, washed with warm water, and 7-chloro-4,4-difluoro-2,3,4,5. -Tetrahydro-1H-1-benzoazepine-5-one (138 g) was obtained.

Reference example 141
7-Chloro-4,4-difluoro-5- (hydroxymethyl) -1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (286 mg) ), Mg (250 mg) and I ₂ (34.7 mg) were added to MeOH (10 mL) at room temperature, and the mixture was stirred under a nitrogen atmosphere. After refluxing for 4 hours, saturated _{aqueous LVDS 3} solution was added, and the mixture was filtered through Celite and washed with AcOEt. The organic layer was separated and dried over _{anhydrous Na 2} SO _4. After filtration and concentration, the obtained residue is purified by column chromatography (Hexane / AcOEt) to 7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-. 1-Benzoazepine-5-ol (90 mg) was obtained.

Reference example 142
7-Chloro-4,4-difluoro-5- (hydroxymethyl) -1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (250 mg) ), Im (122 mg) was added to a solution of THF (2 mL) at room temperature in a nitrogen atmosphere, and then TBDMSCl (135 mg) was added at 0 ° C. After stirring at the same temperature for 1 hour, water was added to dilute the mixture, and the mixture was extracted with AcOEt. The organic layer was _{dried over anhydrous Na 2} SO ₄ , filtered, and concentrated. The obtained residue was purified by column chromatography (Hexane / AcOEt) and 5-{[(tert-butyldimethylsilyl) oxy] methyl}. -7-Chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (278 mg) was obtained.

Reference example 143
5-{[(tert-butyldimethylsilyl) oxy] methyl} -7-chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1- Benzoazepine-5-ol (278 mg), MeOH (5 mL) and Mg (63.5 mg) were stirred under a nitrogen atmosphere at room temperature. After refluxing for 5 hours, saturated _{aqueous LVDS 3} solution was added, and the mixture was filtered through Celite and washed with AcOEt. The organic layer was separated and dried over _{anhydrous Na 2} SO _4. Filtration, concentration, and the resulting residue were purified by column chromatography (Hexane / AcOEt) and 5-{[(tert-butyldimethylsilyl) oxy] methyl} -7-chloro-4,4-difluoro-2,3. , 4,5-Tetrahydro-1H-1-benzoazepine-5-ol (102 mg) was obtained.

Reference example 144
7-Chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-one (113 g), THF (400 mL), Boc ₂ O (114 mL) and DMAP The mixture of (1.79 g) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of IPA / Hexane. The filtrate was further concentrated under reduced pressure, recrystallized from a mixed solvent of IPA / Hexane, washed with Hexane, and tert-butyl 7-chloro-4,4-difluoro-5-oxo-2,3,4,5-tetrahydro-. 1H-1-benzoazepine-1-carboxylate (117 g) was obtained.

Reference example 145
7-Chloro-4,4-difluoro-5-methyl-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (0.769 g) MeOH Mg (0.465 g) was added to the (20 mL) solution at room temperature under a nitrogen atmosphere, and the mixture was refluxed for 5 hours. A saturated _{aqueous solution of LVDS 3} was added, and the mixture was filtered through Celite and washed with AcOEt. The organic layer was separated and dried over _{anhydrous Na 2} SO _4. The residue obtained after filtration and concentration is purified by column chromatography (Hexane / AcOEt) and 7-chloro-4,4-difluoro-5-methyl-2,3,4,5-tetrahydro-1H-1-benzo. Azepine-5-ol (0.414 g) was obtained.

Reference example 146
KOtBu (0.375 g) was added to a DMSO (12 mL) solution of trimethyl sulfoxide (0.982 g), and the mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere, and then tert-butyl 7-chloro-4,4-difluoro-. 5-Oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (0.74 g) was added at room temperature. After stirring at room temperature for 2 hours, water was added and the mixture was extracted with AcOEt. The combined organic layers were washed with water and brine and dried over anhydrous Na ₂ SO ₄ . After filtration and concentration, DMF / H ₂ O = 4: 1 (12 mL) and AcONa (1.464 g) were added to the obtained residue at room temperature, and the mixture was stirred at 80 ° C. for 24 hours. The reaction was extracted with AcOEt, washed with water and brine, and dried over _{anhydrous Na 2} SO _4. After filtration and concentration, the obtained residue is recrystallized from DCM-Hexane and tert-butyl 7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5- Tetrahydro-1H-1-benzoazepine-1-carboxylate (0.491 g) was obtained.

Reference example 147
7-Chloro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-one (20.0 g), n-butylamine (8.48 mL), cyclohexane (150) The mixture of mL) and TFA (0.661 mL) was stirred under heating under reflux for 12 hours with water distilling off in a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure, the residue was washed with a mixed solvent of AcOEt / Hexane, and N-[(5Z) -7-chloro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H. -1-Benzeneazepine-5-iriden] butane-1-amine (21.4 g) was obtained.

Reference example 150
tert-Butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5-({[(2R) -2- (4-methylbenzenesulfonamide) -3-phenylpropanoyl] oxy} methyl ) -2,3,4,5-Tetrahydro-1H-1-benzoazepine-1-carboxylate (0.20 g), EtOH (1.0 mL) and 5N NaOH aqueous solution (0.18 mL) are stirred at room temperature for 3 hours. did. Water was added to the reaction solution, and the mixture was extracted with AcOEt. The organic layer was _{dried over Na 2} SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and tert-butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5. -Tetrahydro-1H-1-benzoazepine-1-carboxylate (99 mg) was obtained.

Reference example 151
[(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl (2S) -2- (naphthalene-) A mixture of 1-sulfonamide) -3-phenylpropanoate (1.10 g), potassium trimethylsilanolate (1.05 g), and THF (9.0 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and dispersed and washed with a mixed solvent of DCM / Hexane (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3. , 4,5-Tetrahydro-1H-1-benzoazepine-5-ol (350 mg) was obtained.

Reference example 152
tert-Butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate ( 500 mg) was dissolved in EtOH (10 mL), 12N HCl (0.115 mL) was added, and the mixture was refluxed. Since it was unreacted after 1 hour, 12N HCl (0.5 eq) was added and refluxed for 1 hour. It was concentrated, dissolved in AcOEt, and concentrated again to obtain crystals. Vacuum dried (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-olhydrochloride (412.51 mg) Got

Reference example 153
tert-Butyl 7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (200 mg), TEA (0.230 mL), THF (2 mL), 4-bromobenzoyl chloride (145 mg) and DMAP (6.72 mg) were added at room temperature and stirred for 30 minutes. The residue obtained by concentrating the reaction solution was purified by column chromatography (Hexane / AcOEt) to purify tert-butyl 5-[(4-bromobenzoyloxy) methyl] -7-chloro-4,4-difluoro-5. -Hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (317 mg) was obtained.

Reference example 154
tert-Butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate ( 21.86 g) was dissolved in THF (200 mL), TEA (25.1 mL) and 4-bromobenzoyl chloride (13.19 g) were added, and the mixture was stirred at room temperature for 3 hours. Water was added and diluted with AcOEt. The cells were washed with 1N HCl, 1N NaOH and saturated brine, and dried over anhydrous Na ₂ SO ₄ . After filtration and concentration under reduced pressure, AcOEt (20 mL) and DCM (30 mL) were added to the obtained residue to form crystals. After dispersion washing with a mixed solvent of AcOEt: DCM: Hexane = 2: 3: 2, it is collected by filtration, dried at 60 ° C, and tert-butyl (5R) -5-[(4-bromobenzoyloxy) methyl]-. 7-Chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (24.7 g; Lot 1) was obtained. The filtrate was concentrated under reduced pressure and purified by column chromatography (AcOEt / Hexane). After concentration, it is crystallized from DCM / AcOEt / Hexane, collected by filtration, dried at 60 ° C, and tert-butyl (5R) -5-[(4-bromobenzoyloxy) methyl] -7-chloro-4,4-difluoro. -5-Hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (6.1 g; Lot 2) was obtained. After further concentrating the filtrate, it was crystallized from DCM / Hexane and collected by filtration. Dry at 60 ° C, tert-butyl (5R) -5-[(4-bromobenzoyloxy) methyl] -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro- 1H-1-benzoazepine-1-carboxylate (2.2 g; Lot 3) was obtained. The structures of Lot 1, Lot 2 and Lot 3 ^{were confirmed by 1} H-NMR. The optical purity was 100% ee, 99.9% ee and 100% ee, respectively. Together these are tert-butyl (5R) -5-[(4-bromobenzoyloxy) methyl] -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H- 1-Benzoazepine-1-carboxylate (33.0 g) was obtained (possibly present in the form of a 1: 1 co-crystal with DCM or a solvate with DCM).

Reference example 155
tert-Butyl (5R) -5-[(4-Bromobenzoyloxy) methyl] -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine -1-carboxylate (33.0 g) was dissolved in DCM (100 mL), TFA (46.5 mL) was added, and the mixture was stirred at room temperature. The mixture was stirred for 3 hours and neutralized with saturated aqueous sodium hydrogen carbonate under ice-cooling. It was extracted with AcOEt, washed with saturated brine, and dried over anhydrous Na ₂ SO ₄ . The solid was filtered, concentrated under reduced pressure, and the resulting solid was collected by filtration. Dry at 60 ° C and [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromo Benzoart (23.35 g) was obtained.

Reference example 156
tert-Butyl 7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (50 mg) It was dissolved in THF (2 mL), TEA (0.057 mL) and 4-bromobenzoyl chloride (30.2 mg) were added, and the mixture was stirred at room temperature. Quenched with water and diluted with AcOEt. The cells were washed with 1N HCl, 1N NaOH and saturated brine, and dried over anhydrous Na ₂ SO ₄ . It was filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (AcOEt / Hexane) and dried in vacuum. The resulting tert-butyl 5-[(4-bromobenzoyloxy) methyl] -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine- 1-carboxylate was dissolved in DCM (2 mL), TFA (0.318 mL) was added, and the mixture was stirred at room temperature for 2 hours. It was ice-cooled and neutralized with saturated aqueous sodium hydrogen carbonate. The residue was extracted with AcOEt, _{dried over anhydrous Na 2} SO ₄ , filtered, concentrated under reduced pressure, and the obtained residue was purified by column chromatography (Hexane / AcOEt). After concentration, vacuum dried to (7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl) methyl 4-bromobenzoate ( 38.3 mg) was obtained.

