JP2007039466A - Nitrogen-containing condensed ring compound and application thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an excellent URAT1 (urate transporter 1) activity inhibitor effective in treatment, etc., of pathological conditions in which uric acid is associated such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal function disorder, coronary artery disease and ischemic heart disease. <P>SOLUTION: The URAT1 activity inhibitor comprises the nitrogen-containing condensed ring compound represented by general formula [1] or its pharmaceutically acceptable salt as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a nitrogen-containing fused ring compound and its use.

  Uric acid (uric acid) is a substance having a molecular weight of 168 and a dissociation constant (pKa value) of 5.75, and exists in body fluid as uric acid (urate) which is uric acid or its conjugate base depending on pH. In humans, the function of urate oxidase (uricase) in the liver is lost due to mutation, so uric acid is the final metabolite of purines. That is, the dietary and endogenously produced purines are converted from adenosine to inosine, hypoxanthine to xanthine, or from guanosine to guanine to xanthine, and this xanthine undergoes oxidation by xanthine oxidase or xanthine dehydrogenase to form uric acid and Become. Uric acid is excreted mainly from the kidneys.

  When hyperuricemia develops and the blood level of uric acid exceeds the upper limit of solubility, sodium urate crystals form in cartilage tissue and joints, creating a precipitate called gouty nodules (tophi). This gout nodule causes acute gouty arthritis that, when it progresses, becomes chronic gouty arthritis. In addition, it is clear that renal dysfunction (gout kidney) and urinary calculi are associated as complications due to crystal deposition of sodium urate due to hyperuricemia, and hyperuricemia itself causes renal dysfunction. Is also known (see Non-Patent Document 1).

  Hyperuricemia patients have many complications such as hyperlipidemia, diabetes, hypertension and obesity. Each of these complications alone is a risk factor for coronary artery disease and mortality, but hyperuricemia patients have a significantly higher complication rate for coronary artery disease than patients with normal blood uric acid levels And it has been known for some time that survival is short. Fang et al. Conducted a large-scale study of mortality from coronary artery disease in 5926 patients aged 25 to 74 years who were able to measure blood uric acid levels during 22 years from 1971 to 1992, and blood uric acid levels It was clarified that an increase in the risk of ischemic heart disease alone (see Non-Patent Document 2). In addition to the treatment of complications, treatment that lowers blood uric acid level itself is useful for preventing the onset of coronary artery disease and reducing mortality, and treatment for lowering blood uric acid level in asymptomatic hyperuricemia is also possible. It has also been reported that this should be done actively (see Non-Patent Document 3). Recently, it has become definitive that hyperuricemia associated with hypertension is an independent risk factor for cardiovascular disease (see Non-Patent Document 4). In addition, according to Non-Patent Document 5, 1) gout and hyperuricemia are complicated by renal disorder (also referred to as gout kidney) and urinary stones, which are complications due to crystal deposition of sodium urate, 2) It is important to control blood uric acid level from the viewpoint of preventing recurrence of brain and cardiovascular accidents. 3) Hyperlipidemia and gout patients often have hyperlipidemia. 4) Hyperuricemia Obesity cannot be ignored as a cause or exacerbation factor of infectious diseases. 5) In principle, uric acid excretion-promoting agents should be used for hypouricemia. 6) Hyperuricemia associated with hypertension is cardiovascular. Since it is described that it is likely to be an independent risk factor of an accident, etc., reducing blood uric acid levels is not only effective for the treatment or prevention of the diseases listed above, Drugs that lower blood uric acid levels are therapeutic agents for these diseases It can be said that it is effective in the treatment or prevention of these above-mentioned diseases in combination with prophylactic agent.

  Uric acid is mainly excreted from the kidney, but blood uric acid is almost completely filtered from the kidney glomerulus and then reabsorbed most of the uric acid in the proximal tubules, so there is little in the urine. Only uric acid is excreted. The reabsorption of uric acid in the proximal tubule was revealed to be transport via a transporter by experiments using membrane vesicles prepared from the renal cortex (see Non-Patent Document 6). Substrate selectivity, its inhibitor, etc. have been clarified (see Non-Patent Documents 7 and 8).

  In recent years, a gene (SLC22A12) encoding a human renal urate transporter has been identified (see Non-Patent Document 9). The transporter (urate transporter 1, URAT1) encoded by this gene is a 12-transmembrane molecule belonging to the organic anion transporter (OAT) family. In Northern blotting using the full length cDNA as a probe, And it was revealed that it was specifically expressed in fetal kidney. In addition, immunostaining in a human kidney tissue section performed using a specific polyclonal antibody against the C-terminal peptide confirmed that the localization was on the proximal tubular lumen side of the cortex. Experiments using the Xenopus laevis oocyte expression system showed that uric acid uptake via URAT1 increased in a time-dependent manner, and that uric acid uptake was characterized by carrier transport saturating at high uric acid concentrations. Furthermore, the uptake is performed by exchange with organic anions such as lactic acid, pyrazinecarboxylic acid, and nicotinic acid, and the uptake is inhibited by uric acid excretion promoting agents such as probenecid and benzbromarone. This also revealed that URAT1 is a transporter that has been clarified by experiments using the above-mentioned membrane vesicles (see Non-Patent Document 10). That is, it was revealed that URAT1 is a central transporter responsible for uric acid reabsorption in the kidney.

  Furthermore, genetic analysis of patients with idiopathic renal hypouricemia identified URAT1 gene mutations, and it was found that uric acid transport activity was lost when these mutants URAT1 were expressed in Xenopus laevis oocytes did. This fact also reveals that URAT1 is involved in the regulation of blood uric acid levels (see Non-Patent Document 9 above).

In addition, regarding the relationship between URAT1 and diseases, probenecid or benzbromarone, which inhibits the uric acid transport activity of URAT1, is a therapeutic agent for hyperuricemia, and high blood uric acid levels are involved. It has already been reported to be useful as a therapeutic or prophylactic agent for pathological conditions such as hyperuricemia, gout nodule, gout arthritis, gout kidney, urolithiasis, and renal dysfunction (see Non-Patent Document 11). ).
In addition, for example, drugs such as nucleic acid antimetabolites, antihypertensive diuretics, antituberculosis drugs, anti-inflammatory analgesics, hyperlipidemia drugs, asthma drugs, immunosuppressive drugs and the like include drugs that increase blood uric acid levels, There is a problem of progression or deterioration due to the above-described increase in blood uric acid level.

  Thus, a substance having an inhibitory action on URAT1 is a pathological condition involving uric acid, for example, a pathological condition involving a high blood uric acid level, specifically, hyperuricemia, gouty nodule, gout arthritis, gouty kidney. Remedies or preventives for urinary stones, renal dysfunction, etc., and further by reducing blood uric acid levels, hyperlipidemia, diabetes, obesity or cardiovascular diseases such as hypertension, coronary artery disease, vascular endothelium It can be said that it is also useful as a therapeutic or prophylactic agent for disorders or ischemic heart diseases. Furthermore, it can be said that the combined use of these other therapeutic agents or preventive agents and substances having a URAT1 activity inhibitory action is more effective for the treatment or prevention of these diseases.

  In addition, substances having an inhibitory activity on URAT1 include, for example, blood uric acid levels such as nucleic acid metabolism antagonists, antihypertensive diuretics, antituberculosis drugs, anti-inflammatory analgesics, hyperlipidemia drugs, asthma drugs, and immunosuppressants. It can be said that it is useful in that an increase in blood uric acid level can be prevented by using it together with a drug to be increased.

  By the way, the following compounds are known as compounds similar in structure to the present invention. For example, Japanese Patent Publication No. 7-76214 discloses a compound represented by the following general formula as a compound exhibiting vasopressin antagonistic activity (see Patent Document 1).

(In the formula, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group, or an amino group or a lower alkoxy group that may have a lower alkyl group as a substituent. R ² represents a hydrogen atom, a halogen atom, or a lower alkoxy group. Group, phenyl lower alkoxy group, hydroxyl group, lower alkyl group, amino group which may have lower alkyl group, carbamoyl substituted lower alkoxy group, amino group substituted lower alkoxy group which may have lower alkyl group as substituent, or phenyl A benzoyloxy group which may have a halogen atom as a substituent on the ring, R ³ represents —NR ⁴ R ⁵ , —CONR ¹¹ R ¹² , W represents a group — (CH ₂ ) p- (p 3-5 integer) or a group _{-CH = CH- (CH 2) q-} (q is 1 or 2).)

  However, these compounds are different in structure from the compounds of the present invention, and no description suggesting the compounds of the present invention is found.

  Next, known uric acid excretion promoters and compounds that are considered to be relatively close to the compounds of the present invention will be described. For example, the specification of CS265559 discloses the following compound, that is, benzbromarone, as a compound exhibiting a uric acid excretion promoting action (see Patent Document 2).

  However, this compound is different in structure from the compound of the present invention, and no description suggesting the compound of the present invention is found. In addition, the compound has a strong inhibitory action on CYP2C8, CYP2C9, CYP2C19 and CYP3A4 molecular species of cytochrome P450 (CYP), which is a drug metabolizing enzyme, and may cause pharmacokinetic drug interaction. Has been suggested. (Refer nonpatent literature 12).

Japanese Patent Publication No. 7-76214 CS265559 specification Johnson RJ, Kivil SD, Kim YG et al. Reappraisal of the pathogenesis and consequences of hyperemia in hypertension, cardiovascular disease, and random disease. Am. J. et al. Kidney Dis. 33, 225-234 (1999) Fang J. Alderman MH. JAMA 283 (18) 2404-2410 (2000) Toru Nakamura Hyperuricemia and gout 9 (1) 61-65 (2001) Ichiro Kurume, Nikkei Medical, January 2004, 100-101 Guidelines for Treatment of Hyperuricemia and Gout (1st Edition), Gout and Nucleic Acid Metabolism, Vol. 26, Appendix 1, 2002 Japanese Society of Gout and Nucleic Acid Metabolism Sica DA and Schoolwert AC. The Kidney, 6th edition, pp. 680-700, Saunders, Philadelphia (2000) Roch-Ramel F.R. , Werner D. , And Guisan B., et al. Am. J. et al. Physiol. 266, F797-F805 (1994) Roch-Ramel F.R. , Guisan B. et al. , And Diezi J. et al. J. et al. Pharmacol. Exp. Ther. 280, 839-845 (1997) Enomoto A. et al. , Nature 417, 447-452 (2002) Naohiko Anzai et al. Biochemistry 76 (2) 101-110 (2004) Hisashi Yamanaka Diagnosis and Treatment Vol.92, No.1, 125-128 (2004) Chiyoko Kunishima et al. Saitama Medical University Journal Saitama Med School Vol.30 No.4 p187-194 (2004)

  Currently, benzbromarone, which is a uric acid excretion promoter having a URAT1 activity inhibitory action, is used as a therapeutic or preventive agent for hyperuricemia. However, the inhibitory action of benzbromarone on URAT1 activity is not sufficient. In addition, it has a CYP inhibitory action, suggesting the possibility of causing pharmacokinetic drug interactions. Accordingly, there has been a strong demand for the development of a therapeutic or preventive agent for hyperuricemia that has a stronger URAT1 activity inhibitory action and no or very weak CYP inhibitory action. The present invention provides a novel therapeutic or preventive agent for hyperuricemia that is stronger than conventional URAT1 activity inhibitors and has no or very little CYP inhibitory activity, that is, URAT1 activity inhibitors, etc. The task is to do.

  As a result of intensive research to develop a new therapeutic or preventive drug for hyperuricemia that replaces the conventional therapeutic or preventive drug for hyperuricemia, the present inventors have found that nitrogen having an excellent URAT1 activity inhibitory action The present inventors have found a condensed ring compound containing the present invention and completed the present invention.

That is, the present invention is as follows.
<1>
A URAT1 activity inhibitor comprising a substance that inhibits URAT1 activity and does not substantially inhibit CYP.
<2>
The URAT1 activity inhibitor according to <1>, wherein CYP is CYP2C9.
<3>
The URAT1 activity inhibitor according to the above <1> or <2>, wherein the substance that inhibits URAT1 activity and does not substantially inhibit CYP has a 50% inhibitory concentration against CYP2C9 of 1 μM or more.

<4>
A URAT1 activity inhibitor comprising a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof.

[Where:
R ¹ , R ² and R ³ are the same or different,
1) a hydrogen atom, or 2) a group selected from the following group A, or 3) saturated or unsaturated having 3 to 14 carbon atoms together with the carbon atom to which R ¹ and R ² are bonded Or the carbocycle may be substituted with one or more substituents selected from group A below, or 4) R ² and R ³ are bonded to each other A saturated or unsaturated carbocycle having 3 to 14 carbon atoms together with the carbon atom to be substituted (the carbocycle may be substituted with one or more substituents selected from the following group A). May form;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is,
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom, or (b) a group selected from group A below, or (c) R ³ and R ⁴ are saturated with 3 to 14 carbon atoms together with the carbon atom to which they are bonded. Alternatively, an unsaturated carbocycle (the carbocycle may be substituted with one or more substituents selected from the same or different groups selected from group A below) may be formed. )
Is;
X ² is,
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below. ),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the following group A;
(E) a cycloalkylalkoxy group optionally substituted by one or more substituents selected from the following group A,
(F) an aralkyl group optionally substituted with one or more substituents selected from the following group A, or (g) substituted with one or more substituents selected from the following group A. A good aralkoxy group. ),
4) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above),
5) -N (CONR ⁷ R ⁸ )-(wherein R ⁷ and R ⁸ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the following group A, or the same or different. ) May be formed. ),
6) sulfur atom,
7) -S (= O)-,
8) —S (═O) ₂ —, or 9) —CR ⁹ R ¹⁰ — (wherein R ⁹ and R ¹⁰ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁹ and R ¹⁰ Together may form an oxo group. )
Is;
-X ³ -X ⁴ -is
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different groups selected from the following group B, or (c) the same carbon atom R ¹¹ and R ^{12 to} be bonded together form an oxo group, or (d) two of n R ¹¹ and R ¹² bonded to the same or adjacent two carbon atoms are the carbon atoms And a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle may be substituted with one or more substituents selected from the following group A). May be. )
And ring A is
1) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following group A), or 2) A saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is substituted with one or more substituents selected from the following group A; May be.)
It is.
[Group A]
1) a halogen atom,
2) —OR ¹³ (wherein R ¹³ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group which may be substituted with one or different substituents selected from the following group B, or (c) —COR ¹⁴ (wherein R ¹⁴ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
7) —COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
8) —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ¹⁵ and R ¹⁶ A nitrogen-containing saturated heterocycle comprising a single ring together with the nitrogen atom to which they are bonded (the heterocycle is substituted with one or more substituents selected from the following (i) and (ii)): May be.
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ) May be formed. ),
9) -CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
10) —NR ¹⁷ COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above, and R ¹⁷ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below. ),
11) —NR ¹⁷ S (═O) ₂ R ¹⁴ (wherein R ¹⁴ and R ¹⁷ are as defined above),
12) —NR ¹⁷ CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above),
13) —SR ¹³ (wherein R ¹³ has the same meaning as described above),
14) —S (═O) R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
18) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
19) Aryloxy group (the aryloxy group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
20) Cyano group, and 21) Nitro group [Group B]
1) a halogen atom,
2) a hydroxyl group,
3) a C _1-6 alkoxy group,
4) -NR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁸ and R ¹⁹ together with a nitrogen atom to which they are bonded to form a monocycle. A ring may be formed. ),
5) -CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are as defined above),
6) -COR ²⁰ (wherein R ²⁰ represents
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7) —NR ²¹ COR ²⁰ (wherein R ²⁰ has the same meaning as described above, and R ²¹ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8) —NR ²¹ CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ , R ¹⁹ and R ²¹ are as defined above),
9) —NR ²¹ S (═O) ₂ R ²² (wherein R ²¹ has the same meaning as described above, and R ²² represents a C _1-6 alkyl group), and 10) —S (═O ₂ R ²² (wherein R ²² has the same meaning as described above.)
Here, the C _1-6 alkyl group and the C _1-6 alkoxy group in the above 3) to 10) may be further substituted with one or more substituents selected from Group B, Moreover, the nitrogen-containing saturated heterocyclic ring consisting of a single ring in the above 4), 5) and 8) may be further substituted with one or more substituents selected from group B and C _1-6 alkyl group. ]]

<5>
A nitrogen-containing fused ring compound represented by the following general formula [2] or a pharmaceutically acceptable salt thereof.

[Wherein, R ¹ , R ² , R ³ , Y, X ¹ , X ³ and X ⁴ are as defined in claim 4,
Ring A ′ is
1) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group is substituted with one or more substituents selected from the following group C), or 2) nitrogen A saturated or unsaturated heterocyclic group having at least one heteroatom selected from an atom, an oxygen atom and a sulfur atom (the heterocyclic group is substituted with one or more substituents selected from the following group C; ing.)
And the ring A ′ is substituted with at least one —OR ¹³ ′ (R ¹³ ′ is defined in group C below);
X ² '
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below. ),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the following group A;
(E) a cycloalkylalkoxy group optionally substituted by one or more substituents selected from the following group A,
(F) an aralkyl group optionally substituted with one or more substituents selected from the following group A, or (g) substituted with one or more substituents selected from the following group A. A good aralkoxy group. ),
4) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above),
5) -N (CONR ⁷ R ⁸ )-(wherein R ⁷ and R ⁸ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the following group A, or the same or different. ) May be formed. ),
6) sulfur atom,
7) -S (= O)-,
8) —S (═O) ₂ —, or 9) —CH ₂ —.
It is.
(However, when X ² ′ is —CH ₂ —,
-X ³ -X ⁴ -is
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or
(B) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n two R ¹¹ and R ¹² are bonded to the same or adjacent two carbon atoms. The two bonded together with the carbon atom are a saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (the carbocyclic ring is substituted with one or more substituents selected from the following group A; May be formed). )
Is;
R ¹³ ′ is a hydrogen atom; and ring A ′ is further substituted with at least one halogen atom;
However, when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms. )
[Group A]
1) a halogen atom,
2) —OR ¹³ (wherein R ¹³ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group which may be substituted with one or different substituents selected from the following group B, or (c) —COR ¹⁴ (wherein R ¹⁴ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
7) —COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
8) —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ¹⁵ and R ¹⁶ A nitrogen-containing saturated heterocycle comprising a single ring together with the nitrogen atom to which they are bonded (the heterocycle is substituted with one or more substituents selected from the following (i) and (ii)): May be.
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ) May be formed. ),
9) -CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
10) —NR ¹⁷ COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above, and R ¹⁷ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below. ),
11) —NR ¹⁷ S (═O) ₂ R ¹⁴ (wherein R ¹⁴ and R ¹⁷ are as defined above),
12) —NR ¹⁷ CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above),
13) —SR ¹³ (wherein R ¹³ has the same meaning as described above),
14) —S (═O) R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
18) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
19) Aryloxy group (the aryloxy group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
20) Cyano group, and 21) Nitro group [Group B]
1) a halogen atom,
2) a hydroxyl group,
3) a C _1-6 alkoxy group,
4) -NR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁸ and R ¹⁹ together with a nitrogen atom to which they are bonded to form a monocycle. A ring may be formed. ),
5) -CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are as defined above),
6) -COR ²⁰ (wherein R ²⁰ represents
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7) —NR ²¹ COR ²⁰ (wherein R ²⁰ has the same meaning as described above, and R ²¹ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8) —NR ²¹ CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ , R ¹⁹ and R ²¹ are as defined above),
9) —NR ²¹ S (═O) ₂ R ²² (wherein R ²¹ has the same meaning as described above, and R ²² represents a C _1-6 alkyl group), and 10) —S (═O ₂ R ²² (wherein R ²² has the same meaning as described above.)
Here, the C _1-6 alkyl group and the C _1-6 alkoxy group in the above 3) to 10) may be further substituted with one or more substituents selected from Group B, Moreover, the nitrogen-containing saturated heterocyclic ring consisting of a single ring in the above 4), 5) and 8) may be further substituted with one or more substituents selected from group B and C _1-6 alkyl group. )
[Group C]
1) a halogen atom,
2) —OR ¹³ ′ (wherein R ¹³ ′ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B, or (c) —COR ¹⁴ ′ (wherein R ¹⁴ ′ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
7) —COR ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
8) -NR ¹⁵ 'R ¹⁶ ' (wherein R ¹⁵ 'and R ¹⁶ ' are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B, or (c) R ¹⁵ ′ and R ¹⁶ 'is a nitrogen-containing saturated heterocycle consisting of a single ring together with the nitrogen atom to which they are bonded (wherein the heterocycle is one or more substituents selected from the following (i) and (ii): May be substituted.
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ) May be formed. ),
9) —NR ¹⁷ ′ COR ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above, and R ¹⁷ ′ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
_{^{10) -NR 17 'S (=}} O) 2 R 14' ( ^{wherein, R 14} 'and ^{R 17'} has the same meaning as defined above.)
11) —NR ¹⁷ ′ CONR ¹⁵ ′ R ¹⁶ ′ (wherein R ¹⁵ ′, R ¹⁶ ′ and R ¹⁷ ′ are as defined above),
12) —SR ¹³ ′ (wherein R ¹³ ′ has the same meaning as described above),
13) —S (═O) R ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
14) —S (═O) ₂ R ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
15) —S (═O) ₂ NR ¹⁵ ′ R ¹⁶ ′ (wherein R ¹⁵ ′ and R ¹⁶ ′ are as defined above),
16) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
17) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
18) Aryloxy group (The aryloxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
19) cyano group, and 20) nitro group]

