Cross-Reference to Related Application

This application claims the benefit of

U.S. Application No. 62/438,753, filed December 23, 2016, expressly incorporated herein by reference in its

entirety .

Field of the Invention

The present invention relates to a novel oxazepine compound or a pharmacologically acceptable salt thereof which has excellent tissue non-specific alkaline

phosphatase (hereinafter, referred to as TNAP) inhibitory activity .

The present invention also relates to a therapeutic agent and/or prophylactic agent (preferably a therapeutic agent) for pseudoxanthoma elasticum (PXE) , generalized arterial calcification of infancy (GACI),

craniometaphyseal dysplasia (CMD) , ossification of the yellow ligament (OYL) , ossification of ligamentum flavum, arterial calcification due to deficiency of CD73 (ACDC) , calcification of joints and arteries (CALJA) , arthrosis deformans, osteoarthritis, ankylosis of the joint, idiopathic infantile arterial calcification (IIAC), ankylosing spondylitis (AS), tumoral calcinosis (TC) , progressive osseous heteroplasia (POH) , Keutel syndrome, vascular calcification associated with chronic renal failure (including glomerulonephritis, IgA nephropathy, hypertensive nephropathy, and diabetic nephropathy) and secondary parathyroid hyperplasia, metastatic

calcification, calciphylaxis , calcific tendinitis of the longus colli muscle, fibrodysplasia ossificans

progressiva (FOP), calcific aortic stenosis, pericarditis calculosa, atherosclerotic vascular calcification, calcific uremic arteriopathy (CUA) , Kawasaki disease, calcification due to obesity and aging, tibial arterial calcification, bone metastasis, prosthetic calcification, Paget 's disease, idiopathic basal ganglia calcification

(IBGC), heterotopic ossification (HO), calcific aortic valve disease (aortic valve stenosis), calcific

tendinitis, ossification of the posterior longitudinal ligament (OPLL) ossification of the anterior longitudinal ligament (OALL) , diffuse idiopathic skeletal hyperostosis

(DISH) , meniscal calcification, or peritoneal

calcification, comprising the compound or the

pharmacologically acceptable salt thereof as an active ingredient .

The present invention further relates to a

composition for the treatment or prophylaxis of the aforementioned diseases, comprising the compound or the pharmacologically acceptable salt thereof as an active ingredient, use of the compound or the pharmacologically acceptable salt thereof for manufacturing a

pharmaceutical for the treatment or prophylaxis of the disease, and a method for the treatment or prophylaxis of the disease, comprising administering a pharmacologically effective amount of the compound or the pharmacologically acceptable salt thereof to a mammal (preferably a human) .

Description of the Related Art

In vivo calcification is strictly regulated by the balance of activation between osteoblasts and osteoclasts, phosphorus and calcium concentrations in plasma, and parathyroid hormone or vitamin D secreted in order to maintain the homeostasis of these concentrations

(Non Patent Literature 1) . Ectopic calcification is found in diseases, for example, pseudoxanthoma elasticum

(PXE) , generalized arterial calcification of infancy

(GACI), craniometaphyseal dysplasia (CMD) , ossification of the yellow ligament (OYL) , ossification of ligamentum flavum, arterial calcification due to deficiency of CD73

(ACDC) , calcification of joints and arteries (CALJA) , arthrosis deformans, osteoarthritis, ankylosis of the joint, idiopathic infantile arterial calcification (IIAC), ankylosing spondylitis (AS), tumoral calcinosis (TC) , progressive osseous heteroplasia (POH) , Keutel syndrome, vascular calcification associated with chronic renal failure (including glomerulonephritis, IgA nephropathy, hypertensive nephropathy, and diabetic nephropathy) and secondary parathyroid hyperplasia, metastatic

calcification, calciphylaxis , calcific tendinitis of the longus colli muscle, fibrodysplasia ossificans

progressiva (FOP), calcific aortic stenosis, pericarditis calculosa, atherosclerotic vascular calcification, calcific uremic arteriopathy (CUA) , Kawasaki disease, calcification due to obesity and aging, tibial arterial calcification, bone metastasis, prosthetic calcification, Paget 's disease, idiopathic basal ganglia calcification

(IBGC), heterotopic ossification (HO), calcific aortic valve disease (aortic valve stenosis), calcific

tendinitis, ossification of the posterior longitudinal ligament (OPLL) ossification of the anterior longitudinal ligament (OALL) , diffuse idiopathic skeletal hyperostosis

(DISH) , meniscal calcification, and peritoneal

calcification. In these pathological conditions,

calcification in tissues (blood vessels, soft tissues, etc.) that are usually not calcified is caused by the failure of the regulatory mechanism mentioned above, and is known to bring about significantly reduced quality of life (QOL) due to the limitation of activity and an increased cardiovascular risk (Non Patent Literatures 2 and 3) . No existing therapeutic agent is effective for ectopic calcification. Thus, there are very high unmet medical needs for this disease (Non Patent Literature 4) .

TNAP, one of alkaline phosphatases, includes

membrane-bound and secretory forms. TNAP is expressed in the bone, the liver, and the kidney and highly expressed particularly in the matrix vesicles of chondrocytes and osteoblasts. This enzyme is known to play an important role in in vivo calcification via the degradation of pyrophosphate, which is an endogenous anti-calcification factor (Non Patent Literature 5) . A large number of reports show the increased expression level or elevated activity of TNAP at lesion sites of ectopic calcification, and ectopic calcification also occurs in mice which overexpress human TNAP, suggesting the importance of TNAP for ectopic calcification (Non Patent Literatures 6 and 7) . Thus, the inhibition of TNAP is considered to

elevate pyrophosphate concentrations in blood and in tissues and suppress ectopic calcification (Non Patent Literature 8 ) .

Some compounds are known to have TNAP inhibitory activity (see e.g., Patent Literatures 1 and 2 and,

Non Patent Literatures 9 to 12) . Among them, compounds partially having a common skeleton are disclosed.

Nonetheless, a compound having a 7-membered ring

condensed with a pyridine ring has not yet been disclosed.

[Patent Literature]

[Patent Literature 1] International Publication No.

WO 2009/017863 ( PCT/US2008 / 063106 )

[Patent Literature 2] International Publication No.

WO 2013/126608 (U.S. Patent Publication No. 2015-0011551) [Non Patent Literature]

[Non Patent Literature 1] J. Bone Miner Res, 2006,

vol. 24, p. 176-181

[Non Patent Literature 2] Clin. Kidery. J., 2014, vol. 7, p. 167-173

[Non Patent Literature 3] Eur. Heart. J., 2014, vol. 35, p. 1515-1525.

[Non Patent Literature 4] Int. J. Nephrol. Renovasc. Dis., 2014, vol. 7, p. 161-168

[Non Patent Literature 5] J. Histochem. Cytochem., 2002, vol. 50, p. 333-340

[Non Patent Literature 6] J. Am. Soc. Nephrol., 2004, vol. 15, p. 1392-1401

[Non Patent Literature 7] J. Bone Miner Res, 2013, vol. 7, p. 1587-1598

[Non Patent Literature 8] J. Bone Miner Res, 2007,

vol. 22, p. 1700-1710

[Non Patent Literature 9] Bioorg. Med. Chem. Lett., 2009, vol. 19, p. 222-225

[Non Patent Literature 10] J. Med. Chem., 2009, vol. 52, p. 6919-6925

[Non Patent Literature 11] Bioorg. Med. Chem., 2013, vol. 21, p. 7981-7987

[Non Patent Literature 12] J. Bone Miner Res, 2015, vol.30, p. 824-836 SUMMARY OF THE INVENTION

The present inventors have conducted diligent studies and consequently found that a compound

represented by the formula (I) mentioned later has excellent TNAP inhibitory activity based on its specific chemical structure, further has excellent properties in terms of the physicochemical properties (e.g., stability) of a pharmaceutical, and serves as a safe and useful pharmaceutical as a prophylactic or therapeutic agent for a pathological condition or a disease associated with ectopic calcification. On the basis of these findings, the present invention has been completed.

Specifically, the compound of the present invention has excellent properties in terms of TNAP inhibitory activity, solubility, cell membrane permeability, oral absorbability, concentration in blood, metabolic

stability, tissue penetration, bioavailability

(hereinafter, also referred to as BA) , in vitro activity, in vivo activity, ex vivo activity, quick onset of drug efficacy, persistence of drug efficacy, physical

stability, drug interaction, safety (e.g., cardiotoxicity or hepatotoxicity) , etc., and is useful as a

pharmaceutical [particularly, a pharmaceutical for the treatment or prophylaxis (preferably treatment) of pseudoxanthoma elasticum (PXE) , generalized arterial calcification of infancy (GACI), craniometaphyseal dysplasia (CMD) , ossification of the yellow ligament (OYL) , ossification of ligamentum flavum, arterial calcification due to deficiency of CD73 (ACDC) ,

calcification of joints and arteries (CALJA) , arthrosis deformans, osteoarthritis, ankylosis of the joint, idiopathic infantile arterial calcification (IIAC), ankylosing spondylitis (AS), tumoral calcinosis (TC) , progressive osseous heteroplasia (POH) , Keutel syndrome, vascular calcification associated with chronic renal failure (including glomerulonephritis, IgA nephropathy, hypertensive nephropathy, and diabetic nephropathy) and secondary parathyroid hyperplasia, metastatic

calcification, calciphylaxis , calcific tendinitis of the longus colli muscle, fibrodysplasia ossificans

progressiva (FOP), calcific aortic stenosis, pericarditis calculosa, atherosclerotic vascular calcification, calcific uremic arteriopathy (CUA) , Kawasaki disease, calcification due to obesity and aging, tibial arterial calcification, bone metastasis, prosthetic calcification, Paget 's disease, idiopathic basal ganglia calcification

(IBGC), heterotopic ossification (HO), calcific aortic valve disease (aortic valve stenosis), calcific

tendinitis, ossification of the posterior longitudinal ligament (OPLL) ossification of the anterior longitudinal ligament (OALL) , diffuse idiopathic skeletal hyperostosis

(DISH) , meniscal calcification, or peritoneal

calcification] .

The present invention provides: (1) a compound represented by the following general formula ( I ) :

wherein

R ¹ represent

a hydrogen atom,

a Cl-6 alkyl group (wherein the alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A ^B ) , a C6-10 aryl group (wherein the aryl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^B ) , or a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^B ) ,

R ² represents

a hydrogen atom, , a Cl-6 alkyl group (wherein the alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A ^B ) , a C3-8 cycloalkyl group (wherein the cycloalkyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^B and) ,

a C6-10 aryl group (wherein the aryl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^B and a Cl-6 halogenoalkyl group) ,

a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^B and

a Cl-6 halogenoalkyl group) ,

a Cl-6 alkylcarbonyl group (wherein the alkylcarbonyl group is optionally substituted by one to three groups, which may be the same or different, selected from the following substituents :

a hydroxy group,

a Cl-6 alkoxy group optionally substituted by one group selected from substituent group A ^c ,

a C3-8 cycloalkyl group optionally substituted by one group selected from substituent group A ^D , a C6-10 aryl group optionally substituted by one or two groups selected from substituent group A ^D ,

a carboxyl group,

a Cl-6 alkylcarbonyl group,

a Cl-6 alkoxycarbonyl group,

an amino group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups ,

an aminocarbonyl group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups ,

a 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur, an aminocarbonyloxy group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups,

a 4- to 7-membered saturated heterocyclylcarbonyloxy group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur,

a halogeno group, and

a cyano group) ,

a C3-8 cycloalkylcarbonyl group (wherein the

cycloalkylcarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^B ) , a C6-10 arylcarbonyl group (wherein the arylcarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from

substituent group A ^B and

a Cl-6 halogenoalkyl group) ,

a 3- to 10-membered heterocyclylcarbonyl group containing one to four heteroatoms, which may be the same or

different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclylcarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^B and a Cl-6 halogenoalkyl group) ,

a Cl-6 alkoxycarbonyl group (wherein the alkoxycarbonyl group is optionally substituted by one to three groups, which may be the same or different, selected from

substituent group A ^E ) ,

a C3-8 cycloalkyloxycarbonyl group (wherein the

cycloalkyloxycarbonyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A ^E ) ,

a 4- to 7-membered saturated heterocyclyloxycarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclyloxycarbonyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A ^F ), an aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from the following substituents :

a Cl-6 alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A ^D ,

a C3-8 cycloalkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A ^D ,

a C6-10 aryl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^B and

a Cl-6 halogenoalkyl group) ,

a C6-10 arylaminocarbonyl group (wherein the

arylaminocarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^F and

a Cl-6 halogenoalkyl group) , or

a 3- to 10-membered heterocyclylaminocarbonyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclylaminocarbonyl group is

optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^F and

a Cl-6 halogenoalkyl group) , R ³ and R ⁴ are the same or different and each

represent

a hydrogen atom,

a Cl-6 alkyl group (wherein the alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from the following substituents : a hydroxy group,

a Cl-6 alkoxy group optionally substituted by one group selected from substituent group A ^c ,

a C3-8 cycloalkyl group optionally substituted by one group selected from substituent group A ^D ,

a C6-10 aryl group optionally substituted by one or two groups selected from substituent group A ^D ,

a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur and optionally substituted by one or two groups selected from

substituent group A ^D ,

a carboxyl group,

a Cl-6 alkylcarbonyl group,

a Cl-6 alkoxycarbonyl group,

an amino group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups ,

an aminocarbonyl group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups , a 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur, an aminocarbonyloxy group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups,

a 4- to 7-membered saturated heterocyclylcarbonyloxy group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur,

a halogeno group, and

a cyano group) ,

a C6-10 aryl group (wherein the aryl group is optionally substituted by one or two groups, which may be the same or different, selected from the following substituents : a hydroxy group,

a Cl-6 alkoxy group optionally substituted by one to three groups, which may be the same or different halogeno groups ,

a Cl-6 alkyl group optionally substituted by one group selected from substituent group A ^H ,

a C3-8 cycloalkyl group optionally substituted by one group selected from substituent group A ^H ,

a C6-10 aryl group optionally substituted by one group selected from substituent group A ^H ,

a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur and optionally substituted by one group selected from substituent group A ^H ,

an amino group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups ,

a carboxyl group,

a Cl-6 alkylcarbonyl group,

a Cl-6 alkoxycarbonyl group,

an aminocarbonyl group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups ,

a 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur, an aminocarbonyloxy group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups,

a 4- to 7-membered saturated heterocyclylcarbonyloxy group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur,

a halogeno group, and

a cyano group) ,

a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is optionally substituted by one or two groups, which may be the same or different, selected from the following substituents :

a hydroxy group,

a Cl-6 alkoxy group optionally substituted by one to three groups, which may be the same or different halogeno groups ,

a Cl-6 alkyl group optionally substituted by one group selected from substituent group A ^H ,

a C3-8 cycloalkyl group optionally substituted by one group selected from substituent group A ^H ,

a C6-10 aryl group optionally substituted by one group selected from substituent group A ^H ,

a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur, and

optionally substituted by one group selected from

substituent group A ^H ,

an amino group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups ,

a carboxyl group,

a Cl-6 alkylcarbonyl group,

a Cl-6 alkoxycarbonyl group,

an aminocarbonyl group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups , a 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur, an aminocarbonyloxy group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups,

a 4- to 7-membered saturated heterocyclylcarbonyloxy group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur,

a halogeno group, and

a cyano group) ,

a Cl-6 alkylcarbonyl group (wherein the alkylcarbonyl group is optionally substituted by one to three groups, which may be the same or different, selected from

substituent group A ^F ) ,

a C6-10 arylcarbonyl group (wherein the arylcarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from

substituent group A ^F and a Cl-6 halogenoalkyl group) , a 3- to 10-membered heterocyclylcarbonyl group containing one to four heteroatoms, which may be the same or

different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclylcarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^F and a Cl-6 halogenoalkyl group) , a carboxyl group,

a Cl-6 alkoxycarbonyl group (wherein the alkoxycarbonyl group is optionally substituted by one to three groups, which may be the same or different, selected from

substituent group A ^G ) ,

an aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups each

optionally substituted by one to three groups, which may be the same or different, selected from substituent group A ^G ) ,

a C6-10 arylaminocarbonyl group (wherein the

arylaminocarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^F and

a Cl-6 halogenoalkyl group) , or

a 3- to 10-membered heterocyclylaminocarbonyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclylaminocarbonyl group is

optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^F and

a Cl-6 halogenoalkyl group) ,

or

the Cl-6 alkyl groups of R ³ and R ⁴ are optionally bonded to each other to form a 3- to 6-membered saturated carbocyclic ring or to form a 4- to 6-membered saturated heterocyclic ring via one nitrogen or oxygen atom

(wherein one nitrogen atom in the 4- to 6-membered saturated heterocyclic ring is optionally substituted with a hydrogen atom, a Cl-6 alkyl group, a Cl-6

alkylcarbonyl group, a Cl-6 alkoxycarbonyl group) ,

R ⁵ and R ⁶ are the same or different and each

represent

a hydrogen atom,

a Cl-6 alkyl group (wherein the alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A ^G ) , a C6-10 aryl group (wherein the aryl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^D ) , or a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^D ) ,

R ⁷ represents

a hydrogen atom,

a Cl-6 alkyl group (R ⁷ is a carbon substituent of the pyridinyl ring, not a nitrogen substituent) or

a hydroxy group, each substituent R may be the same or different and may be each represent

a Cl-6 alkyl group (wherein the alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A ^B ) , a Cl-6 alkoxy group (wherein the alkoxy group is

optionally substituted by one to three groups, which may be the same or different, selected from substituent group A ^B ) ,

a halogeno group,

a C6-10 aryl group (wherein the aryl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^D ) , a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A ^G ) ,

a hydroxy group,

an amino group (wherein the amino group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups each optionally

substituted by one to three groups, which may be the same or different, selected from substituent group A ^J ) , a carboxyl group, a Cl-6 alkoxycarbonyl group (wherein the alkoxycarbonyl group is optionally substituted by one to three groups, which may be the same or different, selected from

substituent group A ^J ) ,

an aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups each

optionally substituted by one to three groups, which may be the same or different, selected from substituent group A ^J ) , or

a cyano group,

m represents an integer selected from 1 to 4, the substituent groups represent

A ^B : a hydroxy group,

a Cl-6 alkoxy group,

a C3-8 cycloalkyl group,

a C6-10 aryl group,

a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur,

a carboxyl group,

a Cl-6 alkoxycarbonyl group,

an aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups), an amino group (wherein the amino group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups),

a halogeno group, and

a cyano group;

A ^c : a C6-10 aryl group,

a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur, and

a halogeno group;

A ^D : a hydroxy group,

a Cl-6 alkyl group (wherein the alkyl group is optionally substituted by one to three halogeno groups),

a Cl-6 alkoxy group (wherein the alkoxy group is

optionally substituted by one to three halogeno groups) , a halogeno group,

an amino group, and

a cyano group;

A ^E : a hydroxy group,

a Cl-6 alkoxy group,

an amino group (wherein the amino group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups),

a halogeno group, and

a cyano group;

A ^F : a hydroxy group,

a Cl-6 alkoxy group, a C3-8 cycloalkyl group,

a C6-10 aryl group,

a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur,

an amino group (wherein the amino group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups),

a halogeno group, and

a cyano group;

A ^G : a Cl-6 alkoxy group,

a C3-8 cycloalkyl group,

a C6-10 aryl group,

a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur,

a halogeno group, and

a cyano group;

A ^H : a hydroxy group,

a Cl-6 alkoxy group,

an amino group,

a halogeno group, and

a cyano group; and

A ^J : a Cl-6 alkoxy group,

a C3-8 cycloalkyl group,

a C6-10 aryl group, a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur,

a carboxyl group,

a Cl-6 alkoxycarbonyl group,

an aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups),

a halogeno group, and

a cyano group,

X represents -CH=, -C(-R ⁸ )=, or -N=,

or a pharmacologically acceptable salt thereof;

(2) a compound represented by the following general formula ( la) :

(la) wherein

R ² represents a 3- to 10-membered heterocyclyl group containing one nitrogen, a Cl-6 alkylcarbonyl group

(wherein the alkylcarbonyl group is optionally substituted by a hydroxy group, a Cl-6 alkoxy group, a 4- to 7-membered saturated heterocyclyl group containing one or two heteroatoms, which may be the same or

different, selected from nitrogen and oxygen, or

an aminocarbonyloxy group substituted by one Cl-6 alkyl group) , a Cl-6 alkoxycarbonyl group (wherein the

alkoxycarbonyl group is optionally substituted by a hydroxy group or a Cl-6 alkoxy group) , an aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different, each optionally substituted by a Cl-6 alkyl groups), 3- to 10-membered heterocyclylcarbonyl group containing one nitrogen, 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two

heteroatoms, which may be the same or different, selected from nitrogen and oxygen, 3- to 10-membered

heterocyclylaminocarbony group containing one nitrogen, or 4- to 7-membered saturated heterocyclyloxycarbonyl group containing one oxygen,

R ³ and R ⁴ are the same or different and each

represent a hydrogen atom, a Cl-6 alkyl group, a C6-10 aryl group, or

the Cl-6 alkyl groups of R ³ and R ⁴ are optionally bonded to each other to form a 3- to 6-membered saturated carbocyclic ring,

each substituent R ⁸ may be the same or different and may represent a Cl-6 alkoxy group or a halogeno group, m represents an integer selected from 1 to 2,

X represents -CH= or -N=,

or a pharmacologically acceptable salt thereof;

(3) the compound according to 2 above, wherein X is -N=, or a pharmacologically acceptable salt thereof;

(4) the compound according to 2 above, wherein R ² is a Cl-6 alkoxycarbonyl group (wherein the alkoxycarbonyl group is optionally substituted by a hydroxy group or a Cl-6 alkoxy group, or 4- to 7-membered saturated

heterocyclyloxycarbonyl group containing one oxygen, or a pharmacologically acceptable salt thereof;

(5) the compound according to 2 above, wherein R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a methyl group,

or a pharmacologically acceptable salt thereof;

( 6 ) 5-chloro-N- [ 4- (hydroxyacetyl ) -2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] -2- methoxybenzenesulfonamide,

2-methoxyethyl 7-{ [ ( 5-chloro-2-methoxypyridin-3- yl ) sulfonyl ] amino } -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate, 5-chloro-iV- [ (3R) -4- (hydroxyacetyl ) -3-methyl-2, 3,4,5- tetrahydropyrido [3, 2 - f] [ 1 , 4 ] oxazepin-7-yl ] -2- methoxybenzenesulfonamide,

or a pharmacologically acceptable salt thereof;

(7) ( 3S) -tetrahydrofuran-3-yl 7- { [ ( 5-chloro-2- methoxypyridin-3-yl ) sulfonyl] amino}-2, 3- dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate,

( 3R) -tetrahydrofuran-3-yl 7-{ [ ( 5-chloro-2-methoxypyridin- 3-yl ) sulfonyl ] amino } -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate,

( 3R) -tetrahydrofuran-3-yl (3R) -Ί- { [ (5-chloro-2- methoxypyridin-3-yl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate, or a pharmacologically acceptable salt thereof;

(8) 2-methoxyethyl ( 3R) -7- { [ ( 5-chloro-2-methoxypyridin- 3-yl ) sulfonyl ] amino } -3-methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate,

or a pharmacologically acceptable salt thereof;

(9) (3S) -tetrahydrofuran-3-yl ( 3R) -7- { [ ( 5-chloro-2- methoxypyridin-3-yl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate, or a pharmacologically acceptable salt thereof; (10) 2-methoxyethyl {3R) -7- { [ (2-ethoxy-5-fluoropyridin-3- yl ) sulfonyl ] amino } -3-methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate,

or a pharmacologically acceptable salt thereof;

(11) a compound according to 1 to 10 above, wherein the pharmacologically acceptable salt is sodium salt;

(12) a compound according to 1 to 10 above, wherein the pharmacologically acceptable salt is potassium salt;

(13) a pharmaceutical composition comprising a compound according to 1 to 10 above, or a pharmacologically acceptable salt thereof, as an active ingredient;

(14) the pharmaceutical composition according to

13 above, wherein the pharmaceutical composition is intended for the treatment or prophylaxis of ectopic calcification, pseudoxanthoma elasticum (PXE) ,

generalized arterial calcification of infancy (GACI), calcification of joints and arteries (CALJA) , vascular calcification in CKD/ESRD, calciphylaxis , ossification of posterior longitudinal ligaments (OPLL) , ossification of yellow ligaments (OYLL) , or aortic stenosis; (15) a TNAP inhibitor comprising a compound according to the 1 to 10 above, or a pharmacologically acceptable salt thereof, as an active ingredient;

(16) Use of a compound according to 1 to 10 above, or a pharmacologically acceptable salt thereof, for the manufacturing a pharmaceutical composition;

(17) a method for the treatment or prophylaxis of a disease or condition selected from the group consisting of ectopic calcification, pseudoxanthoma elasticum (PXE) , generalized arterial calcification of infancy (GACI), calcification of joints and arteries (CALJA) , vascular calcification in CKD/ESRD, calciphylaxis , ossification of posterior longitudinal ligaments (OPLL) , ossification of yellow ligaments (OYLL) , and aortic stenosis, comprising administering a therapeutically effective amount of a compound according to 1 to 10 above, or a

pharmacologically acceptable salt thereof, to a subject in need thereof;

(18) a method according to 17 above, wherein the disease or condition is pseudoxanthoma elasticum (PXE) ;

(19) a method for inhibiting TNAP in a subject,

comprising administering an effective amount of a

compound according to 1 to 10 above, or a pharmacologically acceptable salt thereof, to the

sub ect ;

(20) a method according to 17 to 19 above, wherein the subject is a human;

(21) a compound according to 1 to 10 above, or a

pharmacologically acceptable salt thereof, for use in the treatment of disease or condition selected from the group consisting of ectopic calcification, pseudoxanthoma elasticum (PXE) , generalized arterial calcification of infancy (GACI), calcification of joints and arteries

(CALJA) , vascular calcification in CKD/ESRD,

calciphylaxis , ossification of posterior longitudinal ligaments (OPLL) , ossification of yellow ligaments (OYLL) , and aortic stenosis; and

(22) a compound according to 1 to 10 above, or a

pharmacologically acceptable salt thereof, for use in the treatment of pseudoxanthoma elastic (PXE) .