Reference examples 157 and 158
tert-Butyl 7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (1 g), Add TEA (1.149 ml), THF (10 mL), (S) -2- (4-methylphenylsulfonamide) -3-phenylpropanoyl chloride (0.929 g) and DMAP (0.034 g) at room temperature, 20 Stirred for hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was purified by column chromatography (Hexane / AcOEt), recrystallized by DCM / n-Hexane, and tert-butyl (5S) -7-chloro-4,4- Difluoro-5-Hydroxy-5-({[(2S) -2- (4-Methylbenzenesulfonamide) -3-phenylpropanoyl] Oxy} Methyl) -2,3,4,5-Tetrahydro-1H-1 -Benzeneazepine-1-carboxylate (430 mg; Reference Example 157) and tert-butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5-({[(2S) -2-( 4-Methylbenzenesulfonamide) -3-phenylpropanoyl] Oxy} Methyl) -2,3,4,5-Tetrahydro-1H-1-benzoazepine-1-carboxylate (740 mg; Reference Example 158) It was.

Reference example 159
7-Chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-one (1.50 g) anhydrous THF (20 mL) ) Lithium aluminum hydride (0.163 g) was added to the solution at 0 ° C., and the mixture was stirred overnight. Water (0.16 mL), 15% aqueous NaOH solution (0.16 mL) and water (0.48 mL) were added to the reaction mixture, and the mixture was stirred, filtered through Celite, and washed with AcOEt. Water was added to the filtrate and extracted with AcOEt. The combined organic layer was washed with water and saturated brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt), 7- chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro ^(5-2 H) -1H-1-benzoazepine-5-ol (1.04 g) was obtained.

Reference example 160
7-chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro (5- ² H) -1H-1- benzazepine-5-ol (1.04 g) Magnesium (0.390 g) was added to a solution of anhydrous MeOH (20 mL), and the mixture was stirred at room temperature for 3 hours. After diluting with AcOEt (20 mL), 5N HCl (10.16 mL) was added at 0 ° C., water was added, and the mixture was stirred. The mixture was stirred at room temperature and extracted with AcOEt. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure to 7-chloro-4,4-difluoro-2,3,4,5-tetrahydro ^(5-2 H) -1H-1-benzoazepine-5-ol (473 mg) was obtained.

Reference example 161
tert-Butyl 7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (133 g), THF (1200 mL), TEA (153 mL), DMAP (4.47 g) and (R) -2- (4-methylphenylsulfonamide) -3-phenylpropanoyl chloride (148 g) were mixed under ice-cooling and mixed. The mixture was stirred at room temperature for 3 hours. The precipitate was separated by filtration and concentrated under reduced pressure. The residue was recrystallized (Ether / Hexane). The filtrate is purified by silica gel column chromatography (Hexane / AcOEt) and recrystallization (Ether / Hexane), and combined, tert-butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5-({ [(2R) -2- (4-Methylbenzenesulfonamide) -3-phenylpropanoyl] Oxy} Methyl) -2,3,4,5-Tetrahydro-1H-1-benzoazepine-1-carboxylate (92.4) g) was obtained.

Reference example 162
tert-Butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5-({[(2R) -2- (4-methylbenzenesulfonamide) -3-phenylpropanoyl] oxy} methyl ) -2,3,4,5-Tetrahydro-1H-1-benzoazepine-1-carboxylate as a filtrate as tert-butyl (5S) -7-chloro-4,4-difluoro-5-hydroxy-5- ({[(2R) -2- (4-Methylbenzenesulfonamide) -3-phenylpropanoyl] oxy} methyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (128 g) was obtained.

Reference example 163
5-Fluoro-2- (pyridin-2-yl) benzoic acid (688 mg) was dissolved in DMA (20 mL), SOCl ₂ (0.301 mL) was added, and the mixture was stirred at room temperature for 2 hours. Methyl 4-amino-3-fluorobenzoart hydrochloride (651 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. _{Aqueous acrylamide 3} solution was added to the reaction mixture, and the mixture was extracted with AcOEt. The organic layer was washed with _{aqueous LVDS 3} solution and brine, dried over anhydrous Na ₂ SO ₄ , and concentrated. The precipitated solid was dispersed and washed with AcOEt / Hexane = 1/2, the solid was collected by filtration, air-dried, and methyl 3-fluoro-4- [5-fluoro-2- (pyridin-2-yl) benzamide] benzoate ( 970 mg) was obtained.

Reference example 164
Methyl 3-fluoro-4- [5-fluoro-2- (pyridin-2-yl) benzamide] benzoate (970 mg) was dissolved in MeOH / THF = 3/1, and 5N NaOH aqueous solution (2.63 mL) was added. The mixture was stirred at 60 ° C. for 6 hours. The reaction mixture was concentrated, 5N HCl (3.68 mL) was added to make it acidic, and the mixture was concentrated and dried under reduced pressure. The residue was dissolved in ethanol, the inorganic material was filtered off, and the filtrate was concentrated. THF was added to the residue, concentrated again, and dried under reduced pressure at 50 ° C. 3-Fluoro-4- [5-fluoro-2- (pyridin-2-yl) benzamide] benzoate salt salt (1.02 g) was obtained.

Reference example 165
tert-Butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5-({[(2R) -2- (4-methylbenzenesulfonamide) -3-phenylpropanoyl] oxy} methyl ) -2,3,4,5-Tetrahydro-1H-1-benzoazepine-1-carboxylate (2 g) was added to a DCM (4 mL) solution of TFA (2.317 mL) at room temperature and stirred for 1 hour. .. After neutralization with a saturated _{aqueous solution of LVDS 3} , it was diluted with AcOEt and the precipitated solid was collected by filtration. By washing with water and AcOEt, [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl (2R) -2- (4-Methylbenzenesulfonamide) -3-phenylpropanoate (1.35 g) was obtained.

Reference example 166
Trimethyl sulfoxide iodide (228 mg), DMSO (4 mL) and KOtBu (87 mg) were stirred at room temperature for 30 minutes under a nitrogen atmosphere. 7-Chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-one (200 mg) was added thereto at room temperature. , Stirred for 2 hours. It was diluted with water and extracted with AcOEt. The organic layer was washed with water and saturated brine _{, dried, filtered and concentrated with anhydrous Na 2} SO ₄ , and the obtained residue was purified by column chromatography (Hexane / AcOEt). 7-Chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -1,2,3,4-tetrahydrospiro [1-benzoazepine-5,2'-oxylan] (200 mg; AcOEt ca. 0.2 eq. Including) was obtained.

Reference example 167
Methyltriphenylphosphonium bromide (956 mg) and 7-chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-one KOtBu (300 mg) was added to a solution of (860 mg) anhydrous THF (10 mL) at 0 ° C. under a nitrogen atmosphere. After stirring at room temperature for 2 hours, water was added and the mixture was extracted with AcOEt. The organic layer is _{dried over anhydrous Na 2} SO ₄ , filtered, and the residue obtained by concentration is purified by column chromatography (Hexane / AcOEt) to 7-chloro-4,4-difluoro-1- (4-methylbenzene). Sulfonyl) -5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepine (270 mg) was obtained.

Reference example 168
_{THF / H 2} O of 7-chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepine (270 mg) _{NMO (165 mg) and 4% OsO 4} aq. (447 mg) were added to a solution of / acetone (1/1/2; 8 mL) under a nitrogen atmosphere. After stirring at room temperature for 1 week, saturated _{aqueous Na 2} SO ₃ solution was added, and the mixture was extracted with AcOEt. The organic layer was washed with water and dried over _{anhydrous Na 2} SO _4. The residue obtained by filtration and concentration is purified by column chromatography (Hexane / AcOEt) to 7-chloro-4,4-difluoro-5- (hydroxymethyl) -1- (4-methylbenzenesulfonyl) -2, 3,4,5-Tetrahydro-1H-1-benzoazepine-5-ol (210 mg) was obtained.

Reference example 169
THF (10 mL) of 7-chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-one (1 g) 1.0 M methylmagnesium bromide (3.37 mL) was added dropwise to the solution at 0 ° C. under a nitrogen atmosphere. After stirring at 0 ° C. for 2 hours, a saturated _{aqueous solution of NH 4} Cl was added, and the mixture was extracted with AcOEt. The organic layer was _{dried with anhydrous Na 2} SO ₄ , filtered, and the residue obtained by concentration was recrystallized (DCM / AcOEt / Hexane) to 7-chloro-4,4-difluoro-5-methyl-1- (4). -Methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (769 mg) was obtained.

Reference example 170
KOtBu (30.4 g) was added to a solution of trimethyl sulfoxide (80 g) in DMSO (500 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. To this, tert-butyl 7-chloro-4,4-difluoro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (60 g) was added at room temperature, and the mixture was added. After stirring for 2.5 hours, ice water (2 L) was poured. The mixture was filtered, washed with water, AcOEt and water were added to the obtained residue, and the mixture was extracted with AcOEt. The organic layer was washed with saturated brine and dried over anhydrous Na ₂ SO ₄ . After filtration and concentration, DMF / H ₂ O = 2: 1 (600 mL) and AcONa (119 g) were added to the obtained residue at room temperature, and the mixture was stirred at 80 ° C. for 24 hours. The reaction mixture was poured into ice water (2 L), the mixture was filtered, and the residue obtained by washing with water was added with AcOEt and water, and extracted with AcOEt. The organic layer was washed with saturated brine and dried over anhydrous Na ₂ SO ₄ . After filtration and concentration, DCM (2 mL / g) and Hexane (2 mL / g) were added to the obtained residue and crushed. The insoluble material was filtered off and tert-butyl 7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1- Carboxylate (29.4 g) was obtained, the filtrate was concentrated, and the residue was purified by column chromatography (Hexane / AcOEt). With tert-butyl 7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (4.82 g) t-Butyl 7-chloro-4,4-difluoro-1,2,3,4-tetrahydrospiro [1-benzoazepine-5,2'-oxetane] -1-carboxylate (18.38 g) was obtained.

Reference examples 171 and 172
tert-Butyl 7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (2.0 g), A mixture of THF (20 mL), TEA (2.3 mL), DMAP (0.067 g), and N- (1-naphthalenesulfonyl) -L-phenylalanyl chloride (2.47 g) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (Hexane / AcOEt). As a highly polar component, tert-butyl (5S) -7-chloro-4,4-difluoro-5-hydroxy- 5-({[(2S) -2- (naphthalen-1-sulfonamide) -3-phenylpropanoyl] oxy} methyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1- Carboxylate (1.56 g; Reference Example 171) was obtained. As a low-polarity component, tert-butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5-({[(2S) -2- (naphthalene-1-sulfonamide) -3-phenylpropanoyl) ] Oxy} methyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (1.51 g; Reference Example 172) was obtained.