<6>
(A) X ² ′ is
1) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
2) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different groups selected from the group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the same or different groups selected from the group A;
(E) a cycloalkylalkoxy group that may be substituted with one or more substituents selected from the same or different groups selected from the group A;
(F) an aralkyl group optionally substituted with one or more substituents selected from the group A, or (g) substituted with one or more substituents selected from the group A. A good aralkoxy group. ),
3) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above), or 4) —N (CONR ⁷ R ⁸ ) — (wherein R ⁷ and R ⁸ is the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from Group B, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the group A or the same or different. ) May be formed. )
If it is,
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
(B) X ² ′
1) -S (= O)-, or 2) -S (= O) _2-
If it is,
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - is;
(C) X ² ′ is a sulfur atom, and Y is
1) -CO-, or 2) -CS-,
If it is,
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
(D) X ² ′ is an oxygen atom and Y is
1) -CO-, or 2) -CS-,
If it is,
R ¹ , R ² and R ³ are the same or different,
1) a hydrogen atom, or 2) a group selected from the following group D, or 3) R ¹ and R ² together with the carbon atom to which they are bonded, saturated or unsaturated having 3 to 14 carbon atoms Or the carbocycle may be substituted with one or more substituents selected from group D below or the same or different from each other, or 4) R ² and R ³ are bonded to each other And a saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (the carbocyclic ring may be substituted with one or more substituents selected from the following group D). And —X ³ —X ⁴ — is —CH ₂ —CH ₂ —;
(E) X ² '
When 1) an oxygen atom, or 2) a sulfur atom and Y is —S (═O) ₂ —,
When —X ³ —X ⁴ — is —CH ₂ —CH ₂ —; and R ¹³ ′ is a hydrogen atom; or (F) X ² ′ is —CH ₂ —,
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or (b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n R ¹¹ and R ¹² Two of them bonded to the same or adjacent two carbon atoms together with the carbon atom are saturated or unsaturated carbocycles having 3 to 14 carbon atoms (the carbocycle is the same or selected from the group A or May be substituted with one or more different substituents. )
Is;
R ¹³ ′ is a hydrogen atom; and ring A ′ is further substituted with at least one halogen atom;
However, in the case of (F), R ¹¹ and R ¹² are both hydrogen atoms, and when n is 2, R ¹ , R ² and R ³ are all hydrogen atoms;
<5> or a pharmaceutically acceptable salt thereof.
[Group D]
1) a halogen atom,
2) —OR ¹³ ″ (wherein R ¹³ ″ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B, or (c) —COR ¹⁴ ″ (wherein R ¹⁴ ″ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
7) —COR ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
8) —NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B, or (c) R ¹⁵ ″ and R ¹⁶ ″ is a nitrogen-containing saturated heterocyclic ring composed of a single ring together with a nitrogen atom to which they are bonded (the heterocyclic ring is one or more selected from the same or different selected from the following (i) and (ii)) It may be substituted with a substituent.
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ) May be formed. ),
9) -CONR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are as defined above),
10) —NR ¹⁷ ″ COR ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above, and R ¹⁷ ″ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
11) —NR ¹⁷ ″ S (═O) ₂ R ¹⁴ ″ (wherein R ¹⁴ ″ and R ¹⁷ ″ are as defined above),
12) —NR ¹⁷ ″ CONR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″, R ¹⁶ ″ and R ¹⁷ ″ are as defined above),
13) -SR ¹³ ″ (wherein R ¹³ ″ has the same meaning as described above),
14) —S (═O) R ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
18) Aryloxy group (The aryloxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
19) Cyano group, and 20) Nitro group

<7>
X ² '
1) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
2) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different groups selected from the group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the same or different groups selected from the group A;
(E) a cycloalkylalkoxy group that may be substituted with one or more substituents selected from the same or different groups selected from the group A;
(F) an aralkyl group optionally substituted with one or more substituents selected from the group A, or (g) substituted with one or more substituents selected from the group A. A good aralkoxy group. ),
3) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above), or 4) —N (CONR ⁷ R ⁸ ) — (wherein R ⁷ and R ⁸ is the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from Group B, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the group A or the same or different. ) May be formed. );
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
<5> or a pharmaceutically acceptable salt thereof.

<8>
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
<7> The compound according to <7> or a pharmaceutically acceptable salt thereof.

<9>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
2) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group, or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (wherein the carbocyclic group is the same or different one or more selected from a halogen atom and a hydroxyl group) . it may be substituted with group)), or _{3) -N (S (= O} ) 2 -C 1-6 alkyl) -,
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
<7> The compound according to <7> or a pharmaceutically acceptable salt thereof.

<10>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
2) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group, or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (wherein the carbocyclic group is the same or different one or more selected from a halogen atom and a hydroxyl group) . it may be substituted with group)), or _{3) -N (S (= O} ) 2 -C 1-6 alkyl) -,
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
<7> The compound according to <7> or a pharmaceutically acceptable salt thereof.

<11>
X ² '
1) -S (= O)-, or 2) -S (= O) _2-
In it; and ^-X 3 -X ⁴ - it _is, -CH ₂ -CH 2 - is;
<5> or a pharmaceutically acceptable salt thereof.

<12>
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is —OR ¹³ ′ (R ¹³ ′ is as defined in claim 5). is there. );
<11> or a pharmaceutically acceptable salt thereof.

<13>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) -S (= O)-, or 2) -S (= O) _2-
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group that may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups;
5) -O-CO-C _1-6 alkyl group,
6) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
7) -COOH,
8) —CO—C _1-6 alkoxy group,
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group, or 11) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group, a C _1-6 alkoxy group (the C _{1 -6} alkoxy groups may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups) and —O—CO—C _1-6 alkyl groups. The group to be selected. );
<11> or a pharmaceutically acceptable salt thereof.

<14>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) -S (= O)-, or 2) -S (= O) _2-
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
<11> or a pharmaceutically acceptable salt thereof.

<15>
Y is
1) -CO-, or 2) -CS-,
Is;
X ² 'is a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
<5> or a pharmaceutically acceptable salt thereof.

<16>
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
<15> or a pharmaceutically acceptable salt thereof.

<17>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-, or 2) -CS-,
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
<15> or a pharmaceutically acceptable salt thereof.

<18>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
<15> or a pharmaceutically acceptable salt thereof.

<19>
R ¹ , R ² and R ³ are the same or different,
1) a hydrogen atom, or 2) a group selected from the following group D, or 3) R ¹ and R ² together with the carbon atom to which they are bonded, saturated or unsaturated having 3 to 14 carbon atoms Or the carbocycle may be substituted with one or more substituents selected from group D below or the same or different from each other, or 4) R ² and R ³ are bonded to each other And a saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (the carbocyclic ring may be substituted with one or more substituents selected from the following group D). May form;
Y is
1) -CO-, or 2) -CS-,
Is;
X ² ′ is an oxygen atom; and —X ³ —X ⁴ — is —CH ₂ —CH ₂ —;
<5> or a pharmaceutically acceptable salt thereof.
[Group D]
1) a halogen atom,
2) —OR ¹³ ″ (wherein R ¹³ ″ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B, or (c) —COR ¹⁴ ″ (wherein R ¹⁴ ″ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
7) —COR ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
8) —NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B, or (c) R ¹⁵ ″ and R ¹⁶ ″ is a nitrogen-containing saturated heterocyclic ring composed of a single ring together with a nitrogen atom to which they are bonded (the heterocyclic ring is one or more selected from the same or different selected from the following (i) and (ii)) It may be substituted with a substituent.
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ) May be formed. ),
9) -CONR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are as defined above),
10) —NR ¹⁷ ″ COR ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above, and R ¹⁷ ″ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
11) —NR ¹⁷ ″ S (═O) ₂ R ¹⁴ ″ (wherein R ¹⁴ ″ and R ¹⁷ ″ are as defined above),
12) —NR ¹⁷ ″ CONR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″, R ¹⁶ ″ and R ¹⁷ ″ are as defined above),
13) -SR ¹³ ″ (wherein R ¹³ ″ has the same meaning as described above),
14) —S (═O) R ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
18) Aryloxy group (The aryloxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
19) Cyano group, and 20) Nitro group

<20>
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is —OR ¹³ ′ (R ¹³ ′ is as defined in claim 5). is there. );
<19> or a pharmaceutically acceptable salt thereof.

<21>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) R ¹⁵ ″ and R ¹⁶ ″ together with the nitrogen atom to which they are attached comprise a single ring A nitrogen-containing saturated heterocyclic ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is an oxygen atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group that may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups;
5) -O-CO-C _1-6 alkyl group,
6) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
7) -COOH,
8) —CO—C _1-6 alkoxy group,
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group, or 11) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group, a C _1-6 alkoxy group (the C _{1 -6} alkoxy groups may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups) and —O—CO—C _1-6 alkyl groups. The group to be selected. );
<19> or a pharmaceutically acceptable salt thereof.

<22>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are the same or different;
(A) a C _1-6 alkyl group, or (b) R ¹⁵ ″ and R ¹⁶ ″ together with the nitrogen atom to which they are attached form a nitrogen-containing saturated heterocycle consisting of a single ring. May be. Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is an oxygen atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
<19> or a pharmaceutically acceptable salt thereof.

<23>
Y is —S (═O) ₂ —;
X ² '
1) an oxygen atom, or 2) a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
<5> or a pharmaceutically acceptable salt thereof.

<24>
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
<23> or a pharmaceutically acceptable salt thereof.

<25>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is —S (═O) ₂ —;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) an oxygen atom, or 2) a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
<23> or a pharmaceutically acceptable salt thereof.

<26>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is —S (═O) ₂ —;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) an oxygen atom, or 2) a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
<23> or a pharmaceutically acceptable salt thereof.

<27>
X ² ′ is —CH ₂ —;
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or (b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n R ¹¹ and R ¹² Two of them bonded to the same or adjacent two carbon atoms together with the carbon atom are saturated or unsaturated carbocycles having 3 to 14 carbon atoms (the carbocycle is the same or selected from the group A or May be substituted with one or more different substituents. )
Is;
R ¹³ ′ is a hydrogen atom; and ring A ′ is further substituted with at least one halogen atom;
Provided that when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms;
<5> or a pharmaceutically acceptable salt thereof.

<28>
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, at least one of R ^{23 to} R ²⁷ is a hydroxyl group, and at least one of R ^{23 to} R ²⁷ is a halogen atom. . );
<27> or a pharmaceutically acceptable salt thereof.

<29>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² ′ is —CH ₂ —;
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3, and n R ¹¹ and R ¹² are the same or different, respectively, (a) are hydrogen atoms, or ( b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) Bonded to two identical or adjacent carbon atoms of n R ¹¹ and R ¹² And two of them, together with the carbon atom, a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle is substituted with one or more substituents selected from the same or different group A) Or may be formed.)
And ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group, and at least any of R ^{23 to} R ²⁷ One of them is a halogen atom. );
Provided that when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms;
<27> or a pharmaceutically acceptable salt thereof.

<30>
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² ′ is —CH ₂ —;
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3, and n R ¹¹ and R ¹² are the same or different, respectively, (a) are hydrogen atoms, or ( b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) Bonded to two identical or adjacent carbon atoms of n R ¹¹ and R ¹² And two of them, together with the carbon atom, a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle is substituted with one or more substituents selected from the same or different group A) Or may be formed.)
And ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group, and at least one of R ^{23 to} R ²⁷ is a halogen atom. );
Provided that when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms;
<27> or a pharmaceutically acceptable salt thereof.

<31>
The compound according to the above <5> or a pharmaceutically acceptable salt thereof selected from the following group.
(1) (3-Chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(2) (3-Bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(3) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(4) (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(5) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone,
(6) (3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(7) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone,
(8) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone,
(9) (3,5-dichloro-4-hydroxyphenyl)-(1-oxo-2,3-dihydro-1H-1λ ⁴ -benzo [1,4] thiazin-4-yl) -methanone,
(10) (3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone,
(11) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanethione,
(12) (3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(13) (3,5-dichloro-4-hydroxyphenyl)-(7-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(14) (3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(15) (3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(16) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone,
(17) (3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(18) (3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(19) (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(20) (3,5-dichloro-4-hydroxyphenyl)-(7-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(21) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide,
(22) 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-sulfonyl) phenol,
(23) (6-tert-butyl-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(24) 4- (3,5-dichloro-4-hydroxybenzoyl) -4H-benzo [1,4] oxazin-3-one,
(25) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid amide,
(26) (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone,
(27) (3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone,
(28) (4-amino-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(29) (5-chloro-6-hydroxypyridin-3-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(30) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dinitrophenyl) -methanone,
(31) (3-Chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(32) (3,5-dichloro-4-hydroxyphenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(33) (3,5-dichloro-4-hydroxyphenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone,
(34) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid ethylamide,
(35) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid dimethylamide;
(36) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone,
(37) 5- (3,5-dichloro-4-hydroxybenzoyl) -1,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-2-one,
(38) (3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(39) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone,
(40) (3-Chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(41) (4-Chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(42) (2,6-dichloropyridin-4-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(43) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-nitrophenyl) -methanone,
(44) (3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(45) 2- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(46) methyl 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate,
(47) 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(48) methyl 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate,
(49) 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(50) (3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(51) (6-Chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(52) (7-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(53) [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl]-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(54) (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(55) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester,
(56) (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(57) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid,
(58) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-5-carboxylic acid methyl ester,
(59) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid methyl ester,
(60) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid,
(61) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid methyl ester,
(62) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid,
(63) (3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(64) (3,5-dichloro-4-hydroxyphenyl)-(phenoxazin-10-yl) -methanone,
(65) (3,5-dichloro-4-hydroxyphenyl)-(6-phenyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(66) (3,5-dichloro-4-hydroxyphenyl)-(6,8-dimethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(67) (3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(68) (6-Amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(69) (3,5-dibromo-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(70) (3,5-dichloro-4-hydroxyphenyl)-(7-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(71) (7-amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(72) N- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazin-7-yl] -methanesulfonamide,
(73) 1- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone,
(74) (3,5-dichloro-4-hydroxyphenyl)-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(75) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-nitrophenyl) -methanone,
(76) (3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone,
(77) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl) -methanone,
(78) (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(79) (3,5-dibromo-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(80) (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone,
(81) (3,5-dibromo-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(82) (6-Chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dibromo-4-hydroxyphenyl) -methanone,
(83) (3,5-dichloro-4-hydroxyphenyl)-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(84) (3,5-dichloro-4-hydroxyphenyl)-(6-ethanesulfonyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(85) (3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(86) (3,5-dichloro-4-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(87) Acetic acid 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl ester,
(88) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxyphenyl) -methanone,
(89) (3,5-dichloro-4-hydroxyphenyl)-(5-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(90) (3,5-dichloro-4-hydroxyphenyl)-(8-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(91) [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid ethyl ester,
(92) [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid,
(93) (3,5-dichloro-4-hydroxyphenyl)-(3-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(94) N- [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide, and (95) (3,5-dichloro-4 -Hydroxyphenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone.

<32>
A pharmaceutical composition comprising the compound according to any one of the above <5> to <31> or a pharmaceutically acceptable salt thereof.
<33>
A URAT1 activity inhibitor comprising the compound according to any one of <5> to <31> or a pharmaceutically acceptable salt thereof.
<34>
A blood uric acid level-lowering agent comprising a substance that inhibits URAT1 activity and does not substantially inhibit CYP according to any one of <1> to <3> above.
<35>
A blood uric acid level lowering agent comprising the compound of the general formula [1] described in <4> above or a pharmaceutically acceptable salt thereof.
<36>
A blood uric acid level-lowering agent comprising the compound according to any one of <5> to <31> or a pharmaceutically acceptable salt thereof.
<37>
A therapeutic or prophylactic agent for a pathological condition involving uric acid, which comprises a substance that inhibits URAT1 activity and does not substantially inhibit CYP as described in any one of <1> to <3> above.
<38>
A therapeutic or prophylactic agent for a disease state involving uric acid, comprising the compound of the general formula [1] described in <4> above or a pharmaceutically acceptable salt thereof.
<39>
A therapeutic or prophylactic agent for a disease state involving uric acid, comprising the compound according to any one of <5> to <31> or a pharmaceutically acceptable salt thereof.
<40>
<37> above, wherein the pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease Thru | or <39> any one of the treatment or prevention agent of the disease state in which uric acid is concerned.