In the present invention, the "Cl-6 alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Examples thereof can include methyl, ethyl, n-propyl, n-butyl, isobutyl, s-butyl, tert-butyl,

n-pentyl, isopentyl, 2-methylbutyl , neopentyl,

1-ethylpropyl , n-hexyl, isohexyl, 4-methylpentyl , 3-methylpentyl , 2-methylpentyl , 1-methylpentyl ,

3, 3-dimethylbutyl, 2 , 2-dimethylbutyl , 1 , 1-dimethylbutyl , 1 , 2-dimethylbutyl , 1 , 3-dimethylbutyl , 2 , 3-dimethylbutyl , and 2-ethylbutyl groups. For R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , A ^B , A ^D , A ^E , A ^F , or A ^J , the Cl-6 alkyl group is preferably an alkyl group having 1 to 3 carbon atoms, most

preferably an ethyl or methyl group.

In the present invention, the "Cl-6 halogenoalkyl group" refers to the aforementioned "Cl-6 alkyl group" substituted by one to six halogen atoms. Examples

thereof can include linear or branched halogenoalkyl groups each having 1 to 6 carbon atoms, such as

fluoromethyl , difluoromethyl, trifluoromethyl,

2, 2, 2-trifluoroethyl, 1,1,1,3,3, 3-hexafluoro-2-propyl , chloromethyl , 2-chloroethyl , 3-chloro-n-propyl , 4-chloro- n-butyl, 5-chloro-n-pentyl , and 6-chloro-n-hexyl groups.

In the present invention, the "C3-8 cycloalkyl group" refers to a 3- to 8-membered saturated cyclic hydrocarbon group. Examples thereof can include

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

cycloheptyl, and cyclooctyl groups. For R ² , R ³ , R ⁴ , R ⁸ , A ^B , A ^F , A ^G , or A ^J , the C3-8 cycloalkyl group is preferably a 3- to 6-membered saturated cyclic hydrocarbon group, more preferably a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. In the present invention, the "C6-10 aryl group" refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples thereof can include phenyl, indenyl, and naphthyl groups. For R , R , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , A ^B , A ^c , A ^F , A ^G , or A ^J , the C6-10 aryl group is preferably a phenyl group.

In the present invention, the "4- to 7-membered saturated heterocyclyl group containing one or two

heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" refers to a 4- to

7-membered saturated heterocyclic group containing one or two atoms of nitrogen, oxygen, and sulfur. Examples thereof can include oxetanyl, morpholinyl,

thiomorpholinyl , pyrrolidinyl , pyrrolinyl, imidazolidinyl , imidazolinyl , pyrazolidinyl , pyrazolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl , tetrahydropyranyl , and 5-oxo-4 , 5-dihydro-l , 2 , 4-oxadiazolyl groups .

In the present invention, the "3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from

nitrogen, oxygen, and sulfur" refers to a 3- to

10-membered heterocyclic group containing one to four atoms of nitrogen, oxygen, and sulfur. Examples thereof can include the groups listed as the examples of the aforementioned "4- to 7-membered heterocyclyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur", and aromatic heterocyclic groups such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl , 1,2,3- oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl , pyranyl, pyridyl, pyridazinyl, pyrimidinyl , and pyrazinyl. The "3- to 10-membered heterocyclic group" may be condensed with an additional cyclic group. Examples thereof can include benzofuranyl , chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl , naphthyridinyl , quinoxalinyl , quinazolinyl , isoindolinyl , 2, 3-dihydro-l-benzofuranyl, 3, 4-dihydro-lH-isochromenyl, 1,2,3, 4-tetrahydroquinolinyl , and 1 , 2 , 3 , 4-tetrahydroisoquinolinyl groups.

In the present invention, the "Cl-6 alkoxy group" refers to the aforementioned "Cl-6 alkyl group" bonded to an oxygen atom. Examples thereof can include linear or branched alkoxy groups each having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy,

2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy,

3-methylpentoxy, 2-methylpentoxy, 3 , 3-dimethylbutoxy, 2, 2-dimethylbutoxy, 1, 1-dimethylbutoxy,

1 , 2-dimethylbutoxy, 1 , 3-dimethylbutoxy, and

2, 3-dimethylbutoxy . For R ² , R ³ , R ⁴ , R ⁸ , A ^B , A ^D , A ^E , A ^F , A ^G , A ^H , or A ^J , the Cl-6 alkoxy group is preferably a methoxy or ethoxy group.

In the present invention, the "Cl-6 alkylcarbonyl group" refers to the aforementioned "Cl-6 alkyl group" bonded to a carbonyl group. Examples thereof can include methylcarbonyl , ethylcarbonyl , n-propylcarbonyl , n-butylcarbonyl , isobutylcarbonyl , s-butylcarbonyl , tert- butylcarbonyl , n-pentylcarbonyl , isopentylcarbonyl ,

2-methylbutylcarbonyl , neopentylcarbonyl ,

1-ethylpropylcarbonyl , n-hexylcarbonyl , isohexylcarbonyl , 4-methylpentylcarbonyl , 3-methylpentylcarbonyl ,

2-methylpentylcarbonyl , 1-methylpentylcarbonyl ,

3, 3-dimethylbutylcarbonyl , 2, 2-dimethylbutylcarbonyl , 1, 1-dimethylbutylcarbonyl , 1, 2-dimethylbutylcarbonyl, 1 , 3-dimethylbutylcarbonyl , 2 , 3-dimethylbutylcarbonyl , and 2-ethylbutylcarbonyl groups. For R ² , R ³ , or R ⁴ , the Cl-6 alkylcarbonyl group is preferably an alkylcarbonyl group having 1 to 3 carbon atoms, most preferably a

methylcarbonyl group.

In the present invention, the "C3-8

cycloalkylcarbonyl group" refers to the aforementioned "C3-8 cycloalkyl group" bonded to a carbonyl group.

Examples thereof can include cyclopropylcarbonyl,

cyclobutylcarbonyl , cyclopentylcarbonyl ,

cyclohexylcarbonyl , cycloheptylcarbonyl , and

cyclooctylcarbonyl groups.

In the present invention, the "C6-10 arylcarbonyl group" refers to the aforementioned "C6-10 aryl group" bonded to a carbonyl group. Examples thereof can include phenylcarbony, indenylcarbony, and naphthylcarbony groups.

In the present invention, the "4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" refers to the aforementioned "4- to 7-membered saturated heterocyclyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" bonded to a carbonyl group. Examples thereof can include morpholinylcarbonyl , thiomorpholinylcarbonyl , pyrrolidinylcarbonyl , pyrrolinylcarbonyl ,

piperidinylcarbonyl , piperazinylcarbonyl ,

tetrahydrofuranylcarbonyl , tetrahydropyranylcarbonyl , and 5-oxo-4 , 5-dihydro-l , 2 , 4-oxadiazolylcarbonyl groups .

In the present invention, the "3- to 10-membered heterocyclylcarbonyl group containing one to four

heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" refers to the

aforementioned "3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" bonded to a carbonyl group. Examples thereof can include the groups listed as the examples of the aforementioned "4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur", such as furylcarbonyl , thienylcarbonyl , pyrrolylcarbonyl , azepinylcarbonyl , pyrazolylcarbonyl , imidazolylcarbonyl , oxazolylcarbonyl , oxadiazolylcarbonyl , isoxazolylcarbonyl , thiazolylcarbonyl , isothiazolylcarbonyl , 1,2,3- oxadiazolylcarbonyl , triazolylcarbonyl , tetrazolylcarbonyl , thiadiazolylcarbonyl , pyranylcarbonyl , pyridylcarbonyl , pyridazinylcarbonyl , pyrimidinylcarbonyl , and pyrazinylcarbonyl groups.

In the present invention, the "Cl-6 alkoxycarbonyl group" refers to the aforementioned "Cl-6 alkoxy group" bonded to a carbonyl group. Examples thereof can include linear or branched alkoxycarbonyl groups each having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl , n-propoxycarbonyl , isopropoxycarbonyl , n-butoxycarbonyl , isobutoxycarbonyl , s-butoxycarbonyl , tert-butoxycarbonyl , n-pentoxycarbonyl , isopentoxycarbonyl ,

2-methylbutoxycarbonyl , neopentoxycarbonyl ,

n-hexyloxycarbonyl , 4-methylpentoxycarbonyl ,

3-methylpentoxycarbonyl , 2-methylpentoxycarbonyl ,

3, 3-dimethylbutoxycarbonyl , 2, 2-dimethylbutoxycarbonyl , 1, 1-dimethylbutoxycarbonyl , 1, 2-dimethylbutoxycarbonyl, 1 , 3-dimethylbutoxycarbonyl , and 2,3- dimethylbutoxycarbonyl . For R ² , R ³ , R ⁴ , R ⁸ , A ^B , or A ^J , the Cl-6 alkoxycarbonyl group is preferably a methoxycarbonyl or ethoxycarbonyl group.

In the present invention, the "C3-8

cycloalkoxycarbonyl group" refers to the aforementioned "C3-8 cycloalkyl group" bonded to a carbonyl group via an oxygen atom. Examples thereof can include

eyelopropyloxycarbonyl , cyclobutyloxycarbonyl ,

cyclopentyloxycarbonyl , eyelohexyloxycarbonyl ,

cycloheptyloxycarbonyl , and cyclooctyloxycarbonyl groups. In the present invention, the "4- to 7-membered saturated heterocyclyloxycarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" refers to the aforementioned "4- to 7-membered saturated

heterocyclylcarbonyl group containing one or two

heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" bonded to a carbonyl group via an oxygen atom. Examples thereof can include oxetanyloxycarbonyl , pyrrolidinyloxycarbonyl ,

piperidinyloxycarbonyl , tetrahydrofuranyloxycarbonyl and tetrahydropyranyloxycarbonyl groups .

In the present invention, the "C6-10

arylaminocarbonyl group" refers to the aforementioned "C6-10 aryl group" bonded to a carbonyl group via an amino group. Examples thereof can include

phenylaminocarbony, indenylaminocarbony, and

naphthylaminocarbony groups. For R ² , R ³ , or R ⁴ , the C6-10 arylaminocarbonyl group is preferably a

phenylaminocarbonyl group.

In the present invention, the "3- to 10-membered heterocyclylaminocarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" refers to the

aforementioned "3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" bonded to a carbonyl group via an amino group. Examples thereof can include such as furylaminocarbonyl ,

thienylaminocarbonyl , pyrrolylaminocarbonyl ,

azepinylaminocarbonyl , pyrazolylaminocarbonyl ,

imidazolylaminocarbonyl , oxazolylaminocarbonyl ,

oxadiazolylaminocarbonyl , isoxazolylaminocarbonyl , thiazolylaminocarbonyl , isothiazolylaminocarbonyl ,

1, 2, 3-oxadiazolylaminocarbonyl , triazolylaminocarbonyl , tetrazolylaminocarbonyl , thiadiazolylaminocarbonyl , pyrany1aminocarbonyl , pyridylaminocarbonyl ,

pyridazinylaminocarbonyl , pyrimidinylaminocarbonyl , pyrazinylaminocarbonyl groups, oxetanylaminocarbonyl , pyrrolidinylaminocarbonyl , piperidinylaminocarbonyl , tetrahydrofurany1aminocarbonyl and

tetrahydropyranylaminocarbonyl .

In the present invention, the "aminocarbonyloxy group" refers to the aforementioned "aminocarbonyl group" bonded to an oxygen atom.

In the present invention, the "4- to 7-membered saturated heterocyclylcarbonyloxy group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" refers to the aforementioned "4- to 7-membered saturated

heterocyclylcarbonyl group containing one or two

heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" bonded to an oxygen atom. Examples thereof can include morpholinylcarbonyloxy, thiomorpholinylcarbonyloxy, pyrrolidinylcarbonyloxy, pyrrolinylcarbonyloxy,

piperidinylcarbonyloxy, piperazinylcarbonyloxy,

tetrahydrofuranylcarbonyloxy,

tetrahydropyranylcarbonyloxy, and 5-oxo-4 , 5-dihydro- 1,2, 4-oxadiazolylcarbonyloxy groups .

In the present invention, the "halogeno group" refers to a fluoro, chloro, bromo, or iodo group. For R ² , R ³ , R ⁴ , R ⁸ , A ^B , A ^c , A ^D , A ^E , A ^F , A ^G , A ^H , or A ^J , the halogeno group is preferably a fluoro, chloro, or bromo group.

Preferably, R ¹ of the present invention is a

hydrogen atom.

Preferably, R ² of the present invention is a 3- to 10-membered heterocyclyl group containing one nitrogen, a Cl-6 alkylcarbonyl group (wherein the alkylcarbonyl group is optionally substituted by a hydroxy group, a Cl-6 alkoxy group, a 4- to 7-membered saturated heterocyclyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen and oxygen, or an aminocarbonyloxy group substituted by one Cl-6 alkyl groups), a Cl-6 alkoxycarbonyl group (wherein the

alkoxycarbonyl group is optionally substituted by a hydroxy group or a Cl-6 alkoxy group) , an aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different, each optionally substituted by Cl-6 alkyl groups), 3- to 10-membered heterocyclylcarbonyl group containing one nitrogen, 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two

heteroatoms, which may be the same or different, selected from nitrogen and oxygen, 3- to 10-membered

heterocyclylaminocarbony group containing one nitrogen, or 4- to 7-membered saturated heterocyclyloxycarbonyl group containing one oxygen

Preferably, R ³ and R ⁴ of the present invention are the same or different and each represent a hydrogen atom or a Cl-6 alkyl group, or the Cl-6 alkyl groups of R ³ and R ⁴ are bonded to each other to form a 3- to 6-membered saturated carbocyclic ring.

Preferably, each of R ⁵ and R ⁶ of the present

invention is a hydrogen atom.

Preferably, R ⁷ of the present invention is a

hydrogen atom.

Preferably, each R ⁸ of the present invention, which may be the same or different, represents a Cl-6 alkoxy group or a halogeno group.

Preferably, X of the present invention is -CH= or

-N=.

The compound represented by the general formula (I) of the present invention can form a salt with a base. Such a salt with a base is included in the scope of the present invention. Examples of the salt with a base can include: alkali metal salts such as lithium salt, sodium salt, potassium salt, and cesium salt; alkaline earth metal salts such as magnesium salt, calcium salt, and barium salt; inorganic nitrogen compound salts such as ammonium salt and hydrazine salt; primary amine salts such as methylamine salt, ethylamine salt, n-propylamine salt, isopropylamine salt, n-butylamine salt,

2-butylamine salt, isobutylamine salt, and

tert-butylamine salt; secondary amine salts such as dimethylamine salt, diethylamine salt, diisopropylamine salt, pyrrolidine salt, piperidine salt, and morpholine salt; tertiary amine salts such as triethylamine salt and N-methylmorpholine salt; and aromatic amine salts such as pyridine salt, 4- (N, N-dimethylamino ) pyridine salt, imidazole salt, and 1-methylimidazole salt. The salt is preferably an alkali metal salt, most preferably sodium salt or potassium salt. The compound represented by the general formula (I) of the present invention can form any ratio of a salt with a base. The respective salts with bases or mixtures thereof are included in the scope of the present invention.

The compound represented by the general formula (I) of the present invention can form an acid-addition salt, depending on its substituent. Such an acid-addition salt is included in the scope of the present invention. The compound represented by the general formula (I) of the present invention can form any ratio of an acid-addition salt, depending on its substituent. The respective acid- addition salts (e.g., monoacid salt and hemi-acid salt) or mixtures thereof are included in the salt of the present invention.

The compound represented by the general formula (I) of the present invention or the pharmacologically

acceptable salt thereof can form an anhydrate, a hydrate, or a solvate. The respective forms or mixtures thereof are included in the scope of the present invention.

When the compound represented by the general

formula (I) of the present invention or the

pharmacologically acceptable salt thereof has at least one asymmetric center, carbon-carbon double bond, axial chirality, tautomerism, or the like, optical isomers

(including enantiomers and diastereomers ) , geometric isomers, rotational isomers, and tautomers may exist. These isomers and mixtures thereof are represented by a single formula such as the formula (I) . The present invention encompasses these isomers and mixtures

(including racemates) thereof at any ratio.

The compound represented by the general formula (I) of the present invention or the pharmacologically

acceptable salt thereof can form an isotopic compound by the replacement of one or more atoms constituting the compound or the salt with isotopes at nonnatural ratios. The isotopes can be radioactive or nonradioactive.

Examples thereof include deuterium ( ² H; D) , tritium

( ³ H; T) , carbon-13 ( ¹³ C), carbon-14 ( ¹⁴ C), and iodine-125

( I) . The radioactive or nonradioactive isotopic compound may be used as a pharmaceutical for the

treatment or prophylaxis of a disease, a reagent for research (e.g., a reagent for assay), a diagnostic agent (e.g., a diagnostic imaging agent), or the like. The present invention encompasses these radioactive or nonradioactive isotopic compounds.

The compound represented by the general formula (I) of the present invention can be produced by, for example, the following method:

Method A:

In the structural formulas of the compounds in the method A and the description below, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , m, and X are as defined in the formula (I) ;

L ¹ represents a halogeno group or an amino group (wherein the amino group is optionally substituted by Cl-6 alkoxycarbonyl group) , and is preferably a bromo group; and

L ² represents a halogeno group and is preferably a fluoro group or a chloro group.

When a compound serving as a reactive substrate in the reaction of each step in the method A has a group inhibiting the reaction of interest, such as an amino group, a hydroxy group, or a carbonyl group, an

appropriate protective group may be introduced to the functional group and the introduced protective group may be removed, if necessary. Such a protective group is not particularly limited as long as the protective group is one usually used. The protective group can be a

protective group described in, for example, T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, Fifth Edition, 2014, John Wiley & Sons, Inc. The

reactions for the introduction and removal of these protective groups can be carried out according to routine methods such as methods described in the literature.

The solvent for use in the reaction of each step in the method A is not particularly limited as long as the solvent partially dissolves starting materials without inhibiting the reaction. The solvent is selected from, for example, the following solvent group: aliphatic hydrocarbons such as hexane, pentane, heptane, petroleum ether, and cyclohexane ; aromatic hydrocarbons such as toluene, benzene, and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon

tetrachloride, dichloroethane, chlorobenzene, and

dichlorobenzene ; ethers such as diethyl ether,

diisopropyl ether, cyclopentylmethyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane,

dimethoxyethane, and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone ; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and diethyl carbonate; nitriles such as acetonitrile, propionitrile, butyronitrile, and isobutyronitrile ;

organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, and pentafluoropropionic acid; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-l-propanol, and 2-methyl-2-propanol ; amides such as formamide,

N, N-dimethylformamide, N, N-dimethylacetamide,

N-methylpyrrolidone, N, N ' -dimethylpropyleneurea, and hexamethylphosphortriamide ; sulfoxides such as dimethyl sulfoxide and sulfolane; water; and mixtures thereof.

The acid for use in the reaction of each step in the method A mentioned below is not particularly limited as long as the acid does not inhibit the reaction. The acid is selected from the following acid group: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, and

pentafluoropropionic acid; and organic sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid.

The base for use in the reaction of each step in the method A mentioned below is not particularly limited as long as the base does not inhibit the reaction. The base is selected from the following base group: alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium

bicarbonate, and potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal phosphates such as sodium phosphate and potassium phosphate; alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; alkali metal amides such as lithium amide, sodium amide, and potassium amide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; lithium amides such as lithium diisopropylamide (LDA) , lithium cyclohexylisopropylamide, and lithium tetramethylpiperazide ; alkali metal

silylamides such as lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and potassium

bistrimethylsilylamide; alkyllithiums such as methyllithium, n-butyllithium, sec-butyllithium, and tert-butyllithium; alkyl magnesium halides such as methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, ethyl magnesium chloride, ethyl

magnesium bromide, isopropyl magnesium chloride,

isopropyl magnesium bromide, and isobutyl magnesium chloride; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, diethylamine, diisopropylamine, N-methylpiperidine, N-methylmorpholine, N-ethylmorpholine, pyridine, picoline, 2 , 6-lutidine,

4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,

N, N-diethylaniline, 1, 5-diazabicyclo [4, 3, 0] non-5-ene, 1 , 4-diazabicyclo [ 2 , 2 , 2 ] octane (DABCO) , and

1, 8-diazabicyclo [5, 4, 0] -7-undecene (DBU) .

In the reaction of each step in the method A

mentioned below, the reaction temperature differs

depending on solvents, starting materials, reagents, etc., and the reaction time differs depending on solvents, starting materials, reagents, etc.

After the completion of the reaction of each step in the method A mentioned below, the compound of interest of each step is isolated from the reaction mixture according to a routine method. The compound of interest is

obtained, for example, by: (i) if necessary, filtering off insoluble matter such as a catalyst; (ii) adding water and a water-immiscible solvent (e.g., methylene chloride, chloroform, diethyl ether, ethyl acetate, or toluene) to the reaction mixture to extract the compound of interest; (iii) washing the organic layer with water, followed by drying using a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate; and

(iv) distilling off the solvent. The obtained compound of interest can be further purified, if necessary, by a routine method, for example, recrystallization,

reprecipitation, or silica gel column chromatography. Alternatively, the compound of interest of each step may be used directly in the next reaction without being purified.

In the reaction of each step in the method A

mentioned below, optical isomers can be resolved by resolution using a chiral column.

Hereinafter, the reaction of each step in the method A will be described.

(Step A-l)

Step A-l is the step of reductive condensation of compound (1) and compound (2) to produce compound (3) . The compound (1) and (2) are known in the art or is easily obtained from a compound known in the art.

The method for reductive condensation of a carbonyl compound and an amine differs depending on the type of the carbonyl compound and the amine can be generally carried out by a method well known in the techniques of organic synthetic chemistry, for example, a method described in Comprehensive Organic Transformations

(Second Edition, 1999, John Wiley & Sons, Inc.,

pp. 835-846) . The method is preferably a method using a combination of a reducing agent and an additive.

Examples of the reducing agent used can include:

boran tetrahydrofuran complex, boran pyridine complex, boran dimethylsulfide complex, lithium borohydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride,

diisobutyl aluminum hydride, sodium

bis (methoxyethoxy) aluminum hydride. The reducing agent is preferably sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.

Examples of the additive used can include: acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, methanesulfonic acid, ethanesulfounic acid,

benzenesulfonic acid, p-toluenesulfonic acid,

10-camphorsulfonic acid, hydrogen chloride, hydrogen bromide, sulfuric acid, anhydrous magnesium sulfate and anhydrous sodium sulfate.

The method is preferably a method using a

combination of sodium triacetoxyborohydride and acetic acid .

Examples of the solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated

hydrocarbons, alcohols, ethers, esters, water and

mixtures thereof. The solvent is preferably a halogenated hydrocarbon, more preferably methylene chloride .

The reaction temperature is preferably 0°C to 100°C, more preferably room temperature.

The reaction time is preferably 15 minutes to

24 hours.

(Step A-2)

Step A-2 is the step of reacting the compound (3) obtained in the step A-l with allylating agent in the presence of a base to produce compound (4) .

The method for allylation of a nitrogen atom of a cyclic amine differs depending on the type of the amine can be generally carried out by a method well known in the techniques of organic synthetic chemistry, for example, a method described in T. W. Greene,

P. G. M. Wuts, Protective Groups in Organic Synthesis (Fifth Edition, 2014, John Wiley & Sons, Inc.,

pp. 1031-1034) . The method is preferably a method using an allylating agent in the presence of a base.

Examples of the allylating agent used can include allylchloride, allylbromide, allyliodide, allyl acetate, allyl methanesulfonate, allyl benzenesulfonate and allyl p-toluenesulfonate . The allylating agent is preferably allylbromide .

Examples of the base used can include alkali metal carbonates, alkali metal bicarbonates , alkali metal hydrides, lithium amides, alkali metal silylamides, alkyllithiums , and organic amines. The base is

preferably an alkali metal carbonate, more preferably potassium carbonate or cesium carbonate.

Examples of the solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated

hydrocarbons, ethers, esters, ketones, nitriles and amides. The solvent is preferably a nitrile and an amide, more preferably acetonitrile or N, N-dimethylformamide .

The reaction temperature is preferably 0°C to 120°C, more preferably room temperature to 80°C.

The reaction time is preferably 30 minutes to

48 hours.

(Step A-3)

Step A-3 is the step of intramolecularly cyclizing the compound (4) obtained in the step A-2 in the presence of a base to produce compound (5) . The compound (5) of interest of this step can also be converted, if necessary, to another compound (5) of interest through N-Boc amide forming reaction on the halogeno group of L ¹ . The

compound (5) of interest of this step can also be

converted, if necessary, to another compound (5) of interest through removal of the allyl group. The

compound (5) of interest of this step can also be

converted, if necessary, to another compound (5) of interest through modification reaction on the nitrogen atom of the amino group.