Reference example 174
Under a nitrogen atmosphere, tert-butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5-({[(2S) -2- (naphthalen-1-sulfonamide) -3-phenylpropanoyl) ] Oxy} methyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (1.3 g) was added to TFA (2.143 mL) in a DCM (8.0 mL) solution. The resulting solution was stirred at room temperature for 1.5 hours. A saturated _{aqueous solution of LVDS 3} was added thereto, and the mixture was extracted with AcOEt. The collected organic layer is _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H. -1-Benzoazepine-5-yl] methyl (2S) -2- (naphthalene-1-sulfonamide) -3-phenylpropanoate (1.18 g, containing about 0.9 equivalents of AcOEt) was obtained.

Reference example 175
[(5S) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl (2S) -2- (naphthalene-) A mixture of 1-sulfonamide) -3-phenylpropanoate (827 mg), potassium trimethylsilanolate (784 mg) and THF (7.0 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and dispersed and washed with a mixed solvent of DCM / Hexane to (5S) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3. , 4,5-Tetrahydro-1H-1-benzoazepine-5-ol (257 mg) was obtained.

Reference example 176
tert-Butyl (5S) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate ( A mixture of 0.97 g), EtOH (10 mL) and concentrated HCl (0.667 mL) was stirred at 70 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. AcOEt was added to the residue and concentrated again under reduced pressure. (5S) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5- All hydrochloride (820 mg) was obtained.

Reference example 177
tert-Butyl 7-chloro-4,4-difluoro-1,2,3,4-tetrahydrospiro [1-benzoazepine-5,2'-oxetane] -1-carboxylate (200 mg) and tetrabutylammonium sulfate After adding salt (377 mg) and toluene / H ₂ O = 1: 1 (1 mL) at room temperature, the mixture was stirred at 100 ° C. for 1.5 days. The reaction mixture was purified by basic silica gel column chromatography (Hexane / AcOEt) and 7-chloro-4,4-difluoro-5- (2-hydroxyethyl) -2,3,4,5-tetrahydro-1H-1. -Benzoazepine-5-ol (122 mg) was obtained.

Reference example 178
7-Chloro-4,4-difluoro-5- (2-hydroxyethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (1.728 g) and Im (1.271 g) TBDMSCl (1.125 g) was added to the DCM (30 mL) solution at 0 ° C. After stirring at room temperature for 10 minutes, the mixture was diluted with water and extracted with AcOEt. The combined organic layers were _{dried over anhydrous Na 2} SO ₄ , filtered and concentrated, and the obtained residue was purified by column chromatography (Hexane / AcOEt) and 5-{2-[(tert-butyldimethylsilyl) oxy. ] Ethyl} -7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (2.016 g) was obtained.

Reference example 179
DMF of 7-chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -1,2,3,4-tetrahydrospiro [1-benzoazepine-5,2'-oxylan] (8 g): _{NaN 3} (6.50 g) was added to H ₂ O = 4: 1 (50 mL) at room temperature under a nitrogen atmosphere. After stirring at 70 ° C. for 4 hours, water was added, and the precipitated crystals were collected by filtration and washed with water. By washing this with IPA, 5- (azidomethyl) -7-chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzo Azepine-5-ol (quantitative yield) was obtained.

Reference example 180
5- (Azidomethyl) -7-Chloro-4,4-difluoro-1- (4-Methylbenzenesulfonyl) -2,3,4,5-Tetrahydro-1H-1-Benzodiazepine-5-ol (9.8 g) Zn powder (5.79 g) was added to EtOH (80 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was filtered, the filtrate was concentrated, and the obtained crude product was vacuum dried. _{Boc 2} O (6.10 mL) was added to this THF (80 mL) solution, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction mixture was concentrated and the obtained residue was purified by column chromatography (Hexane / AcOEt) to purify it with tert-butyl N-{[7-chloro-4,4-difluoro-5-hydroxy-1- (4-methylbenzene). Sulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl} carbamate (6.92 g) was obtained.

Reference example 181
tert-butyl N-{[7-Chloro-4,4-difluoro-5-hydroxy-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5- To a solution of yl] methyl} carbamate (6.92 g) in MeOH (80 mL) was added iodine (3.40 mg) and magnesium (3.7 g) under a nitrogen atmosphere, and the mixture was refluxed for 3 hours. 1N HCl (294 mL) was added to the reaction mixture, and the mixture was extracted with AcOEt. The combined organic layers were _{dried, filtered and concentrated with anhydrous Na 2} SO ₄ , and the obtained residue was purified by column chromatography (Hexane / AcOEt) and tert-butyl N-[(7-chloro-4,4-,4-). Difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl) methyl] carbamate (4.05 g) was obtained.

Reference example 182
_{SOCl 2} (0.316 mL) was added to a solution of 4- (2-chloro-5-fluorobenzamide) -3-methoxybenzoic acid (1.338 g) in DMA (15 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 2 hours. There tert-butyl N-[(7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl) methyl] carbamate (1 g) ) Was added at room temperature and stirred for 1 day. Saturated LVDS ₃ aqueous solution is added, the precipitated solid is filtered, and the obtained crude crystals are purified by column chromatography (Hexane / AcOEt), and tert-butyl N- ({7-chloro-1- [4-({7-chloro-1- [4- ( 2-Chloro-5-fluorobenzamide) -3-methoxybenzoyl] -4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl} methyl) carbamate (1.73 g; including AcOEt ca. 0.7 eq.) Was obtained.

Reference example 183
Under a nitrogen atmosphere, tert-butyl (5S) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1 -55% NaH (154 mg) was added under ice-cooling to a solution of carboxylate (515 mg) in anhydrous THF (5.0 mL). At the same temperature, TsCl (283 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. A 1N NaOH aqueous solution was added to the reaction mixture, and the mixture was extracted with AcOEt. The organic layer was _{dried over anhydrous Na 2} SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and tert-butyl (5S) -7-chloro-4,4-difluoro-1,2,3,4-tetrahydrospiro [1-benzoazepine-5, 2'-Oxylan] -1-carboxylate (371 mg) was obtained.

Reference example 185
tert-Butyl (5S) -7-chloro-4,4-difluoro-1,2,3,4-tetrahydrospiro [1-benzoazepine-5,2'-oxylane] -1-carboxylate (371 mg), A mixture of EtOH (5.5 mL) and NaBH ₄ (81 mg) was stirred at 50 ° C. for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with AcOEt. The organic layer was _{dried over anhydrous Na 2} SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and tert-butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5-methyl-2,3,4,5-tetrahydro- 1H-1-benzoazepine-1-carboxylate (334 mg) was obtained.

Reference example 187
tert-Butyl (5R) -7-chloro-4,4-difluoro-5-hydroxy-5-methyl-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carboxylate (334 mg) , DCM (4.0 mL) and TFA (0.740 mL) were stirred for 1 hour. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with AcOEt. The organic layer was _{dried over anhydrous Na 2} SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and (5R) -7-chloro-4,4-difluoro-5-methyl-2,3,4,5-tetrahydro-1H-1-benzoazepine- 5-ol (183 mg) was obtained.

Reference example 189
2-Chloro-N- {5- [7-Chloro-4,4-Difluoro-5-Hydroxy-5- (Hydroxymethyl) -2,3,4,5-Tetrahydro-1H-1-Benzamide-1- TMPDA (0.736 mL) and TsCl (337 mg) were added to a solution of carbonyl] pyridine-2-yl} -5-fluorobenzamide (820 mg) in DCM (5 mL) at 0 ° C. After stirring at 0 ° C. for 6 hours, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with AcOEt. Dry, filter and concentrate with anhydrous Na ₂ SO ₄ and N- [5-({7-chloro-4,4-difluoro-1,2,3,4-tetrahydrospiro [1-benzoazepine-5,2' -Oxylan] -1-yl} carbonyl) pyridin-2-yl] -2- (trifluoromethyl) benzamide (882 mg) was obtained.

Reference example 190
Pentamethylcyclopentadienyl iridium (III) chloride dimer (0.829 g) and N-((1R, 2R) -2-amino-1,2-diphenylethyl) -2,3,4,5,6-pentafluoro A suspension of benzenesulfonamide (1.48 g) in water (800 mL) was stirred under a nitrogen atmosphere at 50 ° C. for 4 hours. After cooling, HCO ₂ Na (198 g) was added and the mixture was stirred at room temperature for 1 hour. Lower to 0 ° C, add DCM (500 mL), 7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-one (225 g) in sequence, and add 0 ° C. Stirred overnight. By separating and concentrating the DCM layer, (5R) -7-chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine -Oll (228 g) was obtained.

Reference example 191
(5R) -7-chloro-4,4-difluoro-1- (4-methylbenzenesulfonyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (284 g) MeOH Magnesium (17.80 g) was added to the solution (1 L) at room temperature, and the mixture was stirred while heating at 70 ° C. AcOEt (1 L) was added to the reaction solution and the mixture was stirred. The reaction solution was slowly poured into a mixture of 5N HCl (1.465 L), water (500 mL) and AcOEt (1 L) and stirred. When the solid was dissolved, it was extracted with AcOEt, the organic phase was washed with saturated aqueous sodium hydrogen carbonate and dried with anhydrous DDL ₄ . The filtrate was filtered and concentrated. Hexane (1 L) and Et ₂ O (300 mL) are added thereto, and the mixture is stirred, heated and refluxed, dispersed and washed, and then filtered at hot time to collect the powder and dried to obtain (5R) -7-chloro-4. , 4-Difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (119 g) was obtained.

Reference example 192
6- [2- (Trifluoromethyl) benzamide] Pyridine-3-carboxylic acid (2.280 g) in DMA (40 mL) solution, SOCl ₂ (1.0 mL) was added, and the mixture was stirred overnight at room temperature, and then (5R) -7- A solution of chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (1.145 g) in DMA (20 mL) was added, and the mixture was stirred overnight at room temperature. AcOEt and water were added, extracted with AcOEt, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, filtered and concentrated, and the residue was purified by medium pressure column chromatography (Hexane / AcOEt). The obtained crude crystals were recrystallized from AcOEt / Hexane and (5R) -N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5- Tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridin-2-yl} -2- (trifluoromethyl) benzamide (1.2 g) was obtained.