<41>
A method for treating a pathological condition involving uric acid, comprising administering a pharmaceutically effective amount of a substance that inhibits the URAT1 activity described in any one of <1> to <3> and does not substantially inhibit CYP. Or prevention method.
<42>
A method for treating or preventing a pathological condition involving uric acid, comprising administering a pharmaceutically effective amount of the compound of the general formula [1] described in <4> above or a pharmaceutically acceptable salt thereof.
<43>
A method for treating or preventing a pathological condition involving uric acid, which comprises administering a pharmaceutically effective amount of the compound according to any one of <5> to <31> above or a pharmaceutically acceptable salt thereof.
<44>
<41> above, wherein the pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease Thru | or the treatment method or prevention method in any one of <43>.
<45>
A method for inhibiting URAT1 activity, comprising administering a pharmaceutically effective amount of a substance that inhibits URAT1 activity according to any one of the above <1> to <3> and does not substantially inhibit CYP.
<46>
A method for inhibiting URAT1 activity, comprising administering a pharmaceutically effective amount of a compound of the general formula [1] described in <4> above or a pharmaceutically acceptable salt thereof.
<47>
A method for inhibiting URAT1 activity, comprising administering a pharmaceutically effective amount of the compound according to any one of <5> to <31> above or a pharmaceutically acceptable salt thereof.
<48>
A method for lowering a blood uric acid level, comprising administering a pharmaceutically effective amount of a substance that inhibits the URAT1 activity described in any one of <1> to <3> and does not substantially inhibit CYP.
<49>
A method for lowering blood uric acid level, comprising administering a pharmaceutically effective amount of the compound of the general formula [1] described in <4> above or a pharmaceutically acceptable salt thereof.
<50>
A method for reducing a blood uric acid level, comprising administering a pharmaceutically effective amount of the compound according to any one of <5> to <31> above or a pharmaceutically acceptable salt thereof.

<51>
Use of a substance that inhibits URAT1 activity and does not substantially inhibit CYP according to any one of the above <1> to <3> for producing a therapeutic or prophylactic agent for a pathological condition involving uric acid.
<52>
Use of the compound of the general formula [1] described in the above <4> or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a pathological condition involving uric acid.
<53>
Use of the compound according to any one of the above <5> to <31> or a pharmaceutically acceptable salt thereof for producing a therapeutic or prophylactic agent for a pathological condition involving uric acid.
<54>
<51> above, wherein the pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease Thru | or <53> use.
<55>
Use of a substance that inhibits URAT1 activity and does not substantially inhibit CYP, according to any one of <1> to <3> above, for producing a URAT1 activity inhibitor.
<56>
Use of the compound of the general formula [1] described in the above <4> or a pharmaceutically acceptable salt thereof for producing a URAT1 activity inhibitor.
<57>
Use of the compound according to any one of the above <5> to <31> or a pharmaceutically acceptable salt thereof for producing a URAT1 activity inhibitor.
<58>
Use of a substance that inhibits URAT1 activity and does not substantially inhibit CYP, according to any one of <1> to <3> above, for producing a blood uric acid level-lowering agent.
<59>
Use of the compound of the general formula [1] described in the above <4> or a pharmaceutically acceptable salt thereof for producing a blood uric acid level-lowering agent.
<60>
Use of the compound according to any one of the above <5> to <31> or a pharmaceutically acceptable salt thereof for producing a blood uric acid level lowering agent.

<61>
A pharmaceutical composition for the treatment or prevention of a pathological condition involving uric acid, which comprises a substance that inhibits URAT1 activity and does not substantially inhibit CYP according to any one of <1> to <3> above.
<62>
A pharmaceutical composition for treating or preventing a pathological condition involving uric acid, comprising the compound of the general formula [1] described in <4> above or a pharmaceutically acceptable salt thereof.
<63>
A pharmaceutical composition for treating or preventing a pathological condition involving uric acid, comprising the compound according to any one of <5> to <31> or a pharmaceutically acceptable salt thereof.
<64>
<61> above, wherein the pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease Thru | or <63> pharmaceutical composition in any one of.
<65>
The pharmaceutical composition according to any one of the above <61> to <64> and the pharmaceutical composition comprising hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, kidney A commercial package comprising a description relating to the pharmaceutical composition which can be used or should be used for the treatment or prevention of a disease selected from dysfunction, coronary artery disease and ischemic heart disease.

<66>
The pharmaceutical composition according to the above <32>, which is used in combination with 1 to 3 agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist

<67>
The URAT1 activity inhibitor according to any one of <1> to <4> and <33> above, which is used in combination with one to three agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist

<68>
The blood uric acid level-lowering agent according to any one of <34> to <36> above, which is used in combination with one to three agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist

<69>
The therapeutic or preventive agent for a disease state involving uric acid according to any one of <37> to <40> above, which is used in combination with one to three agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist

<70>
The method for treating or preventing a disease state involving uric acid according to any one of the above <41> to <44>, further comprising administering 1 to 3 agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist

<71>
The method for inhibiting URAT1 activity according to any one of <45> to <47>, further comprising administering 1 to 3 agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist

<72>
The method for reducing blood uric acid level according to any one of <48> to <50>, further comprising administering 1 to 3 agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist

<73>
Any one of the above <51> to <54> for producing a therapeutic or prophylactic agent for a pathological condition involving uric acid for use in combination with one to three agents selected from the following groups (1) to (11) Use of description.
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist

<74>
Use in any one of said <55> thru | or <57> for manufacturing the URAT1 activity inhibitor used together with 1 thru | or 3 agents chosen from the following group (1) thru | or (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist

<75>
Use in any one of said <58> thru | or <60> for manufacturing the blood uric acid level lowering agent for using together with 1 thru | or 3 agents chosen from the following group (1) thru | or (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist

<76>
The pharmaceutical composition according to the above <32>, for suppressing an increase in blood uric acid level in combination with a drug that increases blood uric acid level.
<77>
The URAT1 activity inhibitor according to any one of <1> to <4> and <33> above, which is used in combination with a drug that increases blood uric acid level to suppress an increase in blood uric acid level.
<78>
URAT1 activity inhibition method in any one of said <45> thru | or <47> which further includes administering the chemical | medical agent which a blood uric acid level raises.
<79>
Use in any one of said <55> thru | or <57> for manufacturing the URAT1 activity inhibitor for using together with the chemical | medical agent which raises a blood uric acid level, and suppressing the raise of a blood uric acid level.
<80>
A method for suppressing an increase in blood uric acid level, comprising administering together a drug that increases blood uric acid level and the URAT1 activity inhibitor according to any one of <1> to <4> and <33> above.

The inventors have also found crystals of the above compounds. That is, the present invention also includes the following crystals and pharmaceutical compositions containing the same.
<81>
A crystal of a nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof selected from the following group.
(1) It has characteristic diffraction peaks at 12.94 °, 17.36 °, 23.50 °, 26.10 ° and 26.94 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 1),
(2) It has characteristic diffraction peaks at 16.96 °, 17.54 °, 21.66 °, 25.68 ° and 26.62 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 2),
(3) It has characteristic diffraction peaks at 7.40 °, 14.90 °, 22.68 °, 22.92 ° and 26.46 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 3),
(4) It has characteristic diffraction peaks at 7.40 °, 14.92 °, 16.64 °, 22.68 ° and 26.12 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 4),
(5) It has characteristic diffraction peaks at 7.28 °, 15.84 °, 23.10 °, 29.54 ° and 37.16 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone (Example 5),
(6) It has characteristic diffraction peaks at 15.58 °, 17.92 °, 18.48 °, 19.86 ° and 25.90 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 6),
(7) It has characteristic diffraction peaks at 12.46 °, 23.38 °, 23.98 °, 24.32 ° and 25.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone (Example 7),
(8) It has characteristic diffraction peaks at 16.62 °, 18.64 °, 19.20 °, 21.60 ° and 23.14 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone (Example 10),
(9) It has characteristic diffraction peaks at 11.58 °, 14.36 °, 22.18 °, 22.48 ° and 23.36 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 12),
(10) It has characteristic diffraction peaks at 11.82 °, 14.88 °, 22.62 °, 25.56 ° and 26.62 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 14),
(11) It has characteristic diffraction peaks at 7.02 °, 14.14 °, 21.30 °, 21.80 ° and 26.56 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 15),
(12) It has characteristic diffraction peaks at 12.40 °, 18.36 °, 21.34 °, 23.66 ° and 24.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone (Example 16),
(13) It has characteristic diffraction peaks at 10.54 °, 11.24 °, 21.24 °, 21.60 ° and 24.38 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 17),
(14) It has characteristic diffraction peaks at 12.32 °, 13.52 °, 22.70 °, 24.88 ° and 26.10 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 18),
(15) It has characteristic diffraction peaks at 11.16 °, 14.58 °, 21.38 °, 22.54 °, and 22.76 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 19),
(16) It has characteristic diffraction peaks at 15.46 °, 20.90 °, 22.92 °, 24.68 ° and 25.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(7-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 20),
(17) 4 having characteristic diffraction peaks at 13.48 °, 15.52 °, 19.18 °, 20.58 °, and 21.80 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction 4 -(3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide (Example 21),
(18) It has characteristic diffraction peaks at 11.66 °, 22.20 °, 22.48 °, 24.68 ° and 25.52 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone (Example 26),
(19) It has characteristic diffraction peaks at 17.60 °, 21.78 °, 22.78 °, 24.96 ° and 32.98 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone (Example 27),
(20) It has characteristic diffraction peaks at 12.16 °, 14.90 °, 22.16 °, 23.46 ° and 24.52 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 31),
(21) It has characteristic diffraction peaks at 11.58 °, 14.78 °, 18.80 °, 23.66 ° and 25.52 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone (Example 36),
(22) It has characteristic diffraction peaks at 19.94 °, 21.86 °, 22.52 °, 23.84 ° and 26.14 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 38),
(23) It has characteristic diffraction peaks at 7.58 °, 12.10 °, 15.24 °, 22.30 ° and 24.40 ° at diffraction angles (2θ) measured by powder X-ray crystal diffraction ( 2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone (Example 39),
(24) It has characteristic diffraction peaks at 10.06 °, 17.10 °, 17.48 °, 21.78 °, and 22.26 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 40),
(25) It has characteristic diffraction peaks at 19.06 °, 20.76 °, 22.30 °, 26.58 ° and 27.60 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 4-chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 41),
(26) It has characteristic diffraction peaks at 11.70 °, 22.44 °, 22.74 °, 23.58 ° and 23.90 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 44),
(27) It has characteristic diffraction peaks at 7.26 °, 22.62 °, 25.12 °, 25.70 ° and 27.92 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 50),
(28) It has characteristic diffraction peaks at 11.72 °, 21.78 °, 22.54 °, 22.82 ° and 23.68 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (Example 51),
(29) It has characteristic diffraction peaks at 21.04 °, 22.22 °, 23.74 °, 24.72 ° and 27.38 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 56),
(30) It has characteristic diffraction peaks at 14.80 °, 16.44 °, 22.28 °, 22.76 ° and 24.14 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6,8-dimethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 66),
(31) It has characteristic diffraction peaks at 14.52 °, 21.52 °, 21.88 °, 27.84 ° and 30.92 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 67),
(32) It has characteristic diffraction peaks at 7.16 °, 14.40 °, 20.96 °, 27.58 ° and 34.62 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 69),
(33) 1 having characteristic diffraction peaks at 15.48 °, 19.24 °, 22.48 °, 25.54 ° and 30.30 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction -[4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone (Example 73),
(34) It has characteristic diffraction peaks at 10.48 °, 11.32 °, 20.18 °, 22.84 ° and 25.76 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone (Example 76),
(35) It has characteristic diffraction peaks at 12.10 °, 22.48 °, 23.40 °, 24.42 ° and 25.98 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl) -methanone (Example 77),
(36) It has characteristic diffraction peaks at 9.30 °, 14.52 °, 18.64 °, 23.96 ° and 27.12 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 79),
(37) It has characteristic diffraction peaks at 8.92 °, 17.98 °, 18.26 °, 21.10 ° and 23.40 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone (Example 80),
(38) It has characteristic diffraction peaks at 7.12 °, 14.32 °, 21.62 °, 21.92 ° and 22.80 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 81),
(39) It has characteristic diffraction peaks at 7.22 °, 14.54 °, 22.34 °, 29.08 ° and 33.22 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dibromo-4-hydroxyphenyl) -methanone (Example 82),
(40) It has characteristic diffraction peaks at 17.58 °, 19.00 °, 21.04 °, 21.52 ° and 23.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 85), and (41) Powder X 2,6-dichloroacetate having characteristic diffraction peaks at 15.76 °, 16.38 °, 24.12 °, 25.88 ° and 27.62 ° at diffraction angles (2θ) measured by line crystal diffraction -4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl ester (Example 87).

<82>
The pharmaceutical composition containing the crystal | crystallization of said <81> description.

  Since the nitrogen-containing fused ring compound of the present invention effectively inhibits the activity of URAT1, hyperuricemia, gouty nodules, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal dysfunction, It is effective as a therapeutic or prophylactic agent for pathological conditions involving uric acid such as coronary artery disease and ischemic heart disease. In addition, unlike conventional therapeutic or preventive drugs for hyperuricemia, since CYP is not substantially inhibited, the possibility of causing pharmacokinetic drug interaction is extremely low. Therefore, the effect of reducing side effects is also achieved. Be expected.

  The definition of each substituent used in the present specification is as follows.

The “C _1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl. Group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group and the like. Preferably, it is a C _1-4 alkyl group. Particularly preferred are a methyl group, an ethyl group, an isopropyl group, and a tert-butyl group.

The “C _1-4 alkyl group” is a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl. Group, sec-butyl group, tert-butyl group and the like. Preferably, they are a methyl group, an ethyl group, an isopropyl group, and a tert-butyl group.

The “C _2-6 alkenyl group” is a straight chain or branched alkenyl group having 2 to 6 carbon atoms, such as a vinyl group, an n-propenyl group, an isopropenyl group, and an n-butenyl group. , Isobutenyl group, sec-butenyl group, n-pentenyl group, isopentenyl group, 1-methylpropenyl group, n-hexenyl group, isohexenyl group, 1,1-dimethylbutenyl group, 2,2-dimethylbutenyl group 3,3-dimethylbutenyl group, 3,3-dimethylpropenyl group, 2-ethylbutenyl group and the like can be mentioned. Preferably, it is a linear or branched alkenyl group having 2 to 4 carbon atoms. Particularly preferred are vinyl group, n-propenyl group and isopropenyl group.

  The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The “C _1-6 alkoxy group” is an alkoxy group whose alkyl moiety is the “C _1-6 alkyl group” defined above, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group. , Isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like. Preferably, the alkyl group part is an alkoxy group which is the “C _1-4 alkyl group” defined above. Particularly preferred are a methoxy group and an ethoxy group.

The “C _1-4 alkoxy group” is an alkoxy group whose alkyl moiety is the “C _1-4 alkyl group” defined above, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group. , Isobutoxy group, sec-butoxy group, tert-butoxy group and the like. Particularly preferred are a methoxy group and an ethoxy group.

  The “saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms” is a saturated or unsaturated cyclic hydrocarbon group having 3 to 14 carbon atoms, and specifically includes an aryl group, a cycloalkyl group, a cycloalkyl group. It means an alkenyl group or a group derived from a condensed carbocyclic ring in which two or more of the rings constituting the alkenyl group are condensed.

  The “aryl group” is an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, a biphenyl group, an anthryl group, an azulenyl group, a phenanthryl group, and a pentarenyl group. Preferably, it is a phenyl group.

  The “cycloalkyl group” is a cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Preferred is a cycloalkyl group having 3 to 6 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. Particularly preferred are a cyclopropyl group and a cyclohexyl group.

  The “cycloalkenyl group” is a cycloalkenyl group having 3 to 8 carbon atoms and includes at least one, preferably 1 or 2, double bonds. For example, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group, cyclohexadienyl group (2,4-cyclohexadien-1-yl group, 2,5-cyclohexadien-1-yl Group), cycloheptenyl group, cyclooctenyl group and the like. A cycloalkenyl group having 3 to 6 carbon atoms is preferable, and a cyclohexenyl group is particularly preferable.

  Examples of the group derived from a condensed carbocyclic ring in which two or more of the rings constituting these “aryl group”, “cycloalkyl group”, and “cycloalkenyl group” are condensed include, for example, indenyl group, indanyl group, fluorenyl group, 1, 4-dihydronaphthyl group, 1,2,3,4-tetrahydronaphthyl group (1,2,3,4-tetrahydro-2-naphthyl group, 5,6,7,8-tetrahydro-2-naphthyl group, etc.), A perhydronaphthyl group is exemplified.

  The “saturated or unsaturated carbocycle having 3 to 14 carbon atoms” is a ring constituting the “saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms” defined above.

An “aralkyl group” is an arylalkyl group in which the aryl moiety is the “aryl group” defined above and the alkyl moiety is the “C _1-6 alkyl group” defined above. For example, a benzyl group, phenethyl Group, 3-phenylpropyl group, 4-phenylbutyl group, 6-phenylhexyl group and the like. Preferred is an aralkyl group having 7 to 14 carbon atoms. Particularly preferred is a benzyl group.

The “aralkoxy group” is an arylalkoxy group whose aryl moiety is the “aryl group” as defined above and whose alkoxy moiety is the “C _1-6 alkoxy group” as defined above. For example, a benzyloxy group, A 3-phenylpropyloxy group, a 4-phenylbutyloxy group, a 6-phenylhexyloxy group, and the like can be given. Preferred is an aralkoxy group having 7 to 14 carbon atoms. Particularly preferred is a benzyloxy group.

The term "cycloalkyl alkoxy group", the "cycloalkyl group" of the cycloalkyl portion is as defined above, and a cycloalkyl alkoxy radical is a "C _1-6 alkoxy group" of the alkoxy portion is defined above, e.g. , Cyclopropylmethoxy group, cyclobutylmethoxy group, cyclopentylmethoxy group, cyclohexylmethoxy group and the like. Preferred is a cycloalkylalkoxy group having 4 to 8 carbon atoms. Particularly preferred are a cyclopropylmethoxy group and a cyclohexylmethoxy group.

  The “aryloxy group” is an aryloxy group whose aryl moiety is the “aryl group” defined above, and examples thereof include a phenoxy group, a naphthyloxy group, and a biphenyloxy group. Preferably, it is a phenoxy group.

  “Saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom” means at least one selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. And preferably a saturated or unsaturated (including partially unsaturated and fully unsaturated) monocyclic 5-membered or 6-membered heterocyclic group having 1 to 4 heteroatoms, or the heterocycles thereof A condensed ring group in which two or more of these are condensed or a condensed ring group in which a heterocyclic ring thereof and a carbocyclic ring selected from benzene, cyclopentane and cyclohexane are condensed.

  Examples of the “saturated monocyclic 5-membered or 6-membered heterocyclic group” include, for example, pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, imidazolidinyl group, pyrazolidinyl group, 1,3-dioxolanyl group, 1,3- Oxathiolanyl group, oxazolidinyl group, thiazolidinyl group, piperidinyl group, piperazinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, dioxanyl group, morpholinyl group, thiomorpholinyl group, 2-oxopyrrolidinyl group, 2-oxopiperidinyl group , 4-oxopiperidinyl group, 2,6-dioxopiperidinyl group and the like.

  Examples of the “unsaturated monocyclic 5- or 6-membered heterocyclic group” include, for example, pyrrolyl group, furyl group, thienyl group, imidazolyl group, 1,2-dihydro-2-oxoimidazolyl group, pyrazolyl group, Oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, triazolyl group (eg, 1,2,4-triazolyl group, 1,2,3-triazolyl group, etc.), tetrazolyl group, 1,3,4-oxadiazolyl group, 1 , 2,4-oxadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, furazanyl group, pyridyl group, pyrimidinyl group, 3,4-dihydro-4-oxopyrimidinyl group, pyridazinyl group, Pyrazinyl group, 1,3,5-triazinyl group, imidazolinyl group, pyrazolinyl group, oxazolinyl group (eg , 2-oxazolinyl group, 3-oxazolinyl group, 4-oxazolinyl group, etc.), isoxazolinyl group, thiazolinyl group, isothiazolinyl group, pyranyl group, 2-oxopyranyl group, 2-oxo-2,5-dihydrofuranyl group 1,1-dioxo-1H-isothiazolyl group and the like.