When L ¹ is a bromo group, step A-3 comprises:

(Step A-3-1) is the step of intramolecularly cyclizing the compound (4) obtained in the step A-2 in the presence of a base to produce compound (5);

(step A-3-2) : the step of converting the bromo group of the compound obtained in the step A-3-1 to a N-Boc amide group using a metal catalyst in the presence of a base to produce another compound (5);

(step A-3-3) : the step of removal of allyl group of the amino group of the compound obtained in the

step A-3-2 to produce another compound (5); and

(step A-3-4) : the step of modification reaction of the amino group of the compound obtained in the

step A-3-3 to produce another compound (5) .

(Step A-3-1)

Examples of the base used can include alkali metal carbonates, alkali metal bicarbonates , alkali metal hydrides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal alkoxides, lithium amides, alkali metal silylamides, and organic amines. The base is preferably an alkali metal hydride, more preferably sodium hydride.

Examples of the solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, nitriles, ketones, and amides. The solvent is preferably an ether or an amide, more preferably 1 , 2-dimethoxyethane or

N, N-dimethylformamide .

The reaction temperature is preferably 0°C to 100°C. The reaction time is preferably 30 minutes to

24 hours.

(Step A-3-2)

The method for converting the bromo group on the aromatic ring to a N-Boc amide group is not particularly limited as long as the method does not influence the other parts of the compound. This method can be carried out according to a method well known in the techniques of organic synthetic chemistry, for example, a method

described in A. P. Dishington, P. D. Johnson,

J. G. Kettle, Tetrahedron Letters, 45, 3733 (2004) or S. Bhagwanth, A. G. Waterson, G. M. Adjabeng,

K. R. Hornberger, Journal of Organic Chemistry, 74, 4634 (2009) .

The metal catalyst used is preferably a combination of tris (dibenzylideneacetone ) dipalladium ( 0 ) chloroform complex and 9, 9-dimethyl-4 , 5- bis (diphenylphosphino) xanthene (Xantphos (TM) ) or a

combination of tris (dibenzylideneacetone ) dipalladium ( 0 ) chloroform complex and di-tert-butyl ( 2 ' , 4 ' , 6 ' - triisopropylbiphenyl-2-yl ) phosphine (tBuXPhos (TM) ) . The base used is preferably an alkali metal

carbonate, an alkali metal phosphate, or an alkali metal alkoxide, more preferably potassium carbonate, cesium carbonate, potassium phosphate, or sodium tert-butoxide .

Examples of the solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated

hydrocarbons, alcohols, ethers, esters, nitriles, ketones, amides, and mixtures thereof. The solvent is preferably an aromatic hydrocarbon, an ether, a nitrile, or an amide, more preferably toluene, 1,4-dioxane, acetonitrile, or N, N-dimethylformamide .

The reaction temperature is preferably room

temperature to 100°C.

The reaction time is preferably 1 hour to 48 hours.

(Step A-3-3)

The method for removal of allyl group on amino group is not particularly limited as long as the method does not influence the other parts of the compound. This method can be carried out according to a method well known in the techniques of organic synthetic chemistry, for example, a method described in T. W. Greene,

P. G. M. Wuts, Protective Groups in Organic Synthesis (Fifth Edition, 2014, John Wiley & Sons, Inc., pp. 1031- 1034) . The method is preferably a method using a metal catalyst in the presence of a nucleophile. The metal catalyst used is preferably tetrakis ( triphenylphsphine ) palladium ( 0 ) or a combination of tris (dibenzylideneacetone ) dipalladium ( 0 ) chloroform complex and triphenylphosphine .

Example of the nucleophile used can include

pyrrolidine, sodium benzenesulfinate, sodium

2-ethylhexanoate, dimethyl malonate, dimedone, and

N, N-dimethylbarbituric acd. The nucleophile is

preferably N, N-dimethylbarbituric acd.

Examples of the solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated

hydrocarbons, ethers, esters, nitriles, amides, and mixtures thereof. The solvent is preferably a

halogenated hydrocarbons, more preferably methylene chloride .

The reaction temperature is preferably 0°C to room temperature .

The reaction time is preferably 15 minutes to

24 hours.

(Step A-3-4)

The reaction for converting the compound (5) of interest obtained in this step to another compound (5) of interest through modification on the nitrogen atom of the amino group is not particularly limited as long as the reaction does not influence the other parts of the compound. This reaction can be carried out by, for example, a method described in Comprehensive Organic Transformations (Second Edition, 1999, John Wiley & Sons, Inc., pp. 789-792, 1941-1949, 1953-1954, 1957-1958,

1973-1976 and 1978-1982) .

(Step A-4)

Step A-4 is the step of reacting the compound (5) obtained in the step A-3-4 with compound (6) in the presence of a base to produce compound (I) . The compound (6) is known in the art or is easily obtained from a compound known in the art. The compound (I) of interest of this step can also be converted, if necessary, to another compound (I) of interest through deprotection reaction. The reaction for converting the obtained compound (I) of interest to another compound (I) of interest by the removal of the protective group is not particularly limited as long as the reaction does not influence the other parts of the compound. This reaction can be carried out according to a routine method, for example, a method described in T . W. Greene,

P. G. M. Wuts, Protective Groups in Organic Synthesis, Fifth Edition, 2014, John Wiley & Sons, Inc.

When L ¹ is a N-Boc group, step A-4 comprises:

(step A-4-1) : the step of removing of the N-Boc group of the compound (5) obtained in the step A-3-4 into an amino group; and (step A-4-2) : the step of reacting the compound obtained in the step A-4-1 with compound (6) in the presence of a base to produce compound (I) .

(Step A-4-1)

The method for removing of the N-Boc group is not particularly limited as long as the method does not influence the other parts of the compound. This method can be generally carried out by a method well known in the techniques of organic synthetic chemistry, for

example, a method described in T . W. Greene,

P. G. M. Wuts, Protective Groups in Organic Synthesis (Fifth Edition, 2014, John Wiley & Sons, Inc., pp. 930- 946) . The method is preferably a method using an acid.

Examples of the acid for use in the removing of the N-Boc group can include inorganic acids and organic acids. The acid is preferably hydrochloric acid.

The solvent for use in the removing of the N-Boc group is not particularly limited as long as the solvent is inert to this reaction. Examples of the solvent can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, nitriles, ketones, amides, and mixtures thereof. The solvent is preferably an alcohol, more preferably

methanol .

The reaction temperature in the removing of the

N-Boc group is preferably 0°C to 60°C. The reaction time in the removing of the N-Boc group is preferably 10 minutes to 24 hours.

(Step A-4-2)

Examples of the base used can include alkali metal carbonates, alkali metal bicarbonates , alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, lithium amides, alkali metal silylamides, and organic amines. The base is preferably an organic amine, more preferably pyridine.

Examples of the solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated

hydrocarbons, ethers, esters, nitriles, ketones, and amides. Alternatively, the solvent may not be used.

Preferably, the solvent is not used.

The reaction temperature is preferably 0°C to 100°C, more preferably room temperature to 80°C.

The reaction time is preferably 15 minutes to

24 hours, more preferably 30 minutes to 6 hours.

The reaction for converting the obtained compound (I) of interest obtained in this step to another compound (I) of interest by the removal of the protective group is not particularly limited as long as the reaction does not influence the other parts of the compound. This reaction can be carried out according to a routine method, for example, a method described in T . W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, Fifth Edition, 2014, John Wiley & Sons, Inc.

When L ¹ is a bromo group, the compound (I) can also be produced through the reaction of the compound (5) with the following compound (7) :

using a metal catalyst in the presence of a base.

The method for converting the bromo group on the aromatic ring to a benzenesulfonamide group is not

particularly limited as long as the method does not influence the other parts of the compound. This method can be carried out according to a method well known in the techniques of organic synthetic chemistry, for

example, a method described in X. Wang, A. Guram, M. Ronk, J. E. Milne, J. S. Tedrow, M. M. Faul, Tetrahedron

Letters, 53, 7 (2012), W. Deng, L. Liu, C. Zhang,

M. Liu, ; Q.-X. Guo, Tetrahedron Letters, 46, 7295 (2005), or D. K. Luci, J. B. Jameson, A. Yasgar, G. Diaz,

N. Joshi, A. Kantz, K. Markham, S. Perry, N. Kuhn,

J. Yeung, E. H. Kerns, L. Schultz, M. Holinstat,

J. Nadler, D. A. Taylor-Fishwick, A. Jadhav, A. Simeonov, T. R. Holman, D. J. Maloney, Journal of Medicinal

Chemistry, 57, 495 (2014) . The metal catalyst used is preferably a combination of copper(I) iodide and N, N ¹ -dimethylethane-1 , 2-diamine, and a combination of copper (I) iodide and trans-N, N ¹ - dimethyleyelohexane-1 , 2-diamine .

The base used is preferably an alkali metal

carbonate, an alkali metal phosphate, or an alkali metal alkoxide, more preferably potassium carbonate or cesium carbonate .

Examples of the solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated

hydrocarbons, alcohols, ethers, esters, nitriles, ketones, amides, and mixtures thereof. The solvent is preferably an aromatic hydrocarbon, an ether, a nitrile, or an amide, more preferably xylene, 1,4-dioxane, acetonitrile, or N, N-dimethylformamide .

The reaction temperature is preferably room

temperature to 100°C.

The reaction time is preferably 1 hour to 48 hours.

When the compound represented by the general formula (I) of the present invention or the pharmacologically acceptable salt thereof is used as a pharmaceutical, the compound or the salt can be administered alone (i.e., as a bulk) or can be administered orally as an appropriate pharmaceutically acceptable preparation such as a tablet, a capsule, granules, a powder, or a syrup or parenterally as an appropriate pharmaceutically acceptable preparation such as an injection, a suppository, or a patch

(preferably orally) .

These preparations are produced by well-known methods using additives such as excipients, binders, disintegrants , lubricants, emulsifiers, stabilizers, corrigents, diluents, solvents for injections, oleaginous bases, and water-soluble bases.

Examples of the excipients can include organic excipients and inorganic excipients. Examples of the organic excipients can include: sugar derivatives such as lactose, saccharose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, and carboxymethyl starch; cellulose derivatives such as crystalline cellulose,

low-substituted hydroxypropylcellulose,

hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internally

cross-linked carboxymethylcellulose sodium; gum arabic; dextran; and pullulan. Examples of the inorganic

excipients can include: light anhydrous silicic acid and silicate derivatives such as synthetic aluminum silicate and calcium silicate; phosphates such as calcium

phosphate; and sulfates such as calcium sulfates.

Examples of the binders can include: the excipients listed above; gelatin; polyvinylpyrrolidone; and

polyethylene glycol. Examples of the disintegrants can include: the excipients listed above; chemically modified starch or cellulose derivatives such as croscarmellose sodium and carboxymethyl starch sodium; and cross-linked

polyvinylpyrrolidone .

Examples of the lubricants can include: talc;

stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as bees wax and spermaceti; boric acid; glycol;

D, L leucine; carboxylic acids such as fumaric acid and adipic acid; carboxylic acid sodium salts such as sodium benzoate; sulfates such as sodium sulfate; lauryl

sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the starch derivatives listed as the excipients.

Examples of the emulsifiers can include: colloidal clay such as bentonite and veegum; anionic surfactants such as sodium lauryl sulfate and calcium stearate;

cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester.

Examples of the stabilizers can include:

p-hydroxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol , benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal;

dehydroacetic acid; and sorbic acid.

Examples of the corrigents can include sweeteners, acidulants, and flavors usually used.

Examples of the diluents can include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.

Examples of the solvents for injections can include water, ethanol, and glycerin.

Examples of the oleaginous bases can include cacao butter, laurin butter, coconut oil, palm kernel oil, camellia oil, liquid paraffin, white petrolatum, purified lanoline, glycerin monostearate, polyoxyethylene

hydrogenated castor oil, sorbitan fatty acid ester, sucrose fatty acid ester, stearyl alcohol, and cetanol.

Examples of the water-soluble bases can include glycerin, polyethylene glycol, ethanol, and purified water .

The dose of the compound represented by the general formula (I) of the present invention or the

pharmacologically acceptable salt thereof serving as an active ingredient differs depending on the symptoms and age of a patient, etc. The single dose thereof is

0.001 mg/kg (preferably 0.01 mg/kg) as the lower limit and 10 mg/kg (preferably 1 mg/kg) as the upper limit for oral administration and 0.001 mg/kg (preferably 0.01 mg/kg) as the lower limit and 10 mg/kg (preferably 1 mg/kg) as the upper limit for parenteral administration and can be administered once to six times a day according to the symptoms.

The compound of the present invention can be used in combination with any of various therapeutic or

prophylactic agents for the aforementioned disease for which the compound of the present invention is probably effective. In this combined use, the compound of the present invention and the agent may be administered simultaneously, separately but continuously, or at the desired time interval. The preparations to be

administered simultaneously may be formulated as a combination drug or formulated as separate preparations.

The oxazepine compound or the pharmacologically acceptable salt thereof, which is the compound of the present invention, has an excellent TNAP inhibitory effect and is useful as a therapeutic or prophylactic agent for pseudoxanthoma elasticum (PXE) , generalized arterial calcification of infancy (GACI),

craniometaphyseal dysplasia (CMD) , ossification of the yellow ligament (OYL) , arterial calcification due to deficiency of CD73 (ACDC) , arthrosis deformans,

osteoarthritis, ankylosis of the joint, idiopathic infantile arterial calcification (IIAC), ankylosing spondylitis (AS), tumoral calcinosis (TC) , progressive osseous heteroplasia (POH) , Keutel syndrome, vascular calcification associated with chronic renal failure

(including glomerulonephritis, IgA nephropathy,

hypertensive nephropathy, and diabetic nephropathy) and secondary parathyroid hyperplasia, metastatic

calcification, calciphylaxis , calcific tendinitis of the longus colli muscle, fibrodysplasia ossificans

progressiva (FOP), calcific aortic stenosis, pericarditis calculosa, atherosclerotic vascular calcification, calcific uremic arteriopathy (CUA) , Kawasaki disease, calcification due to obesity and aging, tibial arterial calcification, bone metastasis, prosthetic calcification, Paget' s disease, or peritoneal calcification. Moreover, the compound of the present invention has low toxicity and excellent safety and as such, is very useful as a pharmaceutical .

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Hereinafter, the present invention will be described in more detail with reference to Examples, etc. However, the scope of the present invention is not intended to be limited by them.

The chemical structural formulas described in

Examples represent the chemical structures of

corresponding compounds in a free form or a possible salt form.

Elution in column chromatography in Examples was carried out under observation by thin layer

chromatography (TLC) . In the TLC observation, silica gel 6OF254 manufactured by Merck KGaA was used as a TLC plate; a solvent used as an eluting solvent in column

chromatography was used as a developing solvent; and a UV detector or a chromogenic method using a coloring agent (e.g., a ninhydrin coloring solution, an

anisaldehyde coloring solution, an ammonium

phosphomolybdate coloring solution, a cerium ammonium nitrate (CAM) coloring solution, or an alkaline

permanganate coloring solution) was used as a detection method. Silica gel SK-85 (230-400 mesh) also

manufactured by Merck KGaA, silica gel 60 N (40-50 μπι) manufactured by Kanto Chemical Co., Inc., or Chromatorex NH (200-350 mesh) manufactured by Fu i Silysia Chemical Ltd. was used as silica gel for columns. In addition to general column chromatography, an automatic

chromatography apparatus (Purif-a.2 or Purif-espoir2 ) manufactured by Shoko Scientific Co., Ltd., an automatic chromatography apparatus (W-Prep 2XY) manufactured by Yamazen Corp., an automatic chromatography apparatus (Isolera One) manufactured by Biotage Japan Ltd., or an automatic chromatography apparatus (CombiFlash Rf) manufactured by Teledyne Isco, Inc. was appropriately used. The eluting solvent was determined on the basis of the TLC observation.

In Examples, nuclear magnetic resonance (½ NMR) spectra were indicated by chemical shift δ values (ppm) determined with tetramethylsilane as a standard. Splitting patterns were indicated by s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, and br for broad. Mass spectrometry (hereinafter,

referred to as MS) was conducted by the electron

ionization (EI), electron spray ionization (ESI),

atmospheric pressure chemical ionization (APCI), electron spray atmospheric pressure chemical ionization (ES/APCI), or fast atom bombardment (FAB) method.

In each step of Examples, the adjustment of a

reaction solution and reaction were carried out at room temperature unless the temperature is otherwise specified. Examples

(Example 1) methyl 7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl ] amino } -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(la) 2- { [ ( 5-bromo-2-fluoropyridin-3-yl ) methyl ] (prop-2-en- 1-yl ) amino } ethanol

To a solution of 5-bromo-2-fluoropyridine-3- carbaldehyde (5.00 g, 24.5 mmol) in methylene chloride (250 mL) , 2-aminoethanol (1.76 mL, 29.4 mmol) and acetic acid (1.68 mL, 29.3 mmol) were added at room temperature, and the mixture was stirred at the same temperature as above for 5 minutes. Subsequently, sodium

triacetoxyborohydride (7.79 g, 36.8 mmol) was added thereto at room temperature, and the mixture was stirred at the same temperature as above for 1 hour. The mixture was diluted by addition of a saturated aqueous solution of sodium bicarbonate (100 mL) and isopropanol (33 mL) , followed by extraction with a mixed solvent of methylene chloride/isopropanol = 3/1 (180 mL) . The organic layer was dried over anhydrous sodium sulfate. After

filtration, the solvent was distilled off under reduced pressure to obtain a crude product of 2- { [ ( 5-bromo-2- fluoropyridin-3-yl ) methyl ] amino } ethanol (5.80 g) . To a mixture of a crude product of 2- { [ ( 5-bromo-2- fluoropyridin-3-yl ) methyl ] amino } ethanol (5.80 g) obtained in the above step and potassium carbonate (9.65 g,

69.8 mmol) in acetonitrile (120 mL) , 3-bromoprop-l-ene (3.0 mL, 35 mmol) was added at room temperature, and the mixture was stirred at 60°C for 3.5 hours in an oil bath. The reaction mixture was cooled, and then concentrated under reduced pressure. The residue was diluted by addition of water, followed by extraction with ethyl acetate twice. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 3/2 - 1/1) to obtain the title compound (5.52 g, yield for 2 steps: 78%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.17-8.17 (1H, m) , 7.94-7.92 (1H, m) , 5.89-5.79 (1H, m) , 5.23-5.21 (2H, m) , 3.66-3.63 (4H, m) , 3.16 (2H, br d, J = 6.3 Hz), 2.70 (2H, t, J = 5.3 Hz), 2.37 (1H, br s) .

(lb) 7-bromo-4- (prop-2-en-l-yl) -2,3,4,5- tetrahydropyrido [3,2-f] [ 1 , 4 ] oxazepine

To a solution of 2- { [ ( 5-bromo-2-fluoropyridin-3- yl) methyl] (prop-2-en-l-yl ) amino } ethanol (5.50 g,

19.0 mmol) obtained in Example (la) in N,N- dimethylformamide (190 mL) , sodium hydride (approximately 63% content, 1.09 g, 28.6 mmol) was added at room

temperature in several portions, the mixture was stirred at 60°C for 4.5 hours in an oil bath, and subsequently stirred at 80°C for 6.5 hours in an oil bath. The mixture was cooled to room temperature, acetic acid

(0.54 mL, 9.4 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated into approximately 1/5 of the amount under reduced pressure. The concentrated mixture was diluted by addition of water, followed by extraction with ethyl acetate twice. The organic layer was washed with water twice and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 3/2 - 2/3) to obtain the title compound (3.27 g,

yield: 64%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.21 (1H, d, J =

2.7 Hz), 7.61 (1H, d, J = 2.7 Hz), 5.91-5.81 (1H, m) , 5.24-5.18 (2H, m) , 4.20-4.18 (2H, m) , 3.71 (2H, s),

3.17-3.16 (2H, m) , 3.08-3.06 (2H, m) .

(lc) tert-butyl 2 , 3 , 4 , 5-tetrahydropyrido [ 3 , 2- f] [ 1 , 4 ] oxazepin-7-ylcarbamate

To a mixture of 7-bromo-4- (prop-2-en-l-yl) -2, 3, 4, 5- tetrahydropyrido [ 3 , 2-f] [ 1 , 4 ] oxazepine (3.27 g, 12.1 mmol) obtained in Example (lb), tert-butyl carbamate (1.86 g, 15.9 mmol), tris (dibenzylideneacetone ) dipalladium ( 0 ) - chloroform adduct (625.6 mg, 0.60 mmol), 2-di-tert- butylphosphino-2 ' , 4 ' , 6 ' -triisopropylbiphenyl (1.03 g, 2.43 mmol) in toluene (120 mL) , sodium tert-butoxide

(2.69 g, 28.0 mmol) was added at room temperature, and the mixture was stirred under nitrogen atmosphere at the same temperature as above for 6 hours . The mixture was diluted by addition of a saturated aqueous solution of ammonium chloride, water and ethyl acetate, and then an insoluble material was filtered off through pad of Celite 545 (R) . The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane/methanol = 2/1/0 - 1/0/0 - 10/0/1) to obtain tert-butyl [4-(prop-2- en-l-yl ) -2 , 3 , 4 , 5-tetrahydropyrido [3, 2 -f] [ 1 , 4 ] oxazepin-7- yl] carbamate (3.44 g) . To a solution of tert-butyl

[4- (prop-2-en-l-yl ) -2,3,4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate (3.44 g) obtained in the above step and 1 , 3-dimethylbarbituric Acid (4.40 g, 28.2 mmol) in methylene chloride (150

mL) , tetrakis ( triphenylphosphine ) palladium ( 0 ) (0.651 g, 0.56 mmol) was added at room temperature, and the mixture was stirred under nitrogen atmosphere at the same temperature as above for 6 hours. The solvent was distilled off under reduced pressure, and the residue was diluted by addition of a 1.0 mol/L aqueous solution of sodium hydroxide (20 mL) , followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column

chromatography (ethyl acetate) . To the obtained solid, diisopropyl ether (60 mL) and ethyl acetate (30 mL) were added, and the precipitated solid was collected by filtration, washed with a mixed solvent of diisopropyl ether/ethyl acetate = 3/1, and then dried to obtain the title compound (2.25 g, yield for 2 steps: 70%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.91-7.89 (2H, m) , 6.47 (1H, br s), 4.14-4.12 (2H, m) , 3.93 (2H, s),

3.25-3.24 (2H, m) , 1.52 (9H, s) .

(Id) methyl 7- [ ( tert-butoxycarbonyl ) amino ] -2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a mixture of tert-butyl 2,3,4,5- tetrahydropyrido [3,2- f] [1,4] oxazepin-7-ylcarbamate

(350 mg, 1.32 mmol) obtained in Example (lc) in a mixed solvent of ethyl acetate (13 mL) and water (13 mL) , sodium bicarbonate (443 mg, 5.28 mmol) and methyl chloroformate (0.152 mL, 1.98 mmol) at room temperature, and the mixture was stirred at the same temperature as above for 45 minutes. The mixture was diluted by

addition of ethyl acetate, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus

(ethyl acetate/n-hexane = 95/5 - 100/0) to obtain the title compound (321 mg, yield: 75%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.11-7.84 (2H, m) , 6.55-6.39 (1H, m) , 4.48 (2H, d, J = 15.9 Hz), 4.20-4.14 (2H, m) , 3.93-3.83 (2H, m) , 3.69 (3H, d, J = 12.8 Hz), 1.55-1.47 (9H, m) .

(le) methyl 7-amino-2 , 3-dihydropyrido [ 3 , 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a solution of methyl l-[ (tert- butoxycarbonyl ) amino] -2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (319 mg, 0.99 mmol) obtained in Example (Id) in methanol (4 mL) , a 4.0 mol/L solution of hydrogen chloride in 1,4-dioxane (2 mL, 8 mmol) was added at room temperature, the mixture was stirred at room temperature for 4.5 hours. The mixture was poured into a saturated aqueous solution of sodium bicarbonate, followed by extraction with a mixed solvent of methylene chloride/isopropanol = 4/1. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (methylene chloride/methanol = 100/0 - 96/4) to obtain the title compound (125 mg, yield: 57%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.64-7.63 (1H, m) , 7.04-6.94 (1H, m) , 4.41-4.37 (2H, m) , 4.11-4.08 (2H, m) , 3.87-3.83 (2H, m) , 3.70-3.67 (3H, m) , 3.56 (2H, br s) . (If) methyl 7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl ] amino } -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a mixture of methyl 7-amino-2,3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(60 mg, 0.27 mmol) obtained in Example (le) and pyridine (1.0 mL, 12 mmol), 5-chloro-2-methoxybenzenesulfonyl chloride (71 mg, 0.30 mmol) was added at room temperature, and the mixture was stirred at 80°C for 20 minutes in an oil bath. After cooling, the mixture was concentrated under reduced pressure, the residue was diluted by

addition of ethyl acetate, and then the solvent was distilled off under reduced pressure again. To the residue, isopropanol (2 mL) and water (0.2 mL) were added, the precipitated solid was collected by filtration, washed with a mixed solvent of isopropanol/water =10/1, and then dried to obtain the title compound (67.5 mg, yield: 59%) .

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.23 (1H, br s), 7.76 (1H, d, J = 3.1 Hz), 7.68-7.66 (2H, m) , 7.40 (1H, d, J = 3.1 Hz), 7.26-7.24 (1H, m) , 4.43 (2H, br s), 4.15 (2H, br s), 3.86 (3H, s), 3.72 (2H, br s), 3.56-3.52 (3H, m) . MS spectrum (ES/APCI ⁺ ) : 428 (M+H) , 430 (M+2+H) .