Reference example 195
_{SOCl 2} (0.104 mL) was added dropwise to a DMA (20 mL) solution of 6-{[1,1'-biphenyl] -2-amide} pyridine-3-carboxylic acid (440 mg) under a water bath. After stirring at the same temperature for 40 minutes, DMA (3) of (5R) -7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (323 mg) mL) The solution was added. After stirring for 2 hours, ₃ aqueous LVDS solution was added, and the mixture was extracted with AcOEt / Hexane (10/1). The combined organic layers were washed with water and dried over _{anhydrous DDL 4.} The residue obtained by filtration and concentration was purified by column chromatography (Hexane / AcOEt), crystallized from acetone-hexane, collected by filtration, _{and washed with Et 2} O / hexane (1/20). N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridin-2-yl }-[1,1'-biphenyl] -2-carboxamide (390 mg) was obtained.

Reference example 196
_{SOCl 2} (75 μL) was added to a DMA (3.0 mL) solution of 4- (2-chloro-5-fluorobenzamide) benzoic acid (264 mg), and the mixture was stirred at room temperature for 30 minutes. (5R) -7-Chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (200 mg) was added at 0 ° C. After stirring for 4 hours, a saturated acrylamide ₃ aqueous solution was added, and the mixture was extracted with AcOEt. The organic layer was _{dried over anhydrous Na 2} SO ₄ , filtered, and concentrated. The obtained residue was purified by column chromatography (Hexane / AcOEt) and crystallized from AcOEt / Hexane. 2-Chloro-N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] phenyl } -5-Fluorobenzamide (374.4 mg) was obtained.

Reference example 199
_{SOCl 2} (86.0) in a DMA (4.0 mL) solution of 6- {4-fluoro- [1,1'-biphenyl] -2-amide} pyridine-3-carboxylic acid (360 mg) under ice-cooling under a nitrogen atmosphere. μL) was added, and the mixture was stirred at the same temperature for 2 hours. At the same temperature, (5R) -7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (250 mg) was added, and the mixture was stirred at room temperature for 3 days. .. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with AcOEt. The organic layer was washed with 1N aqueous NaOH solution and saturated brine, and dried over Na ₂ SO ₄ . Na ₂ SO ₄ was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (Hexane / AcOEt) and N- {5-[(5R) -7-chloro-4,4-difluoro. -5-Hydroxy-2,3,4,5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridine-2-yl} -4-fluoro- [1,1'-biphenyl] -2-carboxamide ( 429 mg) was obtained.

Reference example 201
4- {4-Fluoro- [1,1'-biphenyl] -2-amide} Benzoic acid (746 mg) is dissolved in DMA (10 mL), SOCl ₂ (0.187 mL) is added, and the mixture is added at room temperature for 2 hours. Stirred. (5R) -7-Chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (400 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. .. A 1N NaOH aqueous solution was added to the reaction mixture, and the mixture was extracted with AcOEt. The organic layer was washed with 1N aqueous NaOH solution and brine, dried over anhydrous Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (Hexane / AcOEt) and N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H- 1-Benzoazepine-1-carbonyl] phenyl} -4-fluoro- [1,1'-biphenyl] -2-carboxamide (940 mg) was obtained.

[Example]
Example 1
_{SOCl 2} (30.0 μL) under ice-cooling was added to a DMA (1.0 mL) solution of 6- (2-chlorobenzamide) pyridine-3-carboxylic acid (113 mg) under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 2 hours. .. Add 7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (90.0 mg) at room temperature and 3 at room temperature. Stirred for days. _{Saturated LVDS 3} aqueous solution and water are added to the reaction solution, the precipitate is collected by filtration, purified by basic silica gel column chromatography (Hexane / AcOEt), and 2-chloro-N- {5- [7-chloro- 4,4-Difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridin-2-yl} benzamide (50.0 mg) Obtained.

Example 2
_{SOCl 2} (38 μL) was added to a DMA (2 mL) solution of 6- [2- (trifluoromethyl) benzamide] pyridine-3-carboxylic acid (164 mg), and the mixture was stirred at 0 ° C. for 2 hours under a nitrogen atmosphere. 5-{[(tert-butyldimethylsilyl) oxy] methyl} -7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (100 mg) Was added at 0 ° C. After stirring at room temperature for 3 days, a saturated acrylamide ₃ aqueous solution was added, and the precipitated solid was collected by filtration and washed with water. The solid was dissolved in THF (2 mL), 1M TBAF THF solution (0.529 mL) was added and stirred under a nitrogen atmosphere for 2 hours. Water was added and the mixture was extracted with AcOEt. The organic layer was _{dried, filtered and concentrated with anhydrous Na 2} SO ₄ , and the obtained residue was purified by column chromatography (Hexane / AcOEt) and recrystallized from EtOH to obtain N- {5- [7-chloro. -4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridine-2-yl} -2- (tri) Fluoromethyl) benzamide (86 mg) was obtained.

Example 3
_{SOCl 2} (0.161 mL) was added to DMA (7 mL) of 6- (2-chloro-5-fluorobenzamide) pyridine-3-carboxylic acid (654 mg), and the mixture was stirred at 0 ° C. for 2 hours under a nitrogen atmosphere. 7-Chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (450 mg) was added at 0 ° C and at room temperature 18 Stirred for hours. A saturated _{aqueous solution of LVDS 3} was added, and the precipitated solid was washed with water. This was purified by column chromatography (Hexane / AcOEt) and 2-chloro-N- {5- [7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3, 4,5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridin-2-yl} -5-fluorobenzamide (740 mg) was obtained.

Example 8
_{Under a nitrogen atmosphere, SOCl 2} (152 μL) under ice-cooling was added to a DMA (7.0 mL) solution of 6- [2- (trifluoromethyl) benzamide] pyridine-3-carboxylic acid (651 mg), and the temperature was the same for 2 hours. Stirred. 7-Chloro-4,4-difluoro-5-methyl-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (400 mg) was added at the same temperature, and the mixture was stirred at room temperature for 2.5 days. .. _{Saturated LVDS 3} aqueous solution and water are added to the reaction solution, the precipitate is collected by filtration, washed with water, purified by basic silica gel column chromatography (Hexane / AcOEt) and recrystallization (Hexane / AcOEt), and N- [5-(7-Chloro-4,4-difluoro-5-hydroxy-5-methyl-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl) pyridine-2-yl]- 2- (Trifluoromethyl) benzamide (836 mg) was obtained.

Example 13
_{SOCl 2} (0.128 mL) under ice-cooling was added to a DMA (6 mL) solution of 6- (2-trifluorobenzamide) nicotinic acid (549 mg) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. Add (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (500 mg) at room temperature and add. Stirred for 3 days. _{A saturated aqueous solution of LVDS 3} and water were added to the reaction solution, and the precipitate was collected by filtration. The obtained solid was mixed with ethanol (10 mL) and 5N aqueous NaOH solution (0.885 mL) and stirred at room temperature for 30 minutes. Ice water and 5N HCl were added to the reaction mixture to neutralize the reaction mixture, and the precipitate was collected by filtration and washed with water. The solid was purified by basic silica gel column chromatography (Hexane / AcOEt) and N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2, 3,4,5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridine-2-yl} -2- (trifluoromethyl) benzamide (400 mg) was obtained.

Example 14
_{Under a nitrogen atmosphere, add SOCl 2} (39 μL) under ice-cooling to a DMA (2.0 mL) solution of 6- (2-chloro-5-fluorobenzamide) pyridine-3-carboxylic acid (160 mg), and add 2 at the same temperature. Stirred for hours. At the same temperature (5S) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-benzo [b] azepine-5-ol (110 mg) In addition, the mixture was stirred at room temperature for 3 hours. _{A saturated aqueous solution of LVDS 3} and water are added to the reaction solution, the precipitate is collected by filtration, purified by basic silica gel column chromatography (Hexane / AcOEt / MeOH), and 2-chloro-N- {5-[(5S)-. 7-Chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridine-2-yl} -5 -Fluorobenzamide (156 mg) was obtained.

Example 15
_{SOCl 2} (50 μL) was stirred in a DMA (2.5 mL) solution of 6- (2-chloro-5-fluorobenzamide) pyridine-3-carboxylic acid (203 mg) at 0 ° C. for 2 hours under a nitrogen atmosphere. Add (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (140 mg) to 0 ° C. And stirred at room temperature for 3 hours. Saturated LVDS ₃ aqueous solution is added, precipitated crystals are collected by filtration, washed with water, purified by basic silica gel column chromatography (Hexane / AcOEt / MeOH) and recrystallized (Hexane / AcOEt), and 2-chloro-N- {5- [(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridine-2 -Il} -5-fluorobenzamide (202 mg) was obtained.

Example 16
_{Under a nitrogen atmosphere, SOCl 2} (136 μL) under ice-cooling was added to a DMA (5.0 mL) solution of 6- [2- (trifluoromethyl) benzamide] pyridine-3-carboxylic acid (581 mg), and 2 at the same temperature. Stirred for hours. Add 7-chloro-4,4-difluoro-5- (hydroxyethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (400 mg) at room temperature and 3 at room temperature. Stirred for hours. _{Saturated LVDS 3} aqueous solution and water are added to the reaction solution, and the precipitate is collected by filtration, purified by basic silica gel column chromatography (Hexane / AcOEt), and N- {5- [7-chloro-4,4-difluoro. -5-Hydroxy-5- (2-Hydroxyethyl) -2,3,4,5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridine-2-yl} -2- (trifluoromethyl) benzamide (53 mg) was obtained.

Example 17
_{SOCl 2} (65.0 μL) under ice-cooling was added to a DMA (1.5 mL) solution of 6- (2-chlorobenzamide) pyridine-3-carboxylic acid (248 mg) under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 2 hours. .. At the same temperature [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromobenzoate ( 400 mg) was added, and the mixture was stirred at room temperature for 1 day. _{A saturated aqueous solution of LVDS 3} and water were added to the reaction solution, and the precipitate was collected by filtration. Ethanol (2.0 mL) and 5N NaOH aqueous solution (0.448 mL) were added to the obtained solid, and the mixture was stirred at room temperature for 20 minutes. Ice water and 5N HCl were added to the reaction mixture to neutralize the reaction mixture, and the precipitate was collected by filtration and washed with water. The solid was purified by silica gel column chromatography (Hexane / AcOEt) and recrystallized (Hexane / AcOEt) and 2-chloro-N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy. -5- (Hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridine-2-yl} benzamide (200 mg) was obtained.