  Examples of the “heterocyclic group which is a condensed ring” include, for example, an indolyl group (for example, 4-indolyl group, 7-indolyl group, etc.), isoindolyl group, 1,3-dihydro-1,3-dioxoisoindolyl group. Benzofuranyl group (for example, 4-benzofuranyl group, 7-benzofuranyl group, etc.), indazolyl group, isobenzofuranyl group, benzothiophenyl group (for example, 4-benzothiophenyl group, 7-benzothiophenyl group, etc.), Benzoxazolyl group (for example, 4-benzoxazolyl group, 7-benzoxazolyl group, etc.), benzimidazolyl group (for example, 4-benzimidazolyl group, 7-benzimidazolyl group, etc.), benzothiazolyl group (for example, 4-benzothiazolyl group, 7-benzothiazolyl group, etc.), indolizinyl group, quinolyl group, isoquinolyl 1,2-dihydro-2-oxoquinolyl group, quinazolinyl group, quinoxalinyl group, cinnolinyl group, phthalazinyl group, quinolidinyl group, purinyl group, pteridinyl group, indolinyl group, isoindolinyl group, 5,6,7,8-tetrahydroquinolyl Group, 1,2,3,4-tetrahydroquinolyl group, 2-oxo-1,2,3,4-tetrahydroquinolyl group, benzo [1,3] dioxolyl group, 3,4-methylenedioxypyridyl group 4,5-ethylenedioxypyrimidinyl group, chromenyl group, chromanyl group, isochromanyl group and the like.

  The “nitrogen-containing saturated heterocycle consisting of a single ring” formed together with the adjacent nitrogen atom is, for example, a saturated 5-membered or saturated member having at least one nitrogen atom such as piperidine, morpholine, piperazine, pyrrolidine, etc. A heterocycle consisting of 6-membered monocycles.

  “It may be substituted with one or more substituents which are the same or different” means unsubstituted or substituted with at least one and up to the maximum number of substituents allowed. For example, a methyl group means that it may be substituted with 1 to 3 substituents, and an ethyl group means that it may be substituted with 1 to 5 substituents. The substituents when substituted with two or more substituents may be the same or different, and the position of the substituent is arbitrary and is not particularly limited. Preferred is “may be substituted with 1 to 3 substituents which are the same or different”.

  Next, suitable groups for each group are as follows.

R ¹ , R ² and R ³ are preferably the same or different,
1) hydrogen atom,
2) a halogen atom,
³⁾ -OR ^{13 (R} 13 has the same meaning as defined above.)
4) a C _1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group B;
5) -COR ¹⁴ (R ¹⁴ is as defined above),
^{6) -NR 15 R 16 (R} 15 and ^{R 16} have the same meanings as defined above.)
7) —NR ¹⁷ S (═O) ₂ R ¹⁴ (R ¹⁴ and R ¹⁷ are as defined above),
8) —S (═O) ₂ R ¹⁴ (R ¹⁴ has the same meaning as described above),
^{_{9) -S (= O) 2}} NR 15 R 16 (R 15 and ^{R 16} have the same meanings as defined above.)
10) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; Or 11) a nitro group, or
12) R ¹ and R ² or R ² and R ³ together with the carbon atom to which they are bonded together are an unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle is the same selected from the group A) Or may be substituted with one or more different substituents, preferably 2 or 3 substituents).

R ¹ , R ² and R ³ are more preferably the same or different,
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group, an isopropyl group, and a tert-butyl group.), A trifluoromethyl group, and a hydroxymethyl group.
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
8) an amino group,
9) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group is there.),
10) —S (═O) ₂ —C _1-6 alkyl group (preferably —S (═O) ₂ —C _1-4 alkyl group, more preferably —S (═O) ₂ -ethyl group; is there.),
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group or an ethyl group), or (c) R ¹⁵ And R ¹⁶ together with the nitrogen atom to which they are bonded form a monocyclic nitrogen-containing saturated heterocyclic ring (for example, pyrrolidine, piperidine, imidazolidine, piperazine, etc., preferably pyrrolidine). May be. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (preferably an aryl group, more preferably a phenyl group), or 13) a nitro group.

The following are more preferable for each of R ¹ , R ² , and R ³ .
R ¹ is more preferably
1) hydrogen atom,
2) a hydroxyl group,
3) C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group or an isopropyl group),
4) —COOH, or 5) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group).
It is.

R ² is more preferably
1) hydrogen atom,
2) a halogen atom (preferably a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group),
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
8) an amino group,
9) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group Or 10) a nitro group.

R ³ is more preferably
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group and a tert-butyl group.), A trifluoromethyl group and a hydroxymethyl group.
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
8) an amino group,
9) —S (═O) ₂ —C _1-6 alkyl group (preferably —S (═O) ₂ —C _1-4 alkyl group, more preferably —S (═O) ₂ -ethyl group; is there.),
10) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same as or different from each other;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group or an ethyl group), or (c) R ¹⁵ And R ¹⁶ together with the nitrogen atom to which they are bonded form a monocyclic nitrogen-containing saturated heterocyclic ring (for example, pyrrolidine, piperidine, imidazolidine, piperazine, etc., preferably pyrrolidine). May be. ),
11) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (preferably an aryl group, more preferably a phenyl group), or 12) a nitro group.

R ¹ , R ² and R ³ are particularly preferably the same or different,
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group, an isopropyl group, and a tert-butyl group.), A trifluoromethyl group, and a hydroxymethyl group.
6) -CO- _C1-6 alkoxy group (preferably -CO- _C1-4 alkoxy group, more preferably -CO-methoxy group),
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably an ethyl group), or (b) a nitrogen to which R ¹⁵ and R ¹⁶ are bonded. A nitrogen-containing saturated heterocyclic ring consisting of a single ring (preferably pyrrolidine) may be formed together with the atom. Or 8) a nitro group.

The following are particularly preferable for each of R ¹ , R ² , and R ³ .
R ¹ is particularly preferably
1) hydrogen atom,
2) a hydroxyl group,
3) C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group or isopropyl group), or 4) —CO—C _1-6 alkoxy group (preferably —CO -C _1-4 alkoxy group, more preferably -CO-methoxy group.)
It is.

R ² is particularly preferably
1) hydrogen atom,
2) a halogen atom (preferably a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group),
6) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group), or 7) nitro group.

R ³ is particularly preferably
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group and a tert-butyl group.), A trifluoromethyl group and a hydroxymethyl group.
6) -CO- _C1-6 alkoxy group (preferably -CO- _C1-4 alkoxy group, more preferably -CO-methoxy group),
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably an ethyl group), or (b) a nitrogen to which R ¹⁵ and R ¹⁶ are bonded. A nitrogen-containing saturated heterocyclic ring consisting of a single ring (preferably pyrrolidine) may be formed together with the atom. Or 8) a nitro group.

  Y is preferably —CO— or —CS—.

X ¹ is preferably
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (d) a —CO—C _1-6 alkoxy group (preferably —CO— A C _1-4 alkoxy group, more preferably a —CO-methoxy group), or (e) R ³ and R ⁴ (R ³ is as defined above), A saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) may be formed together with the carbon atoms to be bonded. )
It is.

X ¹ is more preferably CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (d) a —CO—C _1-6 alkoxy group (preferably —CO— A C _1-4 alkoxy group, more preferably a —CO-methoxy group), or (e) R ³ and R ⁴ (R ³ is as defined above), A saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) may be formed together with the carbon atoms to be bonded. )
It is.

X ² is preferably
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group)),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms ( Preferably, it is an aryl group, more preferably a phenyl group, and the carbocyclic group is substituted with one or more substituents selected from a halogen atom (preferably a chlorine atom) and a hydroxyl group. May be good),
_{4) -N (S (= O} ) 2 -C 1-6 alkyl) - (preferably _{-N (-S (= O) 2} -C 1-4 alkyl group) -, and more preferably -N (—S (═O) ₂ -methyl group) —).
5) sulfur atom,
6) -S (= O)-,
7) —S (═O) ₂ — or 8) —CH ₂ —
It is.

X ² 'is preferably
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms ( Preferably, it is an aryl group, more preferably a phenyl group, and the carbocyclic group is substituted with one or more substituents selected from a halogen atom (preferably a chlorine atom) and a hydroxyl group. May be good),
_{4) -N (S (= O} ) 2 -C 1-6 alkyl) - (preferably _{-N (-S (= O) 2} -C 1-4 alkyl group) -, and more preferably -N (—S (═O) ₂ -methyl group) —).
5) sulfur atom,
6) -S (= O)-,
7) —S (═O) ₂ — or 8) —CH ₂ —
It is.

X ² ′ is more preferably an oxygen atom.

-X ³ -X ⁴ - is preferably,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different, respectively, (a) are hydrogen atoms, or
(B) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n two R ¹¹ and R ¹² are bonded to the same or adjacent two carbon atoms. The two bonded together may form a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) together with the carbon atom. Good. )
It is.
N in — (CR ¹¹ R ¹² ) n— represented by —X ³ —X ⁴ — is preferably 2 or 3, more preferably 2.

As-(CR ¹¹ R ¹² ) n-, specifically,
1) —CH ₂ —,
_{2) -CH (CH 3) -} ,
_{3) -CH (CH 2 CH 3} ) -,
_{4) -CH (CH (CH 3} ) 2) -,
_{5) -CH} 2 -CH 2 -,
_{6) -CH (CH 3) -CH} 2 -,
_{7) -CH (CH 2 CH 3} ) -CH 2 -,
8) —CH (CH (CH ₃ ) ₂ ) —CH ₂ —,
_{9) -CH 2 -CH (CH 3} ) -,
_{10) -CH 2 -CH (CH 2} CH 3) -,
_{11) -CH 2 -CH (CH (} CH 3) 2) -,
_{12) -CH 2 -CH 2 -CH 2} -,
_{13) -CH 2 -CH (CH 3} ) -CH 2 -,
_{14) -CH 2 -CH 2 -CH (} CH 3) -,
15) -CO-,
16) _-CO-CH 2 -,
₁₇₎ -CH 2 -CO-,
18) _-CO-CH 2 -,
_{19) -CO-CH 2 -CH 2} -,
_{20) -CH 2 -CO-CH 2} -,
₂₁₎ -CH ₂ -CH ₂ -CO-,
22)

Etc.

-X ³ -X ⁴ - is more preferably _-CH 2 -CH ₂ -.

Ring A is preferably an unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group is one or more substituents selected from Group A, preferably 2 or 3 Substituted with a substituent), or an unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or selected from the group A) One or more different substituents, preferably substituted with 2 or 3 substituents.
Ring A is more preferably

(Wherein R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group A. ).

R ^{23 to} R ²⁷ on ring A are preferably the same or different from each other,
1) hydrogen atom,
2) a halogen atom,
³⁾ -OR ^{13 (R} 13 has the same meaning as defined above.)
4) a C _1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group B;
5) -COR ¹⁴ (R ¹⁴ is as defined above),
^{6) -NR 15 R 16 (R} 15 and ^{R 16} have the same meanings as defined above.)
7) —NR ¹⁷ S (═O) ₂ R ¹⁴ (R ¹⁴ and R ¹⁷ are as defined above), or 8) a nitro group.

R ^{23 to} R ²⁷ on ring A are more preferably the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) -COOH and _{-CO-C 1-6} alkoxy group (preferably a _{-CO-C 1-4} alkoxy group, more preferably a -CO- ethoxy group.) From the same or different 1 or more selected A C _1-6 alkoxy group (preferably a C _1-4 alkoxy group (preferably a methoxy group), a carboxymethoxy group, or an (ethoxycarbonyl) methoxy group) that may be substituted with a substituent of
5) —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, more preferably —O—CO-methyl group);
6) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
7) -COOH,
8) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group; Or 11) a nitro group.

For each of R ^{23 to} R ²⁷ on ring A, the following are more preferable.
R ²³ on ring A is more preferably
1) hydrogen atom,
2) Hydroxyl group, or 3) -COOH
It is.

R ²⁴ on ring A is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-6 alkoxy group, more preferably a methoxy group),
5) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group), or 8) nitro group.

R ²⁵ on ring A is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) -COOH and _{-CO-C 1-6} alkoxy group (preferably a _{-CO-C 1-4} alkoxy group, more preferably a -CO- ethoxy group.) From the same or different 1 or more selected A C _1-6 alkoxy group (preferably a C _1-4 alkoxy group (preferably a methoxy group), a carboxymethoxy group, or an (ethoxycarbonyl) methoxy group) that may be substituted with a substituent of
5) —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, more preferably —O—CO-methyl group);
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group);
8) an amino group,
9) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group Or 10) a nitro group.

R ²⁶ on ring A is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-6 alkoxy group, more preferably a methoxy group),
5) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group), or 8) nitro group.

R ²⁷ on ring A is more preferably
1) hydrogen atom,
2) Hydroxyl group, or 3) -COOH
It is.

  As such a ring A,

Etc.

R ^{23 to} R ²⁷ on ring A are particularly preferably the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group), or 5) a nitro group.

For each of R ^{23 to} R ²⁷ on ring A, the following are particularly preferable.
R ²³ on ring A is particularly preferably
1) a hydrogen atom, or 2) a hydroxyl group.

R ²⁴ on ring A is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group), or 5) a nitro group.

R ²⁵ on ring A is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) a hydroxyl group, or 4) a nitro group.

R ²⁶ on ring A is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group), or 5) a nitro group.

R ²⁷ on ring A is particularly preferably
1) a hydrogen atom, or 2) a hydroxyl group.

Ring A ′ is preferably an unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group is one or more substituents selected from Group C, and preferably 2 or 3 Or an unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same selected from the group C) Or substituted with one or more different substituents, preferably substituted with 2 or 3 substituents.), Wherein the ring A ′ is at least one —OR ¹³ ′ (wherein R ¹³ ′ is as defined above). Is synonymous.)
Ring A ′ is preferably

(Wherein R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is —OR ¹³ ′ (R ¹³ ′ is as defined above). ).

R ^{23 to} R ²⁷ on ring A ′ are preferably the same or different from each other,
1) hydrogen atom,
2) a halogen atom,
3) —OR ¹³ ′ (R ¹³ ′ is as defined above),
4) a C _1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group B;
5) -COR ¹⁴ '(R ¹⁴ ' is as defined above),
^{6) -NR 15 'R 16'} (R 15 ' and ^{R 16'} has the same meaning as defined above.)
7) —NR ¹⁷ ′ S (═O) ₂ R ¹⁴ ′ (R ¹⁴ ′ and R ¹⁷ ′ are as defined above), or 8) a nitro group and at least one of R ^{23 to} R ²⁷ One of them is —OR ¹³ ′ (R ¹³ ′ is as defined above).

R ^{23 to} R ²⁷ on ring A ′ are more preferably the same or different from each other,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) -COOH and _{-CO-C 1-6} alkoxy group (preferably a _{-CO-C 1-4} alkoxy group, more preferably a -CO- ethoxy group.) From the same or different 1 or more selected A C _1-6 alkoxy group (preferably a C _1-4 alkoxy group (preferably a methoxy group), a carboxymethoxy group, or an (ethoxycarbonyl) methoxy group) that may be substituted with a substituent of
5) —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, more preferably —O—CO-methyl group);
6) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
7) -COOH,
8) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group; Or 11) a nitro group and at least one of R ^{23 to} R ²⁷ is a hydroxyl group or a C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group). And the C _1-6 alkoxy group is —COOH and —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-ethoxy group). And may be substituted with one or more of the same or different substituents selected from:) and —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, More preferably -O CO- is a methyl group.) Is a group selected from.

For each of R ^{23 to} R ²⁷ on ring A ′, the following are more preferable.
R ²³ on ring A ′ is more preferably
1) hydrogen atom,
2) Hydroxyl group, or 3) -COOH
It is.

R ²⁴ on ring A ′ is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-6 alkoxy group, more preferably a methoxy group),
5) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group), or 8) nitro group.

R ²⁵ on ring A ′ is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) -COOH and _{-CO-C 1-6} alkoxy group (preferably a _{-CO-C 1-4} alkoxy group, more preferably a -CO- ethoxy group.) From the same or different 1 or more selected A C _1-6 alkoxy group (preferably a C _1-4 alkoxy group (preferably a methoxy group), a carboxymethoxy group, or an (ethoxycarbonyl) methoxy group) that may be substituted with a substituent of
5) —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, more preferably —O—CO-methyl group);
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group);
8) an amino group,
9) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group Or 10) a nitro group.

R ²⁶ on ring A ′ is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-6 alkoxy group, more preferably a methoxy group),
5) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group), or 8) nitro group.

R ²⁷ on ring A ′ is more preferably
1) hydrogen atom,
2) a hydroxyl group, or 3) -COOH.

  As such a ring A ′,

Etc.

R ^{23 to} R ²⁷ on ring A ′ are particularly preferably the same or different from each other,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. ), Or 5) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group.

For each of R ^{23 to} R ²⁷ on ring A ′, the following are particularly preferable.
R ²³ on ring A ′ is particularly preferably
1) a hydrogen atom, or 2) a hydroxyl group.

R ²⁴ on ring A ′ is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group), or 5) a nitro group.

R ²⁵ on ring A ′ is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) a hydroxyl group, or 4) a nitro group.

R ²⁶ on ring A ′ is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group), or 5) a nitro group.

R ²⁷ on ring A ′ is particularly preferably
1) a hydrogen atom, or 2) a hydroxyl group.