(Example 2) 7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl ] amino } -N, N-dimethyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxamide

(2a) tert-butyl [4- (dimethylcarbamoyl) -2, 3, 4, 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

The title compound (100 mg, yield: 32%) was obtained by production according to the method described in

Example (Id) using tert-butyl 2,3,4,5- tetrahydropyrido [3,2- f] [1,4] oxazepin-7-ylcarbamate

(250 mg, 0.94 mmol) obtained in Example (lc) and

N, N-dimethylcarbamoyl chloride (0.108 mL, 1.18 mmol) as starting materials.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.96-7.93 (2H, m) , 6.45 (1H, br s), 4.33 (2H, br s), 4.25 (2H, t , J =

4.9 Hz), 3.69 (2H, t, J = 4.9 Hz), 2.82 (6H, s), 1.51 (9H, s) .

(2b) 7- { [ ( 5-chloro-2-methoxyphenyl ) sulfonyl ] amino } -N, N- dimethyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) - carboxamide

The title compound (62.9 mg, yield for 2 steps: 49%) was obtained by production according to the method described in Examples (le) and (If) using tert-butyl

[4- (dimethylcarbamoyl) -2,3,4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate (98.9 mg, 0.29 mmol) obtained in Example (2a) and 5-chloro-2- methoxybenzenesulfonyl chloride (36 mg, 0.15 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.18 (1H, s), 7.70- 7.65 (3H, m) , 7.41 (1H, d, J = 2.4 Hz), 7.25 (1H, d, J = 9.2 Hz), 4.27 (2H, br s), 4.22-4.21 (2H, m) , 3.89 (3H, s), 3.52-3.50 (2H, m) , 2.64 (6H, s) .

MS spectrum (ES/APCI ⁺ ) : 441 (M+H) , 443 (M+2+H) .

(Example 3) 5-chloro-2-methoxy-N- [ 4- (morpholin-4- ylcarbonyl ) -2 , 3 , 4 , 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin- 7-yl ] benzenesulfonamide

(3a) tert-butyl [ 4- (morpholin-4-ylcarbonyl ) -2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

The title compound (190 mg, yield: 67%) was obtained by production according to the method described in

Example (Id) using tert-butyl 2,3,4,5- tetrahydropyrido [3,2- f] [1,4] oxazepin-7-ylcarbamate

(200 mg, 0.75 mmol) obtained in Example (lc) and

morpholine-4-carbonyl chloride (0.129 mL, 1.13 mmol) as starting materials. ½ NMR spectrum (CDCI ₃ , 400MHz) δ: 7.96-7.96 (2H, m) , 6.45 (1H, br s), 4.36 (2H, s), 4.26 (2H, t, J = 4.9 Hz), 3.72-3.68 (6H, m) , 3.29-3.24 (4H, m) , 1.51 (9H, s) .

(3b) 5-chloro-2-methoxy-N- [4- (morpholin-4-ylcarbonyl ) - 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] benzenesulfonamide

The title compound (22.5 mg, yield for 2 steps: 17%) was obtained by production according to the method described in Examples (le) and (If) using tert-butyl

[4- (morpholin-4-ylcarbonyl ) -2,3,4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate (189 mg, 0.50 mmol) obtained in Example (3a) and 5-chloro-2- methoxybenzenesulfonyl chloride (31 mg, 0.13 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.19 (1H, br s), 7.69-7.65 (3H, m) , 7.42 (1H, d, J = 2.4 Hz), 7.25 (1H, d, J = 8.5 Hz), 4.32 (2H, s), 4.24-4.23 (2H, m) , 3.87 (3H, s) , 3.57-3.55 (6H, m) , 3.05-3.04 (4H, m) .

MS spectrum (ES/APCI ⁺ ) : 483 (M+H) , 485 (M+2+H) .

(Example 4) 5-chloro-2-methoxy-N- [ 4- (methoxyacetyl ) - 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] benzenesulfonamide

(4a) tert-butyl [ 4- (methoxyacetyl ) -2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

The title compound (190 mg, yield: 60%) was obtained by production according to the method described in

Example (Id) using tert-butyl 2,3,4,5- tetrahydropyrido [3,2- f] [1,4] oxazepin-7-ylcarbamate

(250 mg, 0.94 mmol) obtained in Example (lc) and

methoxyacetyl chloride (0.107 mL, 1.18 mmol) as starting materials .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.04-7.95 (1H, m) , 6.50 (0.5H, br s), 6.42 (0.5H, br s), 4.61 (1H, s), 4.57 (1H, s), 4.24-4.19 (3H, m) , 4.07 (1H, s), 4.02 (1H, t, J = 4.6 Hz), 3.92 (1H, t, J = 4.6 Hz), 3.38 (1.5H, s), 3.35 (1.5H, s), 1.52 (4.5H, s), 1.51 (4.5H, s) .

(4b) 5-chloro-2-methoxy-N- [4- (methoxyacetyl) -2,3,4,5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] benzenesulfonamide

The title compound (39.5 mg, yield for 2 steps: 16%) was obtained by production according to the method described in Examples (le) and (If) using tert-butyl [4- (methoxyacetyl ) -2,3,4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate (189 mg, 0.56 mmol) obtained in Example (4a) and 5-chloro-2- methoxybenzenesulfonyl chloride (38 mg, 0.16 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.24 (1H, br s), 7.77-7.75 (1H, m) , 7.68-7.65 (2H, m) , 7.49 (0.5H, d, J = 2.4 Hz), 7.42 (0.5H, d, J = 2.4 Hz), 7.25-7.23 (1H, m) , 4.56 (1H, s), 4.50 (1H, s), 4.23-4.18 (2H, m) , 4.06 (1H, s), 3.96 (1H, s), 3.88 (1.5H, s), 3.86 (1.5H, s), 3.77-3.75 (2H, m) , 3.20 (1.5H, s), 3.04 (1.5H, s) .

MS spectrum (ES/APCI ⁺ ) : 442 (M+H) , 444 (M+2+H) .

(Example 5) 5-chloro-iV- [ 4- (hydroxyacetyl ) -2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] -2- methoxybenzenesulfonamide

(5a) tert-butyl [ 4- (hydroxyacetyl ) -2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

To a mixture of tert-butyl 2,3,4,5- tetrahydropyrido [3,2- f] [1,4] oxazepin-7-ylcarbamate (202 mg, 0.76 mmol) obtained in Example (lc), glycolic acid (69.5 mg, 0.91 mmol), N- [3- (dimethylamino) propyl] - N ¹ -ethylcarbodiimide hydrochloride (190 mg, 0.99 mmol) and lfi-benzotriazol-l-ol (HOBt, 103 mg, 0.76 mmol) in methylene chloride (4 mL) , N, N-diisopropylethylamine (0.265 mL, 1.52 mmol) was added at room temperature, and the mixture was stirred at the same temperature as above for 1 hour. The mixture was diluted by addition of ethyl acetate, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (ethyl acetate/methanol = 95/5 - 80/20) to obtain the title compound (157 mg, yield: 64%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.05-7.95 (2H, m) , 6.56 (0.5H, br s), 6.48 (0.5H, br s), 4.69 (1H, s), 4.36 (1H, s), 4.27-3.45 (6H, m) , 1.53 (4.5H, s), 1.52

(4.5H, s) .

(5b) 5-chloro-N- [4- (hydroxyacetyl ) -2,3,4,5- tetrahydropyrido [3,2-f] [ 1 , 4 ] oxazepin-7-yl ] -2- methoxybenzenesulfonamide

The title compound (73.7 mg, yield for 2 steps: 37%) was obtained by production according to the method described in Examples (le) and (If) using tert-butyl

[4- (hydroxyacetyl) -2,3,4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate (154 mg, 0.48 mmol) obtained in Example (5a) and 5-chloro-2- methoxybenzenesulfonyl chloride (59 mg, 0.24 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.24 (1H, br s), 7.75 (1H, br s), 7.67-7.64 (2H, m) , 7.50 (0.5H, d, J = 2.4 Hz), 7.44 (0.5H, d, J = 2.4 Hz), 7.25-7.23 (1H, m) , 4.69-4.67 (1H, m) , 4.55-4.52 (2H, m) , 4.22-4.20 (2H, m) , 4.07-4.05 (1H, m) , 3.95-3.94 (1H, m) , 3.83-3.75 (5H, m) . MS spectrum (ES/APCI ⁺ ) : 428 (M+H) , 430 (M+2+H) .

(Example 6) potassium [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] [4- (hydroxyacetyl ) -2,3,4,5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] azanide

(potassium salt of Example 5)

To a suspension of 5-chloro-iV- [ 4- (hydroxyacetyl ) - 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] -2- methoxybenzenesulfonamide (30.0 mg, 0.070 mmol) obtained in Example (5b) in ethanol (0.7 mL) and water (0.0064 mL) , a solution of 0.5 N potassium hydroxide in ethanol

(0.142 mL, 0.071 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure to obtain a crude solid. To the crude solid, isopropanol was added, the precipitated solid was collected by filtration, and then dried to obtain the title compound (30.8 mg, yield: 94%) .

½ NMR spectrum (DMSO-d6, 400MHz) δ: 7.68-7.63 (1H, m) , 7.45-7.38 (1H, m) , 7.35-7.30 (1H, m) , 7.19-7.14 (1H, m) , 7.00-6.95 (1H, m) , 4.65-4.53 (1H, m) , 4.41-4.29 (2H, m) , 4.08-4.02 (2H, m) , 4.02-3.90 (2H, m) , 3.82-3.76 (1H, m) , 3.69-3.60 (4H, m) .

(Example 7) 5-chloro-2-methoxy-N- [ 4- (pyridin-3- ylcarbonyl ) -2 , 3 , 4 , 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin- 7-yl ] benzenesulfonamide

(7a) tert-butyl [ 4- (pyridin-3-ylcarbonyl ) -2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

The title compound (176 mg, yield: 62%) was obtained by production according to the method described in

Example (5a) using tert-butyl 2,3,4,5- tetrahydropyrido [3,2- f] [1,4] oxazepin-7-ylcarbamate

(203 mg, 0.77 mmol) obtained in Example (lc) and

nicotinic acid (113 mg, 1.18 mmol) as starting materials. ½ NMR spectrum (CDCI ₃ , 400MHz) δ: 8.78-8.55 (2H, m) , 8.14-8.00 (2H, m) , 7.76-7.67 (1H, m) , 7.48-7.32 (1H, m) ,

6.62- 6.45 (1H, m) , 4.79 (1H, s), 4.52-4.30 (2H, m) , 4.18 (2H, br s), 3.87 (1H, br s), 1.52 (9H, s) .

(7b) 5-chloro-2-methoxy-N- [4- (pyridin-3-ylcarbonyl ) - 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] benzenesulfonamide

The title compound (32.0 mg, yield for 2 steps: 28%) was obtained by production according to the method described in Examples (le) and (If) using tert-butyl

[4- (pyridin-3-ylcarbonyl ) -2,3,4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate (174 mg, 0.47 mmol) obtained in Example (7a) and 5-chloro-2- methoxybenzenesulfonyl chloride (49.6 mg, 0.21 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.26-10.20 (1H, m) ,

8.63- 8.45 (2H, m) , 7.83-7.02 (7H, m) , 4.72 (1H, br s), 4.40-4.29 (3H, m) , 3.91-3.77 (5H, m) .

MS spectrum (ES/APCI ⁺ ) : 475 (M+H) , 477 (M+2+H) .

(Example 8) 2-methoxyethyl 7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl ] amino } -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(8a) 1- { [ (2-methoxyethoxy) carbonyl] oxy } pyrrolidine-2 , 5- dione

To a solution of 2-methoxyethanol (0.18 mL,

2.3 mmol) in acetonitrile (2 mL) , triethylamine (0.956 mL, 6.90 mmol) and 1, 1 ' - [carbonylbis (oxy) ] dipyrrolidine-2, 5- dione (0.884 g, 3.45 mmol) were added at room temperature, and the mixture was stirred at the same temperature as above for 21 hours. The mixture was concentrated under reduced pressure, the residue was diluted with a

saturated aqueous solution of sodium bicarbonate,

followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (508 mg, yield: quantitative) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 4.49-4.43 (2H, m) , 3.71-3.66 (2H, m) , 3.41 (3H, s), 2.84 (4H, s) .

(8b) 2-methoxyethyl 7- [ ( tert-butoxycarbonyl ) amino ] -2 , 3- dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate To a mixture of a crude product of l-{ [ (2- methoxyethoxy) carbonyl ] oxy }pyrrolidine-2 , 5-dione (530 mg, 2.30 mmol ) obtained in Example (8a) in methylene chloride

(4 mL) , tert-butyl 2 , 3 , 4 , 5-tetrahydropyrido [ 3 , 2- f] [ 1 , 4 ] oxazepin-7-ylcarbamate (530 mg, 2.00 mmol) obtained in Example (lc) and triethylamine (0.515 mL, 3.00 mmol) were added at room temperature, and the mixture was stirred at the same temperature as above for 3 days. The mixture was diluted by addition of ethyl acetate, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus

(ethyl acetate/n-hexane = 70/30 - 100/0) to obtain the title compound (585 mg, yield: 80%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.12-7.82 (2H, m) , 6.54-6.39 (1H, m) , 4.53-4.45 (2H, m) , 4.26-4.12 (4H, m) , 3.93-3.86 (2H, m) , 3.62-3.52 (2H, m) , 3.37-3.35 (3H, m) , 1.52 (9H, s) .

(8c) 2-methoxyethyl 7-amino-2 , 3-dihydropyrido [ 3 , 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a solution of 2-methoxyethyl l-[ (tert- butoxycarbonyl ) amino] -2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (530 mg, 1.44 mmol) obtained in Example (8b) in methanol (4 mL) , a 4.0 mol/L solution of hydrogen chloride in 1,4-dioxane (8 mL, 32 mmol) was added at room temperature, the mixture was stirred at the same temperature as above for 15 hours. The mixture was concentrated under reduced pressure, methanol (4 mL) and N, N-diisopropylethylamine (8 mL, 46 mmol) were added thereto, and the solvent was

distilled off under reduced pressure again. The residue was purified in an automatic chromatography apparatus (Yamazen Co. Ltd., High-flash™ column Amino, methylene chloride/methanol = 100/0 - 96/4) to obtain the title compound (411 mg, yield: quantitative) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.64-7.63 (1H, m) , 7.02-6.99 (1H, m) , 4.41-4.40 (2H, m) , 4.22-4.21 (2H, m) , 4.11-4.09 (2H, m) , 3.88-3.86 (2H, m) , 3.55 (4H, br s), 3.38-3.35 (3H, m) .

(8d) 2-methoxyethyl 7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl ] amino } -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (14.5 mg, yield: 16%) was obtained by production according to the method described in Example (If) using 2-methoxyethyl 7-amino-2,3- dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (53.1 mg, 0.20 mmol) obtained in Example (8c) and

5-chloro-2-methoxybenzenesulfonyl chloride (49.6 mg, 0.21 mmol) as starting materials. ½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.25-10.23 (1H, 7.75-7.66 (3H, m) , 7.43-7.41 (1H, m) , 7.25-7.24 (1H, 4.43 (2H, br s), 4.17-4.03 (4H, m) , 3.86 (3H, br s), (2H, br s), 3.45-3.42 (2H, m) , 3.19 (3H, br s) .

MS spectrum (ES/APCI ⁺ ) : 473 (M+H) , 475 (M+2+H) .

(Example 9) (3S) -tetrahydrofuran-3-yl 7- { [ ( 5-chloro-2 methoxyphenyl ) sulfonyl ] amino } -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(9a) 1- ( { [ (3S) -tetrahydrofuran-3- yloxy] carbonyl } oxy) pyrrol idine-2 , 5-dione

To a solution of ( 3S) -tetrahydrofuran-3-ol (0.175 mL, 2.20 mmol) in acetonitrile (2 mL) , triethylamine

(0.915 mL, 6.60 mmol) and 1,1'-

[carbonylbis (oxy) ] dipyrrolidine-2 , 5-dione (0.845 g,

3.30 mmol) were added at room temperature, and the mixture was stirred at the same temperature as above for 21.5 hours. The mixture was concentrated under reduced pressure, the residue was diluted with a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (474 mg, yield: 94%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 5.40-5.32 (1H, m) , 4.05-3.83 (4H, m) , 2.85 (4H, s), 2.27-2.18 (2H, m) .

(9b) (3S) -tetrahydrofuran-3-yl l-[ (tert- butoxycarbonyl ) amino] -2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a mixture of tert-butyl 2,3,4,5- tetrahydropyrido [3,2- f] [1,4] oxazepin-7-ylcarbamate

(220 mg, 0.83 mmol) obtained in Example (lc) in methylene chloride (2 mL) , triethylamine (0.172 mL, 1.24 mmol) and a crude product of 1- ( { [ ( 3S) -tetrahydrofuran-3- yloxy] carbonyl } oxy) pyrrolidine-2 , 5-dione (0.219 g,

0.95 mmol) obtained in Example (9a) were added at room temperature, and the mixture was stirred at the same temperature as above for 3 hours and 20 minutes. The mixture was diluted by addition of ethyl acetate, the organic layer was washed with a saturated aqueous

solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (ethyl acetate/n-hexane = 80/20 - 100/0) to obtain the title compound (315 mg, yield: quantitative) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.09-7.98 (1H, m) , 7.98-7.84 (1H, m) , 6.61-6.39 (1H, m) , 5.28-5.19 (1H, m) , 4.53-4.41 (2H, m) , 4.21-4.11 (2H, m) , 4.01-3.76 (6H, m) , 2.19-1.94 (2H, m) , 1.52 (9H, s) .

(9c) (3S) -tetrahydrofuran-3-yl 7-amino-2,3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a solution of ( 3S) -tetrahydrofuran-3-yl l-[ (tert- butoxycarbonyl ) amino] -2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (315 mg, 0.83 mmol) obtained in Example (9b) in methanol (2.5 mL) , a

4.0 mol/L solution of hydrogen chloride in 1,4-dioxane

(5 mL, 20 mmol) was added at room temperature, the mixture was stirred at the same temperature as above for 2.5 hours . The mixture was concentrated under reduced pressure, methanol (2.5 mL) and N, N-diisopropylethylamine

(5 mL, 29 mmol) were added thereto, and the solvent was distilled off under reduced pressure again. The residue was purified in an automatic chromatography apparatus

(Yamazen Co. Ltd., High-flash™ column Amino, methylene chloride/methanol = 100/0 - 96/4) to obtain the title compound (218 mg, yield: 94%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.66-7.60 (1H, m) , 7.03 (0.5H, d, J = 3.0 Hz), 6.92 (0.5H, d, J = 3.0 Hz), 5.30-5.19 (1H, m) , 4.48-4.30 (2H, m) , 4.17-4.03 (2H, m) , 3.95-3.75 (6H, m) , 3.65-3.52 (2H, m) , 2.21-2.10 (1H, m) , 2.02-1.94 (1H, m) .

(9d) ( 3S) -tetrahydrofuran-3-yl 7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl ] amino } -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (68.5 mg, yield: 66%) was

obtained by production according to the method described in Example (If) using ( 3S) -tetrahydrofuran-3-yl 7-amino- 2 , 3-dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(65.8 mg, 0.24 mmol) obtained in Example (9c) and

5-chloro-2-methoxybenzenesulfonyl chloride (62.2 mg, 0.25 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.26-10.22 (1H, m) , 7.73-7.68 (3H, m) , 7.43-7.41 (1H, m) , 7.26-7.24 (1H, m) , 5.07-5.04 (1H, m) , 4.43-4.41 (2H, m) , 4.15-4.13 (2H, m) , 3.82-3.58 (9H, m) , 2.09-1.97 (1H, m) , 1.85-1.76 (1H, m) . MS spectrum (ES/APCI ⁺ ) : 484 (M+H) , 486 (M+2+H) .

(Example 10) ( 3R) -tetrahydrofuran-3-yl 7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl ] amino } -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(10a) 1- ( { [ (3R) -tetrahydrofuran-3- yloxy] carbonyl } oxy) pyrrol idine-2 , 5-dione

To a solution of ( 3R) -tetrahydrofuran-3-ol (0.175 mL, 2.20 mmol) in acetonitrile (11 mL) , triethylamine

(0.915 mL, 6.60 mmol) and 1,1'-

[carbonylbis (oxy) ] dipyrrolidine-2 , 5-dione (0.845 g,

3.30 mmol) were added at room temperature, and the mixture was stirred at the same temperature as above for 21.5 hours. The mixture was concentrated under reduced pressure, the residue was diluted with a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product of the title compound

(481 mg, yield: 95%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 5.38-5.35 (1H, m) , 4.03-3.88 (4H, m) , 2.85 (4H, s), 2.31-2.16 (2H, m) . (10b) ( 3R) -tetrahydrofuran-3-yl l-[ (tert- butoxycarbonyl ) amino] -2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a mixture of tert-butyl 2,3,4,5- tetrahydropyrido [3,2- f] [1,4] oxazepin-7-ylcarbamate

(220 mg, 0.83 mmol) obtained in Example (lc) in methylene chloride (2 mL) , triethylamine (0.172 mL, 1.24 mmol) and a crude product of 1- ({ [ ( 3R) -tetrahydrofuran-3- yloxy] carbonyl } oxy) pyrrolidine-2 , 5-dione (0.231 g,

0.95 mmol) obtained in Example (10a) were added at room temperature, and the mixture was stirred at the same temperature as above for 4 hours . The mixture was diluted by addition of ethyl acetate, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (ethyl acetate/n-hexane = 80/20 - 100/0) to obtain the title compound (315 mg,

yield: quantitative) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.09-7.98 (1H, m) , 7.98-7.84 (1H, m) , 6.61-6.39 (1H, m) , 5.28-5.19 (1H, m) , 4.53-4.41 (2H, m) , 4.21-4.11 (2H, m) , 4.01-3.76 (6H, m) , 2.19-1.94 (2H, m) , 1.52 (9H, s) . (10c) ( 3R) -tetrahydrofuran-3-yl 7-amino-2,3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a solution of ( 3R) -tetrahydrofuran-3-yl l-[ (tert- butoxycarbonyl ) amino] -2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (315 mg, 0.83 mmol) obtained in Example (10b) in methanol (2.5 mL) , a

4.0 mol/L solution of hydrogen chloride in 1,4-dioxane

(5 mL, 20 mmol) was added at room temperature, the mixture was stirred at the same temperature as above for 3 hours . The mixture was concentrated under reduced pressure, methanol (2.5 mL) and N, N-diisopropylethylamine

(5 mL, 29 mmol) were added thereto, and the solvent was distilled off under reduced pressure again. The residue was purified in an automatic chromatography apparatus

(Yamazen Co. Ltd., High-flash™ column Amino, methylene chloride/methanol = 100/0 - 96/4) to obtain the title compound (219 mg, yield: 94%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.66-7.61 (1H, m) , 7.03 (0.5H, d, J = 3.0 Hz), 6.92 (0.5H, d, J = 3.0 Hz), 5.30-5.19 (1H, m) , 4.48-4.30 (2H, m) , 4.15-4.04 (2H, m) , 3.95-3.74 (6H, m) , 3.65-3.50 (2H, m) , 2.21-2.10 (1H, m) , 2.03-1.92 (1H, m) .

(lOd) ( 3R) -tetrahydrofuran-3-yl 7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl ] amino } -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate The title compound (62.8 mg, yield: 71%) was

obtained by production according to the method described in Example (If) using ( 3R) -tetrahydrofuran-3-yl 7-amino- 2 , 3-dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (62.8 mg, 0.23 mmol) obtained in Example (10c) and

5-chloro-2-methoxybenzenesulfonyl chloride (58.9 mg, 0.24 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.26-10.22 (1H, m) , 7.73-7.68 (3H, m) , 7.43-7.41 (1H, m) , 7.26-7.24 (1H, m) , 5.07-5.04 (1H, m) , 4.43-4.41 (2H, m) , 4.15-4.13 (2H, m) , 3.82-3.58 (9H, m) , 2.09-1.97 (1H, m) , 1.85-1.76 (1H, m) . MS spectrum (ES/APCI ⁺ ) : 484 (M+H) , 486 (M+2+H) .