Example 19
6- (2,3-dichlorobenzamide) Pyridine-3-carboxylic acid (153 mg) is dissolved in DMA (1 mL), SOCl ₂ (42 μL) is added under ice-cooling, and the mixture is stirred for 30 minutes, and then (5R)-. 7-Chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (100 mg) was added, and the mixture was stirred overnight at room temperature. A saturated _{aqueous solution of LVDS 3} was added, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by column chromatography (Hexane / AcOEt). Crystallized from Hexane / AcOEt, collected by filtration, 2,3-dichloro-N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2, 3,4,5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridin-2-yl} benzamide (135 mg) was obtained.

Example 21
4- [2- (Trifluoromethyl) benzamide] benzoic acid (152 mg) was dissolved in DMA (2 mL), SOCl ₂ (42 μL) was added, and the mixture was stirred at room temperature for 2.5 hours. Add (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (100 mg) and at room temperature 3 Stirred for hours. Diluted with AcOEt, water was added, extracted with AcOEt / Hexane, the organic layer was washed with 1N HCl, 1N NaOH and saturated brine and dried over anhydrous Na ₂ SO ₄ . Na ₂ SO ₄ was filtered, concentrated under reduced pressure, and the obtained residue was purified by column chromatography (AcOEt / Hexane then AcOEt / MeOH). After concentration, crystals were formed, so they were dispersed and washed with AcOEt / Hexane and collected by filtration. Vacuum dried at 60 ° C and N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H- 1-Benzodiazepine-1-carbonyl] phenyl} -2- (trifluoromethyl) benzamide (135.8 mg) was obtained.

Example 23
4- (2-Chloro-5-fluorobenzamide) benzoic acid (145 mg) was dissolved in DMA (2 mL), SOCL ₂ (42 μL) was added, and the mixture was stirred at room temperature for 2.5 hours. Add (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (100 mg) and at room temperature 3 Stirred for hours. Dilute with AcOEt, add water, extract with AcOEt / Hexane, wash the organic layer with 1N HCl, 1N NaOH and saturated brine _{, dry with anhydrous Na 2} SO ₄ , filter and concentrate the filtrate under reduced pressure. .. The residue was purified by column chromatography (AcOEt / Hexane, then AcOEt / MeOH). After concentration, crystals were formed, so they were dispersed and washed with AcOEt / Hexane and collected by filtration. Vacuum dried at 60 ° C, 2-chloro-N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5- Tetrahydro-1H-1-benzoazepine-1-carbonyl] phenyl} -5-fluorobenzamide (124.7 mg) was obtained.

Example 24
4- (2-Chloro-5-fluorobenzamide) -3-fluorobenzoic acid (154 mg) was dissolved in DMA (2 mL), SOCl ₂ (42 μL) was added, and the mixture was stirred at room temperature for 2.5 hours. Add (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (100 mg) and at room temperature 3 Stirred for hours. Diluted with AcOEt, water was added, extracted with AcOEt / Hexane and washed with 1N HCl, 1N NaOH and saturated brine. The organic layer was _{dried over anhydrous Na 2} SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt / Hexane, then AcOEt / MeOH). The crystals formed after concentration were dispersed and washed with AcOEt / Hexane and collected by filtration. Vacuum dried at 60 ° C, 2-chloro-N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5- Tetrahydro-1H-1-benzoazepine-1-carbonyl] -2-fluorophenyl} -5-fluorobenzamide (114.9 mg) was obtained.

Example 25
4- (2,5-dichlorobenzamide) benzoic acid (153 mg) was dissolved in DMA (2 mL), SOCl ₂ (42 μL) was added, and the mixture was stirred at room temperature for 2.5 hours. Add (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (100 mg) and at room temperature 3 Stirred for hours. Dilute with AcOEt, add water, extract with AcOEt / Hexane, wash the organic layer with 1N HCl, 1N NaOH and saturated brine _{, dry with anhydrous Na 2} SO ₄ , filter and concentrate the filtrate under reduced pressure. .. The residue was purified by column chromatography (AcOEt / Hexane, then AcOEt / MeOH). After concentration, the amorphous material produced by vacuum drying was vacuum dried at 60 ° C. 2,5-dichloro-N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1 -Benzodiazepine-1-carbonyl] phenyl} benzamide (95.8 mg) was obtained.

Example 26
4- (2,5-dichlorobenzamide) -3-fluorobenzoic acid (162 mg) was dissolved in DMA (2 mL), SOCl ₂ (42 μL) was added, and the mixture was stirred at room temperature for 2.5 hours. Add (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (100 mg) and at room temperature 3 Stirred for hours. Dilute with AcOEt, add water, extract with AcOEt / Hexane, wash the organic layer with 1N HCl, 1N NaOH and saturated brine _{, dry with anhydrous Na 2} SO ₄ , filter and concentrate the filtrate under reduced pressure. .. The residue was purified by column chromatography (AcOEt / Hexane, then AcOEt / MeOH). After concentration, the amorphous material produced by vacuum drying was vacuum dried at 60 ° C. 2,5-dichloro-N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1 -Benzodiazepine-1-carbonyl] -2-fluorophenyl} benzamide (154 mg) was obtained.

Example 33
6- (2,3-dichlorobenzamide) pyridine-3-carboxylic acid (124 mg) was dissolved in DMA (1 mL), ice-cooled, _{SOCL 2} (34 μL) was added, and the mixture was stirred for 30 minutes. (5S) -7-Chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol hydrochloride (100 mg) was added. The mixture was stirred at room temperature for 2 hours. A saturated _{aqueous solution of LVDS 3} was added, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (Hexane / AcOEt). Crystallized from Hexane / AcOEt, collected by filtration, 2,3-dichloro-N- {5-[(5S) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2, 3,4,5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridin-2-yl} benzamide (120 mg) was obtained.

Example 34
_{Under a nitrogen atmosphere, add SOCL 2} (120 μL) under ice-cooling to a DMA (6.0 mL) solution of 4- (2-chloro-5-fluorobenzamide) -3-methoxybenzoic acid (459 mg), and add 2 at the same temperature. Stirred for hours. 5- (2- (tert-butyldimethylsilyloxy) ethyl) -7-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1H-benzo [b] azepine-5-ol at room temperature (500 mg) was added and the mixture was stirred at room temperature for 1 day. _{In a separate reaction vessel, under a nitrogen atmosphere, add SOCl 2} (120 μL) under ice-cooling to a DMA (6.0 mL) solution of 4- (2-chloro-5-fluorobenzamide) -3-methoxybenzoic acid (459 mg). In addition, the mixture was stirred at the same temperature for 2 hours. This was added to the reaction solution at room temperature and stirred for 1 day. _{A saturated aqueous solution of LVDS 3} and water were added to the reaction solution, and the precipitate was collected by filtration. A 1 M TBAF / THF solution (2.55 mL) was added to the obtained solid THF (4.0 mL) solution, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with AcOEt. The organic layer was washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Hexane / AcOEt / MeOH) and recrystallization (Hexane / AcOEt) and 2-chloro-N- {4- [7-chloro-4,4-difluoro-5-hydroxy-5- (2-Hydroxyethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] -2-methoxyphenyl} -5-fluorobenzamide (205 mg) was obtained.

Example 37
_{SOCl 2} (43.0 μL) under ice-cooling was added to a DMA (2.5 mL) solution of 4- (5-fluoro-2-methylbenzamide) benzoic acid (162 mg) under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 2 hours. .. At the same temperature, add (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (120 mg). , Stirred at room temperature for 1 day. _{A saturated aqueous solution of LVDS 3} and water are added to the reaction solution, the precipitate is collected by filtration, purified by basic silica gel column chromatography (Hexane / AcOEt / MeOH), and N- {4-[(5R) -7-chloro- 4,4-Difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] phenyl} -5-fluoro-2-methylbenzamide ( 159 mg) was obtained.

Example 51
6- (2,4-dichlorobenzamide) pyridine-3-carboxylic acid (165 mg) was dissolved in DMA (2 mL), SOCl ₂ (44 μL) was added, and the mixture was stirred at room temperature. After stirring for 2 hours, (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (100 mg) ) Was added and the mixture was stirred overnight. After diluting with AcOEt, water was added, the mixture was extracted with AcOEt / Hexane, washed with 1N HCl, 1N NaOH and saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt / Hexane, then AcOEt / MeOH). After concentration, the amorphous material produced by vacuum drying is vacuum dried at 60 ° C. to 2,4-dichloro-N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5-( Hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridin-2-yl} benzamide (80.5 mg) was obtained.

Example 52
6- (2,4-dichloro-5-fluorobenzamide) pyridine-3-carboxylic acid (175 mg) was dissolved in DMA (2 mL), SOCl ₂ (44 μL) was added, and the mixture was stirred at room temperature. After 2 hours, (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (100 mg) In addition, it was stirred overnight. After diluting with AcOEt, water was added, extracted with AcOEt / Hexane, the organic layer was washed with 1N HCl, 1N NaOH and saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate concentrated under reduced pressure. .. The residue was purified by column chromatography (AcOEt / Hexane, then AcOEt / MeOH). After concentration, the amorphous material produced by vacuum drying is vacuum dried at 60 ° C. to 2,4-dichloro-N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5-( Hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridin-2-yl} -5-fluorobenzamide (61.8 mg) was obtained.

Example 57
3-Methoxy-4- (2-methylfuran-3-amide) benzoic acid (161 mg) was dissolved in DMA (2 mL), SOCl ₂ (48 μL) was added, and the mixture was stirred at room temperature for 2 hours. (5R) -7-Chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (110 mg) was added and stirred for 3 days. did. Dilute with AcOEt, add water, extract with AcOEt / Hexane, wash the organic layer with 1N HCl, 1N NaOH and saturated brine _{, dry with anhydrous Na 2} SO ₄ , filter and concentrate the filtrate under reduced pressure. .. The residue was purified by column chromatography (AcOEt / Hexane, then AcOEt / MeOH). After concentration, it was vacuum dried. The resulting solid was collected by filtration and vacuum dried at 60 ° C. to N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4. , 5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] -2-methoxyphenyl} -2-methylfuran-3-carboxamide (132.7 mg) was obtained.