Of the compounds [1], the compound [2] is preferable. Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group, an isopropyl group, and a tert-butyl group.), A trifluoromethyl group, and a hydroxymethyl group.
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
8) an amino group,
9) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group is there.),
10) —S (═O) ₂ —C _1-6 alkyl group (preferably —S (═O) ₂ —C _1-4 alkyl group, more preferably —S (═O) ₂ -ethyl group; is there.),
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group or an ethyl group), or (c) R ¹⁵ And R ¹⁶ together with the nitrogen atom to which they are bonded form a monocyclic nitrogen-containing saturated heterocyclic ring (for example, pyrrolidine, piperidine, imidazolidine, piperazine, etc., preferably pyrrolidine). May be. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (preferably an aryl group, more preferably a phenyl group), or 13) a nitro group;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (d) a —CO—C _1-6 alkoxy group (preferably —CO— A C _1-4 alkoxy group, more preferably a —CO-methoxy group), or (e) R ³ and R ⁴ (R ³ is as defined above), A saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) may be formed together with the carbon atoms to be bonded. )
Is;
X ² '
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group)),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms ( Preferably, it is an aryl group, more preferably a phenyl group, and the carbocyclic group is substituted with one or more substituents selected from a halogen atom (preferably a chlorine atom) and a hydroxyl group. May be good),
_{4) -N (S (= O} ) 2 -C 1-6 alkyl) - (preferably _{-N (-S (= O) 2} -C 1-4 alkyl group) -, and more preferably -N (—S (═O) ₂ -methyl group) —).
5) sulfur atom,
6) -S (= O)-,
7) —S (═O) ₂ — or 8) —CH ₂ —
Is;
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different, respectively, (a) are hydrogen atoms, or
(B) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n two R ¹¹ and R ¹² are bonded to the same or adjacent two carbon atoms. The two bonded together may form a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) together with the carbon atom. Good. )
And ring A ′ is

(Wherein R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) -COOH and _{-CO-C 1-6} alkoxy group (preferably a _{-CO-C 1-4} alkoxy group, more preferably a -CO- ethoxy group.) From the same or different 1 or more selected A C _1-6 alkoxy group (preferably a C _1-4 alkoxy group (preferably a methoxy group), a carboxymethoxy group, or an (ethoxycarbonyl) methoxy group) that may be substituted with a substituent of
5) —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, more preferably —O—CO-methyl group);
6) A C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. A trifluoromethyl group. ),
7) -COOH,
8) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group; Or 11) a nitro group and at least one of R ^{23 to} R ²⁷ is a hydroxyl group or a C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group). And the C _1-6 alkoxy group is —COOH and —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-ethoxy group). ) than may be substituted by the same or different one or more substituents selected) and _{-O-CO-C 1-6} alkyl group (preferably a _{-O-CO-C 1-4} alkyl group, more Preferably -O- An O- methyl group.) Is a group selected from. );
(However, when X ² ′ is —CH ₂ —,
-X ³ -X ⁴ -is
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or (b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n R ¹¹ and R ¹² Two of them bonded to the same or adjacent two carbon atoms together with the carbon atom are saturated or unsaturated carbocycles having 3 to 14 carbon atoms (preferably aromatic hydrocarbons, more preferably benzene A ring). )
Is;
R ¹³ ′ is a hydrogen atom; and ring A ′ is further substituted with at least one halogen atom;
However, when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms. )
Compounds are preferred.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group, an isopropyl group, and a tert-butyl group.), A trifluoromethyl group, and a hydroxymethyl group.
6) -CO- _C1-6 alkoxy group (preferably -CO- _C1-4 alkoxy group, more preferably -CO-methoxy group),
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably an ethyl group), or (b) a nitrogen to which R ¹⁵ and R ¹⁶ are bonded. A nitrogen-containing saturated heterocyclic ring consisting of a single ring (preferably pyrrolidine) may be formed together with the atom. Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (d) a —CO—C _1-6 alkoxy group (preferably —CO— A C _1-4 alkoxy group, more preferably a —CO-methoxy group), or (e) R ³ and R ⁴ (R ³ is as defined above), A saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) may be formed together with the carbon atoms to be bonded. )
Is;
X ² 'is an oxygen atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. ), Or 5) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
More preferred are compounds.

In particular, a compound selected from the following group or a pharmaceutically acceptable salt thereof is preferred.
(1) (3-Chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(2) (3-Bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(3) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(4) (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(5) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone,
(6) (3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(7) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone,
(8) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone,
(9) (3,5-dichloro-4-hydroxyphenyl)-(1-oxo-2,3-dihydro-1H-1λ ⁴ -benzo [1,4] thiazin-4-yl) -methanone,
(10) (3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone,
(11) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanethione,
(12) (3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(13) (3,5-dichloro-4-hydroxyphenyl)-(7-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(14) (3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(15) (3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(16) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone,
(17) (3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(18) (3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(19) (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(20) (3,5-dichloro-4-hydroxyphenyl)-(7-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(21) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide,
(22) 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-sulfonyl) phenol,
(23) (6-tert-butyl-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(24) 4- (3,5-dichloro-4-hydroxybenzoyl) -4H-benzo [1,4] oxazin-3-one,
(25) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid amide,
(26) (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone,
(27) (3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone,
(28) (4-amino-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(29) (5-chloro-6-hydroxypyridin-3-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(30) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dinitrophenyl) -methanone,
(31) (3-Chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(32) (3,5-dichloro-4-hydroxyphenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(33) (3,5-dichloro-4-hydroxyphenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone,
(34) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid ethylamide,
(35) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid dimethylamide;
(36) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone,
(37) 5- (3,5-dichloro-4-hydroxybenzoyl) -1,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-2-one,
(38) (3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(39) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone,
(40) (3-Chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(41) (4-Chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(42) (2,6-dichloropyridin-4-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(43) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-nitrophenyl) -methanone,
(44) (3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(45) 2- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(46) methyl 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate,
(47) 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(48) methyl 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate,
(49) 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(50) (3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(51) (6-Chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(52) (7-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(53) [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl]-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(54) (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(55) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester,
(56) (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(57) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid,
(58) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-5-carboxylic acid methyl ester,
(59) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid methyl ester,
(60) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid,
(61) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid methyl ester,
(62) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid,
(63) (3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(64) (3,5-dichloro-4-hydroxyphenyl)-(phenoxazin-10-yl) -methanone,
(65) (3,5-dichloro-4-hydroxyphenyl)-(6-phenyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(66) (3,5-dichloro-4-hydroxyphenyl)-(6,8-dimethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(67) (3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(68) (6-Amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(69) (3,5-dibromo-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(70) (3,5-dichloro-4-hydroxyphenyl)-(7-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(71) (7-amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(72) N- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazin-7-yl] -methanesulfonamide,
(73) 1- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone,
(74) (3,5-dichloro-4-hydroxyphenyl)-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(75) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-nitrophenyl) -methanone,
(76) (3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone,
(77) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl) -methanone,
(78) (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(79) (3,5-dibromo-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(80) (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone,
(81) (3,5-dibromo-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(82) (6-Chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dibromo-4-hydroxyphenyl) -methanone,
(83) (3,5-dichloro-4-hydroxyphenyl)-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(84) (3,5-dichloro-4-hydroxyphenyl)-(6-ethanesulfonyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(85) (3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(86) (3,5-dichloro-4-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(87) Acetic acid 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl ester,
(88) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxyphenyl) -methanone,
(89) (3,5-dichloro-4-hydroxyphenyl)-(5-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(90) (3,5-dichloro-4-hydroxyphenyl)-(8-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(91) [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid ethyl ester,
(92) [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid,
(93) (3,5-dichloro-4-hydroxyphenyl)-(3-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(94) N- [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide, and (95) (3,5-dichloro-4 -Hydroxyphenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone.

In addition, the nitrogen-containing fused ring compound of the present invention is divided into the following 6 types (A type to F type) depending on the type of X ² ′, and preferred compounds for each are listed below.

A type A type is compound [2],
X ² '
1) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
2) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different groups selected from the group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the same or different groups selected from the group A;
(E) a cycloalkylalkoxy group that may be substituted with one or more substituents selected from the same or different groups selected from the group A;
(F) an aralkyl group optionally substituted with one or more substituents selected from the group A, or (g) substituted with one or more substituents selected from the group A. A good aralkoxy group. ),
3) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above), or 4) —N (CONR ⁷ R ⁸ ) — (wherein R ⁷ and R ⁸ is the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from Group B, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the group A or the same or different. ) May be formed. );
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
A compound.

this house,
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
Compounds are preferred.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
2) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group, or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (wherein the carbocyclic group is the same or different one or more selected from a halogen atom and a hydroxyl group) . it may be substituted with group)), or _{3) -N (S (= O} ) 2 -C 1-6 alkyl) -,
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
More preferred are compounds.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
2) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group, or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (wherein the carbocyclic group is the same or different one or more selected from a halogen atom and a hydroxyl group) . it may be substituted with group)), or _{3) -N (S (= O} ) 2 -C 1-6 alkyl) -,
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
Compounds are particularly preferred.

B type B type is compound [2],
X ² '
1) -S (= O)-, or 2) -S (= O) _2-
In it; and ^-X 3 -X ⁴ - it _is, -CH ₂ -CH 2 - is;
A compound.

this house,
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is —OR ¹³ ′ (R ¹³ ′ is as defined above). );
Compounds are preferred.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) -S (= O)-, or 2) -S (= O) _2-
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group that may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups;
5) -O-CO-C _1-6 alkyl group,
6) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
7) -COOH,
8) —CO—C _1-6 alkoxy group,
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group, or 11) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group, a C _1-6 alkoxy group (the C _{1 -6} alkoxy groups may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups) and —O—CO—C _1-6 alkyl groups. The group to be selected. );
More preferred are compounds.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) -S (= O)-, or 2) -S (= O) _2-
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
Compounds are particularly preferred.

C type C type is compound [2],
Y is
1) -CO-, or 2) -CS-,
Is;
X ² 'is a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
A compound.

this house,
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
Compounds are preferred.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-, or 2) -CS-,
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
More preferred are compounds.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
Compounds are particularly preferred.

D type D type is compound [2].
R ¹ , R ² and R ³ are the same or different,
1) a hydrogen atom, or 2) a group selected from the above group D, or 3) R ¹ and R ² together with the carbon atom to which they are bonded, saturated or unsaturated having 3 to 14 carbon atoms Or the carbocycle may be substituted with one or more substituents selected from the group D, or 4) R ² and R ³ are bonded to each other A saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms together with the carbon atom to be substituted (the carbocyclic ring may be substituted with one or more substituents selected from the group D). May form;
Y is
1) -CO-, or 2) -CS-,
Is;
X ² ′ is an oxygen atom; and —X ³ —X ⁴ — is —CH ₂ —CH ₂ —;
A compound.

this house,
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is —OR ¹³ ′ (R ¹³ ′ is as defined above). );
Compounds are preferred.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) R ¹⁵ ″ and R ¹⁶ ″ together with the nitrogen atom to which they are attached comprise a single ring A nitrogen-containing saturated heterocyclic ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is an oxygen atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group that may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups;
5) -O-CO-C _1-6 alkyl group,
6) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
7) -COOH,
8) —CO—C _1-6 alkoxy group,
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group, or 11) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group, a C _1-6 alkoxy group (the C _{1 -6} alkoxy groups may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups) and —O—CO—C _1-6 alkyl groups. The group to be selected. );
More preferred are compounds.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are the same or different;
(A) a C _1-6 alkyl group, or (b) R ¹⁵ ″ and R ¹⁶ ″ together with the nitrogen atom to which they are attached form a nitrogen-containing saturated heterocycle consisting of a single ring. May be. Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is an oxygen atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
Compounds are particularly preferred.

E type E type is compound [2],
Y is —S (═O) ₂ —;
X ² '
1) an oxygen atom, or 2) a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
A compound.

this house,
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
Compounds are preferred.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is —S (═O) ₂ —;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) an oxygen atom, or 2) a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
More preferred are compounds.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group,
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is —S (═O) ₂ —;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) an oxygen atom, or 2) a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
Compounds are particularly preferred.

F type F type is compound [2] wherein X ² ′ is —CH ₂ —;
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or (b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n R ¹¹ and R ¹² Two of them bonded to the same or adjacent two carbon atoms together with the carbon atom are saturated or unsaturated carbocycles having 3 to 14 carbon atoms (the carbocycle is the same or selected from the group A or May be substituted with one or more different substituents. )
Is;
R ¹³ ′ is a hydrogen atom; and ring A ′ is further substituted with at least one halogen atom;
Provided that when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms;
A compound.

this house,
Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, at least one of R ^{23 to} R ²⁷ is a hydroxyl group, and at least one of R ^{23 to} R ²⁷ is a halogen atom. . );
Compounds are preferred.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² ′ is —CH ₂ —;
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3, and n R ¹¹ and R ¹² are the same or different, respectively, (a) are hydrogen atoms, or ( b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) Bonded to two identical or adjacent carbon atoms of n R ¹¹ and R ¹² And two of them, together with the carbon atom, a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle is substituted with one or more substituents selected from the same or different group A) Or may be formed.)
And ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group, and at least any of R ^{23 to} R ²⁷ One of them is a halogen atom. );
Provided that when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms;
More preferred are compounds.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² ′ is —CH ₂ —;
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3, and n R ¹¹ and R ¹² are the same or different, respectively, (a) are hydrogen atoms, or ( b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) Bonded to two identical or adjacent carbon atoms of n R ¹¹ and R ¹² And two of them, together with the carbon atom, a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle is substituted with one or more substituents selected from the same or different group A) Or may be formed.)
And ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group, and at least one of R ^{23 to} R ²⁷ is a halogen atom. );
Provided that when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms;
Compounds are particularly preferred.

The nitrogen-containing fused ring compound of the present invention can also be obtained as crystals. For example,
(1) It has characteristic diffraction peaks at 12.94 °, 17.36 °, 23.50 °, 26.10 ° and 26.94 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 1),
(2) It has characteristic diffraction peaks at 16.96 °, 17.54 °, 21.66 °, 25.68 ° and 26.62 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 2),
(3) It has characteristic diffraction peaks at 7.40 °, 14.90 °, 22.68 °, 22.92 ° and 26.46 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 3),
(4) It has characteristic diffraction peaks at 7.40 °, 14.92 °, 16.64 °, 22.68 ° and 26.12 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 4),
(5) It has characteristic diffraction peaks at 7.28 °, 15.84 °, 23.10 °, 29.54 ° and 37.16 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone (Example 5),
(6) It has characteristic diffraction peaks at 15.58 °, 17.92 °, 18.48 °, 19.86 ° and 25.90 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 6),
(7) It has characteristic diffraction peaks at 12.46 °, 23.38 °, 23.98 °, 24.32 ° and 25.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone (Example 7),
(8) It has characteristic diffraction peaks at 16.62 °, 18.64 °, 19.20 °, 21.60 ° and 23.14 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone (Example 10),
(9) It has characteristic diffraction peaks at 11.58 °, 14.36 °, 22.18 °, 22.48 ° and 23.36 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 12),
(10) It has characteristic diffraction peaks at 11.82 °, 14.88 °, 22.62 °, 25.56 ° and 26.62 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 14),
(11) It has characteristic diffraction peaks at 7.02 °, 14.14 °, 21.30 °, 21.80 ° and 26.56 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 15),
(12) It has characteristic diffraction peaks at 12.40 °, 18.36 °, 21.34 °, 23.66 ° and 24.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone (Example 16),
(13) It has characteristic diffraction peaks at 10.54 °, 11.24 °, 21.24 °, 21.60 ° and 24.38 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 17),
(14) It has characteristic diffraction peaks at 12.32 °, 13.52 °, 22.70 °, 24.88 ° and 26.10 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 18),
(15) It has characteristic diffraction peaks at 11.16 °, 14.58 °, 21.38 °, 22.54 °, and 22.76 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 19),
(16) It has characteristic diffraction peaks at 15.46 °, 20.90 °, 22.92 °, 24.68 ° and 25.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(7-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 20),
(17) 4 having characteristic diffraction peaks at 13.48 °, 15.52 °, 19.18 °, 20.58 °, and 21.80 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction 4 -(3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide (Example 21),
(18) It has characteristic diffraction peaks at 11.66 °, 22.20 °, 22.48 °, 24.68 ° and 25.52 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone (Example 26),
(19) It has characteristic diffraction peaks at 17.60 °, 21.78 °, 22.78 °, 24.96 ° and 32.98 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone (Example 27),
(20) It has characteristic diffraction peaks at 12.16 °, 14.90 °, 22.16 °, 23.46 ° and 24.52 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 31),
(21) It has characteristic diffraction peaks at 11.58 °, 14.78 °, 18.80 °, 23.66 ° and 25.52 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone (Example 36),
(22) It has characteristic diffraction peaks at 19.94 °, 21.86 °, 22.52 °, 23.84 ° and 26.14 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 38),
(23) It has characteristic diffraction peaks at 7.58 °, 12.10 °, 15.24 °, 22.30 ° and 24.40 ° at diffraction angles (2θ) measured by powder X-ray crystal diffraction ( 2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone (Example 39),
(24) It has characteristic diffraction peaks at 10.06 °, 17.10 °, 17.48 °, 21.78 °, and 22.26 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 40),
(25) It has characteristic diffraction peaks at 19.06 °, 20.76 °, 22.30 °, 26.58 ° and 27.60 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 4-chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 41),
(26) It has characteristic diffraction peaks at 11.70 °, 22.44 °, 22.74 °, 23.58 ° and 23.90 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 44),
(27) It has characteristic diffraction peaks at 7.26 °, 22.62 °, 25.12 °, 25.70 ° and 27.92 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 50),
(28) It has characteristic diffraction peaks at 11.72 °, 21.78 °, 22.54 °, 22.82 ° and 23.68 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (Example 51),
(29) It has characteristic diffraction peaks at 21.04 °, 22.22 °, 23.74 °, 24.72 ° and 27.38 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 56),
(30) It has characteristic diffraction peaks at 14.80 °, 16.44 °, 22.28 °, 22.76 ° and 24.14 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6,8-dimethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 66),
(31) It has characteristic diffraction peaks at 14.52 °, 21.52 °, 21.88 °, 27.84 ° and 30.92 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 67),
(32) It has characteristic diffraction peaks at 7.16 °, 14.40 °, 20.96 °, 27.58 ° and 34.62 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 69),
(33) 1 having characteristic diffraction peaks at 15.48 °, 19.24 °, 22.48 °, 25.54 ° and 30.30 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction -[4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone (Example 73),
(34) It has characteristic diffraction peaks at 10.48 °, 11.32 °, 20.18 °, 22.84 ° and 25.76 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone (Example 76),
(35) It has characteristic diffraction peaks at 12.10 °, 22.48 °, 23.40 °, 24.42 ° and 25.98 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl) -methanone (Example 77),
(36) It has characteristic diffraction peaks at 9.30 °, 14.52 °, 18.64 °, 23.96 ° and 27.12 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 79),
(37) It has characteristic diffraction peaks at 8.92 °, 17.98 °, 18.26 °, 21.10 ° and 23.40 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone (Example 80),
(38) It has characteristic diffraction peaks at 7.12 °, 14.32 °, 21.62 °, 21.92 ° and 22.80 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 81),
(39) It has characteristic diffraction peaks at 7.22 °, 14.54 °, 22.34 °, 29.08 ° and 33.22 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dibromo-4-hydroxyphenyl) -methanone (Example 82),
(40) It has characteristic diffraction peaks at 17.58 °, 19.00 °, 21.04 °, 21.52 ° and 23.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 85),
(41) Acetic acid having characteristic diffraction peaks at 15.76 °, 16.38 °, 24.12 °, 25.88 ° and 27.62 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction 2,6-Dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl ester (Example 87)
Etc.

  The “pharmaceutically acceptable salt” may be any salt as long as it forms a nontoxic salt with the compounds [1] and [2] (hereinafter collectively referred to as the compound of the present invention). , Salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid; oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid Salts with organic acids such as ascorbic acid, methanesulfonic acid, benzenesulfonic acid; salts with inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide; methylamine, diethylamine , Organic salts such as triethylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, guanidine, choline, cinchonine Salts with; lysine, arginine, salts with amino acids alanine and the like.

In the present invention, hydrates, hydrates and solvates of the compounds of the present invention are also included.
In the compound of the present invention, various isomers exist. For example, E isomer and Z isomer exist as geometric isomers, and when an asymmetric carbon atom exists, enantiomers and diastereomers as stereoisomers based on these exist, and tautomerism There can also be a body. Accordingly, the present invention includes all these isomers and mixtures thereof. In addition to the compounds of the present invention, the present invention also includes prodrug compounds and metabolic compounds of these compounds as equivalent compounds.