(Example 11) 2-methoxyethyl 7- { [ ( 5-chloro-2- methoxypyridin-3-yl ) sulfonyl] amino}-2, 3- dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(11a) 5-chloro-2-methoxypyridine-3-sulfonyl chloride

To a mixture of 3-bromo-5-chloro-2-methoxypyridine (2.24 g, 10.1 mmol), phenylmethanethiol (1.18 mL,

10.1 mmol), Tris (dibenzylideneacetone ) dipalladium ( 0 ) (0.2319 g, 0.25 mmol) and ( 9, 9-dimethyl-9fi-xanthene-4 , 5- diyl) bis (diphenylphosphane) (0.2955 g, 0.51 mmol) in 1,4- dioxane (100 mL) , N, N-Diisopropylethylamine (3.5 mL, 20 mmol) was added at room temperature, the mixture was stirred under nitrogen atmosphere at 100°C for 30 minutes in an oil bath. The mixture was cooled, and concentrated under reduced pressure. The residue was diluted by addition of water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ ethyl acetate = 15/1) to obtain

3- (benzylsulfanyl ) -5-chloro-2-methoxypyridine (2.76 g) as a mixture containing unknown materials. To a mixture of 3- (benzylsulfanyl ) -5-chloro-2-methoxypyridine (2.76 g) obtained in the above step, acetic acid (5.8 mL,

100 mmol) and water (2.5 mL, 139 mmol) in acetonitrile (50 mL) , 1 , 3-dichloro-5, 5-dimethylhydantoin (3.97 g, 20.2 mmol) was added under ice cooling over 5 minutes in several portions, and the mixture was stirred at the same temperature as above for 20 minutes. The mixture was concentrated under reduced pressure, and diluted by addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over

anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography

(n-hexane/ethyl acetate = 4/1 - 2/1) . To the obtained solid, n-hexane (4 mL) was added, the precipitated solid was collected by filtration, washed with n-hexane, and then dried to obtain the title compound (1.86 g, yield for 2 steps : 76%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.43 (1H, d, J =

2.7 Hz), 8.22 (1H, d, J = 2.7 Hz), 4.19 (3H, s) .

(lib) 2-methoxyethyl 7- { [ ( 5-chloro-2-methoxypyridin-3- yl ) sulfonyl ] amino } -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a mixture of 2-methoxyethyl 7-amino-2,3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(73.5 mg, 0.28 mmol) obtained in Example (8c) and

pyridine (1.0 mL, 12 mmol), 5-chloro-2-methoxypyridine-3- sulfonyl chloride (68.9 mg, 0.28 mmol) obtained in

Example (11a) was added at room temperature, and the mixture was stirred at 80°C for 40 minutes in an oil bath. After cooling, the mixture was concentrated under reduced pressure, the residue was purified in an automatic

chromatography apparatus (methylene chloride/methanol = 100/0 - 91/9) . To the obtained solid, a mixed solvent of ethyl acetate/benzene = 1/1 was added, the precipitated solid was collected by filtration, and then dried to obtain the title compound (83.2 mg, yield: 64%) .

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.53 (1H, s), 8.49 (1H, d, J = 2.4 Hz), 8.15 (1H, d, J = 2.4 Hz), 7.83-7.76 (1H, m) , 7.47-7.40 (1H, m) , 4.44 (2H, s), 4.22-4.11 (2H, m) , 4.10-4.00 (2H, m) , 3.93 (3H, s), 3.76-3.69 (2H, m) ,

3.49-3.38 (2H, m) , 3.22-3.15 (3H, m) .

MS spectrum (ES/APCI ⁺ ) : 473 (M+H) , 475 (M+2+H) .

(Example 12) potassium [ ( 5-chloro-2-methoxypyridin-3- yl) sulfonyl] { 4- [ ( 2-methoxyethoxy) carbonyl] -2,3,4,5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl } azanide

(potassium salt of Example 11)

To a suspension of 2-methoxyethyl 7- { [ ( 5-chloro-2- methoxypyridin-3-yl ) sulfonyl] amino}-2, 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (33.5 mg, 0.069 mmol) obtained in Example (lib) in ethanol (0.7 mL) , a solution of 0.5 N potassium hydroxide in ethanol (0.15 mL, 0.075 mmol) was added at room temperature, and the mixture was stirred at room

temperature for 14 hours. The solvent was distilled off under reduced pressure to obtain a crude solid. To the crude solid, diisopropyl ether was added, the precipitated solid was collected by filtration, and then dried to obtain the title compound (29.2 mg, yield: 82%) ½ NMR spectrum (DMSO-d6, 400MHz) δ: 8.16 (1H, d, J = 2.4 Hz), 7.93 (1H, d, J = 2.4 Hz), 7.49-7.41 (1H, m) , 7.19-7.07 (1H, m) , 4.32-4.24 (2H, m) , 4.09-3.89 (4H, m) , 3.76 (3H, s), 3.73-3.65 (2H, m) , 3.49-3.39 (2H, m) , 3.21 (3H, s) .

(Example 13) ( 3S) -tetrahydrofuran-3-yl 7- { [ ( 5-chloro-2- methoxypyridin-3-yl ) sulfonyl] amino}-2, 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a mixture of ( 3S) -tetrahydrofuran-3-yl 7-amino- 2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (71.1 mg, 0.26 mmol) obtained in Example (9c) and

pyridine (1.0 mL, 12 mmol), 5-chloro-2-methoxypyridine-3- sulfonyl chloride (65.5 mg, 0.28 mmol) obtained in

Example (11a) was added at room temperature, and the mixture was stirred at 80°C for 70 minutes in an oil bath. After cooling, the mixture was concentrated under reduced pressure, the residue was purified in an automatic chromatography apparatus (methylene chloride/methanol = 100/0 - 91/9) . To the obtained solid, ethyl acetate was added, the precipitated solid was collected by filtration, and then dried to obtain the title compound (74.3 mg, yield: 60%) .

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.59-10.49 (1H, m) , 8.49 (1H, d, J = 1.8 Hz), 8.17-8.12 (1H, m) , 7.80 (1H, s), 7.46-7.40 (1H, m) , 5.13-4.98 (1H, m) , 4.48-4.39 (2H, m) , 4.21-4.09 (2H, m) , 3.97-3.90 (3H, m) , 3.80-3.64 (5H, m) , 3.63-3.50 (1H, m) , 2.09-1.96 (1H, m) , 1.86-1.73 (1H, m) . MS spectrum (ES/APCI ⁺ ) : 485 (M+H) , 487 (M+2+H) .

(Example 14) potassium [ ( 5-chloro-2-methoxypyridin-3- yl ) sulfonyl ] ( 4- { [ ( 3S) -tetrahydrofuran-3-yloxy] carbonyl } - 2,3,4, 5-tetrahydropyrido [3, 2 - f] [ 1 , 4 ] oxazepin-7-yl ) azanide

(potassium salt of Example 13)

To a suspension of ( 3S) -tetrahydrofuran-3-yl 7-{ [ (5- chloro-2-methoxypyridin-3-yl ) sulfonyl] amino}-2, 3- dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(33.4 mg, 0.069 mmol) obtained in Example 13 in ethanol (0.7 mL) , a solution of 0.5 N potassium hydroxide in ethanol (0.155 mL, 0.078 mmol) was added at room

temperature, and the mixture was stirred at room

temperature for 14 hours. The solvent was distilled off under reduced pressure to obtain a crude solid. To the crude solid, diisopropyl ether was added, the

precipitated solid was collected by filtration, and then dried to obtain the title compound (32.2 mg, yield: 89%) . ½ NMR spectrum (DMSO-d6, 400MHz) δ: 8.16 (1H, d, J = 2.4 Hz), 7.93 (1H, d, J = 2.4 Hz), 7.51-7.41 (1H, m) , 7.19-7.05 (1H, m) , 5.15-4.97 (1H, m) , 4.35-4.17 (2H, m) , 4.02-3.55 (11H, m) , 2.14-1.73 (2H, m) .

(Example 15) ( 3R) -tetrahydrofuran-3-yl 7- { [ ( 5-chloro-2- methoxypyridin-3-yl ) sulfonyl] amino}-2, 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a mixture of ( 3R) -tetrahydrofuran-3-yl 7-amino- 2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (82.0 mg, 0.29 mmol) obtained in Example (10c) and pyridine (1.0 mL, 12 mmol), 5-chloro-2-methoxypyridine-3- sulfonyl chloride (75.1 mg, 0.31 mmol) obtained in

Example (11a) was added at room temperature, and the mixture was stirred at 80°C for 70 minutes in an oil bath. After cooling, the mixture was concentrated under reduced pressure, the residue was purified in an automatic

chromatography apparatus (methylene chloride/methanol = 100/0 - 91/9) . To the obtained solid, ethyl acetate was added, the precipitated solid was collected by filtration, and then dried to obtain the title compound (80.1 mg, yield: 56%) .

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.59-10.51 (1H, m) , 8.49 (1H, d, J = 2.4 Hz), 8.15 (1H, s), 7.80 (1H, s), 7.48-7.39 (1H, m) , 5.11-5.00 (1H, m) , 4.49-4.38 (2H, m) , 4.22-4.07 (2H, m) , 3.97-3.89 (3H, m) , 3.80-3.65 (5H, m) , 3.62-3.50 (1H, m) , 2.13-1.93 (1H, m) , 1.86-1.72 (1H, m) . MS spectrum (ES/APCI ⁺ ) : 485 (M+H) , 487 (M+2+H) .

(Example 16) potassium [ ( 5-chloro-2-methoxypyridin-3- yl ) sulfonyl ] ( 4- { [ (3R) -tetrahydrofuran-3-yloxy] carbonyl } - 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ) azanide

(potassium salt of Example 15)

To a suspension of ( 3R) -tetrahydrofuran-3-yl 7-{ [ (5- chloro-2-methoxypyridin-3-yl ) sulfonyl] amino}-2, 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (33.5 mg, 0.069 mmol) obtained in Example 15 in ethanol (0.7 mL) , a solution of 0.5 N potassium hydroxide in ethanol (0.145 mL, 0.073 mmol) was added at room

temperature, and the mixture was stirred at room

temperature for 14 hours. The solvent was distilled off under reduced pressure to obtain a crude solid. To the crude solid, diisopropyl ether was added, the

precipitated solid was collected by filtration, and then dried to obtain the title compound (29.5 mg, yield: 82%) . ½ NMR spectrum (DMSO-d6, 400MHz) δ: 8.16 (1H, d, J = 2.4 Hz), 7.93 (1H, d, J = 2.4 Hz), 7.50-7.41 (1H, m) , 7.18-7.07 (1H, m) , 5.14-4.97 (1H, m) , 4.344.18- (2H, m) , 4.01--3.54 (11H, m) , 2.11-1.72 (2H, m) .

(Example 17) 5-chloro-2-methoxy-N- [ 4- (pyridin-3-yl ) - 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] benzenesulfonamide

(17a) tert-butyl [ 4- (pyridin-3-yl ) -2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate A mixture of tert-butyl 2,3,4,5- tetrahydropyrido [3,2-f] [1,4] oxazepin-7-ylcarbamate

(300 mg, 1.13 mmol) obtained in Example (lc),

tris (dibenzylideneacetone ) dipalladium ( 0 ) (613.5 mg,

0.59 mmol), dicyclohexyl [ 2 ' , 4 ' , 6 ' -tri (propan-2- yl ) biphenyl-2-yl ] phosphane (Xphos™, 0.162 g, 0.34 mmol) and sodium tert-butoxide (0.326 g, 3.39 mmol) and

3-bromopyridine (0.214 g, 1.36 mmol) in

N, N-dimethylformamide (5 mL) was stirred under nitrogen atmosphere at 100°C for 9 hours in an oil bath. The mixture was cooled to room temperature, and an insoluble material was filtered off through pad of Celite 545 (R) . The residue was washed with ethyl acetate, and the

filtrate and the washes were combined. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by a preparative thin layer chromatography (methylene chloride/methanol = 10/1) to obtain the title compound (88.7 mg, yield: 23%) as a mixture containing a small amount of 3-bromopyridine. ½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.22 (1H, d, J =

2.7 Hz), 8.09 (1H, br s), 7.99-7.98 (1H, m) , 7.92 (1H, d, J = 2.7 Hz), 7.13-7.05 (2H, m) , 6.57 (1H, s), 4.60 (2H, s) , 4.29 (2H, t, J = 4.3 Hz), 3.93 (2H, t, J = 4.3 Hz),

1.53 (9H, s) . (17b) 5-chloro-2-methoxy-I\/- [4- (pyridin-3-yl ) -2,3,4,5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] benzenesulfonamide

The title compound (9.8 mg, yield for 2 steps: 9%) was obtained by production according to the method described in Examples (le) and (If) using tert-butyl

[4- (pyridin-3-yl ) -2,3,4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate (85 mg, 0.25 mmol) obtained in Example (17a) and 5-chloro-2- methoxybenzenesulfonyl chloride (72 mg, 0.30 mmol) as starting materials.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.15 (1H, br s), 8.01 (1H, br s), 7.71-7.71 (2H, m) , 7.66 (1H, br d, J =

2.7 Hz), 7.46 (1H, dd, J = 8.8, 2.5 Hz), 7.00-6.98 (3H, m) , 4.57 (2H, br s), 4.32 (2H, br t, J = 4.5 Hz),

4.02 (3H, br s), 3.91 (2H, br t, J = 4.5 Hz) .

MS spectrum (ES/APCI ⁺ ) : 447 (M+H) , 449 (M+2+H) .

(Example 18) methyl ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(18a) {2R) -2- { [ ( 5-bromo-2-fluoropyridin-3- yl ) methyl ] amino }propan-l-ol

To a solution of 5-bromo-2-fluoropyridine-3- carbaldehyde (4.09 g, 20.0 mmol) and acetic acid (1.72 mL, 30 mmol) in methylene chloride (100 mL) , (2R)-2- aminopropan-l-ol (2.35 mL, 30.1 mmol) was added at room temperature, and the mixture was stirred at the same temperature as above for 10 minutes. Subsequently, sodium triacetoxyborohydride (6.37 g, 30.1 mmol) was added thereto at room temperature, and the mixture was stirred at the same temperature as above for 3 hours. The mixture was concentrated into approximately 1/5 of the amount under reduced pressure. The concentrated mixture was diluted by addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate three times. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. To obtained solid, diisopropyl ether was added, the

precipitated solid was collected by filtration, washed with diisopropyl ether, and the dried to obtain the title compound (3.99 g, yield: 76%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.16-8.16 (1H, m) ,

7.98 (1H, dd, J = 8.4, 2.5 Hz), 3.92 (1H, d, J = 14.5 Hz),

3.78 (1H, d, J = 14.5 Hz), 3.65 (1H, dd, J = 10.8, 4.1 Hz), 3.35 (1H, dd, J = 10.8, 7.0 Hz), 2.89-2.81 (1H, m) , 1.11 (3H, d, J = 6.3 Hz) .

(18b) {2R) -2- { [ ( 5-bromo-2-fluoropyridin-3- yl) methyl] (prop-2-en-l-yl) amino }propan-l-ol

To a mixture of (2R) -2- { [ (5-bromo-2-fluoropyridin-3- yl ) methyl ] amino }propan-l-ol (3.98 g, 15.1 mmol) obtained in Example (18a) and 3-bromoprop-l-ene (1.92 mL,

22.7 mmol) in acetonitrile (75 mL) , potassium carbonate

(6.27 g, 45.4 mmol) was added at room temperature, the mixture was stirred at the same temperature as above for 15 hours and subsequently stirred at 60°C for 7 hours in an oil bath. The reaction mixture was cooled, and then concentrated under reduced pressure. The residue was diluted by addition of water, followed by extraction with ethyl acetate twice. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography

(n-hexane/ethyl acetate = 2/1) to obtain the title compound (4.43 g, yield: 97%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.16 (1H, br s), 7.90 (1H, dd, J = 8.2, 2.7 Hz), 5.83-5.73 (1H, m) , 5.24-5.15 (2H, m) , 3.76 (1H, d, J = 14.9 Hz), 3.49-3.43 (3H, m) ,

3.27-3.21 (1H, m) , 3.05-2.99 (2H, m) , 2.77 (1H, br s),

0.97 (3H, d, J = 6.7 Hz) . (18c) (3R) -7-bromo-3-methyl-4- (prop-2-en-l-yl) -2,3,4,5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepine

To a solution of (2R) -2- { [ (5-bromo-2-fluoropyridin- 3-yl)methyl] (prop-2-en-l-yl ) amino }propan-l-ol (4.43 g, 14.6 mmol) obtained in Example (18b) in N,N- dimethylformamide (145 mL) , sodium hydride (approximately 63% content, 0.84 g, 22 mmol) was added at room

temperature in several portions, the mixture was stirred at 70°C for 10 hours in an oil bath. The mixture was cooled to room temperature, acetic acid (0.42 mL,

7.3 mmol) was added thereto, and the mixture was stirred at room temperature for 5 minutes. The mixture was concentrated into approximately 1/5 of the amount under reduced pressure. The concentrated mixture was diluted by addition of water, followed by extraction with ethyl acetate twice. The organic layer was washed with water twice and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 2/1) to obtain the title compound (3.10 g, yield: 75%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.17 (1H, d, J =

2.3 Hz), 7.54 (1H, d, J = 2.3 Hz), 5.87-5.77 (1H, m) , 5.16-5.13 (2H, m) , 4.22 (1H, dd, J = 12.9, 2.9 Hz), 4.14 (1H, d, J = 15.6 Hz), 4.05 (1H, dd, J = 12.9, 7.0 Hz), 3.67 (1H, d, J = 15.6 Hz), 3.30-3.12 (3H, m) , 1.21 (3H, d, J = 6.6 Hz) .

(18d) tert-butyl [ ( 3R) -3-methyl-2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

To a mixture of ( 3R) -7-bromo-3-methyl-4- (prop-2-en- 1-yl ) -2 , 3 , 4 , 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepine

(3.10 g, 10.9 mmol) obtained in Example (18c), tert-butyl carbamate (1.67 g, 14.3 mmol),

tris (dibenzylideneacetone ) dipalladium ( 0 ) -chloroform adduct (0.56 g, 0.54 mmol), 2-di-tert-butylphosphino- 2 ' , 4 ' , 6 ' -triisopropylbiphenyl (0.93 g, 2.2 mmol) in toluene (110 mL) , sodium tert-butoxide (2.42 g,

25.2 mmol) was added at room temperature, and the mixture was stirred under nitrogen atmosphere at the same

temperature as above for 3 hours . The mixture was

diluted by addition of a saturated aqueous solution of ammonium chloride, water and ethyl acetate, and then an insoluble material was filtered off through pad of Celite 545 (R) . The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After

filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1 - 2/1 - 1/0) to obtain tert-butyl [ ( 3R) -3-methyl-4- (prop-2-en- 1-yl ) -2 , 3 , 4 , 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl] carbamate (3.41 g) . To a solution of tert-butyl

[ (3R) -3-methyl-4- (prop-2-en-l-yl) -2,3,4,5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

(3.41 g) obtained in the above step and 1,3- dimethylbarbituric Acid (4.16 g, 26.6 mmol) in methylene chloride (105 mL) ,

tetrakis ( triphenylphosphine ) palladium ( 0 ) (0.62 g,

0.54 mmol) was added at room temperature, and the mixture was stirred under nitrogen atmosphere at the same temperature as above for 2 hours. The solvent was distilled off under reduced pressure, and the residue was diluted by addition of a 1.0 mol/L aqueous solution of sodium hydroxide (50 mL) , followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column

chromatography (methylene chloride/methanol = 20/1 - 10/1) and NH silica gel column chromatography (ethyl acetate) . To the obtained solid, diisopropyl ether

(15 mL) was added, and the precipitated solid was

collected by filtration, washed with diisopropyl ether, and then dried to obtain the title compound (1.93 g, yield for 2 steps: 63%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.90-7.88 (2H, m) , 6.45 (1H, br s), 4.34 (1H, dd, J = 12.5, 2.7 Hz), 4.00 - Ill -

(1H, d, J = 15.3 Hz), 3.90 (1H, d, J = 15.3 Hz), 3.54 (1H, dd, J = 12.5, 8.6 Hz), 3.35-3.30 (1H, m) , 1.09 (3H, d, J = 6.7 Hz) .

(18e) methyl ( 3R) -7- [ ( ert-butoxycarbonyl ) amino ] -3- methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) - carboxylate

The title compound (164 mg, yield: 91%) was obtained by production according to the method described in

Example (Id) using tert-butyl [ ( 3R) -3-methyl-2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

(150 mg, 0.54 mmol) obtained in Example (18d) and methyl chloroformate (0.195 mL, 2.54 mmol) as starting materials. ½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.00-7.81 (2H, m) ,

6.53-6.36 (1H, m) , 4.82-4.53 (2H, m) , 4.43-4.35 (1H, m) , 4.21-4.13 (2H, m) , 3.72-3.64 (3H, m) , 1.52 (9H, s), 1.25- 1.17 (3H, m) .

(18f) methyl ( 3R) -7-amino-3-methyl-2 , 3-dihydropyrido [ 3 , 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (98.8 mg, yield: 87%) was

obtained by production according to the method described in Example (le) using methyl ( 3R) -7- [ ( ert- butoxycarbonyl ) amino] -3-methyl-2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (162 mg, 0.48 mmol) obtained in Example (18e) as a starting material. ½ NMR spectrum (CDCI ₃ , 400MHz) δ: 7.65-7.55 (1H, m) , 6.99-6.84 (1H, m) , 4.78-4.40 (2H, m) , 4.384.31- (1H, m) , 4.15-4.07 (2H, m) , 3.73-3.63 (3H, m) , 3.48 (2H, br s), 1.32-1.17 (3H, m) .

(18g) methyl ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (29.3 mg, yield: 31%) was obtained by production according to the method described in Example (If) using methyl ( 3R) -7-amino-3-methyl-2 , 3- dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(50.1 mg, 0.21 mmol) obtained in Example (18f) and

5-chloro-2-methoxybenzenesulfonyl chloride (56.0 mg,

0.23 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.13 (1H, br s), 7.71-7.61 (3H, m) , 7.38-7.31 (1H, m) , 7.28-7.23 (1H, m) , 4.64-4.55 (1H, m) , 4.53-4.33 (2H, m) , 4.32-4.24 (1H, m) , 4.20-4.09 (1H, br m) , 3.88 (3H, s), 3.62-3.45 (3H, m) ,

1.08-1.01 (3H, m) .

MS spectrum (ES/APCI ⁺ ) : 442 (M+H) , 444 (M+2+H) .

(Example 19) propan-2-yl ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(19a) 1- { [ (propan-2-yloxy) carbonyl] oxy } pyrrolidine-2 , 5- dione

A crude product of the title compound (approximately 87% content, 106 mg, yield: quantitative) was obtained by production according to the method described in

Example (8a) using isopropanol (0.035 mL, 0.46 mmol) as a starting material.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 5.05-4.96 (1H, m) , 2.84 (4H, s), 1.40 (6H, d, J = 6.7 Hz) .

(19b) propan-2-yl ( 3R) -7- [ ( ert-butoxycarbonyl ) amino ] -3- methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) - carboxylate

The title compound (107 mg, yield: 82%) was obtained by production according to the method described in

Example (8b) using tert-butyl [ ( 3R) -3-methyl-2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

(100 mg, 0.36 mmol) obtained in Example (18d) and a crude product of 1- { [ (propan-2-yloxy) carbonyl ] oxy jpyrrolidine- 2,5-dione (approximately 87% content, 106 mg, 0.46 mmol) obtained in Example (19a) as starting materials. ½ NMR spectrum (CDCI ₃ , 400MHz) δ: 7.96-7.75 (2H, m) , 6.50-6.32 (1H, m) , 4.98-4.48 (3H, m) , 4.37 (1H, d, J = 16.5 Hz), 4.23-4.12 (2H, m) , 1.51 (9H, s), 1.30-1.03 (9H, m) .

(19c) propan-2-yl ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (104 mg, yield for 2 steps: 78%) was obtained by production according to the method described in Examples (le) and (If) using propan-2-yl

(3R) -7- [ ( ert-butoxycarbonyl ) amino] -3-methyl-2, 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(105 mg, 0.29 mmol) obtained in Example (19b) and

5-chloro-2-methoxybenzenesulfonyl chloride (73 mg,

0.30 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.16-10.08 (1H, m) , 7.71-7.58 (3H, m) , 7.38-7.32 (1H, m) , 7.30-7.22 (1H, m) , 4.80-4.22 (5H, m) , 4.18-4.09 (1H, m) , 3.95-3.84 (3H, m) , 1.23-0.66 (9H, m) .

MS spectrum (ES/APCI ⁺ ) : 470 (M+H) , 472 (M+2+H) .

(Example 20) 5-chloro-N- [ ( 3R) -4- (hydroxyacetyl ) -3-methyl- 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] -2- methoxybenzenesulfonamide C

(20a) 2- [ {3R) -7- [ ( ert-butoxycarbonyl) amino] -3-methyl- 2 , 3-dihydropyrido [3, 2 - f] [ 1 , 4 ] oxazepin-4 ( 5H) -yl ] -2- oxoethyl acetate

The title compound (approximately 87% content, 198 mg, yield: quantitaive) was obtained by production according to the method described in Example (8b) using tert-butyl [ (3R) -3-methyl-2, 3, 4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate (127 mg, 0.46 mmol) obtained in Example (18d) and acetoxyacetyl chloride

(0.059 mL, 0.55 mmol) as starting materials.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.97-7.90 (2H, m) , 6.53-6.42 (1H, m) , 5.09-4.66 (3H, m) , 4.37-4.16 (4H, m) , 2.16-2.11 (3H, m) , 1.52-1.51 (9H, m) , 1.34-1.22 (6H, m) .

(20b) tert-butyl [ ( 3R) -4- (hydroxyacetyl ) -3-methyl- 2,3,4, 5-tetrahydropyrido [3, 2 - f] [ 1 , 4 ] oxazepin-7- yl ] carbamate

To a solution of 2- [ ( 3R) -7- [ ( tert- butoxycarbonyl ) amino] -3-methyl-2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-4 ( 5H) -yl ] -2-oxoethyl acetate

(approximately 87% content, 195 mg, 0.46 mmol) obtained in Example (20a) in methanol (9.1 mL) , potassium

carbonate (0.126 g, 0.91 mmol) was added at room

temperature, and the mixture was stirred at the same temperature as above for 4 hours . The mixture was concentrated under reduced pressure, and the residue was diluted with water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound

(147 mg, yield: 96%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.98-7.88 (2H, m) , 6.56 (0.5H, br s), 6.50 (0.5H, br s), 5.14-5.11 (1H, m) , 4.70-3.48 (7H, m) , 1.53 (4.5H, s), 1.52 (4.5H, s), 1.30 (1.5H, d, J = 6.7 Hz), 1.25 (1.5H, d, J = 6.7 Hz) .