Example 58
4- (2-Chloro-4-fluorobenzamide) -3-methoxybenzoic acid (189 mg) was dissolved in DMA (2 mL), SOCl ₂ (48 μL) was added, and the mixture was stirred at room temperature for 2 hours. (5R) -7-Chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (110 mg) was added and stirred for 3 days. did. Dilute with AcOEt, add water, extract with AcOEt / Hexane, wash the organic layer with 1N HCl, 1N NaOH and saturated brine _{, dry with anhydrous Na 2} SO ₄ , filter and concentrate the filtrate under reduced pressure. .. The residue was purified by column chromatography (AcOEt / Hexane, then AcOEt / MeOH). After concentration, the amorphous substance produced by vacuum drying is vacuum dried at 60 ° C. to 2-chloro-N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl). ) -2,3,4,5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] -2-methoxyphenyl} -4-fluorobenzamide (141.3 mg) was obtained.

Example 63
_{Under a nitrogen atmosphere, SOCl 2} (30.0 μL) was added to a solution of 6-{[1,1'-biphenyl] -2-amide} pyridine-3-carboxylic acid (126 mg) and DMA (1.5 mL) at room temperature. , Stirred for 2 hours. (5R) -7-Chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (80 mg) was added at room temperature. Stirred for 7 hours. _{Saturated LVDS 3} aqueous solution and water are added to the reaction solution, the precipitate is collected by filtration, purified by basic silica gel column chromatography (Hexane / AcOEt / MeOH), and N- {5-[(5R) -7-chloro- 4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridine-2-yl}-[1,1' -Biphenyl] -2-Carboxamide (104 mg) was obtained.

Example 65
Under a nitrogen atmosphere, tert-butyl N-({7-chloro-1- [4- (2-chloro-5-fluorobenzamide) -3-methoxybenzoyl] -4,4-difluoro-5-hydroxy-2,3 , 4,5-Tetrahydro-1H-1-benzoazepine-5-yl} methyl) carbamate (1.2 g), EtOH (10 mL) and concentrated HCl (0.449 mL) were mixed at room temperature and refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt / MeOH) and acidic silica gel column chromatography (Hexane / AcOEt / MeOH), and N- {4- [5- (aminomethyl). ) -7-Chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] -2-methoxyphenyl} -2-chloro-5- Fluorobenzamide (715 mg) was obtained.

Example 66
_{Under a nitrogen atmosphere, SOCl 2} (30 μL) was added to a solution of 6- [2- (trifluoromethyl) pyridine-3-amide] pyridine-3-carboxylic acid (123 mg) and DMA (1.5 mL) at room temperature. Stirred for 2 hours. Add (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (80 mg) at room temperature and add. Stirred for 1 day. _{A saturated acrylamide 3} aqueous solution and water are added to the reaction solution, the precipitate is collected by filtration, washed with water, purified by basic silica gel column chromatography (Hexane / AcOEt / MeOH), and N- {5-[(5R)-. 7-Chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridine-2-yl} -2 -(Trifluoromethyl) pyridine-3-carboxamide (83 mg) was obtained.

Example 71
_{SOCl 2} (43.0 μL) was added to a DMA (2.5 mL) solution of 4- (2-chloro-4-fluorobenzamide) -3-methylbenzoic acid (194 mg) under a nitrogen atmosphere at room temperature, and the mixture was stirred for 2 hours. .. Add (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol hydrochloride (120 mg) at room temperature. , Stirred for 1 day. _{Saturated LVDS 3} aqueous solution and water are added to the reaction solution, the precipitate is collected by filtration, purified by basic silica gel column chromatography (Hexane / AcOEt / MeOH), and 2-chloro-N- {4-[(5R). ) -7-Chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] -2-methylphenyl} -4-Fluorobenzamide (174 mg) was obtained.

Example 91
_{SOCl 2} (SOCl 2) in a DMA (6.0 mL) solution of 6- {4'-fluoro- [1,1'-biphenyl] -2-amide} pyridine-3-carboxylic acid (753 mg) under a nitrogen atmosphere. 162 μL) was added, and the mixture was stirred at the same temperature for 2 hours. At room temperature [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromobenzoate ( 500 mg) was added, and the mixture was stirred at room temperature for 1 day. _{A saturated aqueous solution of LVDS 3} and water were added to the reaction solution, and the precipitate was collected by filtration. The obtained solid was mixed with EtOH (10 mL) and 5N NaOH aqueous solution (1.11 mL) and stirred at room temperature for 10 minutes. Ice water and 5N HCl were added to the reaction mixture to neutralize the reaction mixture, and the precipitate was collected by filtration and washed with water. The solid was purified by basic silica gel column chromatography (Hexane / AcOEt / MeOH) and N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl)- 2,3,4,5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridine-2-yl} -4'-fluoro- [1,1'-biphenyl] -2-carboxamide (620 mg) Obtained.

Example 96
6- {4-Fluoro- [1,1'-biphenyl] -2-amide} Pyridine-3-carboxylic acid (542 mg) dissolved in DMA (5 mL), SOCl ₂ (0.133 mL) was added, and 2 at room temperature. Stirred for hours. [(5R) -7-Chloro-4,4-difluoro-5-Hydroxy-2,3,4,5-Tetrahydro-1H-1-benzoazepine-5-yl] Methyl 4-bromobenzoate (480 mg) Was added and stirred at room temperature for 4 days. Water was added and the resulting solid was collected by filtration. The solid was suspended in EtOH (20 mL), 5N NaOH aqueous solution (1.075 mL) was added, and the mixture was stirred. After 1 hour, 1N HCl was added to pH = 8, extraction was performed with AcOEt, and the organic layer was washed with 1N HCl, 1N NaOH and saturated brine. The organic layer was _{dried over anhydrous Na 2} SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Biotage basic silica gel column (NH-Si): AcOEt / Hexane, then AcOEt / MeOH), and (Biotage acidic silica gel column (Kp-Si): AcOEt / Hexane). .. After concentration, the amorphous material produced by vacuum drying is vacuum dried at 60 ° C., and N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2, 3,4,5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridin-2-yl} -4-fluoro- [1,1'-biphenyl] -2-carboxamide (511.5 mg) was obtained.

Example 97
6- (2-Phenylpyridine-3-amide) pyridine-3-carboxylic acid (160 mg) was dissolved in DMA (2 mL), SOCl ₂ (45 μL) was added, and the mixture was stirred at room temperature for 2 hours. Add (5R) -7-chloro-4,4-difluoro-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (110 mg) and stir for 2 days. did. Dilute with AcOEt and add water. Extracted with AcOEt / Hexane, the organic layer was washed with 1N HCl, 1N NaOH and saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt / Hexane, then AcOEt / MeOH). After concentration, vacuum dried the resulting amorphous material at 60 ° C and vacuum dried N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2, 3,4,5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] pyridine-2-yl} -2-phenylpyridine-3-carboxamide (115.9 mg) was obtained.

Example 99
_{SOCl 2} (162 μL) under ice-cooling was added to a DMA (6.0 mL) solution of 4- (2-chlorobenzamide) -3-methoxybenzoic acid (684 mg) under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 2 hours. .. At room temperature [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromobenzoate ( 500 mg) was added, and the mixture was stirred at room temperature for 1 day. _{A saturated aqueous solution of LVDS 3} and water were added to the reaction solution, and the precipitate was collected by filtration. EtOH (10 mL) and 5N NaOH aqueous solution (1.11 mL) were added to the obtained solid, and the mixture was stirred at room temperature for 30 minutes. Ice water and 5N HCl were added to the reaction mixture to neutralize the reaction mixture, and the precipitate was collected by filtration and washed with water. The solid was dissolved in AcOEt and washed with 1N aqueous NaOH solution and saturated brine. The organic layer was _{dried over anhydrous Na 2} SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and 2-chloro-N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl)- 2,3,4,5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] -2-methoxyphenyl} benzamide (620 mg) was obtained.

Example 100
_{SOCl 2} (43 μL) was added to a solution of 4- (2-chloro-5-fluorobenzamide) -3-methoxybenzoic acid (189 mg) in DMA (4 mL) at 0 ° C., and the mixture was stirred for 2 hours. 7-chloro-4,4-difluoro-2,3,4,5-tetrahydro ^{(5- 2 H) -1H-1-} DMA (2 mL) of benzazepine-5-ol (114 mg) solution was added Stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with AcOEt. The organic layer was washed with water and saturated brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by medium pressure column chromatography (Hexane / AcOEt). Recrystallization from Hexane, 2-chloro -N- {4- [7- Chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro (5- ² H) -1H-1- Benzodiazepine-1-carbonyl] -2-methoxyphenyl} -5-fluorobenzamide (155 mg) was obtained.

Example 101
_{SOCl 2} (48 μL) was added to a solution of 4- (2-chloro-5-fluorobenzamide) -3-methoxybenzoic acid (224 mg) in DMA (4 mL) at 0 ° C., and the mixture was stirred for 2 hours. Room 7-chloro-4,4-difluoro-2,3,4,5-tetrahydro (5- ² H) -1H-1- benzazepine-5-ol was added a DMA (2 mL) solution of (129 mg) Stirred overnight. Water was added to the reaction mixture, extracted with AcOEt, washed with water and saturated brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. Purified by medium pressure column chromatography (Hexane / AcOEt). Recrystallization from MeCN, N- {4- [7- Chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro (5- ² H) -1H-1- benzazepine -1 -Carbonyl] -2-methoxyphenyl} -2- (trifluoromethyl) benzamide (183 mg) was obtained.

Example 102
_{Under a nitrogen atmosphere, add SOCL 2} (23 μL) under ice-cooling to a DMA (1.0 mL) solution of 4- (5-fluoro-2-methylbenzamide) -3-fluorobenzoic acid (92 mg), and add 2 at the same temperature. Stirred for hours. Add (5R) -7-chloro-4,4-difluoro-5-methyl-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (60 mg) at room temperature at room temperature. Stirred for 1 day. _{A saturated aqueous solution of LVDS 3} and water were added to the reaction solution, and the precipitate was collected by filtration. The solid was dissolved in AcOEt and washed with 1N aqueous NaOH solution and saturated brine. The organic layer was _{dried over anhydrous Na 2} SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5-methyl-2,3,4,5 -Tetrahydro-1H-1-benzoazepine-1-carbonyl] -2-fluorophenyl} -5-fluoro-2-methylbenzamide (100 mg) was obtained.