Here, the “prodrug” has a group that can be chemically or metabolically decomposed, and is a derivative that exhibits pharmacological activity by hydrolysis, solvolysis, or decomposition under physiological conditions. It is. Prodrugs are used, for example, for improving absorption in oral administration or for targeting to a target site. Since it is well established in the pharmaceutical field what kind of group that can be chemically or metabolically decomposed and how to introduce the group into a compound, such a known in the present invention. These techniques may be employed. Examples of the modification site for prodrug formation include highly reactive functional groups such as a hydroxyl group, a carboxyl group, an amino group, and a thiol group in the compound of the present invention. For example, the case where —OR ¹³ or —OR ¹³ ′ of the compound of the present invention represented by the general formula [2] is a hydroxyl group is exemplified.

For example, for a hydroxyl group, a —CO—C _1-6 alkyl group, a —CO ₂ —C _1-6 alkyl group, a —CONH—C _1-6 alkyl group, a —CO—C _2-6 alkenyl group, — CO ₂ -C _2-6 alkenyl group, _{-CONH-C 2-6} alkenyl group, -CO- aryl, -CO ₂ - aryl, -CONH- aryl group, -CO- heterocyclic group, -CO ₂ - A heterocyclic group, -CONH-heterocyclic group (the C _1-6 alkyl group, C _2-6 alkenyl group, aryl group and heterocyclic group are each a halogen atom, a C _1-6 alkyl group, a hydroxyl group, C _{1- 6} alkoxy group, a carboxy group, an amino group, an amino acid _{residue, -PO 3 H 2, -SO 3} H, -CO- polyethylene glycol residue, -CO ₂ - polyethylene glycol residue, -CO- polyethylene glycol mono Ruki ether residue, -CO 2 _- include derivatives of polyethylene glycol monoalkyl ether residue and the like may be substituted) substituents such as have been introduced..

For the amino group, -CO-C _1-6 alkyl group, -CO ₂ -C _1-6 alkyl group, -CO-C _2-6 alkenyl group, -CO ₂ -C _2-6 alkenyl group,- CO- aryl group, -CO ₂ - aryl group, -CO- heterocyclic group, -CO ₂ - Hajime Tamaki (said _{C 1-6} alkyl _{groups, C 2-6} alkenyl group, an aryl group, a heterocyclic group, Halogen atom, C _1-6 alkyl group, hydroxyl group, C _1-6 alkoxy group, carboxy group, amino group, amino acid residue, —PO ₃ H ₂ , —SO ₃ H, —CO-polyethylene glycol residue, — CO ₂ - polyethylene glycol residue, -CO- polyethylene glycol monoalkyl ether residue, -CO ₂ - polyethylene glycol monoalkyl ether residue, optionally substituted with _-PO 3 _{H 2,} etc. There.) Substituents such include derivatives that have been introduced.

For a carboxyl group, a C _1-6 alkoxy group and an aryloxy group (the C _1-6 alkoxy group and aryloxy group are a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and a C _1-6 alkoxy group, respectively. , A carboxy group, an amino group, an amino acid residue, —PO ₃ H ₂ , —SO ₃ H, a polyethylene glycol residue, a polyethylene glycol monoalkyl ether residue, etc.) may be substituted. And derivatives thereof.

  The “pharmaceutical composition” includes a combination with other drugs in addition to a so-called “composition” composed of an active ingredient as a medicine and a pharmaceutically acceptable carrier. It goes without saying that the pharmaceutical composition of the present invention may be used in combination with any other drug within a range acceptable in the medical field. Therefore, it can also be said that this pharmaceutical composition is a pharmaceutical composition for combined use with other drugs.

  The pharmaceutical composition of the present invention can be administered not only to humans but also to other mammals (mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkey, etc.). Therefore, the pharmaceutical composition of the present invention is useful not only for humans but also for veterinary drugs.

  “Substantially does not inhibit CYP” means that it does not substantially inhibit the function of the drug metabolizing enzyme cytochrome P450 (CYP), preferably CYP2D6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4, more preferably CYP2C9 For example, based on the conditions of Test Example 2 described later, preferably, under the conditions of Test Example 2, the 50% inhibitory concentration against CYP is 1 μM or more, preferably 3 μM or more, more preferably 10 μM or more, It means even more preferably 25 μM or more, particularly preferably 50 μM or more.

“Inhibiting URAT1 activity” means specifically inhibiting the function of URAT1 as a uric acid transporter to eliminate or attenuate its activity. For example, based on the conditions of Test Example 1 described below, It means specifically inhibiting the function of URAT1, and preferably, under the conditions of Test Example 1 described later, the 50% inhibitory concentration against URAT1 is less than 3 μM, more preferably less than 1 μM, and even more preferably 0.3 μM. Less than, more preferably less than 0.1 μM, even more preferably less than 0.03 μM. URAT1 activity inhibitors do not include URAT1 in vivo substrates such as uric acid.

  “Reducing blood uric acid level” means reducing uric acid (including urate) in blood (including serum or plasma), preferably lowering high blood uric acid level More preferably, it means that the serum uric acid level is lowered to less than 8 mg / dL (preferably less than 7 mg / dl, more preferably less than 6 mg / dL as the serum uric acid level).

  “Pathology involving uric acid” means a pathological condition involving uric acid (including urate) in the body such as blood (including serum or plasma) or urine, specifically high blood Pathological conditions caused by uric acid levels (including serum or plasma) or urinary uric acid levels, such as hyperuricemia, gouty nodules, acute gouty arthritis, chronic gouty arthritis, gouty kidneys, urolithiasis, renal function Disorders, coronary artery disease, ischemic heart disease and the like.

  For example, “high blood uric acid level” means that the serum uric acid level is 6 mg / dL or more, preferably 7 mg / dL or more, more preferably 8 mg / dL or more. In addition, “a pathological condition caused by a high blood uric acid level” is a pathological condition caused by or contributed by a high blood uric acid level. For example, according to “Guideline for Treatment of Hyperuricemia / Gout (1st Edition)” (Gout and Nucleic Acid Metabolism, Vol. 26, Appendix 1, 2002. Japanese Society of Gout and Nucleic Acid Metabolism) Regardless of the upper limit of normal, which is 7 mg / dL, which is the uric acid dissolution concentration in plasma, a value exceeding this is defined as hyperuricemia, and treatment of hyperuricemia / gout, onset of gout arthritis For prevention, it is mentioned that it is desirable to control the serum uric acid level to 6 mg / dL or less.

  As the “pharmaceutically acceptable carrier”, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants, solvents, solubilizers, suspending agents , Isotonic agents, buffering agents, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, sweeteners, colorants and the like can also be used. Preferable examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include polymer compounds such as crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, propylene glycol fatty acid ester and the like. Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; polyvinyl alcohol, polyvinyl Examples include pyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose and the like. Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate, citrate and the like. Preferable examples of the soothing agent include benzyl alcohol. Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite and ascorbic acid. Preferable examples of the sweetening agent include aspartame, saccharin sodium, stevia and the like. Preferable examples of the colorant include food dyes such as food yellow No. 5, food red No. 2 and food blue No. 2, food lake dyes, iron oxide and the like.

  The compound of the present invention can be contained together with a pharmaceutically acceptable carrier as an active ingredient of a pharmaceutical composition, a URAT1 activity inhibitor, a blood uric acid level-lowering agent, or a therapeutic or prophylactic agent for a pathological condition involving uric acid.

  When the compound of the present invention is used as a pharmaceutical composition, a URAT1 activity inhibitor, a blood uric acid level-lowering agent, or a therapeutic or prophylactic agent for a disease state involving uric acid, it is administered systemically or locally, orally or parenterally. can do. The dose varies depending on the age, body weight, symptoms, therapeutic effects, etc. For example, it can be administered once or several times a day, usually in the range of 0.1 mg to 1 g per adult. Moreover, this invention compound can be used also for the treatment and prevention drug of the said disease of animals other than a human as well as a mammal, especially a mammal. The same applies when the compound of the present invention is used as a therapeutic or prophylactic agent for hyperlipidemia, diabetes, obesity or cardiovascular disease such as hypertension, coronary artery disease, vascular endothelial disorder or ischemic heart disease.

  The compound of the present invention can be prepared as an appropriate diluent, dispersant, adsorbent, solubilizer, etc. to form a solid composition and liquid composition for oral administration, or an injection for parenteral administration. Additives can be mixed. In addition, the pharmaceutical composition of the present invention includes, for example, tablets, pills, powders, granules, suppositories, injections, eye drops, solutions, capsules, troches, aerosols, elixirs, suspensions, emulsions. And may have a known form such as a syrup.

  When the pharmaceutical composition, URAT1 activity inhibitor, blood uric acid level-lowering agent, or therapeutic or prophylactic agent for a pathological condition involving uric acid is a solid preparation such as a tablet, pill, powder, granule, etc. Examples of additives include lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium aluminate metasilicate, and anhydrous silicic acid powder. When preparing a tablet or pill, if necessary, it may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose or hydroxymethylcellulose phthalate, or a multilayer tablet consisting of two or more layers. It may be.

  The pharmaceutical composition, URAT1 activity inhibitor, blood uric acid level-lowering agent, or therapeutic or prophylactic agent for pathological conditions involving uric acid can be obtained by dissolving the compound of the present invention in a solvent and further adding an additive. Also included are capsules filled with liquid, semi-solid or solid contents. Examples of the solvent include purified water, ethanol, or vegetable oil, and it is preferable to use ethanol or a mixture of purified water and ethanol. As an additive, the additive normally used in capsule manufacture can be used without a restriction | limiting in particular. Examples of the additive include propylene glycol fatty acid esters; low molecular weight polyethylene glycols such as polyethylene glycol 200 to 600, fatty acid esters of low molecular weight polyethylene glycols such as polyethylene glycol 200 to 600, medium chain fatty acid triglycerides; stearyl alcohol, cetanol , Alcohols such as polyethylene glycol / polyhydric alcohols or esters thereof; oils and fats such as sesame oil, soybean oil, peanut oil, corn oil, hardened oil, paraffin oil, beeswax; triethyl citrate, triacetin, stearic acid, palmitic Examples thereof include organic carboxylic acids such as acid and myristic acid or fatty acids and derivatives thereof, and are suitable for the production of liquid or semi-solid contents. In the capsule of the present invention, it is preferable to use propylene glycol fatty acid esters as additives. Examples of the propylene glycol fatty acid esters include propylene glycol monocaprylate (Capmul PG-8 (trade name), Sepol 218 (trade name), Capryol 90 (trade name)), propylene glycol monolaurate (Lauroglycol FCC (trade name)). ), Propylene glycol monooleate (Myverol P-O6 (trade name)), propylene glycol myristate, propylene glycol monostearate, propylene glycol ricinolate (Propymuls (trade name)), propylene glycol dicaprylate / dicouple (Captex) (Registered trademark) 200 (trade name)), propylene glycol dilaurate, propylene glycol distearate, and propylene glycol di Kutanoeto (Captex (registered trademark) 800 (trade name)), and the like. Although the raw material which comprises the capsule of this invention is not specifically limited, For example, naturally-derived polysaccharides, such as agar, alginate, starch, xanthan, and dextran; Proteins, such as gelatin and casein; Hydroxy starch, pullulan, hydroxypropyl Examples include chemically treated products such as cellulose, hydroxypropylmethylcellulose, polyvinyl alcohol or derivatives thereof, polyacryl derivatives, polyvinylpyrrolidone or derivatives thereof, and polyethylene glycol.

  The pharmaceutical composition, URAT1 activity inhibitor, blood uric acid level-lowering agent, or therapeutic or prophylactic agent for a pathological condition involving uric acid is, for example, a pharmaceutically acceptable emulsion, dissolution agent, suspension, In the case of liquid preparations for oral administration such as syrups and elixirs, examples of the diluent to be used include purified water, ethanol, vegetable oil, and emulsifier. Further, in this liquid preparation, in addition to the diluent, auxiliary agents such as an infiltrating agent, a suspending agent, a sweetening agent, a flavoring agent, a fragrance, and an antiseptic may be mixed.

  When the pharmaceutical composition, URAT1 activity inhibitor, blood uric acid level-lowering agent, or therapeutic or prophylactic agent for a pathological condition involving uric acid is a parenteral preparation such as an injection, the additive is sterile aqueous or Non-aqueous solutions, solubilizers, suspending agents, emulsifiers and the like are used. Examples of aqueous solutions, solubilizers, and suspensions include distilled water for injection; physiological saline, cyclodextrin and derivatives thereof; organic amines such as triethanolamine, diethanolamine, monoethanolamine, and triethylamine; There are alkaline solutions. When using an aqueous solution, for example, vegetable oil such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, and the like may be further added. As solubilizers, for example, surfactants such as polyoxyethylene hydrogenated castor oil and sucrose fatty acid ester (mixed micelle formation), lecithin or hydrogenated lecithin (liposome formation), and the like are also used. The parenteral preparation of the present invention can also be made into an emulsion preparation containing a water-insoluble solubilizer such as vegetable oil and lecithin, polyoxyethylene hydrogenated castor oil or polyoxyethylene polyoxypropylene glycol.

  The compound of the present invention, the pharmaceutical composition of the present invention, a URAT1 activity inhibitor, a blood uric acid level-lowering agent, or a therapeutic or prophylactic agent for a pathological condition involving uric acid is another pharmaceutical composition or drug (hereinafter also referred to as a concomitant drug). ).

  “Combination” means that a plurality of pharmaceutical agents are used in combination as an active ingredient, and specifically, used as a combination agent, as a kit, and separately administered by the same or different administration routes. The combination use etc. which are characterized by this are mentioned.

  The administration time of the compound of the present invention, the pharmaceutical composition of the present invention, the URAT1 activity inhibitor, the blood uric acid level-lowering agent, the therapeutic or prophylactic agent for the pathological condition involving uric acid, and the concomitant drug is not limited, and these are administered On the other hand, they may be administered simultaneously or at a time difference. The dose of the concomitant drug may be in accordance with the clinically used dose, and may be appropriately selected depending on the administration subject, age and weight of the administration subject, symptoms, administration time, dosage form, administration method, combination, etc. it can. The administration form of the concomitant drug is not particularly limited, and the compound of the present invention, the pharmaceutical composition, the URAT1 activity inhibitor, the blood uric acid level lowering agent, or the therapeutic or prophylactic agent for the pathological condition involving uric acid and the concomitant drug at the time of administration are not limited. It only has to be combined.

As a concomitant drug,
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or prophylactic agent (10) treatment and / or prophylactic agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid antimetabolite, and these 1 to 3 drugs and the compound of the present invention Can be used in combination.

  Examples of the “treatment and / or prevention agent for hyperuricemia” include uric acid production inhibitors such as xanthine oxidase inhibitors, uric acid excretion promoters, and the like. Specifically, allopurinol, probenecid, bucolome, febu Xostat, benzbromarone, oxypurinol and the like.

  Examples of the “treatment and / or prevention agent for gout arthritis” include NSAIDs such as indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, colchicine, corticosteroids, and the like.

  Examples of “therapeutic and / or prophylactic agent for gout kidney” include uric acid production inhibitors such as xanthine oxidase inhibitor, uric acid excretion promoters, citric acid preparations, urine alkalizing agents such as sodium bicarbonate, etc. Specific examples include allopurinol, probenecid, bucolome, febuxostat, benzbromarone, and oxypurinol.

  Examples of “therapeutic agent and / or preventive agent for urinary calculus” include urine alkalizing agents such as citric acid preparations and sodium bicarbonate.

  Examples of the “therapeutic and / or preventive agent for hypertension or hypertensive complications” include, for example, loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β blockers, α, β blockers More specifically, for example, furosemide sustained release agent, captopril, captopril sustained release agent, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride , Quinapril hydrochloride, trandolapril, perindopril erbumine, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release agent, nilvadipine, nifedipine, nifedipine sustained release agent, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride Drugs, nisoldipine, nitrendipine, manidipine hydrochloride, varnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, propranolol hydrochloride sustained release, pindolol, pindolol sustained release, indenolol hydrochloride, carteolol hydrochloride, medical chart Orol sustained release agent, bunitrolol hydrochloride, bunitrolol hydrochloride sustained release agent, atenolol, acebutol hydrochloride hydrochloride, metoprolol tartrate, metoprolol tartrate, nipradilol, penbutol sulfate sulfate, tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, Bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, Examples thereof include prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride sustained release agent, urapidil, phentolamine mesylate and the like.

  Examples of “therapeutic and / or prophylactic agent for hyperlipidemia or hyperlipidemic complication” include, for example, statin drugs, anion exchange resins, probucol, nicotinic acid preparations, fibrate drugs, eicocypentaene More specifically, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, colestimide, cholestyramine, niceritrol, nicomol, fenofibrate, bezafibrate, clinofibrate, clofibrate, icosapent Examples include ethyl acid.

  Examples of “therapeutic and / or preventive agent for diabetes or diabetic complications” include, for example, insulin preparations, sulfonylurea drugs, insulin secretagogues, sulfonamide drugs, biguanide drugs, α-glucosidase inhibitors, insulin resistance improving drugs, Angiotensin converting enzyme inhibitor, aldose reductase inhibitor, antiarrhythmic agent and the like, more specifically, for example, insulin, chlorpropamide, glibenclamide, glipizide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, Examples include tolazamide, gliclazide, nateglinide, glybazole, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, pioglitazone hydrochloride, mexiletine.

  Examples of “therapeutic and / or prophylactic agent for obesity or obesity complications” include mazindol, acarbose, voglibose, orlistat and the like.

  Examples of the “therapeutic and / or preventive agent for the primary disease causing hypouria excretion type secondary hyperuricemia” include, for example, chronic kidney disease, polycystic kidney disease, pregnancy toxemia, lead nephropathy, hyperlactic acid blood Treatment, prevention agents such as dehydration, Down syndrome, sarcoidosis, glycogenosis type I (via hyperlactic acidemia), dehydration, and the like.

  Examples of the “agent for treating and / or preventing renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia” include, for example, loop diuretic (eg, furosemide), citric acid preparation, sodium bicarbonate, cation exchange Resin, aluminum hydroxide, alphacalcidol, β-blocker (eg propranolol hydrochloride), ACE inhibitor (eg captopril), cardiotonic agent (eg digoxin), angina treatment (eg isosorbide nitrate), Ca Antagonists (eg, diltiazem hydrochloride), uric acid production inhibitors (eg, allopurinol), amino acid preparations, hyperammonemia-improving agents, antiarrhythmic agents (eg, mexiletine), anemia agents (eg, mepithiostan, erythropoietin), In addition, “therapeutic and / or preventive agent for hypertension or hypertensive complications”, “hyperlipidemia or “Therapeutic and / or preventive for hyperlipidemia complications”, “therapeutic and / or preventive for diabetes or diabetic complications”, “therapeutic and / or preventive for obesity or obesity complications”, etc. Is mentioned.

  Examples of the “nucleic acid metabolism antagonist” include azathioprine, mizoribine, mycophenolic acid and the like.

  The compound of the present invention, the pharmaceutical composition of the present invention, a URAT1 activity inhibitor, a blood uric acid level-lowering agent, or a therapeutic or prophylactic agent for a pathological condition involving uric acid is used in combination with a drug that increases blood uric acid level. An increase in blood uric acid level can also be suppressed.