(20c) 1- [ (3R) -7-amino-3-methyl-2 , 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-4 ( 5H) -yl ] -2-hydroxyethanone

The title compound (92.2 mg, yield: 90%) was

obtained by production according to the method described in Example (le) using tert-butyl [ ( 3R) -4- (hydroxyacetyl ) - 3-methyl-2 , 3,4, 5-tetrahydropyrido [3, 2 - f] [ 1 , 4 ] oxazepin-7- yl] carbamate (145 mg, 0.43 mmol) obtained in

Example (20b) as a starting material.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.65-7.59 (1H, m) , 6.99-6.82 (1H, m) , 5.14-5.01 (1H, m) , 4.65-3.88 (6H, m) , 3.56-3.49 (3H, m) , 1.31-1.23 (3H, m) . (20d) 5-chloro-iV- [ (3R) -4- (hydroxyacetyl ) -3-methyl- 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] -2- methoxybenzenesulfonamide

The title compound (66.5 mg, yield: 71%) was

obtained by production according to the method described in Example (If) using 1- [ ( 3R) -7-amino-3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepin-4 ( 5H) -yl ] -2- hydroxyethanone (50.1 mg, 0.21 mmol) obtained in

Example (20c) and 5-chloro-2-methoxybenzenesulfonyl chloride (53 mg, 0.21 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.14 (1H, br s), 7.70-7.62 (3H, m) , 7.44-7.39 (1H, m) , 7.26-7.23 (1H, m) , 4.79-4.04 (5H, m) , 3.89 (1.8H, s), 3.88 (1.2H, s),

3.43-3.39 (1H, m) , 1.13 (1.2H, d, J = 5.5 Hz), 1.01 (1.8H, d, J = 6.7 Hz) .

MS spectrum (ES/APCI ⁺ ) : 442 (M+H) , 444 (M+2+H) . (Example 21) potassium [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] [ (3R) -4- (hydroxyacetyl) -3-methyl- 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] azanide (potassium salt of Example 20)

The title compound (30.3 mg, yield: 94%) was obtained by production according to the method described in Example 6 using 5-chloro-N- [ ( 3R) -4- (hydroxyacetyl ) -3- methyl-2 , 3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] -2-methoxybenzenesulfonamide (29.7 mg, 0.067 mmol) obtained in Example (20d) as a starting material.

½ NMR spectrum (DMSO-d6, 400MHz) δ: 7.66-7.63 (1H, m) , 7.39-7.30 (2H, m) , 7.14-7.09 (1H, m) , 7.00-6.95 (1H, m) , 4.75-4.00 (7H, m) , 3.68-3.62 (3H, m) , 3.60-3.51 (1H, m) , 1.16-1.03 (3H, m) .

(Example 22) 2- [ ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepin-4 ( 5H) -yl ] -2-oxoethyl methylcarbamate

(22a) 2- [ {3R) -7- [ ( ert-butoxycarbonyl) amino] -3-methyl- 2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepin-4 ( 5H) -yl ] -2- oxoethyl methylcarbamate

To a solution of tert-butyl [ ( 3R) -4- (hydroxyacetyl ) - 3-methyl-2 , 3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl] carbamate (115 mg, 0.34 mmol) obtained in Example (20b) in methylene chloride (2.5 mL) ,

N, N ' -carbonyldiimidazole (85.3 mg, 0.51 mmol) was added at room temperature, and the mixture was stirred under reflux for 2 hours and 15 minutes. The mixture was cooled to room temperature, a 2.0 mol/L solution of methylamine in tetrahydrofuran (0.40 mL, 0.8 mmol) was added thereto, and the mixture was stirred at room temperature for 17 hours. The mixture was diluted by addition of a 1.0 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (ethyl

acetate/methanol = 100/0 - 94/6) to obtain the title compound (126 mg, yield: 94%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.03-7.78 (2H, m) , 6.56 (0.5H, br s), 6.47 (0.5H, br s), 5.18-3.47 (8H, m) , 2.81 (1.5H, d, J = 4.9 Hz), 2.75 (1.5H, d, J = 4.9 Hz), 1.52 (4.5H, s), 1.51 (4.5H, s), 1.33 (1.5H, d, J =

6.1 Hz), 1.22 (1.5H, d, J = 6.7 Hz) .

(22b) 2- [ (3R) -7-amino-3-methyl-2 , 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-4 ( 5H) -yl ] -2-oxoethyl methylcarbamate

The title compound (81.2 mg, yield: 89%) was obtained by production according to the method described in Example (le) using 2- [ ( 3R) -7- [ ( tert- butoxycarbonyl ) amino] -3-methyl-2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-4 ( 5H) -yl ] -2-oxoethyl methylcarbamate (124 mg, 0.31 mmol) obtained in Example (22a) as a starting material.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.63-7.58 (1H, m) , 6.95-6.86 (1H, m) , 5.08-3.45 (10H, m) , 2.82-2.81 (3H, m) , 1.37-1.08 (3H, m) .

(22c) 2- [ (3R) -7-{ [ (5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepin-4 ( 5H) -yl ] -2-oxoethyl methylcarbamate

The title compound (38.9 mg, yield: 55%) was

obtained by production according to the method described in Example (If) using 2- [ ( 3R) -7-amino-3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepin-4 ( 5H) -yl ] -2-oxoethyl methylcarbamate (41.9 mg, 0.14 mmol) obtained in

Example (22b) and 5-chloro-2-methoxybenzenesulfonyl chloride (37.8 mg, 0.16 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.15 (1H, br s), 7.71-7.08 (5H, m) , 4.86-4.14 (5H, m) , 3.85-3.71 (3H, m) , 2.54-2.53 (3H, m) , 1.15-1.02 (3H, m) .

MS spectrum (ES/APCI ⁺ ) : 499 (M+H) , 501 (M+2+H) . (Example 23) 5-chloro-2-methoxy-I\/- [ ( 3R) -3-methyl-4- (morpholin-4-ylacetyl ) -2,3,4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] benzenesulfonamide

(23a) tert-butyl [ ( 3R) -3-methyl-4- (morpholin-4-ylacetyl ) - 2,3,4, 5-tetrahydropyrido [3, 2 - f] [ 1 , 4 ] oxazepin-7- yl ] carbamate

To a mixture of morpholin-4-yl acetic acid (69.1 mg, 0.473 mmol) in methylene chloride (1 mL) and N,N- dimethylformamide (0.010 mL) , oxalyl chloride (0.085 mL, 0.98 mmol) was added under ice cooling, and then the mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to prepare a crude product of morpholin-4-ylacetyl chloride. To a solution of tert-butyl [ ( 3R) -3-methyl-2 , 3 , 4 , 5- tetrahydropyrido [3, 2 - f] [ 1 , 4 ] oxazepin-7- yl ] carbamate ( 115 mg, 0.40 mmol) obtained in Example (18d) and triethylamine (0.165 mL, 1.18 mmol) in methylene chloride (1 mL) , a mixture of morpholin-4-ylacetyl chloride obtained in the above step in methylene

chloride (1 mL) was added under ice cooling, the mixture was stirred at the same temperature as above for

5 minutes, and subsequently stirred at room temperature for 15 hours.

The mixture was diluted by addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (ethyl acetate/methanol = 97/3 - 85/15) to obtain the title compound (114 mg, yield: 71%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.01-7.86 (2H, m) , 6.56-6.45 (1H, m) , 5.04-5.02 (1H, m) , 4.75-4.11 (4H, m) , 3.56-3.21 (6H, m) , 2.48-2.35 (4H, m) , 1.61-1.51 (9H, m) , 1.32-1.17 (3H, m) .

(23b) 5-chloro-2-methoxy-N- [ (3R) -3-methyl-4- (morpholin-4- ylacetyl) -2, 3, 4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] benzenesulfonamide

The title compound (64.7 mg, yield for 2 steps: 47%) was obtained by production according to the method described in Examples (le) and (If) using tert-butyl

[ (3R) -3-methyl-4- (morpholin-4-ylacetyl ) -2,3,4,5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

(112 mg, 0.28 mmol) obtained in Example (23a) and 5-chloro-2-methoxybenzenesulfonyl chloride (59.1 mg,

0.24 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.19 (0.67H, br s), 10.13 (0.33H, br s), 7.69-7.62 (3H, m) , 7.42-7.27 (2H, m) , 4.77-4.13 (4H, m) , 3.91 (2H, s), 3.87 (1H, s), 3.52-2.74 (7H, m) , 2.30-2.08 (4H, m) , 1.19 (1H, d, J = 6.1 Hz), 0.99 (2H, d, J = 6.7 Hz) .

MS spectrum (ES/APCI ⁺ ) : 511 (M+H) , 513 (M+2+H) . (Example 24) ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-N- (propan-2-yl ) - 2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxamide

(24a) tert-butyl [ ( 3R) -3-methyl-4- (propan-2-ylcarbamoyl ) - 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] carbamate

To a solution of isopropylamine (0.34 mL, 0.39 mmol) in methylene chloride (3.5 mL) , N, N-diisopropylethylamine (0.187 mL, 1.07 mmol) and 1,1'-

[ carbonylbis (oxy) ] dipyrrolidine-2 , 5-dione ( 0.1 Olg,

0.39 mmol) were added at room temperature, and the

mixture was stirred at the same temperature as above for 1 hour. Subsequently, tert-butyl [ ( 3R) -3-methyl-2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-T- yl ] carbamate ( 100 mg, 0.36 mmol) obtained in Example (18d) was added thereto, and the mixture was stirred at room temperature for 3 days . The mixture was concentrated under reduced pressure, and the residue was purified in an automatic chromatography apparatus (n-hexane/ethyl acetate/methanol = 25/75/0 - 0/100/0 - 0/92/8, and methylene chloride/methanol = 100/0 - 94/6) . To the obtained solid, ethyl acetate was added, the precipitated solid was collected by filtration to obtain the title compound (70.3 mg, yield: 54%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.90-7.88 (2H, m) , 6.45 (1H, br s), 4.64-3.88 (7H, m) , 1.51 (9H, s), 1.21 (3H, d, J = 6.7 Hz), 1.12 (3H, d, J = 6.7 Hz), 1.09 (3H, d, J = 6.7 Hz) .

(24b) ( 3i ) - 7- { [ ( 5-chloro-2-methoxyphenyl ) sulfonyl ] amino } - 3-methyl-N- (propan-2-yl ) -2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxamide

The title compound (47.4 mg, yield for 2 steps: 53%) was obtained by production according to the method described in Examples (le) and (If) using tert-butyl

[ (3R) -3-methyl-4- (propan-2-ylcarbamoyl ) -2,3,4,5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

(68.8 mg, 0.19 mmol) obtained in Example (24a) and 5-chloro-2-methoxybenzenesulfonyl chloride (45.4 mg, 0.19 mmol) as starting materials.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 10.09 (1H, br s), 7.66-7.62 (3H, m) , 7.45 (1H, br s), 7.25 (1H, d, J = 9.1 Hz), 6.01 (1H, d, J = 7.9 Hz), 4.57-4.42 (3H, m) , 4.24-4.21 (1H, m) , 4.09 (1H, dd, J = 13.1, 5.2 Hz), 3.89 (3H, s), 3.67-3.64 (1H, m) , 1.00 (6H, d, J = 6.7 Hz), 0.90 (3H, d, J = 6.7 Hz) .

MS spectrum (ES/APCI ⁺ ) : 469 (M+H) , 471 (M+2+H) . (Example 25) ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-N- (pyridin-3-yl ) - 2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxamide

(25a) tert-butyl [ ( 3R) -3-methyl-4- (pyridin-3- ylcarbamoyl) -2,3,4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

The title compound (69% content, 239 mg, yield:

quantitative) as a mixture of unknown materials was obtained by production according to the method described in Example (24a) using tert-butyl [ ( 3R) -3-methyl-2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-T- yl ] carbamate ( 115 mg, 0.41 mmol) obtained in Example (18d) and 3-aminopyridine (42.6 mg, 0.45 mmol) as starting materials .

MS spectrum (ES/APCI ⁺ ) : 400 (M+H) .

(25b) ( 3R) -7- { [ ( 5-chloro-2-methoxyphenyl ) sulfonyl ] amino } - 3-methyl-N- (pyridin-3-yl ) -2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxamide

The title compound (28.5 mg, yield for 2 steps: 15%) was obtained by production according to the method described in Examples (le) and (If) using tert-butyl

[ (3R) -3-methyl-4- (pyridin-3-ylcarbamoyl ) -2,3,4,5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

(69% content, 239 mg, 0.41 mmol) obtained in

Example (25a) and 5-chloro-2-methoxybenzenesulfonyl chloride (62.6 mg, 0.26 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.13 (1H, br s), 8.59-8.58 (2H, m) , 8.16 (1H, dd, J = 4.9, 1.2 Hz),

7.83-7.80 (1H, m) , 7.65-7.61 (3H, m) , 7.49 (1H, br s), 7.27 (1H, dd, J = 8.2, 5.2 Hz), 7.21-7.19 (1H, m) ,

4.74-4.63 (3H, m) , 4.36-4.32 (1H, m) , 4.26-4.18 (1H, m) , 3.86 (3H, s), 1.12 (3H, d, J = 6.7 Hz) .

MS spectrum (ES/APCI ⁺ ) : 504 (M+H) , 506 (M+2+H) . (Example 26) 2-methoxyethyl ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(26a) 2-methoxyethyl ( 3R) -7- [ ( ert-butoxycarbonyl ) amino ] - 3-methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) - carboxylate

To a mixture of a crude product of l-{ [ (2- methoxyethoxy) carbonyl ] oxy }pyrrolidine-2 , 5-dione (80.8 mg, 0.37 mmol ) obtained in Example (8a) in methylene chloride

(1 mL) , tert-butyl [ ( 3R) -3-methyl-2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] carbamate ( 80.1 mg, 0.29 mmol) obtained in

Example (18d) and triethylamine (0.515 mL, 3.00 mmol) were added at room temperature, and the mixture was stirred at the same temperature as above for 20.5 hours. The mixture was diluted by addition of ethyl acetate, the organic layer was washed with a saturated aqueous

solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was

distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (ethyl acetate/n-hexane = 90/10 - 100/0) to obtain the title compound (109 mg, yield: quantitative) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.01-7.79 (2H, m) , 6.51-6.35 (1H, m) , 4.85-4.56 (2H, m) , 4.44-4.34 (1H, m) , 4.33-4.06 (4H, m) , 3.63-3.47 (2H, m) , 3.42-3.27 (3H, m) , 1.51 (9H, s), 1.30-1.21 (3H, m) .

(26b) 2-methoxyethyl ( 3R) -7-amino-3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a solution of 2-methoxyethyl ( 3R) -7- [ ( tert- butoxycarbonyl ) amino] -3-methyl-2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (107 mg, 0.28 mmol) obtained in Example (26a) in methanol (1 mL) , a 4.0 mol/L solution of hydrogen chloride in 1,4-dioxane (2 mL, 8 mmol) was added at room temperature, the mixture was stirred at the same temperature as above for 16 hours. The mixture was concentrated under reduced pressure, methanol (4 mL) and N, N-diisopropylethylamine (2 mL, 11 mmol) were added thereto, and the solvent was

distilled off under reduced pressure again. The residue was purified in an automatic chromatography apparatus

(Yamazen Co. Ltd., High-flash™ column Amino, methylene chloride/methanol = 100/0 - 96/4) to obtain the title compound (72.9 mg, yield: 92%) . ½ NMR spectrum (CDCI ₃ , 400MHz) δ: 7.64-7.55 (1H, m) , 6.98-6.85 (1H, m) , 4.75-4.05 (7H, br m) , 3.63-3.28 (7H, br m) , 1.32-1.19 (3H, m) .

(26c) 2-methoxyethyl ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (68.0 mg, yield: 87%) was

obtained by production according to the method described in Example (If) using 2-methoxyethyl ( 3R) -7-amino-3- methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) - carboxylate (45.1 mg, 0.16 mmol) obtained in

Example (26b) and 5-chloro-2-methoxybenzenesulfonyl chloride (40.6 mg, 0.17 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.14 (1H, br s), 7.71-7.61 (3H, m) , 7.38-7.33 (1H, m) , 7.28-7.23 (1H, br m) , 4.64-4.56 (1H, m) , 4.55-4.22 (3H, m) , 4.19-3.92 (3H, m) , 3.90-3.86 (3H, m) , 3.52-3.45 (1H, m) , 3.37-3.35 (1H, m) , 3.26-3.08 (3H, m) , 1.08-1.02 (3H, m) .

MS spectrum (ES/APCI ⁺ ) : 486 (M+H) , 488 (M+2+H) .

(Example 27) tetrahydro-2JJ-pyran-4-yl ( 3R) -7- { [ ( 5-chloro- 2-methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(27a) l-{ [ ( tetrahydro-2JJ-pyran-4- yloxy) carbonyl] oxy }pyrrolidine-2 , 5-dione

A crude product of the title compound (102 mg, yield: 91%) was obtained by production according to the method described in Example (8a) using tetrahydropyran-4- ol (47.0 mg, 0.46 mmol) as a starting material.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 5.01-4.92 (1H, m) , 4.01-3.90 (2H, m) , 3.61-3.51 (2H, m) , 2.85 (4H, s), 2.09-2.02 (2H, m) , 1.91-1.80 (2H, m) .

(27b) tetrahydro-2JJ-pyran-4-yl ( 3R) -7- [ ( tert- butoxycarbonyl ) amino] -3-methyl-2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (157 mg, yield: 98%) was obtained by production according to the method described in

Example (8b) using tert-butyl [ ( 3R) -3-methyl-2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

(110 mg, 0.39 mmol) obtained in Example (18d) and

l-{ [ ( tetrahydro-2JJ-pyran-4- yloxy) carbonyl ] oxy }pyrrolidine-2 , 5-dione (101 mg, 0.42 mmol) obtained in Example (27a) as starting

materials .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.92-7.88 (2H, m) ,

6.49-6.45 (1H, m) , 4.54-3.76 (10H, m) , 1.98-1.20 (16H, m) .

(27c) tetrahydro-2JJ-pyran-4-yl ( 3R) -7-amino-3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (109 mg, yield: 93%) was obtained by production according to the method described in

Example (le) using tetrahydro-2JJ-pyran-4-yl (3R)-1-

[ ( tert-butoxycarbonyl ) amino] -3-methyl-2, 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(155 mg, 0.38 mmol) obtained in Example (27b) as a

starting material.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.61-7.59 (1H, m) ,

6.92-6.86 (1H, m) , 4.87-3.47 (12H, m) , 1.85-1.68 (4H, m) , 1.27-1.23 (3H, m) .

(27d) tetrahydro-2JJ-pyran-4-yl ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (68.3 mg, yield: 78%) was

obtained by production according to the method described in Example (If) using tetrahydro-2JJ-pyran-4-yl (3R)-1- amino-3-methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine- 4 ( 5H) -carboxylate (52.6 mg, 0.17 mmol) obtained in Example (27c) and 5-chloro-2-methoxybenzenesulfonyl chloride (44.2 mg, 0.18 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.12 (1H, br s), 7.68-7.61 (3H, m) , 7.40-7.37 (1H, m) , 7.27-7.25 (1H, m) , 4.72-4.42 (4H, m) , 4.31-4.28 (1H, m) , 4.16-4.13 (1H, m) , 3.91-3.87 (3H, m) , 3.67-3.52 (4H, m) , 1.82-1.79 (2H, m) , 1.51-1.49 (2H, m) , 1.13-1.04 (3H, m) .

MS spectrum (ES/APCI ⁺ ) : 512 (M+H) , 514 (M+2+H) .

(Example 28) ( 3S) -tetrahydrofuran-3-yl ( 3. ) -7- { [ ( 5- chloro-2-methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(28a) (3S) -tetrahydrofuran-3-yl ( 3R) -7- [ ( tert- butoxycarbonyl ) amino] -3-methyl-2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a mixture of tert-butyl [ ( 3R) -3-methyl-2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

(220 mg, 0.79 mmol) obtained in Example (18d) in

methylene chloride (2 mL) , triethylamine (0.164 mL, 1.18 mmol) and a crude product of 1-({ [ (3S)- tetrahydrofuran-3-yloxy] carbonyl } oxy) pyrrol idine-2 , 5- dione (0.211 g, 0.91 mmol) obtained in Example (9a) were added at room temperature, and the mixture was stirred at the same temperature as above for 3 days. The mixture was diluted by addition of ethyl acetate, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (ethyl acetate/n- hexane = 80/20 - 100/0) to obtain the title compound

(317 mg, yield: quantitative) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.91-7.88 (2H, m) , 6.48-6.43 (1H, m) , 5.25-5.22 (1H, m) , 4.78-4.17 (5H, m) , 3.84-3.67 (4H, m) , 2.10-2.01 (2H, m) , 1.51 (9H, br s), 1.35-1.18 (6H, m) .

(28b) (3S) -tetrahydrofuran-3-yl ( 3R) -7-amino-3-methyl-

2.3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a solution of ( 3S) -tetrahydrofuran-3-yl (3R)-1- [ ( tert-butoxycarbonyl ) amino] -3-methyl-2, 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(315 mg, 0.79 mmol) obtained in Example (28a) in methanol (2 mL) , a 4.0 mol/L solution of hydrogen chloride in

1.4-dioxane (4 mL, 16 mmol) was added at room temperature, the mixture was stirred at the same temperature as above for 15.5 hours. The mixture was concentrated under reduced pressure, methanol (2 mL) and N,N- diisopropylethylamine (4 mL, 23 mmol) were added thereto, and the solvent was distilled off under reduced pressure again. The residue was purified in an automatic

chromatography apparatus (Yamazen Co. Ltd., High-flash™ column Amino, methylene chloride/methanol = 100/0 - 96/4) to obtain the title compound (207 mg, yield: 90%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.61-7.59 (1H, m) , 6.93-6.86 (1H, m) , 5.25 (1H, br s), 4.68-3.48 (11H, m) , 2.14-2.06 (2H, m) , 1.29-1.22 (3H, m) .

(28c) (3S) -tetrahydrofuran-3-yl ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (74.3 mg, yield: 73%) was

obtained by production according to the method described in Example (If) using ( 3S) -tetrahydrofuran-3-yl (3R)-1- amino-3-methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine- 4 ( 5H) -carboxylate (65.8 mg, 0.24 mmol) obtained in

Example (28b) and 5-chloro-2-methoxybenzenesulfonyl chloride (53.5 mg, 0.22 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.13-10.11 (1H, m) , 7.67-7.65 (3H, m) , 7.39-7.35 (1H, m) , 7.27-7.24 (1H, m) , 5.08-5.04 (1H, m) , 4.61-3.59 (9H, m) , 2.07-1.81 (2H, m) , 1.05 (3H, br d, J = 6.7 Hz) .

MS spectrum (ES/APCI ⁺ ) : 498 (M+H) , 500 (M+2+H) . (Example 29) ( 3R) -tetrahydrofuran-3-yl ( 3. ) -7- { [ ( 5- chloro-2-methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(29a) (3R) -tetrahydrofuran-3-yl ( 3R) -7- [ ( tert- butoxycarbonyl ) amino] -3-methyl-2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a mixture of tert-butyl [ ( 3R) -3-methyl-2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

(220 mg, 0.79 mmol) obtained in Example (18d) in

methylene chloride (2 mL) , triethylamine (0.164 mL,

1.18 mmol) and a crude product of l-({ [ (3i )- tetrahydrofuran-3-yloxy] carbonyl } oxy) pyrrol idine-2 , 5- dione (0.210 g, 0.91 mmol) obtained in Example (10a) were added at room temperature, and the mixture was stirred at the same temperature as above for 3 days. The mixture was diluted by addition of ethyl acetate, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (ethyl acetate/n- hexane = 80/20 - 100/0) to obtain the title compound

(321 mg, yield: quantitative) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.91-7.83 (2H, m) , 6.48-6.44 (1H, m) , 5.26-5.23 (1H, m) , 4.79-3.79 (9H, m) , 2.13-1.92 (2H, m) , 1.51 (9H, br s), 1.25-1.20 (6H, m) .

(29b) ( 3R) -tetrahydrofuran-3-yl ( 3R) -7-amino-3-methyl-

2.3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a solution of ( 3R) -tetrahydrofuran-3-yl (3R)-1- [ ( tert-butoxycarbonyl ) amino] -3-methyl-2, 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(318 mg, 0.79 mmol) obtained in Example (29a) in methanol (2 mL) , a 4.0 mol/L solution of hydrogen chloride in

1.4-dioxane (4 mL, 16 mmol) was added at room temperature, the mixture was stirred at the same temperature as above for 16 hours. The mixture was concentrated under reduced pressure, methanol (2 mL) and N, N-diisopropylethylamine

(4 mL, 23 mmol) were added thereto, and the solvent was distilled off under reduced pressure again. The residue was purified in an automatic chromatography apparatus

(Yamazen Co. Ltd., High-flash™ column Amino, methylene chloride/methanol = 100/0 - 96/4) to obtain the title compound (107 mg, yield: 46%) . ½ NMR spectrum (CDCI ₃ , 400MHz) δ: 7.60 (1H, br s), 6.93-6.86 (1H, m) , 5.26 (1H, br s), 4.68-3.74 (9H, m) , 3.52-3.48 (2H, m) , 2.19-1.79 (2H, m) , 1.27-1.23 (3H, m) .