Example 125
N- [5-({7-Chloro-4,4-difluoro-1,2,3,4-tetrahydrospiro [1-benzoazepine-5,2'-oxylan] -1-yl} carbonyl) pyridine-2 -Ethanolamine (0.112 mL) was added to a solution of -2- (trifluoromethyl) benzamide (100 mg) in MeOH (1 mL), and the mixture was stirred at 70 ° C. for 4 hours. A saturated _{aqueous solution of LVDS 3} was added, and the mixture was extracted with AcOEt. It was dried over anhydrous Na ₂ SO _4. Na ₂ SO ₄ was filtered, the filtrate was concentrated under reduced pressure, and vacuum dried. N- [5-(7-Chloro-4,4-difluoro-5-hydroxy-5-{[(2-hydroxyethyl) amino] methyl} -2,3,4,5-tetrahydro-1H-1-benzo Azepine-1-carbonyl) pyridin-2-yl] -2- (trifluoromethyl) benzamide (107.2 mg) was obtained.

Example 127
_{SOCl 2} (0.172 mL) was added dropwise to a solution of 4- [5-fluoro-2- (trifluoromethyl) benzamide] benzoic acid (769 mg) in DMA (7 mL). After stirring for 1 hour, [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromobenzo Art (700 mg) was added and stirred for 5 days. A saturated _{aqueous solution of LVDS 3} was added and the solid material was collected by filtration. This was suspended in EtOH (15 mL), a 5N NaOH aqueous solution (1.567 mL) was added dropwise, and the mixture was stirred. After stirring at room temperature for 30 minutes, 5N HCl was added, the solid was collected by filtration, washed with water, dissolved in THF, and dried over _{anhydrous Na 2} SO _4. After filtration and concentration, the crude product is purified by medium pressure column chromatography (Hexane / AcOEt / MeOH), dried under reduced pressure at 60 ° C, and N- {4-[(5R) -7-chloro-4,4- Difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl] phenyl} -5-fluoro-2- (trifluoromethyl) benzamide ( 772 mg) was obtained.

Example 132
_{SOCl 2} (0.172 mL) was added dropwise to a DMA (7 mL) solution of 3-fluoro-4- [5-fluoro-2- (trifluoromethyl) benzamide] benzoic acid (812 mg, 2.351 mmol). After stirring for 1 hour, [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromobenzo Art (700 mg) was added and stirred for 2 days. A saturated _{aqueous solution of LVDS 3} was added and the solid material was collected by filtration. This was suspended in EtOH (15 mL), a 5N NaOH aqueous solution (1.567 mL) was added dropwise, and the mixture was stirred for 30 minutes. 5 N HCl was added, the solid was collected by filtration, washed with water, dissolved in THF, and dried over _{anhydrous Na 2} SO _4. After filtration and concentration, the crude product was purified by column chromatography (Hexane / AcOEt / MeOH) and dried under reduced pressure at 60 ° C. N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1- Carbonyl] -2-fluorophenyl} -5-fluoro-2- (trifluoromethyl) benzamide (840 mg) was obtained.

Example 153
_{SOCl 2} (0.196 mL) was added dropwise to a solution of 4- {4-fluoro- [1,1'-biphenyl] -2-amide} benzoic acid (901 mg) in DMA (7 mL). After stirring for 1 hour, [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromobenzo Art (600 mg) was added and stirred for 2 days. A saturated _{aqueous solution of LVDS 3} was added and the solid material was collected by filtration. This was suspended in EtOH (15 mL), a 5N NaOH aqueous solution (1.343 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. 5N HCl was added, the solid was collected by filtration, washed with water, dissolved in THF, and dried over _{anhydrous Na 2} SO _4. After filtration and concentration, the crude product was purified by column chromatography (Hexane / AcOEt / MeOH) and dried under reduced pressure at 60 ° C. N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1- Carbonyl] phenyl} -4-fluoro- [1,1'-biphenyl] -2-carboxamide (722 mg) was obtained.

Example 157
_{SOCl 2} (0.147 mL) was added dropwise to a DMA (7 mL) solution of 4- [2- (difluoromethyl) -5-fluorobenzamide] -3-fluorobenzoic acid (659 mg). After stirring for 1 hour, [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromobenzo Art (600 mg) was added and stirred for 2 days. A saturated _{aqueous solution of LVDS 3} was added and the solid material was collected by filtration. This was suspended in EtOH (15 mL), 5N NaOH (1.343 mL) was added dropwise, and the mixture was stirred for 30 minutes. 5N HCl was added, the solid was collected by filtration, washed with water, dissolved in THF, and dried over _{anhydrous Na 2} SO _4. After filtration and concentration, the crude product was purified by column chromatography (Hexane / AcOEt / MeOH) and dried under reduced pressure at 60 ° C. N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1- Carbonyl] -2-fluorophenyl} -2- (difluoromethyl) -5-fluorobenzamide (603 mg) was obtained.

Example 160
_{Under a nitrogen atmosphere, SOCl 2} (0.049 mL) was added to a DMA (2 mL) solution of 4-{[1,1'-biphenyl] -2-amide} benzoic acid (167 mg) at room temperature, and the mixture was stirred for 2 hours. , (5S) -7-Chloro-4,4-difluoro-5-methyl-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-ol (100 mg) was added and overnight at room temperature. Stirred. Saturated LVDS ₃ aqueous solution (4 mL) and water were added, and the mixture was extracted 3 times with AcOEt (4 mL). The combined organic layers were washed with 1N aqueous NaOH solution and saturated brine. The mixture was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was distilled off. The residue was purified by silica gel column chromatography (Hexane / AcOEt) and N- {4-[(5S) -7-chloro-4,4-difluoro-5-hydroxy-5-methyl-2,3,4, 5-Tetrahydro-1H-1-benzoazepine-1-carbonyl] phenyl}-[1,1'-biphenyl] -2-carboxamide (163 mg) was obtained.

Example 165
_{SOCl 2} (0.196 mL) was added dropwise to a DMA (7 mL) solution of 6- {2', 4-difluoro- [1,1'-biphenyl] -2-amide} pyridine-3-carboxylic acid (952 mg). .. After stirring for 2 hours, [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromobenzo Art (600 mg) was added and stirred overnight. A saturated _{aqueous solution of LVDS 3} was added and the solid material was collected by filtration. This was suspended in EtOH (15 mL), 5N NaOH (1.343 mL) was added dropwise, and the mixture was stirred for 30 minutes. 5N HCl was added, the solid was collected by filtration, washed with water, dissolved in AcOEt, 1N NaOH was added, the AcOEt layer was washed with water and saturated brine, and dried over anhydrous Na ₂ SO ₄ . The crude product obtained by filtration and concentration was purified by column chromatography (Hexane / AcOEt) and dried under reduced pressure at 60 ° C. N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1- Carbonyl] Pyridine-2-yl} -2', 4-difluoro- [1,1'-biphenyl] -2-carboxamide (642 mg) was obtained.

Example 168
_{SOCl 2} (0.147 mL) was added dropwise to a DMA (7 mL) solution of 4- {2', 4-difluoro- [1,1'-biphenyl] -2-amide} -3-fluorobenzoic acid (748 mg). .. After stirring for 2 hours, [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromobenzo Art (600 mg) was added and stirred for 2 days. A saturated _{aqueous solution of LVDS 3} was added and the solid material was collected by filtration. This was suspended in EtOH (15 mL), 5N NaOH (1.343 mL) was added dropwise, and the mixture was stirred for 30 minutes. 5N HCl was added, the solid was collected by filtration, washed with water, dissolved in THF, and dried over _{anhydrous Na 2} SO _4. After filtration and concentration, the crude product was purified by column chromatography (Hexane / AcOEt / MeOH) and dried under reduced pressure at 60 ° C. N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1- Carbonyl] -2-fluorophenyl} -2', 4-difluoro- [1,1'-biphenyl] -2-carboxamide (706 mg) was obtained.

Example 169
_{SOCl 2} (0.147 mL) was added dropwise to a solution of 4- {2', 4-difluoro- [1,1'-biphenyl] -2-amide} benzoic acid (712 mg) in DMA (7 mL). After stirring for 2 hours, [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromobenzo Art (600 mg) was added and stirred for 2 days. A saturated _{aqueous solution of LVDS 3} was added and the solid material was collected by filtration. This was suspended in EtOH (15 mL), 5N NaOH (1.343 mL) was added dropwise, and the mixture was stirred for 30 minutes. 5N HCl was added, the solid was collected by filtration, washed with water, dissolved in THF, and dried over _{anhydrous Na 2} SO _4. After filtration and concentration, the crude product was purified by column chromatography (Hexane / AcOEt / MeOH) and dried under reduced pressure at 60 ° C. N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1- Carbonyl] phenyl} -2', 4-difluoro- [1,1'-biphenyl] -2-carboxamide (664 mg) was obtained.

Example 187
_{SOCl 2} (49 μL) was added dropwise to a DMA (3 mL) solution of 4- (7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-2-yl) benzoic acid (192 mg). After stirring for 2 hours, [(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-5-yl] methyl 4-bromobenzo Art (150 mg) was added and stirred for 3 days. A saturated _{aqueous solution of LVDS 3} was added and the solid material was collected by filtration. This was suspended in EtOH (10 mL), a 5N NaOH aqueous solution (0.336 mL) was added dropwise, and the mixture was stirred for 30 minutes. 5N HCl was added, the solid was collected by filtration, washed with water, and then dissolved in AcOEt. 1N NaOH was added to this and the organic layer was extracted. It was washed with water and saturated brine, and dried over anhydrous Na ₂ SO ₄ . The crude product obtained by filtration and concentration was purified by column chromatography (Hexane / AcOEt). It was dried under reduced pressure at 60 ° C. 2- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1-benzoazepine-1- Carbonyl] phenyl} -7-fluoro-1,2,3,4-tetrahydroisoquinoline-1-one (126 mg) was obtained.

Example 219
2-Chloro-N- {4-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl]- IBX (0.616 g) was added to a DMSO (5 mL) solution of 2-fluorophenyl} -4,5-difluorobenzamide (0.60 g), and the mixture was stirred overnight at room temperature. 2-Chloro by adding water, extracting with AcOEt, washing with saturated brine, filtering, concentrating, purifying with medium pressure column chromatography (Hexane / AcOEt), and recrystallizing the crude product from Et _{2 O.} -N- [4- (7-Chloro-4,4-difluoro-5,5-dihydroxy-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl) -2-fluorophenyl] -4,5-Difluorobenzamide (460 mg) was obtained.