  Examples of drugs that increase blood uric acid levels include nucleic acid metabolism antagonists, antihypertensive diuretics, antituberculosis drugs, anti-inflammatory analgesics, hyperlipidemia drugs, asthma drugs, immunosuppressants, salicylic acid, pyrazinamide, ethambutol, Examples include nicotinic acid, ethanol, and cyclosporine.

The crystal of the compound of the present invention (hereinafter sometimes abbreviated as the crystal of the present invention) may be contained in the pharmaceutical composition, and preferably contains substantially the crystal of the present invention.
“Substantially containing most of the crystals of the present invention” means containing 80% or more, preferably 90% or more, more preferably 95% or more of the crystals of the compound of the present invention.

  Next, the production method of the compound of the present invention will be specifically described. However, it goes without saying that the present invention is not limited to these production methods. In the production of the compound of the present invention, the order of the reaction can be appropriately changed. The reaction may be performed from a process or a site that seems reasonable.

  In addition, a substituent conversion (substituent conversion or further modification) step may be appropriately inserted between the steps. When there is a reactive functional group, protection and deprotection may be appropriately performed. Moreover, in order to accelerate | stimulate progress of reaction, reagents other than the illustrated reagent can be used suitably. In addition, raw material compounds whose production methods are not described are commercially available or can be easily prepared by combining known synthetic reactions.

The compound obtained in each step can be isolated and purified by a conventional method such as crystallization, recrystallization, column chromatography, preparative HPLC, etc. The process can be proceeded to.
In the following production method, “room temperature” means 1 to 40 ° C.

Manufacturing method 1
In compound [1], a compound in which X ² is an oxygen atom and Y is C═O can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

First Step Compound 2 can be obtained by subjecting Compound 1 to an amidation reaction with acid halide B in a solvent in the presence of a base.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide, dimethyl sulfoxide and water These may be used alone or in combination of two or more. A preferable solvent in this reaction is methylene chloride, chloroform, toluene, ethyl acetate, water or tetrahydrofuran.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium hydride, Alkali metal hydrides such as potassium hydride; Alkali metal carbonates such as sodium carbonate and potassium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and the like, preferably triethylamine, pyridine, sodium hydroxide or carbonic acid Sodium hydride.

The reaction temperature is about 0 ° C. to 80 ° C., preferably about 0 ° C. to room temperature.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Compound 2 can be obtained by subjecting the second step compound 2 to a cyclization reaction in a solvent in the presence of a base, and if necessary, in the presence of a catalytic amount of sodium iodide, potassium iodide or the like.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. A preferred solvent in this reaction is acetone or N, N-dimethylformamide.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium carbonate, carbonate Alkali metal carbonates such as potassium; alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal carboxylates such as sodium acetate and potassium acetate; alkali metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide Alkali metal alkoxides such as sodium methoxide and potassium tert-butoxide; alkyllithiums such as n-butyllithium and s-butyllithium; lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide and the like Alkali metal amides and the like, preferably potassium carbonate.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 100 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 1 hour to 24 hours.

Third Step Compound 4 can be obtained by reducing the compound 3 in a solvent using a reducing agent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; methanol, ethanol and isopropyl alcohol. And alcohol solvents such as tert-butanol, etc., preferably toluene, diethyl ether or tetrahydrofuran.

  Examples of the reducing agent used in the reaction include lithium aluminum hydride, sodium borohydride, diborane, diisobutylaluminum hydride, borane-tetrahydrofuran complex, sodium bis (2-methoxyethoxy) aluminum hydride, and preferably Bis (2-methoxyethoxy) aluminum hydride, lithium aluminum hydride or borane-tetrahydrofuran complex.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 130 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Step 4 Carboxylic acid compound C is reacted with oxalyl chloride, thionyl chloride, etc. in a solvent to give an acid chloride, and then amidated with compound 4 in the presence of a base in a solvent as necessary. Thus, compound 5 can be obtained.

  Examples of the solvent used in the reaction for obtaining the acid chloride include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogenated hydrocarbon solvents such as methylene, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and the like. These may be used alone or in combination of two or more. Can be used. Preferred solvents for this reaction are 1,2-dimethoxyethane, ethyl acetate, or methylene chloride, chloroform, toluene, 1,2-dimethoxyethane, ethyl acetate containing a catalytic amount of N, N-dimethylformamide.

The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. Preferred solvents for this reaction are methylene chloride, chloroform, toluene, ethyl acetate, N, N-dimethylformamide or tetrahydrofuran.

  Examples of the base used in this reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium hydride And alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. This reaction is preferably carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide, sodium hydride or sodium hydrogen carbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Further, the compound 4 and the carboxylic acid compound C are converted into, for example, water-soluble carbodiimide (WSC · HCl: 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide ( Compound 5 can also be obtained by a condensation reaction using DPPA), carbonyldiimidazole (CDI), 1-hydroxy-1H-benzotriazole (HOBT), 4-dimethylaminopyridine (DMAP) or the like. Alternatively, carboxylic acid compound C is reacted with chloroformate such as ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, etc. in the presence of a base such as triethylamine to form a mixed acid anhydride, and then reacted with compound 4 in the presence of a base. To obtain compound 5.

For compounds in which X ⁴ is other than —CH ₂ —, the corresponding compounds can be obtained by the same method as in the fourth step using known compounds.

  Moreover, a 1st process and a 2nd process can obtain the compound 3 by 1 process according to Synthesis, 10,851-852 (1984).

Manufacturing method 2
In compound [1], a compound in which X ² is an oxygen atom and Y is C═O can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Fifth Step Compound 6 can be obtained by subjecting Compound 1 to a silylation reaction using tert-butylchlorodimethylsilane in a solvent in the presence of a base.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. A preferred solvent in this reaction is N, N-dimethylformamide.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, imidazole, 4-dimethylaminopyridine and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; hydrogenation Examples thereof include alkali metal hydrides such as sodium and potassium hydride; alkali metals such as sodium carbonate and potassium carbonate; alkali metals such as sodium hydrogen carbonate and potassium hydrogen carbonate. A preferred base in this reaction is imidazole.

The reaction temperature is about 0 ° C. to 150 ° C., preferably about 0 ° C. to room temperature.
The reaction time is about 10 minutes to 24 hours, preferably about 30 minutes to 12 hours.

Step 6 Carboxylic acid compound C is reacted with oxalyl chloride, thionyl chloride, etc. in a solvent to form an acid chloride, and then amidated with compound 6 in the presence of a base in a solvent as necessary. Thus, compound 7 can be obtained.

  Examples of the solvent used in the reaction for obtaining the acid chloride include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogenated hydrocarbon solvents such as methylene, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and the like. These may be used alone or in combination of two or more. Can be used. Preferred solvents for this reaction are 1,2-dimethoxyethane, ethyl acetate, or methylene chloride, chloroform, toluene, 1,2-dimethoxyethane, ethyl acetate containing a catalytic amount of N, N-dimethylformamide.

The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. A preferred solvent in this reaction is methylene chloride, chloroform, toluene, ethyl acetate or tetrahydrofuran.

  Examples of the base used in this reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium hydride And alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. This reaction is preferably carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide or sodium hydrogen carbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Further, compound 6 and carboxylic acid compound C can be converted into, for example, water-soluble carbodiimide (WSC · HCl: 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide ( Compound 7 can also be obtained by a condensation reaction using DPPA), carbonyldiimidazole (CDI), 1-hydroxy-1H-benzotriazole (HOBT), 4-dimethylaminopyridine (DMAP) or the like. Alternatively, the carboxylic acid compound C is reacted with a chloroformate such as ethyl chloroformate, isopropyl chloroformate, and isobutyl chloroformate in the presence of a base such as triethylamine to form a mixed acid anhydride, and then reacted with compound 6 in the presence of a base. To give compound 7.

Step 7 Compound 8 can be obtained by desilylating compound 7 in a solvent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; acetone, N , N-dimethylformamide, polar solvents such as dimethyl sulfoxide and the like, and these can be used alone or in admixture of two or more. A preferred solvent in this reaction is N, N-dimethylformamide.

  Examples of the reagent used for the reaction include potassium carbonate, tetrabutylammonium fluoride and the like, and potassium carbonate is preferable.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Step 8 Compound 9 can be obtained by cyclizing compound 8 with halide D in the presence of a base in a solvent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. A preferred solvent in this reaction is N, N-dimethylformamide.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium hydride, Examples thereof include alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. A preferred base in this reaction is potassium carbonate.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 100 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 3 hours to 24 hours.

Manufacturing method 3
In compound [1], the compound in which X ² is a carbon atom or a sulfur atom and Y is C═O can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Step 9 Compound 11 can be obtained by subjecting known compound 10 to a reduction reaction in a solvent using a reducing agent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; methanol, ethanol and isopropyl alcohol. And alcohol solvents such as tert-butanol, etc., preferably toluene, diethyl ether or tetrahydrofuran.

  Examples of the reducing agent used in the reaction include lithium aluminum hydride, sodium borohydride, diborane, diisobutylaluminum hydride, borane-tetrahydrofuran complex, sodium bis (2-methoxyethoxy) aluminum hydride, and preferably Bis (2-methoxyethoxy) aluminum hydride, lithium aluminum hydride or borane-tetrahydrofuran complex.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 130 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Step 10 Carboxylic acid compound C is reacted with oxalyl chloride, thionyl chloride, etc. in a solvent to form an acid chloride, and then amidated with compound 11 in the solvent, if necessary, in the presence of a base. Thus, compound 12 can be obtained.

  Examples of the solvent used in the reaction for obtaining the acid chloride include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogenated hydrocarbon solvents such as methylene, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and the like. These may be used alone or in combination of two or more. Can be used. Preferred solvents for this reaction are 1,2-dimethoxyethane, ethyl acetate, or methylene chloride, chloroform, toluene, 1,2-dimethoxyethane, ethyl acetate containing a catalytic amount of N, N-dimethylformamide.

The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. Preferred solvents for this reaction are methylene chloride, chloroform, toluene, ethyl acetate, N, N-dimethylformamide or tetrahydrofuran.

  Examples of the base used in this reaction include organic bases such as triethylamine, pyridine, dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium hydride, hydrogen Examples thereof include alkali metal hydrides such as potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. This reaction is preferably carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide, sodium hydride or sodium bicarbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Further, the compound 11 and the carboxylic acid compound C are converted into, for example, water-soluble carbodiimide (WSC · HCl: 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide ( Compound 12 can also be obtained by a condensation reaction using DPPA), carbonyldiimidazole (CDI), 1-hydroxy-1H-benzotriazole (HOBT), 4-dimethylaminopyridine (DMAP), or the like. Alternatively, the carboxylic acid compound C is reacted with a chloroformate such as ethyl chloroformate, isopropyl chloroformate, and isobutyl chloroformate in the presence of a base such as triethylamine to form a mixed acid anhydride, and then reacted with compound 11 in the presence of a base. To give compound 12.

For compounds in which X ⁴ is other than —CH ₂ —, the corresponding compounds can be obtained by the same method as in Step 10 using known compounds.

Manufacturing method 4
In compound [1], a compound in which X ² is S═O or S (═O) ₂ and Y is C═O can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Step 14 Compound 14 can be obtained by subjecting compound 13 to an oxidation reaction in a solvent using an oxidizing agent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; acetone, N , N-dimethylformamide, dimethyl sulfoxide, water, acetic acid and other polar solvents, and the like can be used alone or in admixture of two or more. A preferred solvent in this reaction is methylene chloride or chloroform.

  Examples of the oxidizing agent used in the reaction include 3-chloroperbenzoic acid, hydrogen peroxide, sodium periodate, tert-butyl hydroperoxide, and the like, preferably 3-chloroperbenzoic acid.

The reaction temperature is about 0 ° C. to 80 ° C., preferably about 0 ° C. to room temperature.
The reaction time is about 10 minutes to 48 hours, preferably about 2 hours to 24 hours.

Manufacturing method 5
In the compound [1], a compound in which X ² is NR ⁵ , N (COR ⁶ ), N (S (═O) ₂ R ⁶ ) or N (CONR ⁷ R ⁸ ) and Y is C═O It can be manufactured by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Step 12 Carboxylic acid compound C is reacted with oxalyl chloride, thionyl chloride, etc. in a solvent to give an acid chloride, and then amidated with known compound 15 in a solvent, if necessary, in the presence of a base. Thus, compound 16 can be obtained.

  Examples of the solvent used in the reaction for obtaining the acid chloride include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogenated hydrocarbon solvents such as methylene, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and the like. These may be used alone or in combination of two or more. Can be used. Preferred solvents for this reaction are 1,2-dimethoxyethane, ethyl acetate, or methylene chloride, chloroform, toluene, 1,2-dimethoxyethane, ethyl acetate containing a catalytic amount of N, N-dimethylformamide.

The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. Preferred solvents for this reaction are methylene chloride, chloroform, toluene, ethyl acetate, N, N-dimethylformamide or tetrahydrofuran.

  Examples of the base used in this reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium hydride And alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. This reaction is preferably carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide, sodium hydride or sodium hydrogen carbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Further, the known compound 15 and the carboxylic acid compound C can be converted into, for example, water-soluble carbodiimide (WSC / HCl: 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide. Compound 16 can also be obtained by a condensation reaction using (DPPA), carbonyldiimidazole (CDI), 1-hydroxy-1H-benzotriazole (HOBT), 4-dimethylaminopyridine (DMAP) or the like. Alternatively, after reacting carboxylic acid compound C with chloroformate such as ethyl chloroformate, isopropyl chloroformate, and isobutyl chloroformate in the presence of a base such as triethylamine to form a mixed acid anhydride, in the presence of known compound 15 and the base Compound 16 can also be obtained by reacting.

R ⁵ , COR ⁶ , S (═O) ₂ R ⁶ or CONR ⁷ R ⁸ can be introduced into the nitrogen atom of X ² either before or after the twelfth step, and react in an order that seems reasonable. Just do it.

Manufacturing method 6
In compound [1], the compound in which Y is C═S can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Step 13 Compound 18 can be obtained by reacting Compound 17 with Lawesson's reagent, diphosphorus pentasulfide and the like in a solvent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; acetone, N , N-dimethylformamide, polar solvents such as dimethyl sulfoxide and the like, and these can be used alone or in admixture of two or more. A preferred solvent in this reaction is tetrahydrofuran or toluene.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 120 ° C.
The reaction time is about 10 minutes to 24 hours, preferably about 30 minutes to 12 hours.

Manufacturing method 7
In compound [1], a compound in which Y is S (═O) ₂ can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Step 14 Compound 20 can be obtained by subjecting compound 19 to an amidation reaction with known acid chloride E in a solvent in the presence of a base as necessary.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. Preferred solvents for this reaction are methylene chloride, chloroform, toluene, ethyl acetate, N, N-dimethylformamide or tetrahydrofuran.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium hydride, Examples thereof include alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Preferably this reaction is carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide, sodium hydride or sodium bicarbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Manufacturing method 8
In compound [1], a compound in which X ² is an oxygen atom and Y is C═O can be produced by the following steps.

(Wherein, TBDMS is tert- butyldimethylsilyl group.-OMs is _{-OS (= O) 2 -CH 3} . Other symbols are as defined above.)

Fifteenth step Compound 22 can be obtained by reacting compound 21 with halide F in a solvent in the presence of a base and, if necessary, in the presence of sodium iodide, potassium iodide or the like.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. A preferred solvent in this reaction is acetone or N, N-dimethylformamide.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium carbonate, carbonate Alkali metal carbonates such as potassium; alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal carboxylates such as sodium acetate and potassium acetate; alkali metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide Alkali metal alkoxides such as sodium methoxide and potassium tert-butoxide; alkyllithiums such as n-butyllithium and s-butyllithium; lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide and the like It includes alkali metal amides such as, preferably sodium hydride or potassium carbonate.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 130 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 1 hour to 24 hours.

Step 16 Compound 23 can be obtained by subjecting compound 22 to a reduction reaction in a solvent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; methanol, ethanol and isopropyl alcohol. Alcohol solvents such as tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide, and the like. The above can be mixed and used. A preferred solvent in this reaction is tetrahydrofuran, ethyl acetate or ethanol.

  Examples of the reduction reaction include a hydrogenation reaction with a noble metal catalyst (eg, palladium carbon, palladium barium sulfate, palladium black, platinum carbon, platinum oxide, rhodium carbon, Raney nickel, etc.), tin dichloride, iron, sodium hydrosulfite. A hydrogenation reaction with a noble metal catalyst (palladium carbon) is preferable.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 100 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

In Step 17 carboxylic acid compound C in a solvent, oxalyl chloride, after an acid chloride by reaction with thionyl chloride, in a solvent, in the presence of a base if necessary, be amidation reaction with compound 23 Thus, compound 24 can be obtained.

  Examples of the solvent used in the reaction for obtaining the acid chloride include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogenated hydrocarbon solvents such as methylene, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and the like. These may be used alone or in combination of two or more. Can be used. Preferred solvents for this reaction are 1,2-dimethoxyethane, ethyl acetate, or methylene chloride, chloroform, toluene, 1,2-dimethoxyethane, ethyl acetate containing a catalytic amount of N, N-dimethylformamide.

The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. A preferred solvent in this reaction is methylene chloride, chloroform, toluene, ethyl acetate or tetrahydrofuran.

  Examples of the base used in this reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium hydride And alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. This reaction is preferably carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide or sodium hydrogen carbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Further, compound 23 and carboxylic acid compound C can be converted into, for example, water-soluble carbodiimide (WSC / HCl: 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide ( Compound 24 can also be obtained by a condensation reaction using DPPA), carbonyldiimidazole (CDI), 1-hydroxy-1H-benzotriazole (HOBT), 4-dimethylaminopyridine (DMAP), or the like. Alternatively, the carboxylic acid compound C is reacted with a chloroformate such as ethyl chloroformate, isopropyl chloroformate, and isobutyl chloroformate in the presence of a base such as triethylamine to form a mixed acid anhydride, and then reacted with compound 23 in the presence of a base. To obtain the compound 24.

Step 18 Compound 25 can be obtained by desilylating compound 24 in a solvent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; acetone, N , N-dimethylformamide, polar solvents such as dimethyl sulfoxide and the like, and these can be used alone or in admixture of two or more. A preferred solvent in this reaction is tetrahydrofuran or N, N-dimethylformamide.

  Examples of the reagent used for the reaction include potassium carbonate and tetrabutylammonium fluoride, and tetrabutylammonium fluoride is preferred.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Step 19 Compound 25 can be converted to Compound 26.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. This reaction is preferably carried out without solvent or in methylene chloride or chloroform.

  Examples of the reagent used for the reaction include carbon tetrachloride in the presence of triphenylphosphine; N-chlorosuccinimide (NCS) in the presence of triphenylphosphine; thionyl chloride; carbon tetrabromide in the presence of triphenylphosphine; N-bromosuccinimide (NBS) in the presence of phosphine; phosphorus tribromide; phosphorus bromide; iodine in the presence of triphenylphosphine and imidazole; methanesulfonyl chloride in the presence of a base (pyridine, triethylamine, etc.), etc. Preferred is methanesulfonyl chloride in the presence of a base (pyridine, triethylamine, etc.).