(29c) (3R) -tetrahydrofuran-3-yl ( 3R) -7- { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (72.5 mg, yield: 85%) was obtained by production according to the method described in Example (If) using ( 3R) -tetrahydrofuran-3-yl 7-amino- 2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(50.2 mg, 0.17 mmol) obtained in Example (29b) and

5-chloro-2-methoxybenzenesulfonyl chloride (45.2 mg, 0.18 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.12 (1H, br s), 7.67-7.62 (3H, m) , 7.38-7.36 (1H, m) , 7.27-7.25 (1H, m) , 5.08-5.02 (1H, m) , 4.61-4.26 (4H, m) , 4.16-4.13 (1H, m) , 3.90-3.87 (3H, m) , 3.72-3.59 (4H, m) , 2.12-1.41 (2H, m) , 1.05 (3H, d, J = 6.7 Hz) .

MS spectrum (ES/APCI ⁺ ) : 498 (M+H) , 500 (M+2+H) .

(Example 30) methyl ( 3R) -7- { [ ( 5-chloro-2-methoxypyridin- 3-yl ) sulfonyl ] amino } -3-methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (76.3 mg, yield: 89%) was obtained by production according to the method described in Example (If) using methyl ( 3R) -7-amino-3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (46.2 mg, 0.20 mmol) obtained in Example (18f) and

5-chloro-2-methoxypyridine-3-sulfonyl chloride (53.2 mg, 0.22 mmol) obtained in Example (11a) as starting

materials .

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.42 (1H, br s), 8.49 (1H, d, J = 2.4 Hz), 8.12 (1H, d, J = 3.1 Hz), 7.73 (1H, d, J = 2.4 Hz), 7.36 (1H, br s), 4.65-4.34 (3H, m) , 4.29 (1H, t, J = 11.9 Hz), 4.21-4.11 (1H, m) , 3.96 (3H, s), 3.62-3.45 (3H, m) , 1.08-1.01 (3H, m) .

MS spectrum (ES/APCI ⁺ ) : 443 (M+H) , 445 (M+2+H) .

(Example 31) 2-methoxyethyl ( 3R) -7- { [ ( 5-chloro-2- methoxypyridin-3-yl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a mixture of 2-methoxyethyl ( 3R) -7-amino-3- methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) - carboxylate (72.6 mg, 0.26 mmol) obtained in

Example (26b) and pyridine (1.0 mL, 12 mmol), 5-chloro-2- methoxypyridine-3-sulfonyl chloride (65.6 mg, 0.27 mmol) obtained in Example (11a) was added at room temperature, and the mixture was stirred at 80°C for 50 minutes in an oil bath. After cooling, the mixture was concentrated under reduced pressure, the residue was purified in an automatic chromatography apparatus (methylene

chloride/methanol = 100/0 - 91/9) . To the obtained solid, ethanol was added, the precipitated solid was collected by filtration, and then dried to obtain the title

compound (78.3 mg, yield: 62%) .

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.44 (1H, br s), 8.49 (1H, d, J = 2.4 Hz), 8.12 (1H, d, J = 2.4 Hz), 7.72 (1H, br s), 7.37 (1H, br d, J = 2.4 Hz), 4.63-3.95 (10H, m) , 3.39-3.21 (5H, m) , 1.10-1.02 (3H, m) .

MS spectrum (ES/APCI ⁺ ) : 487 (M+H) , 489 (M+2+H) .

(Example 32) potassium [ ( 5-chloro-2-methoxypyridin

yl) sulfonyl] { (3R) -4- [ ( 2-methoxyethoxy) carbonyl] -3- 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl } azanide (potassium salt of Example 31)

To a suspension of 2-methoxyethyl ( 3. ) -7- { [ ( 5- chloro-2-methoxypyridin-3-yl ) sulfonyl] amino } -3-methyl- 2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(35.4 mg, 0.073 mmol) obtained in Example 31 in ethanol

(0.7 mL) , a solution of 0.5 N potassium hydroxide in ethanol (0.155 mL, 0.076 mmol) was added at room

temperature, and the mixture was stirred at room

temperature for 3 hours. The solvent was distilled off under reduced pressure to obtain a crude solid. To the crude solid, diisopropyl ether was added, the

precipitated solid was collected by filtration, and then dried to obtain the title compound (35.8 mg, yield: 94%) . ½ NMR spectrum (DMSO-d6, 400MHz) δ: 8.16 (1H, br d, J = 2.4 Hz), 7.92 (1H, br s), 7.39 (1H, br s), 7.09-7.06

(1H, m) , 4.48-3.96 (7H, m) , 3.78 (3H, s), 3.44-3.20

(6H, m) , 1.08 (3H, d, J = 6.7 Hz) .

(Example 33) ( 3S) -tetrahydrofuran-3-yl ( 3. ) -7- { [ ( 5- chloro-2-methoxypyridin-3-yl ) sulfonyl] amino } -3-methyl- 2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a mixture of ( 3S) -tetrahydrofuran-3-yl {3R)-1- amino-3-methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine- 4 ( 5H) -carboxylate (82.2 mg, 0.28 mmol) obtained in

Example (28b) and pyridine (1.0 mL, 12 mmol), 5-chloro-2- methoxypyridine-3-sulfonyl chloride (71.2 mg, 0.29 mmol) obtained in Example (11a) was added at room temperature, and the mixture was stirred at 80°C for 35 minutes in an oil bath. After cooling, the mixture was concentrated under reduced pressure, the residue was purified in an automatic chromatography apparatus (methylene

chloride/methanol = 100/0 - 91/9) . To the obtained solid, ethyl acetate was added, the precipitated solid was collected by filtration, washed with n-hexane, and then dried to obtain the title compound (70.4 mg, yield: 50%) . ½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.42 (1H, br s), 8.49 (1H, br d, J = 2.4 Hz), 8.12 (1H, br d, J = 2.4 Hz), 7.72-7.69 (1H, m) , 7.40-7.37 (1H, m) , 5.08-5.04 (1H, m) , 4.61-4.13 (5H, m) , 3.97-3.95 (3H, m) , 3.78-3.21 (4H, m) , 2.08-1.80 (2H, m) , 1.06 (3H, d, J = 6.1 Hz) .

MS spectrum (ES/APCI ⁺ ) : 499 (M+H) , 501 (M+2+H) . (Example 34) potassium [ ( 5-chloro-2-methoxypyridin-3- yl) sulfonyl] [ (3R) -3-methyl-4- { [ (3S) -tetrahydrofuran-3- yloxy] carbonyl } -2 , 3 , 4 , 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] azanide (potassium salt of

Example 33)

To a suspension of ( 3S) -tetrahydrofuran-3-yl {3R)-1- { [ ( 5-chloro-2-methoxypyridin-3-yl ) sulfonyl] amino}-3- methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) - carboxylate (49.9 mg, 0.100 mmol) obtained in Example 33 in ethanol (1.0 mL) , a solution of 0.5 N potassium

hydroxide in ethanol (0.205 mL, 0.102 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 hour and 15 minutes. The mixture was diluted by addition of diisopropyl ether, and then the solvent was distilled off under reduced pressure to obtain a crude solid. To the crude solid, a mixed

solvent of methylene chloride/diisopropyl ether = 1/1 was added, the precipitated solid was collected by filtration, and then dried to obtain the title compound (32.5 mg, yield: 61%) . ½ NMR spectrum (DMSO-d6, 400MHz) δ: 8.18-8.17 (1H, m) , 7.94 (1H, br d, J = 2.4 Hz), 7.41 (1H, br s), 7.16-7.02 (1H, m) , 5.18-4.92 (1H, m) , 4.52-4.20 (3H, m) , 4.15-3.95 (2H, m) , 3.84-3.54 (7H, m) , 2.12-1.80 (2H, m) , 1.11-1.05 (3H, m) .

(Example 35) ( 3R) -tetrahydrofuran-3-yl ( 3. ) -7- { [ ( 5- chloro-2-methoxypyridin-3-yl ) sulfonyl] amino } -3-methyl- 2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a solution of ( 3R) -tetrahydrofuran-3-yl {3R)-1- [ ( tert-butoxycarbonyl ) amino] -3-methyl-2, 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (118 mg, 0.30 mmol) obtained in Example (29a) in methanol (1 mL) , a 4.0 mol/L solution of hydrogen chloride in 1,4-dioxane (2 mL, 8 mmol) was added at room temperature, the mixture was stirred at the same temperature as above for 1 hour and 20 minutes. The mixture was concentrated under reduced pressure, pyridine (1.0 mL, 12 mmol) and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (74.8 mg, 0.31 mmol) obtained in Example (11a) were added thereto at room temperature, and the mixture was stirred at 80°C for 1 hour in an oil bath. After cooling, the mixture was concentrated under reduced pressure, the residue was purified in an automatic chromatography apparatus

(methylene chloride/methanol = 100/0 - 91/9) . To the obtained solid, diisopropyl ether was added, the

precipitated solid was collected by filtration, washed with diisopropyl ether, and then dried to obtain the title compound (98.3 mg, yield: 66%) .

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.43 (1H, br s), 8.49 (1H, br d, J = 2.4 Hz), 8.12-8.10 (1H, m) , 7.72 (1H, br s), 7.39-7.37 (1H, m) , 5.08-5.02 (1H, m) ,

4.52-4.36 (4H, m) , 4.17-4.14 (1H, m) , 3.97-3.95 (3H, m) , 3.77-3.50 (4H, m) , 2.14-1.40 (2H, m) , 1.05 (3H, d, J = 6.7 Hz) .

MS spectrum (ES/APCI ⁺ ) : 499 (M+H) , 501 (M+2+H) .

(Example 36) potassium [ ( 5-chloro-2-methoxypyridin-3- yl) sulfonyl] [ (3R) -3-methyl-4- { [ (3R) -tetrahydrofuran-3- yloxy] carbonyl } -2 , 3 , 4 , 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] azanide (potassium salt of

Example 35)

To a suspension of ( 3R) -tetrahydrofuran-3-yl {3R)-1- { [ ( 5-chloro-2-methoxypyridin-3-yl ) sulfonyl] amino}-3- methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) - carboxylate (36.4 mg, 0.073 mmol) obtained in Example 35 in ethanol (0.75 mL) , a solution of 0.5 N potassium hydroxide in ethanol (0.155 mL, 0.077 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, benzene (3 mL) was added thereto, and the solvent was distilled off under reduced pressure again to obtain a crude solid. To the crude solid, diisopropyl ether was added, the precipitated solid was collected by filtration, and then dried to obtain the title compound (40.9 mg, yield: quantitative) .

½ NMR spectrum (DMSO-d6, 400MHz) δ: 8.15 (1H, d, J = 2.4 Hz), 7.92-7.91 (1H, m) , 7.40-7.37 (2H, m) , 7.09-7.03 (1H, m) , 5.12-5.01 (1H, m) , 4.48-3.95 (5H, m) , 3.75-3.62 (7H, m) , 2.12-1.46 (2H, m) , 1.08-1.07 (3H, m) .

(Example 37) 2-hydroxyethyl ( 3R) -7- { [ ( 5-chloro-2- methoxypyridin-3-yl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(37a) 2- ( { [ (2, 5-dioxopyrrolidin-l- yl) oxy] carbonyl } oxy) ethyl acetate

A crude product of the title compound (516 mg, yield: 84%) was obtained by production according to the method described in Example (8a) using 2-hydroxyethyl acetate (265 mg, 2.50 mmol) as a starting material.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 4.54-4.50 (2H, m) , 4.38-4.33 (2H, m) , 2.85 (4H, s), 2.11 (3H, s) .

(37b) 2- (acetyloxy) ethyl ( 3R) -7- [ ( tert- butoxycarbonyl ) amino] -3-methyl-2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (175 mg, yield: 72%) was obtained by production according to the method described in

Example (8b) using tert-butyl [ ( 3R) -3-methyl-2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

(167 mg, 0.60 mmol) obtained in Example (18d) and

2- ( { [ (2, 5-dioxopyrrolidin-l-yl) oxy] carbonyl }oxy) ethyl acetate (220 mg, 0.90 mmol) obtained in Example (37a) as starting materials.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.91-7.87 (2H, m) , 6.49-6.42 (1H, m) , 4.79-4.11 (9H, m) , 2.06-2.02 (3H, m) , 1.51 (9H, s), 1.30-1.20 (3H, m) . (37c) 2-hydroxyethyl ( 3R) -7- { [ ( 5-chloro-2-methoxypyridin- 3-yl ) sulfonyl ] amino } -3-methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

The title compound (117 mg, yield: 59%) was obtained by production according to the method described in

Example 35 using 2- ( acetyloxy) ethyl ( 3R) -7- [ ( tert- butoxycarbonyl ) amino] -3-methyl-2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (173 mg, 0.42 mmol) obtained in Example (37b) and 5-chloro-2-methoxypyridine- 3-sulfonyl chloride (113.3 mg, 0.47 mmol) obtained in Example (11a) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.42 (1H, br s), 8.49-8.49 (1H, m) , 8.12-8.11 (1H, m) , 7.72 (1H, br s), 7.41-7.37 (1H, m) , 4.79-4.73 (1H, m) , 4.51-4.38 (4H, m) , 4.17-4.14 (1H, m) , 4.03-3.42 (7H, m) , 1.07-1.05 (3H, m) . MS spectrum (ES/APCI ⁺ ) : 473 (M+H) , 475 (M+2+H) .

(Example 38) 2-methoxyethyl ( 3R) -7- { [ ( 2-ethoxy-5- fluoropyridin-3-yl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(38a) 3-bromo-2-ethoxy-5-fluoropyridine

To a mixture of 3-bromo-5-fluoropyridin-2-amine (1.50 g, 7.85 mmol) and hydrogen fluoride pyridine (4 mL, 44 mmol), sodium nitrite (0.813 g, 11.8 mmol) was added at -10°C in a several portions, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted by addition of a saturated aqueous solution of sodium bicarbonate until it became basic, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product of 3-bromo- 2, 5-difluoropyridine . To a solution of a crude product of 3-bromo-2 , 5-difluoropyridine obtained in the above step in ethanol (40 mL) , a 20% ethanol solution of sodium ethoxide (5.04 mL, 11.8 mmol) was added at room

temperature, the mixture was stirred at the same

temperature as above for 4 days, and subsequently stirred at 80°C for 1 hour in an oil bath. The mixture was cooled, and concentrated under reduced pressure. The residue was purified in an automatic chromatography apparatus (n-hexane/ethyl acetate = 100/0 - 90/10) to obtain the title compound (811 mg, yield for

2 steps : 47%) . ½ NMR spectrum (CDCI3, 400MHz) δ: 7.95 (1H, d, J =

2.7 Hz), 7.63 (1H, dd, J = 7.0, 2.7 Hz), 4.39 (2H, q, J =

7.0 Hz), 1.42 (3H, t, J = 7.0 Hz) .

(38b) 2-ethoxy-5-fluoropyridine-3-sulfonyl chloride

To a mixture of 3-bromo-2-ethoxy-5-fluoropyridine

(2.60 g, 11.8 mmol) obtained in Example (38a),

phenylmethanethiol (1.39 mL, 11.8 mmol),

Tris (dibenzylideneacetone ) dipalladium ( 0 ) (0.2702 g,

0.30 mmol) and ( 9, 9-dimethyl-9ff-xanthene-4 , 5- diyl) bis (diphenylphosphane) (0.3415 g, 0.59 mmol) in 1,4-dioxane (120 mL) , N, N-Diisopropylethylamine (4.11 mL, 23.6 mmol) was added at room temperature, the mixture was stirred under nitrogen atmosphere at 100°C for 4 hours in an oil bath. The mixture was cooled, and concentrated under reduced pressure. The residue was diluted by addition of water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus

(n-hexane/ethyl acetate = 100/0 - 90/10) to obtain

3- (benzylsulfanyl ) -2-ethoxy-5-fluoropyridine (3.11 g) as a mixture containing unknown materials. To a mixture of 3- (benzylsulfanyl ) -2-ethoxy-5-fluoropyridine (3.11 g) obtained in the above step, acetic acid (0.9 mL, 16 mmol) and water (0.6 mL, 33 mmol) in acetonitrile (60 mL) , 1, 3-dichloro-5, 5-dimethylhydantoin (4.65 g, 23.6 mmol) was added under ice cooling in several portions, and the mixture was stirred at the same temperature as above for 3 hours. The mixture was allowed to warm up to room temperature, concentrated under reduced pressure, and the residue was purified in an automatic chromatography apparatus (n-hexane/ethyl acetate = 100/0 - 80/20) to obtain the title compound (2.67 g, yield for

2 steps : 94%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.34 (1H, d, J =

3.1 Hz), 8.02 (1H, dd, J = 6.6, 3.1 Hz), 4.61 (2H, q, J =

7.0 Hz), 1.49 (3H, t, J = 7.0 Hz) .

(38c) 2-methoxyethyl (3R) -7- { [ (2-ethoxy-5-fluoropyridin- 3-yl ) sulfonyl ] amino } -3-methyl-2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

To a solution of 2-methoxyethyl ( 3R) -7- [ ( tert- butoxycarbonyl ) amino] -3-methyl-2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (139 mg, 0.36 mmol) obtained in Example (26a) in methanol (1 mL) , a 4.0 mol/L solution of hydrogen chloride in 1,4-dioxane (2 mL, 8 mmol) was added at room temperature, the mixture was stirred at the same temperature as above for 50 minutes. The mixture was concentrated under reduced pressure, pyridine (1.0 mL, 12 mmol) and 2-ethoxy-5-fluoropyridine- 3-sulfonyl chloride (94.9 mg, 0.40 mmol) obtained in Example (38b) were added thereto at room temperature, and the mixture was stirred at 80°C for 40 minutes in an oil bath. After cooling, the mixture was concentrated under reduced pressure, the residue was purified in an

automatic chromatography apparatus (methylene

chloride/methanol = 99/1 - 91/9, and Yamazen Co. Ltd., High-flash™ column Amino, methylene chloride/methanol = 95/5 - 88/12) . To the obtained solid, diisopropyl ether was added, the precipitated solid was collected by filtration, washed with diisopropyl ether, and then dried to obtain the title compound (81.9 mg, yield: 46%) .

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.35 (1H, br s), 8.43 (1H, d, J = 3.1 Hz), 8.08 (1H, dd, J = 7.3, 3.1 Hz), 7.75 (1H, br d, J = 2.4 Hz), 7.36 (1H, br d, J = 2.4 Hz), 4.62-3.96 (8H, m) , 3.49-3.11 (6H, m) , 1.29-1.22 (3H, m) , 1.06-1.04 (3H, m) .

MS spectrum (ES/APCI ⁺ ) : 485 (M+H) .

(Example 39) potassium [ (2-ethoxy-5-fluoropyridin-3- yl) sulfonyl] { (3R) -4- [ ( 2-methoxyethoxy) carbonyl] -3-methyl-

2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl } azanide

(potassium salt of Example 38)

To a suspension of 2-methoxyethyl ( 3. ) -7- { [ (2- ethoxy-5-fluoropyridin-3-yl ) sulfonyl] amino } -3-methyl-2 , 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate

(36.2 mg, 0.075 mmol) obtained in Example (38c) in

ethanol (0.75 mL) , a solution of 0.5 N potassium

hydroxide in ethanol (0.155 mL, 0.077 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, benzene (3 mL) was added thereto, and the solvent was distilled off under reduced pressure again to obtain a crude solid. To the crude solid, diisopropyl ether was added, the precipitated solid was collected by filtration, and then dried to obtain the title compound (32.5 mg, yield: 83%) .

½ NMR spectrum (DMSO-d6, 400MHz) δ: 8.06 (1H, d, J =

3.1 Hz), 7.82-7.74 (1H, m) , 7.46-7.38 (1H, m) , 7.16-7.05 (1H, m) , 4.51-3.85 (9H, m) , 3.53-3.36 (2H, m) , 3.25 (1.3H, s), 3.15 (1.7H, s), 1.13-1.04 (6H, m) . (Example 40) 5-chloro-N- [ 4 ' - (hydroxyacetyl ) -4 ' , 5 ' - dihydrospiro [ cyclopropane- 1, 3 ' -pyrido [3,2- f] [ 1 , 4 ] oxazepin] -7 ' -yl ] -2 -methoxybenzenesulfonamide

(40a) 7 ' -bromo-4 ' - (prop-2-en-l-yl) -4 ' , 5 ' - dihydrospiro [cyclopropane-1, 3 ' -pyrido [3,2- f] [ 1 , 4 ] oxazepine ]

The title compound (1.85 g, yield for 3 steps: 27%) was obtained by production according to the method described in Examples (18a), (18b) and (18c) using 5-bromo-2-fluoropyridine-3-carbaldehyde (4.69 g,

23.0 mmol) and ( 1-aminocyclopropyl ) methanol (2.00 g, 23.0 mmol) as starting materials.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.23 (1H, d, J = 2.3 Hz), 7.58 (1H, d, J = 2.3 Hz), 5.79-5.69 (1H, m) , 5.17-5.07 (2H, m) , 3.95 (2H, s), 3.95 (2H, s), 3.18 (2H, d, J = 6.6 Hz), 0.88-0.75 (4H, m) .

(40b) tert-butyl 4 ', 5 ' -dihydrospiro [cyclopropane-1, 3 ' - pyrido [3,2- f] [l,4]oxazepin]-7' -ylcarbamate

The title compound (466 mg, yield for 2 steps: 73%) was obtained by production according to the method described in Example (18d) using 7 ' -bromo-4 ' - (prop-2-en- 1-yl) -4 ' , 5 ' -dihydrospiro [ cyclopropane- 1, 3 ' -pyrido [ 3 , 2- f] [ 1 , 4 ] oxazepine ] (658 mg, 2.23 mmol) obtained in

Example (40a) as a starting material.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.92-7.91 (2H, m) , 6.44 (1H, br s), 3.96 (2H, s), 3.94 (2H, s), 0.80-0.75 (4H, m) .

(40c) tert-butyl [ 4 ' - (hydroxyacetyl ) -4 ' , 5 ' - dihydrospiro [cyclopropane-1, 3 ' -pyrido [3,2- f] [ 1 , 4 ] oxazepin] -7 ' -yl ] carbamate

The title compound (198 mg, yield for 2 steps: 98%) was obtained by production according to the method described in Examples (20a) and (20b) using tert-butyl 4 ' , 5 ' -dihydrospiro [cyclopropane-1, 3 ' -pyrido [3,2- f] [ 1 , 4 ] oxazepin] -7 ' -ylcarbamate (120 mg, 0.41 mmol) obtained in Example (40b) and acetoxyacetyl chloride

(0.053 mL, 0.49 mmol) as starting materials.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.16-7.86 (2H, m) , 6.61-6.44 (1H, m) , 4.76-3.78 (6H, m) , 3.43-3.27 (1H, m) , 1.52 (9H, s), 1.24-1.10 (4H, m) .

(40d) 5-chloro-iV- [4 ' - (hydroxyacetyl) -4 ' , 5 ' - dihydrospiro [cyclopropane-1, 3 ' -pyrido [3,2- f] [ 1 , 4 ] oxazepin] -7 ' -yl ] -2-methoxybenzenesulfonamide

The title compound (62.9 mg, yield for 2 steps: 36%) was obtained by production according to the method described in Examples (le) and (If) using tert-butyl [4 ' - (hydroxyacetyl ) -4 ' , 5 ' -dihydrospiro [ cyclopropane- 1, pyrido [ 3 , 2-f] [ 1 , 4 ] oxazepin] -7 ' -yl ] carbamate (136 mg, 0.39 mmol) obtained in Example (40c) and 5-chloro-2- methoxybenzenesulfonyl chloride (59 mg, 0.24 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.32 (1H, br s), 7.82 (1H, d, J = 2.4 Hz), 7.71-7.63 (2H, m) , 7.49 (1H, s) , 7.24 (1H, d, J = 9.1 Hz), 3.61-4.80 (10H, m) ,

1.21-0.82 (4H, m) .

MS spectrum (ES/APCI ⁺ ) : 454 (M+H) , 456 (M+2+H) .

(Example 41) potassium [ ( 5-chloro-2- methoxyphenyl ) sulfonyl ] [ 4 ' - (hydroxyacetyl ) -4 ' , 5 ' - dihydrospiro [cyclopropane-1, 3 ' -pyrido [3,2- f] [ 1 , 4 ] oxazepin] -7 ' -yl ] azanide

(potassium salt of Example 40)

The title compound (31.5 mg, yield: 98%) was obtained by production according to the method described in Example 6 using 5-chloro-N- [ 4 '- (hydroxyacetyl ) -4 5 ' - dihydrospiro [cyclopropane-1, 3 ' -pyrido [3,2- f] [ 1 , 4 ] oxazepin] -7 ' -yl ] -2-methoxybenzenesulfonamide (29.6 mg, 0.065 mmol) obtained in Example (40d) as

starting material.

½ NMR spectrum (DMSO-d6, 400MHz) δ: 7.66 (1H, d, J

2.4 Hz), 7.49-7.40 (1H, m) , 7.36-7.31 (1H, m) , 7.21

(1H, m) , 7.00-6.95 (1H, m) , 4.82-3.84 (6H, m) , 3.72

(4H, m) , 1.10-0.86 (4H, m) .