Example 220
2-Chloro-N- {5- [7-Chloro-4,4-Difluoro-5-Hydroxy-5- (Hydroxymethyl) -2,3,4,5-Tetrahydro-1H-1-Benzoazepine-1- A solution of MsOH in AcOEt (0.046 mL) was added to a solution of carbonyl] pyridine-2-yl} -5-fluorobenzamide (100 mg) in AcOEt (1 mL), and the mixture was stirred at room temperature for 2 days. IPE (1.0 mL) was added and the precipitated solid was collected by filtration. It was dried under reduced pressure at 80 ° C. for 2 days. 2-Chloro-N- {5- [7-Chloro-4,4-Difluoro-5-Hydroxy-5- (Hydroxymethyl) -2,3,4,5-Tetrahydro-1H-1-Benzamide-1- Carbonyl] Pyridine-2-yl} -5-fluorobenzamide Methanesulfonate (112.1 mg) was obtained.

Example 223
2,4-Dichloro-N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1 -A solution of HCl in AcOEt (0.043 mL) was added to a solution of -benzoazepine-1-carbonyl] pyridin-2-yl} -5-fluorobenzamide (100 mg) in AcOEt (1 mL), and the mixture was stirred overnight at room temperature. IPE (1.0 mL) was added and the precipitated solid was collected by filtration. It was dried under reduced pressure at 80 ° C. for 2 days. 2,4-Dichloro-N- {5-[(5R) -7-chloro-4,4-difluoro-5-hydroxy-5- (hydroxymethyl) -2,3,4,5-tetrahydro-1H-1 -Benzodiazepine-1-carbonyl] Pyridine-2-yl} -5-fluorobenzamide hydrochloride (48.3 mg) was obtained.

The structure, manufacturing method and physical property data of the reference example compound and the example compound are shown in the following tables.

表中、REX154はDCMとの1:1共結晶又はDCMとの溶媒和物の形態で存在すると考えられる。

In the table, REX154 is considered to be present in the form of a 1: 1 co-crystal with DCM or a solvate with DCM.

[Test example]
[Test Example 1: Binding affinity for _{vasopressin V 1a} and V _{2 receptors]}
³ H-arginine vasopressin (AVP) (NET800, obtained from PerkinElmer Life Science Co., Ltd.) binding affinity of various compounds to vasopressin receptor using the inhibition _{of vasopressin V 1a} receptor and vasopressin V _{2 receptor binding in rats as an index.} I examined the sex.
(1) Rat V _1a receptor (rV _1a R) binding inhibition test
In each well of a 96-well plate, _{50 μg of a rat liver membrane-derived V 1a} receptor fraction was diluted with a reaction solution (100 mM Tris-HCl (pH 8.0), 0.1% BSA, 5 mM MgCl ₂ , 1 mM EDTA). Added. Compounds of various concentrations (0.3 nM to 100 nM) were added to each well, and 1 nM to ³ nM of 3 H-AVP was added. After reacting the above plates at 4 ° C. for 2 hours, the V _1a receptor fraction after the reaction was recovered with a 96-well glass filter (Unifilter GF / B), and the washing solution (10 mM Tris-HCl (pH 8.). After washing 3 times with 0), 5 mM MgCl ₂ , 1 mM EDTA), ^{the radioactivity of 3} H-AVP was measured with a scintillation counter.
(2) Rat V ₂ receptor (rV ₂ R) binding inhibition test
_{Rat V 2} receptor-expressing CHO cells (rV ₂ R-CHO) were cultured in DMEM / F12 containing 10% FBS in a 24-well plate, and each cell was washed twice with D-PBS. A reaction solution (0.1% BSA, 0.05% sodium azide-containing D-PBS) containing various concentrations of the compound (0.3 nM to 100 nM) was added to each well, and a certain amount of ³ H-AVP was added thereto. (Diluted 100 times). After reacting the above plates at 4 ° C. for 2 hours, the cells were washed twice with D-PBS, 0.1N NaOH was added to each well to collect cells, and ³ H-AVP was emitted at a scintillation counter. The activity was measured.
(3) _{Calculation of IC 50} ^{The 3} H-AVP binding rate in the presence of the compound was calculated by the following formula.
Bonding rate (%) = (B-NSB) / (TB-NSB) x 100
^{(B: Binding amount of 3} H-AVP in the presence of each compound, NSB: Binding amount of ³ H-AVP in the presence of 1 μM unlabeled AVP, TB: ³ H-AVP in the absence of 1 μM unlabeled AVP Bonding amount)
^{Using the 3} H-AVP binding rate and the compound concentration, _{the concentration (IC 50} ^{) of each compound that inhibits 3} H-AVP binding by 50% was calculated.
The results are shown below.

[Test Example 2: Metabolic stability test]
Reaction system and incubation
The method of Obach and Jones et al. (RS Obach, Drug Metab. Dispos. 1999 (27): 1350-1359 and H. Jones and JB Houston, Drug Metab. Dispos. 2004 (32): 973-982). For reference, the reaction system shown below was prepared and the metabolic stability of the evaluation compound (compound of the present invention, tolvaptan) was evaluated. Human liver microsomes were purchased from Corning Inc. and used. The evaluation compound was dissolved in DMSO to 10 mmol / L, further diluted with acetonitrile to prepare 100 μmol / L, and used. A 100 μmol / L solution was used in this test.
<Reaction system>
Evaluation compound 1 μmol / L
Human liver microsomes 1 mg / mL
Coenzymes (NADPH and NADH) 1 mmol / L each
Magnesium chloride 5 mmol / L
100 mmol / L potassium phosphate buffer (pH 7.4)
Number of examples: n = 4
<Reaction conditions>
The reaction system without coenzyme was pre-incubated at 37 ° C. for 5 minutes, and then coenzyme was added to start the reaction. After the addition of coenzyme, the mixture was incubated for 0, 5, 10, 20, 30 and 60 minutes, a part of the reaction solution was withdrawn at predetermined time intervals, added and mixed with a methanol solution containing an internal standard substance (IS), and the reaction was stopped. ..
Analytical method After the reaction was stopped, centrifugation was performed, and the supernatant was injected into a liquid chromatograph-tandem mass spectrometer (LC-MS / MS) to measure the unchanged form remaining in the reaction system. The mass spectrometer performed the electrospray ionization (ESI) method in the cation detection mode, and detected the unchanged form and IS by the selective reaction detection (MRM) method using the set precursor ion and product ion.
The residual rate of the data analysis evaluation compound was calculated by the following formula.
Residual rate = (Ratio of peak area of evaluated compound to internal standard substance at t minutes after incubation) ÷ (Ratio of peak area of evaluated compound to internal standard substance at 0 minutes)
The slopes of the X-axis (incubation time) and the Y-axis (logarithm of residual rate) were determined by nonlinear least squares analysis, and the liver specific clearance (CL _int ) was determined by the following formula.
CL _int (μL / min / mg) = − (slope (min ^-1 )) ÷ 1 (mg / mL) × 1000
The results are shown below.

[Test Example 3: Pharmacokinetic test in mice]
Test method In order to compare the oral absorbability of the compound of the present invention with tolvaptan, a pharmacokinetic (PK) test was conducted using male ICR mice. The evaluation compound was suspended in a 1% hydroxypropyl methylcellulose (HPMC) solution and adjusted to a concentration of 4.5 mg / mL. Here, the compound of the present invention was used as the evaluation compound in the form (including the amorphous form) obtained in the above Examples, or was used as the evaluation compound after being spray-dried if necessary.
Male ICR mice (7 weeks old) were fed freely and water, and the body weight was measured with an electronic balance, and then the evaluation compound was forcibly orally administered at a dose of 30 mg / kg (15 mL / kg). Blood was collected after forced oral administration using a 1 mL syringe equipped with a 26 G needle treated with heparin from the abdominal vena cava under isoflurane anesthesia. Blood was centrifuged at 4 ° C. and 3000 rpm for 10 minutes to obtain supernatant plasma. Measurement of plasma evaluation compound concentration was performed using LC-MS / MS.
Test results The following PK parameters were calculated using the mean plasma unchanged concentrations of the two cases at each blood sampling time point.
C _max : Maximum plasma concentration (μg / mL)
t _max : time to reach maximum plasma concentration (h)
AUC _inf : Area under the plasma concentration time curve up to infinite time after administration (μg h / mL)
_{As a result, C max} and AUC _inf were higher in both of the compounds of the present invention than in tolvaptan. The results are shown below.

[Test Example 4]
The pharmacological effects of some of the compounds of the present invention on polycystic kidney disease were evaluated using PCK mice and PCK rats, which are PKD model animals, according to the tests disclosed in WO2015 / 056805. Good results were obtained for the compounds of the present invention, supporting the results of Test Examples 1-3.

Since the compound of the present invention has a vasopressin antagonism, a pharmaceutical composition containing the compound of the present invention as an active ingredient may be useful for diagnosis, prevention and / or treatment of various diseases involving vasopressin receptors.

Claims (6)

A drug containing a compound selected from the following compound group or a salt thereof.

A drug containing any of the compounds or salts represented by the following structural formulas.

The medicament according to claim 1 or 2, which is a vasopressin receptor antagonist. Meniere's disease, hypertension, edema, ascites, heart failure, acute or chronic renal dysfunction, acute or chronic renal failure, polycystic kidney disease, vasopressin dyssecretion syndrome, liver cirrhosis, hyponatremia, hypopotassium, diabetes, The medicament according to claim 1 or 2, which is used for treating and / or preventing a disease selected from the group consisting of circulatory failure, agitation, water metabolism disorder, and ischemic disease. Meniere's disease, hypertension, edema, ascites, heart failure, acute or chronic renal dysfunction, acute or chronic renal failure, polycystic kidney disease, vasopressin dyssecretion syndrome, liver cirrhosis, hyponatremia, hypopotassium, diabetes, circulatory insufficiency, motion sickness, water metabolism disorder, and use of a pharmaceutical according to claim 1 or 2 in the manufacture of a medicament for treating and / or preventing a disease selected from the group consisting of ischemic disease. The medicament according to claim 1 or 2, and the medicament according to Meniere's disease, hypertension, edema, ascites, heart failure, acute or chronic renal dysfunction, acute or chronic renal failure, polycystic kidney disease, vasopresin dyssecretion syndrome, liver cirrhosis. , hyponatremia, hypokalemia, diabetes, circulatory insufficiency, motion sickness, water metabolism disorder, and package inserts described that can be used in the treatment and / or prophylaxis of selected diseases from the group consisting of ischemic disease And a kit that includes.