(Example 42) 2-methoxyethyl 7 ' - { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl ] amino } spiro [ cyclopropane-1 , 3 pyrido [ 3 , 2-f] [ 1 , 4 ] oxazepine ] -4 ' ( 5 ' H) -carboxylate

(42a) 2-methoxyethyl 7 ' - [ ( tert- butoxycarbonyl ) amino] spiro [cyclopropane-1, 3 ' -pyrido [3,2- f] [ 1 , 4 ] oxazepine ] -4 ' ( 5 ' H) -carboxylate

The title compound (178 mg, yield: quantitaive) was obtained by production according to the method described in Example (8b) using tert-butyl 4 ',5'- dihydrospiro [cyclopropane-1, 3 ' -pyrido [3,2- f] [ 1 , 4 ] oxazepin] -7 ' -ylcarbamate (110 mg, 0.38 mmol) obtained in Example (40b) and l-{ [ (2- methoxyethoxy) carbonyl ] oxy }pyrrolidine-2 , 5-dione (109 mg, 0.46 mmol) obtained in Example (8a) as starting materials. ½ NMR spectrum (CDCI ₃ , 400MHz) δ: 8.22-7.77 (2H, m) , 6.50-6.41 (1H, m) , 4.45 (2H, s), 4.22-4.13 (2H, m) , 3.95 (2H, br s), 3.58-3.51 (2H, m) , 3.34 (3H, br s), 1.51 (9H, s) , 1.03-1.17 (4H, m) .

(42b) 2-methoxyethyl 7 ' -aminospiro [cyclopropane-1, 3 ' - pyrido [ 3 , 2-f] [ 1 , 4 ] oxazepine ] -4 ' ( 5 ' H) -carboxylate

The title compound (98.6 mg, yield: 75%) was

obtained by production according to the method described in Example (le) using 2-methoxyethyl 7 ' - [ ( tert- butoxycarbonyl ) amino] spiro [cyclopropane-1, 3 ' -pyrido [3,2- f] [ 1 , 4 ] oxazepine ] -4 ' ( 5 ' H) -carboxylate (176 mg, 0.45 mmol) obtained in Example (42a) as a starting material.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.42 (1H, d, J =

2.4 Hz), 6.89 (1H, d, J = 2.4 Hz), 5.09 (2H, s), 4.24 (2H, s), 4.11-3.99 (2H, m) , 3.72 (2H, s), 3.49-3.41 (2H, m) , 3.22 (3H, s), 1.11-0.89 (4H, m) .

(42c) 2-methoxyethyl 7 ' - { [ ( 5-chloro-2- methoxyphenyl ) sulfonyl ] amino } spiro [ cyclopropane-1 , 3 ' - pyrido [ 3 , 2-f] [ 1 , 4 ] oxazepine ] -4 ' ( 5 ' H) -carboxylate

The title compound (70.5 mg, yield: 93%) was

obtained by production according to the method described in Example (If) using 2-methoxyethyl 7'- aminospiro [cyclopropane-1, 3 ' -pyrido [3,2- f] [ 1 , 4 ] oxazepine ] -4 ' ( 5 ' H) -carboxylate (44.9 mg,

0.15 mmol) obtained in Example (42b) and 5-chloro-2- methoxybenzenesulfonyl chloride (38.0 mg, 0.16 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.28 (1H, br s), 7.86-7.79 (1H, m) , 7.72-7.60 (2H, m) , 7.51-7.42 (1H, m) , 7.28-7.20 (1H, m) , 4.35-4.24 (2H, m) , 4.08-3.97 (2H, m) , 3.88-3.78 (5H, m) , 3.45-3.36 (2H, m) , 3.17 (3H, br s), 1.08-0.87 (4H, m) .

MS spectrum (ES/APCI ⁺ ) : 498 (M+H) , 500 (M+2+H) .

(Example 43) 5-chloro-N- [ ( 3R) -4- (hydroxyacetyl ) -3-phenyl- 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] -2- methoxybenzenesulfonamide

(43a) (3R) -7-bromo-3-phenyl-4- (prop-2-en-l-yl) -2,3,4,5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepine

The title compound (3.27 g, yield for 3 steps: 48%) was obtained by production according to the method described in Examples (18a), (18b) and (18c) using

5-bromo-2-fluoropyridine-3-carbaldehyde (4.07 g,

20.0 mmol) and ( 2R) -2-amino-2-phenylethanol (2.76 g,

20.1 mmol) as starting materials. ½ NMR spectrum (CDCI3, 400MHz) δ: 8.20 (1H, d, J =

2.3 Hz), 7.58 (1H, d, J = 2.3 Hz), 7.43-7.26 (5H, m) , 5.84-5.74 (1H, m) , 5.16-5.15 (2H, m) , 4.49 (1H, dd, J = 12.9, 3.1 Hz), 4.31 (1H, dd, J = 12.9, 7.0 Hz), 4.05

(1H, d, J = 15.6 Hz), 3.99-3.97 (1H, m) , 3.79 (1H, d, J = 15.6 Hz), 3.25-3.22 (1H, m) , 2.95 (1H, dd, J = 14.5,

7.4 Hz) .

(43b) tert-butyl [ ( 3R) -3-phenyl-2 , 3 , 4 , 5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

The title compound (2.29 g, yield for 2 steps: 71%) was obtained by production according to the method described in Example (18d) using ( 3R) -7-bromo-3-phenyl-4-

(prop-2-en-l-yl ) -2,3,4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepine (3.27 g, 9.47 mmol) obtained in

Example (43a) as a starting material.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.95-7.93 (2H, m) , 7.35-7.29 (5H, m) , 6.48 (1H, br s), 4.44 (1H, dd, J = 12.3, 2.5 Hz), 4.30 (1H, dd, J = 9.2, 2.5 Hz), 4.11 (1H, d, J = 14.5 Hz), 4.00 (1H, d, J = 14.5 Hz), 3.87 (1H, dd, J = 12.3, 9.2 Hz), 2.00 (1H, s) .

(43c) tert-butyl [ ( 3R) -4- (hydroxyacetyl ) -3-phenyl- 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] carbamate

The title compound (252 mg, yield for 2 steps:

quantitative) was obtained by production according to the method described in Examples (8b) and (20b) using tert-butyl [ (3R) -3-phenyl-2, 3, 4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate (200 mg, 0.59 mmol) obtained in Example (43b) and acetoxyacetyl chloride (0.076 mL, 0.70 mmol) as starting materials.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.96-7.90 (2H, m) , 7.46-7.26 (5H, m) , 6.57-6.49 (1H, m) , 6.16-3.36 (7H, m) , 1.52-1.50 (9H, m) .

(43d) 5-chloro-N- [ (3R) -4- (hydroxyacetyl ) -3-phenyl- 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] -2- methoxybenzenesulfonamide

The title compound (93.9 mg, yield for 2 steps: 30%) was obtained by production according to the method described in Examples (le) and (If) using tert-butyl

[ (3R) -4- (hydroxyacetyl) -3-phenyl-2, 3,4,5- tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate

(252 mg, 0.63 mmol) obtained in Example (43c) and

5-chloro-2-methoxybenzenesulfonyl chloride (78.9 mg, 0.32 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.17 (1H, br s), 7.73-7.66 (3H, m) , 7.46-7.23 (7H, m) , 5.82-4.23 (7H, m) , 3.90-3.89 (3H, m) , 3.64-3.54 (1H, m) .

MS spectrum (ES/APCI ⁺ ) : 504 (M+H) , 506 (M+2+H) . (Example 44) N- [ ( 3R) -4-acetyl-3- ( tetrahydro-2JJ-pyran-4- yl ) -2 , 3 , 4 , 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] -5- chloro-2 -methoxybenzenesulfonamide

(44a) {2R) -2-amino-2- ( tetrahydro-2JJ-pyran-4-yl ) ethanol

To a mixture of lithium borohydride (702 mg,

31.4 mmol) in tetrahydrofuran (19 mL) ,

chlorotrimethylsilane (8.0 mL, 63 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 10 minutes. Subsequently, (2R)- amino ( tetrahydro-2H-pyran-4-yl ) acetic acid (2.50 g,

15.7 mmol) was added thereto at room temperature, and the mixture was stirred at the same temperature for 11 hours. The excess reagent was decomposed by addition of methanol, and the solvent was distilled off under reduced pressure. The residue was diluted by addition of water and a

2.0 mol/L aqueous solution of sodium hydroxide until it became basic, followed by extraction with a mixed solvent of chloroform/isopropanol = 3/1 three times. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (1.85 g, yield: 81%) .

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 4.02-3.97 (2H, m) , 3.68 (1H, dd, J = 10.3, 3.6 Hz), 3.43-3.32 (3H, m) , 2.63-2.58 (1H, m) , 1.72-1.32 (5H, m) .

(44b) (3R) -7-bromo-4- (prop-2-en-l-yl) -3- ( tetrahydro-2JJ- pyran-4-yl ) -2 , 3 , 4 , 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepine

The title compound (1.58 g, yield for 3 steps: 37%) was obtained by production according to the method described in Examples (18a), (18b) and (18c) using

5-bromo-2-fluoropyridine-3-carbaldehyde (2.50 g,

12.9 mmol) and a crude product of ( 2R) -2-amino-2-

( tetrahydro-2JJ-pyran-4-yl ) ethanol (1.85 g, 12.9 mmol) obtained in Example (44a) as starting materials.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.17 (1H, d, J =

2.4 Hz), 7.51 (1H, d, J = 2.4 Hz), 5.81-5.71 (1H, m) , 5.13-5.04 (2H, m) , 4.32-4.28 (3H, m) , 4.03-4.01 (2H, m) , 3.61 (1H, d, J = 16.4 Hz), 3.41-3.38 (2H, m) , 3.23-3.14

(2H, m) , 2.73-2.70 (1H, m) , 1.93-1.86 (2H, m) , 1.65-1.55

(2H, m) , 1.47-1.25 (2H, m) .

(44c) tert-butyl [ ( 3R) -3- ( tetrahydro-2JJ-pyran-4-yl ) - 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] carbamate

The title compound (1.31 g, yield for 2 steps: 84%) was obtained by production according to the method described in Example (18d) using ( 3R) -7-bromo-4- (prop-2- en-l-yl) -3- ( tetrahydro-2JJ-pyran-4-yl ) -2,3,4,5- tetrahydropyrido [ 3 , 2-f] [ 1 , 4 ] oxazepine (1.58 g, 4.47 mmol) obtained in Example (44b) as a starting material.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.88-7.86 (2H, m) , 6.44 (1H, br s), 4.41 (1H, dd, J = 12.8, 3.1 Hz),

4.03-3.96 (4H, m) , 3.89 (1H, dd, J = 12.5, 7.6 Hz),

3.41-3.35 (2H, m) , 2.94-2.92 (1H, m) , 1.76-1.67 (2H, m) , 1.56-1.46 (12H, m) .

(44d) tert-butyl [ ( 3R) -4-acetyl-3- ( tetrahydro-2JJ-pyran-4- yl ) -2 , 3 , 4 , 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7- yl ] carbamate

The title compound (227 mg, yield: 97%) was obtained by production according to the method described in

Example (8b) using tert-butyl [ ( 3R) -3- ( tetrahydro-2JJ- pyran-4-yl ) -2 , 3 , 4 , 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin- 7-yl ] carbamate (210 mg, 0.60 mmol) obtained in

Example (44c) and acetyl chloride (0.051 mL, 0.72 mmol) as starting materials.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 8.02-8.00 (1H, m) , 7.87 (1H, d, J = 2.4 Hz), 6.67 (1H, br s), 5.13-3.82

(7H, m) , 3.45-3.34 (2H, m) , 2.09-1.98 (4H, m) , 1.74-1.24

(13H, m) .

(44e) 1- [ (3R) -7-amino-3- ( tetrahydro-2JJ-pyran-4-yl ) -2, 3- dihydropyrido [3,2- f] [ 1 , 4 ] oxazepin-4 ( 5H) -yl ] ethanone The title compound (165 mg, yield: 99%) was obtained by production according to the method described in

Example (le) using tert-butyl [ ( 3R) -4-acetyl-3- ( tetrahydro-2JJ-pyran-4-yl ) -2,3,4, 5-tetrahydropyrido [3, 2- f] [ 1 , 4 ] oxazepin-7-yl ] carbamate (225 mg, 0.58 mmol) obtained in Example (44d) as a starting material.

½ NMR spectrum (CDC1 ₃ , 400MHz) δ: 7.65-7.57 (1H, m) , 7.03-6.87 (1H, m) , 5.06-3.99 (6H, m) , 3.76-3.33 (5H, m) , 2.23-2.08 (4H, m) , 1.78-1.33 (4H, m) .

(44f ) N- [ {3R) -4-acetyl-3- ( tetrahydro-2JJ-pyran-4-yl ) - 2,3,4, 5-tetrahydropyrido [3,2- f] [ 1 , 4 ] oxazepin-7-yl ] -5- chloro-2 -methoxybenzenesulfonamide

The title compound (104.2 mg, yield: 90%) was obtained by production according to the method described in Example (If) using 1- [ ( 3R) -7-amino-3- ( tetrahydro-2JJ- pyran-4-yl ) -2 , 3-dihydropyrido [3,2- f] [ 1 , 4 ] oxazepin-4 ( 5H) - yl]ethanone (68.3 mg, 0.23 mmol) obtained in

Example (44e) and 5-chloro-2-methoxybenzenesulfonyl chloride (60.6 mg, 0.25 mmol) as starting materials.

½ NMR spectrum (DMSO-d ₆ , 400MHz) δ: 10.16 (1H, br s), 7.68-7.63 (3H, m) , 7.44-7.22 (2H, m) , 4.75-4.70 (1H, m) , 4.58-4.22 (4H, m) , 3.96-3.85 (5H, m) , 3.28-3.17 (2H, m) , 1.99-1.15 (8H, m) .

MS spectrum (ES/APCI ⁺ ) : 496 (M+H) , 498 (M+2+H) . <Test Examples>

(Test Example 1) Inhibitory test of TNAP activity

COS1 cells (DS Pharma Biomedical Co., Ltd.) were transfected with human TNAP (OriGene Technologies, Inc.) using Lipofectamine LTX & Plus reagent (Invitrogen Corp.) . On the next day, the medium was replaced with a fresh medium, and the cells were cultured in an incubator for 3 days. After 3 days, the culture supernatant was

collected and concentrated by centrifugation at 5000 G for 30 minutes using Amicon 14, 10 ⁴ cut (Merck Millipore) . The concentrated culture supernatant was dialyzed against

5 L of 50 mM Tris/200 mM NaCl/1 mM MgCl ₂ /20 μΜ ZnCl ₂ twice and used as an enzyme source (enzyme solution) .

The substrate pNPP (ProteoChem Inc.) was adjusted to

3.1 mM with Milli-Q water, and a solution of each test compound dissolved in dimethyl sulfoxide (DMSO; Wako Pure Chemical Industries, Ltd.) by 6 serial dilutions at a 5-fold common ratio from 100 μΜ, or DMSO was added

thereto at a final concentration of 1% by volume. The enzyme solution adjusted to 2 μg/mL with an assay buffer (200 mM Tris/2 mM MgCl ₂ /0.04 mM ZnCl ₂ /0.01% Tween 20) was added in the same amount of the substrate solution and incubated at room temperature for 60 minutes. Then, the absorbance (ABS : 405 nm) was measured using a microplate reader (model plus 384, Molecular Devices, LLC), and the concentration of produced p-nitrophenol was calculated. The inhibition of human TNAP activity by the test compound was evaluated on the basis of the concentration IC ₅₀ at which each test compound suppressed 50% of p-nitrophenol production.

The results are shown in Table 1.

[Table 1]

Example compound No. IC50 (nM)

1 4.9

2 10.8

3 5.2

4 7.9

5 7.4

7 5.6

8 4.0

9 3.0

10 2.2

11 3.3

13 1.9

15 1.4

17 7.5

18 2.3

19 1.5

20 2.8

22 13.8

23 7.1

24 1.8

25 3.4 Example compound No. IC ₅₀ (nM)

26 2.3

27 1.5

28 1.5

29 1.6

30 2.5

31 1.5

33 1.3

35 1.1

37 1.1

38 2.5

40 5.4

42 4.9

43 1.4

44 5.4

The compound of the present invention exhibits the excellent inhibition of human TNAP activity and is useful as a pharmaceutical agent for the treatment or

prophylaxis of ectopic calcification.

(Test Example 2) Specific inhibitory test of TNAP

activity

COS1 cells (DS Pharma Biomedical Co., Ltd.) were transfected with human IAP (small-intestinal alkaline phosphatase, purchased from OriGene Technologies, Inc.) or human PLAP (placental alkaline phosphatase, purchased from OriGene Technologies, Inc.) using Lipofectamine LTX & Plus reagent (Invitrogen Corp.) . On the next day, the medium was replaced with a fresh medium, and the cells were cultured in an incubator for 3 days. After 3 days, the culture supernatant was collected and concentrated by centrifugation at 5000 G for 30 minutes using Amicon 14, 10 ⁴ cut (Merck Millipore) . The concentrated culture supernatant was dialyzed against 5 L of 50 mM Tris/200 mM NaCl/1 mM MgCl ₂ /20 μΜ ZnCl ₂ twice and used as an enzyme source (enzyme solution) . The substrate pNPP (ProteoChem Inc.) was adjusted to 3.1 mM with Milli-Q water, and a solution of each test compound dissolved in dimethyl sulfoxide (DMSO; Wako Pure Chemical Industries, Ltd.) by 6 serial dilutions at a 5-fold common ratio from 100 μΜ, or DMSO was added thereto at a final concentration of 1% by volume. The enzyme solution of human IAP or human

PLAP adjusted to 2 μg/mL with an assay buffer (200 mM Tris/2 mM MgCl ₂ /0.04 mM ZnCl ₂ /0.01% Tween 20) was added in the same amount of the substrate solution and

incubated at room temperature for 60 minutes. Then, the absorbance (ABS : 405 nm) was measured using a microplate reader (model plus 384, Molecular Devices, LLC), and the concentration of produced p-nitrophenol was calculated. The inhibition of human IAP or PLAP activity by the test compound was evaluated on the basis of the concentration IC ₅₀ at which each test compound suppressed 50% of p-nitrophenol production. The compound of the present invention exhibits the excellent specific inhibition of TNAP activity and is useful as a pharmaceutical drug for the treatment or prevention of ectopic calcification.

(Test Example 3) Inhibitory test of plasma TNAP activity in B6 mouse (Charles River Laboratories Japan, Inc.)

After blood sampling from the tail vein using a heparin-treated hematocrit capillary tube (EM Meister Hematocrit Capillary Tube, AS ONE Corp.) (as the sample before compound administration) , each test compound suspended in a 0.5% methylcellulose solution (powder purchased from Wako Pure Chemical Industries, Ltd. was adjusted to 0.5% with Otsuka distilled water) was administered orally to the mouse. 1, 2, 4, 6, and

24 hours after the administration, blood was collected from the tail vein using a heparin-treated hematocrit capillary tube to obtain a plasma sample. The plasma sample was added to an assay buffer (1 M Tris, 1 M MgCl ₂ , 20 mM ZnCl ₂ , and water, pH 7.5), and the mixture was left standing for 5 minutes. Then, the absorbance at 405 nm was measured and used as a blank. The substrate pNPP was added to the plasma sample and incubated at room

temperature for 180 minutes. Then, the absorbance

(ABS : 405 nm) was measured using a microplate reader (model plus 384, Molecular Devices, LLC), and the concentration of produced p-nitrophenol was calculated. The blank was subtracted from all measurement values to calculate TNAP activity at each time point with the TNAP activity of the sample before compound administration defined as 100%. The pharmaceutical effect of the test compound was evaluated by the average inhibition of plasma ALP (80-90% containing TNAP) activity for 6 hours from 0 hour to 6 hour after the administration of the test compound. It was calculated according to the following expression:

100- ( (plasma ALP activity at 0 hr + plasma ALP activity at 1 hr)*l/2 + (plasma ALP activity at 1 hr + plsma ALP activity at 2 hr)*l/2 + (plasma ALP activity at 2 hr + plasma ALP activity at 4 hr) *2/2 + (plasma ALP activity at 4 hr + plasma ALP activity at 6 hr)*2/2)/6

The results are shown in Table 2

[Table 2]

Plasma ALP inhibition ( 6h

Example compound No Dose (mg/kg)

ave .

inhibition %)

6 59.5

12 75.3 14 59.2 16 69.2 21 66.9 32 66.8 34 77.3 36 66.3 Plasma ALP

inhibition

Example compound No. Dose (mg/kg)

ave .

inhibition %)

39 1 61.7

41 3 43.5

The compound of the present invention exhibits an excellent in vivo TNAP inhibitory effect and is useful as a pharmaceutical agent for the treatment or prophylaxis of ectopic calcification.

(Test Example 4) In vivo anti-calcification test in vitamin D-induced calcification model

A DBA/2 mouse (male, 6 weeks old when used, Charles River Laboratories Japan, Inc.) is given powder feed

(FR-2 powder feed, Funabashi Farm Co., Ltd.) containing each test compound. 3.75 mg/kg cholecalciferol (Sigma- Aldrich Corp.) is intraperitoneally administered for 3 days from the next day. Seven days after the final cholecalciferol administration, the animal is sacrificed, and the thoracic aorta and the kidney are sampled. The tissue samples are freeze-dried (FREEZE DRYER, FRD-50M, Iwaki Asahi Techno Glass Corp.) . Then, 10% formic acid

(undiluted solution purchased from Kishida Chemical Co., Ltd. was adjusted to 10% with Milli-Q water) is added to each tissue sample, which was then homogenized using QIAGEN Retsch MM300 TissueLyser (Qiagen N.V.) . The homogenate is centrifuged, and the supernatant is used as a sample. The calcium concentration in the sample is measured as absorbance (ABS 612 nm, Microplate reader, model plus 384, Molecular Devices, LLC) using Calcium assay kit (Wako Pure Chemical Industries, Ltd.) to

calculate the amount of calcium in the tissue.

The compound of the present invention exhibits an excellent anti-calcification effect and is useful as a therapeutic agent for the treatment or prevention of ectopic calcification.

(Test Example 5) In vivo anti-calcification test in nephrectomized mouse

A 5/6 nephrectomized DBA/2 mouse (male, 8 weeks old) is purchased from CLEA Japan, Inc. This mouse is loaded with 1.2% high-phosphorus diet (Oriental Yeast Co., Ltd.) . Each test compound suspended in a 0.5% methylcellulose solution (powder purchased from Wako Pure Chemical

Industries, Ltd. is adjusted to 0.5% with Otsuka

distilled water) is administered orally twice daily for three months. After three months, the animal is

sacrificed, and the kidney is sampled. The tissue sample is freeze-dried (FREEZE DRYER, FRD-50M, Iwaki Asahi

Techno Glass Corp.) . Then, 10% formic acid (undiluted solution purchased from Kishida Chemical Co., Ltd. was adjusted to 10% with Milli-Q water) is added to the tissue sample, which was then homogenized using QIAGEN Retsch MM300 TissueLyser (Qiagen N.V.) . The homogenate is centrifuged, and the supernatant is used as a sample. The calcium concentration in the sample was measured as absorbance (ABS 612 nm, Microplate reader, model plus 384, Molecular Devices, LLC) using Calcium assay kit (Wako Pure Chemical Industries, Ltd.) to calculate the amount of calcium in the tissue.

The compound of the present invention exhibits an excellent anti-calcification effect and is useful as a pharmaceutical drug for the treatment or prophylaxis of ectopic calcification.

(Test Example 6) Pharmacokinetic test

The pharmacokinetic test can be conducted according to a method well-known in the field of pharmacodynamics.

Each test compound was suspended in a 0.5% aqueous methylcellulose solution. The obtained suspension was orally administered at a dose in an appropriate range

(e.g., 0.01 mg/kg to 10 mg/kg) to an animal (e.g., a mouse, a rat, a dog, or a cynomolgus monkey) generally used in the pharmacokinetic test. Also, the test

compound was dissolved in saline. The obtained solution was intravenously (e.g., through the tail vein, the cephalic vein, or the saphenous vein) administered at a dose in an appropriate range (e.g., 0.1 mg/kg to

10 mg/kg) to an animal (e.g., a mouse, a rat, a dog, or a cynomolgus monkey) generally used in the pharmacokinetic test. After given times (e.g., 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours) from the administration, blood was collected from an appropriate blood collection site

(e.g., the jugular vein, the cephalic vein, or the saphenous vein) . The obtained blood was centrifuged to prepare a plasma sample. The concentration of the test compound contained in the plasma sample was measured by quantitative analysis using a liquid chromatography-mass spectrometer (LC-MS/MS) .

The pharmacokinetics of the test compound were evaluated on the basis of maximum plasma concentration

(Cmax) , area under the plasma drug concentration-time curve (AUC) , total clearance (CL) , and bioavailability and analyzed using software (Phoenix, etc.) . Cmax represents the maximum plasma concentration of the orally administered test compound. AUC was calculated according to the trapezium rule from the plasma concentrations of the test compound from the time when the test compound was administered up to the final time when the test compound was quantifiable. The bioavailability was calculated according to the following expression:

[ (AUC after oral administration / Dose of the oral administration) / (AUC after intravenous administration / Dose of the intravenous administration) ] .

The compound of the present invention exhibits excellent pharmacokinetics (Cmax, AUC, CL, or

bioavailability) and is useful as a pharmaceutical (particularly, a pharmaceutical for the treatment or prevention of ectopic calcification) .

<Preparation Examples>

(Preparation Example 1) Capsule

Compound of Example

Lactose

Corn starch

Magnesium stearate

250 mg

A powder having the formulation mentioned above is mixed and sifted through a 60-mesh sieve. Then, this powder is put in a gelatin capsule shell to prepare a capsule .

(Preparation Example 2) Tablet

Compound of Example

Lactose

Corn starch

Magnesium stearate

200 mg

A powder having the formulation mentioned above is mixed, granulated using corn starch paste, and dried, followed by compression in a tableting machine to prepare tablets (200 mg each) . This tablet can be coated, if necessary . The novel oxazepine compound represented by the general formula (I) of the present invention or the pharmacologically acceptable salt thereof has an excellent TNAP inhibitory effect and is useful as a pharmaceutical .