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 100 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Step 20 Compound 27 can be obtained by subjecting compound 26 to a cyclization reaction in a solvent in the presence of a base, and optionally in the presence of sodium iodide, potassium iodide or the like.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. A preferred solvent in this reaction is tetrahydrofuran or N, N-dimethylformamide.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium carbonate, carbonate Alkali metal carbonates such as potassium; alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal carboxylates such as sodium acetate and potassium acetate; alkali metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide Alkali metal alkoxides such as sodium methoxide and potassium tert-butoxide; alkyllithiums such as n-butyllithium and s-butyllithium; lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide and the like It includes alkali metal amides like, preferably potassium or sodium hydride carbonate.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 100 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

The crystal of the present invention can also be produced by crystallization by applying a crystallization method known per se to the compound of the present invention.
Here, examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, and a crystallization method from a melt.

The “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent. In general, a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, a flux method, and the like. Examples of the solvent used include aromatic hydrocarbon solvents (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbon solvents (eg, dichloromethane, chloroform, etc.), saturated hydrocarbon solvents (eg, hexane, Heptane, cyclohexane, etc.), ether solvents (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitrile solvents (eg, acetonitrile, etc.), ketone solvents (eg, acetone, etc.), sulfoxide solvents (eg, Dimethyl sulfoxide, etc.), acid amide solvents (eg, N, N-dimethylformamide, etc.), ester solvents (eg, ethyl acetate, etc.), alcohol solvents (eg, methanol, ethanol, isopropyl alcohol, n-butanol, etc.) Water is used. These solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)).
Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.
Examples of the “crystallization from the melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method). And liquid phase epitaxy method).

As a preferred example of the crystallization method, the compound of the present invention is dissolved in an appropriate solvent (eg, alcohol solvent such as methanol, ethanol, etc.) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved. The method of cooling to below temperature (for example, 0-50 degreeC, Preferably 0-20 degreeC) etc. are mentioned.
The crystals of the present invention thus obtained can be isolated by, for example, filtration.

Next, the production of the compounds of the present invention will be specifically described with reference to examples. However, the present invention is not limited to these examples.
In addition, the room temperature in an Example means 1-40 degreeC.

Example 1
Preparation of (3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 3-chloro-4-methoxybenzoyl chloride Chloroform (20 mL) was added to 3-chloro-4-methoxybenzoic acid (2.0 g), and oxalyl chloride (1.84 mL) and N, N-dimethyl were added under ice cooling. Formamide (1 drop) was added. After stirring at room temperature for 3 hours, the mixture was concentrated and azeotroped with toluene to give the title compound (2.063 g).

Process 2
Preparation of 3,4-dihydro-2H-benzo [1,4] oxazine Synthesis was performed with reference to Australian journal of chemistry, 9, 397-405 (1956). Specifically, lithium aluminum hydride (3 g) was suspended in tetrahydrofuran (120 mL), and 2H-1,4-benzoxazin-3 (4H) -one (6 g) was added little by little under ice cooling. After heating to reflux for 10 hours, water (3 mL), 15% aqueous sodium hydroxide (3 mL), and water (9 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (4.9239 g) as an orange oil.

Process 3
Preparation of (3-Chloro-4-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-Dihydro-2H-benzo [1,4] oxazine (525 mg ) Was dissolved in chloroform (10 mL), and triethylamine (0.65 mL) and 3-chloro-4-methoxybenzoyl chloride (836 mg) were added under ice cooling. After stirring at room temperature for 12 hours, the reaction solution was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (1.180 g) as a white solid.

Process 4
Preparation of (3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (3-chloro-4-methoxyphenyl)-(2,3-dihydro Benzo [1,4] oxazin-4-yl) -methanone (1.175 g) was dissolved in chloroform (10 mL). Boron tribromide (1.0 M methylene chloride solution, 7.74 mL) was added dropwise at −45 ° C., and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with chloroform. The obtained chloroform layer was washed with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 65: 35) to give the title compound (124 mg) as white crystals.

Example 2
Preparation of (3-bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Production of 3-bromo-4-hydroxybenzoyl chloride 1,3-Dimethoxyethane (30 mL) was added to 3-bromo-4-hydroxybenzoic acid (3.25 g), and the mixture was heated to 80 ° C. to dissolve. Thionyl chloride (1.6 mL) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound (3.6181 g) as a white solid.

Process 2
Preparation of (3-bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro-2H obtained in Step 2 of Example 1 -Benzo [1,4] oxazine (203 mg) and 3-bromo-4-hydroxybenzoyl chloride (353 mg) were dissolved in ethyl acetate (4 mL) and stirred at 95 ° C overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (236.7 mg) as beige crystals.

Example 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Production of 3,5-dichloro-4-hydroxybenzoyl chloride 1,5-Dimethoxyethane (30 mL) was added to 3,5-dichloro-4-hydroxybenzoic acid (1.242 g) and heated to 80 ° C. to dissolve. . Thionyl chloride (0.57 mL) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound (1.358 g) as a white solid.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Example 1 -2H-benzo [1,4] oxazine (135 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (225 mg) were dissolved in ethyl acetate (3.2 mL), and the mixture was stirred at 95 ° C overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (282 mg) as white crystals.

Example 4
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Production of 3,5-dibromo-4-hydroxybenzoyl chloride 1,3-Dimethoxyethane (20 mL) was added to 3,5-dibromo-4-hydroxybenzoic acid (2.96 g), and the mixture was heated to 80 ° C. to dissolve. . Thionyl chloride (1.1 mL) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound (3.1562 g) as a white solid.

Process 2
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Example 1 -2H-benzo [1,4] oxazine (270 mg) and 3,5-dibromo-4-hydroxybenzoyl chloride (629 mg) were dissolved in ethyl acetate (10 mL) and stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (700.9 mg) as pale orange crystals.

Example 5
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone

Process 1
Preparation of 4-hydroxy-3,5-diiodobenzoyl chloride Add 1,2-dimethoxyethane (12 mL) to 4-hydroxy-3,5-diiodobenzoic acid (2.34 g), warm to 80 ° C. and dissolve did. Thionyl chloride (0.66 mL) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound (2.4922 g) as a cream solid.

Process 2
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone 3,4-obtained in Step 2 of Example 1 Dihydro-2H-benzo [1,4] oxazine (406 mg) and 4-hydroxy-3,5-diiodobenzoyl chloride (1.26 g) were dissolved in ethyl acetate (15 mL) and stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (1.2887 g) as pale orange crystals.

Example 6
Preparation of (3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Production of 3,5-difluoro-4-methoxybenzoyl chloride Chloroform (20 mL) was added to 3,5-difluoro-4-methoxybenzoic acid (2 g), and oxalyl chloride (1.87 mL) and N, N were added under ice cooling. -Dimethylformamide (1 drop) was added. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound as an oil.

Process 2
Preparation of (3,5-difluoro-4-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Example 1 -2H-benzo [1,4] oxazine (300 mg) was dissolved in chloroform (6 mL), and triethylamine (0.371 mL) and 3,5-difluoro-4-methoxybenzoyl chloride (459 mg) were added under ice cooling. . After stirring at room temperature for 12 hours, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (709 mg) as an oil.

Process 3
Preparation of (3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (3,5-difluoro-4-methoxyphenyl)-(2 , 3-Dihydrobenzo [1,4] oxazin-4-yl) -methanone (672 mg) was dissolved in methylene chloride (7 mL). After cooling to −78 ° C. and boron tribromide (1.0 M methylene chloride solution, 3.3 mL) was added dropwise, the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into water and extracted with chloroform. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 7: 3) to give the title compound (258 mg) as white crystals.

Example 7
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone

Process 1
Preparation of 4-benzyloxy-3,5-dimethylbenzoyl chloride To 4-benzyloxy-3,5-dimethylbenzoic acid (256 mg), methylene chloride (8 mL) was added, and oxalyl chloride (0.1 mL) was added under ice cooling. N, N-dimethylformamide (1 drop) was added. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound (276.7 mg) as a pale yellow solid.

Process 2
Preparation of (4-benzyloxy-3,5-dimethylphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-obtained in Step 2 of Example 1 Dihydro-2H-benzo [1,4] oxazine (135 mg) was dissolved in methylene chloride (7 mL), and triethylamine (0.17 mL) and 4-benzyloxy-3,5-dimethylbenzoyl chloride (275 mg) were cooled with ice. Was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to give the title compound (378.3 mg) as an oil.

Process 3
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone (4-benzyloxy-3,5-dimethylphenyl)-( 2,3-Dihydrobenzo [1,4] oxazin-4-yl) -methanone (370.1 mg) was dissolved in tetrahydrofuran (10 mL). 7.5% Palladium-carbon (37 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to give the title compound (220.1 mg) as white crystals.

Example 8
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone

Process 1
Preparation of ethyl 4-benzyloxy-3,5-dichlorobenzoate Ethyl 3,5-dichloro-4-hydroxybenzoate (55.64 g) was dissolved in N, N-dimethylformamide (280 mL) and potassium carbonate (42 .56 g) was added. Under ice-cooling, benzyl bromide (36 mL) was added dropwise, and the mixture was stirred at 70 ° C. overnight. After the solvent was distilled off, the reaction solution was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was recrystallized from n-hexane to obtain the title compound (32.45 g). The filtrate was concentrated to obtain the title compound (42.19 g).

Process 2
Production of 4-benzyloxy-3,5-dichlorobenzoic acid Ethyl 4-benzyloxy-3,5-dichlorobenzoate (42.19 g) was dissolved in methanol (70 mL) and tetrahydrofuran (140 mL). Under ice cooling, 2N lithium hydroxide water (130 mL) was added dropwise, and the mixture was stirred overnight at room temperature. A small amount of insoluble matter was removed by filtration, the filtrate was concentrated, water was added, and the mixture was acidified with 1N hydrochloric acid dropwise under ice cooling. The precipitated solid was collected by filtration to give the title compound (34.83 g).

Process 3
Preparation of 4-benzyloxy-3,5-dichlorobenzoyl chloride Chloroform (175 mL) was added to 4-benzyloxy-3,5-dichlorobenzoic acid (34.83 g), and oxalyl chloride (15.3 mL) was cooled with ice. And N, N-dimethylformamide (2 drops) were added. After stirring at room temperature for 4 hours, the insoluble material was removed by filtration, and the filtrate was concentrated and azeotroped with toluene to give the title compound (37.371 g) as a pale yellow solid.

Process 4
Production of 3,4-dihydro-2H-benzo [1,4] thiazine Lithium aluminum hydride (1 g) was suspended in tetrahydrofuran (40 mL), and 4H-benzo [1,4] thiazine-3- under ice cooling. On (2 g) was added in small portions. After heating to reflux for 8 hours, water (1 mL), 15% aqueous sodium hydroxide (1 mL), and water (3 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added, dried and concentrated to give the title compound (1.9181 g) as a yellow oil.

Process 5
Preparation of (4-Benzyloxy-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone 3,4-Dihydro-2H-benzo [1,4] thiazine (1 g) was dissolved in chloroform (19 mL), and triethylamine (1.1 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (2.08 g) were added under ice cooling. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to give the title compound (2.3350 g) as an oil.

Step 6
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone (4-Benzyloxy-3,5-dichlorophenyl)-(2 , 3-Dihydrobenzo [1,4] thiazin-4-yl) -methanone (223.7 mg) was dissolved in toluene (2 mL), and trifluoroacetic acid (2 mL) was added at room temperature. The mixture was heated and stirred at 80 ° C. for 1.5 hours and then concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (101.6 mg) as white crystals.

Example 9
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(1-oxo-2,3-dihydro-1H-1λ ⁴ -benzo [1,4] thiazin-4-yl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(1-oxo-2,3-dihydro-1H-1λ ⁴ -benzo [1,4] thiazin-4-yl) -methanone Process of Example 8 (4-benzyloxy-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone (426 mg) obtained in 5 was dissolved in chloroform (10 mL), Under ice-cooling, 3-chloroperbenzoic acid (171 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the mixture was concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 3) to obtain the title compound (398.4 mg) as a white amorphous.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(1-oxo-2,3-dihydro-1H-1λ ⁴ -benzo [1,4] thiazin-4-yl) -methanone (4-benzyloxy 3,5-dichlorophenyl) - (1-oxo-2,3-dihydro-1H-1 [lambda ⁴ - benzo [1,4] thiazin-4-yl) - dissolved methanone (210.9Mg) in toluene (2 mL) And trifluoroacetic acid (2 mL) was added at room temperature. The mixture was heated and stirred at 80 ° C. for 1.5 hours and then concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (157.5 mg) as pale-water crystals.

Example 10
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone

Process 1
Preparation of (4-Benzyloxy-3,5-dichlorophenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone Example 8 (4-Benzyloxy-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone (496.6 mg) obtained in Step 5 of the above was dissolved in chloroform (15 mL). 3-Chloroperbenzoic acid (597 mg) was added under ice cooling, and the mixture was stirred at room temperature overnight. Insoluble material was removed by filtration, saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the filtrate was concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 2: 1) to give the title compound (363.9 mg) as a white solid.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone (4- Benzyloxy-3,5-dichlorophenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone (245 mg) in toluene (2. 5 mL) and trifluoroacetic acid (2.5 mL) was added at room temperature. The mixture was heated and stirred at 80 ° C. for 2 hours and then concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (112 mg) as white crystals.

Example 11
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanethione

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Example 1 -H-benzo [1,4] oxazine (0.4 g) was dissolved in chloroform (20 mL), and tribenzylamine (0.5 mL) and 4-benzyloxy- obtained in Step 3 of Example 8 under ice-cooling. 3,5-Dichlorobenzoyl chloride (0.947 g) was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to give the title compound (1.0635 g) as a white solid.

Process 2
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanethione (4-benzyloxy-3,5-dichlorophenyl)-(2 , 3-Dihydrobenzo [1,4] oxazin-4-yl) -methanone (400 mg) and Lawesson's reagent (235 mg) were suspended in tetrahydrofuran (3 mL), and the mixture was heated and stirred at 95 ° C. for 2 hours. The reaction solution was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to obtain the title compound (372.4 mg) as an orange amorphous.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanethione (4-benzyloxy-3,5-dichlorophenyl)-(2 , 3-Dihydrobenzo [1,4] oxazin-4-yl) -methanethione (366.8 mg) was dissolved in toluene (4 mL) and trifluoroacetic acid (4 mL) was added at room temperature. The mixture was heated and stirred at 80 ° C. for 2 hours and then concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (84.6 mg) as orange crystals.

Example 12
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 6-methyl-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (0.8 g) was suspended in tetrahydrofuran (50 mL), and 6-methyl-4H- was added under ice cooling. Benzo [1,4] oxazin-3-one (1.76 g) was added in small portions. After heating to reflux for 6 hours, water (0.8 mL), 15% aqueous sodium hydroxide (0.8 mL), and water (2.4 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (1.5719 g) as an orange oil.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-methyl-3,4-dihydro-2H -Benzo [1,4] oxazine (298 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (451 mg) obtained in Step 1 of Example 3 were dissolved in ethyl acetate (7 mL) at 95 ° C. Stir overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (606.4 mg) as pale orange crystals.

Example 13
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 7-methyl-4H-benzo [1,4] oxazin-3-one 2-Amino-5-methylphenol (2.463 g) and benzyltriethylammonium chloride (4.56 g) were suspended in chloroform (50 mL). Then, sodium hydrogen carbonate (13.44 g) and chloroacetyl chloride (1.9 mL) were added under ice cooling, and stirring was continued for 1 hour under ice cooling. Thereafter, the mixture was heated and stirred at 55 ° C. overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (1.7636 g) as an ocher solid.

Process 2
Preparation of 7-methyl-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (0.8 g) was suspended in tetrahydrofuran (50 mL), and 7-methyl-4H— was cooled with ice. Benzo [1,4] oxazin-3-one (1.76 g) was added in small portions. After heating to reflux for 6 hours, water (0.8 mL), 15% aqueous sodium hydroxide (0.8 mL), and water (2.4 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (1.5038 g) as a red-brown oil.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 7-methyl-3,4-dihydro-2H -Benzo [1,4] oxazine (298 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (451 mg) obtained in Step 1 of Example 3 were dissolved in ethyl acetate (7 mL) at 95 ° C. Stir overnight. The reaction solution was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (609.3 mg) as an amorphous white solid.

Example 14
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-chloro-N- (2-hydroxy-6-methylphenyl) -acetamide 2-Amino-3-methylphenol (737 mg) was dissolved in tetrahydrofuran (20 mL), and triethylamine (1 mL) and chloromethane were cooled with ice. Acetyl chloride (0.5 mL) was added and stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate, and the resulting ethyl acetate layer was washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.2217 g) as an ocher solid.

Process 2
Preparation of 5-methyl-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2-hydroxy-6-methylphenyl) -acetamide (1.2217 g) was converted to N, N-dimethylformamide ( 7 mL), and potassium carbonate (0.99 g) and sodium iodide (catalytic amount) were added at room temperature. After stirring at 80 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid and water, subsequently washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (813.5 mg) as a pale yellow solid.

Process 3
Preparation of 5-methyl-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (0.4 g) was suspended in tetrahydrofuran (40 mL), and 5-methyl-4H- Benzo [1,4] oxazin-3-one (810 mg) was added in small portions. After heating to reflux for 7 hours, water (0.4 mL), 15% aqueous sodium hydroxide (0.4 mL), and water (1.2 mL) were sequentially added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (471.7 mg) as a red-brown oil.

Process 4
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 5-methyl-3,4-dihydro-2H -Benzo [1,4] oxazine (224 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (338 mg) obtained in Step 1 of Example 3 were dissolved in ethyl acetate (3.5 mL) and treated at 95 ° C. At rt overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (331.9 mg) as gray crystals.

Example 15
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 4-bromo-2-methylphenol o-Cresol (5 g) was dissolved in acetic acid (50 mL) and 48% aqueous hydrogen bromide (25 mL), and dimethyl sulfoxide (25 mL) was added dropwise at room temperature. After stirring at room temperature for 1 hour, the reaction solution was neutralized with sodium carbonate. Water was added and extracted with ethyl ether. The obtained ethyl ether layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, it was used in the next step without purification.

Process 2
Preparation of 4-bromo-2-methyl-6-nitrophenol To a mixture of 4-bromo-2-methylphenol and sodium nitrite (10.4 g) prepared in Step 1, n-hexane (75 mL) and isopropyl ether ( 35 mL) and water (50 mL) were added, and 4.5 N sulfuric acid (110 mL) was added dropwise at room temperature. After stirring at room temperature for 15 hours, the reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to obtain the title compound (7.14 g) as a yellow solid.

Process 3
Preparation of 2-amino-6-methylphenol hydrobromide 4-Bromo-2-methyl-6-nitrophenol (7.1 g) was dissolved in methanol (50 mL). 7.5% Palladium-carbon (1.5 g) was added to this solution to form a hydrogen atmosphere (2 kgf / cm ² ), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through celite and then concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to give the title compound (5.40 g) as a brown solid.

Process 4
Preparation of 2-chloro-N- (2-hydroxy-3-methylphenyl) -acetamide 2-Amino-6-methylphenol hydrobromide (408 mg) was suspended in tetrahydrofuran (10 mL) and triethylamine was cooled with ice. (0.7 mL) and chloroacetyl chloride (0.17 mL) were added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate, and the resulting ethyl acetate layer was washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (384.6 mg) as a dark brown solid.

Process 5
Preparation of 8-methyl-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2-hydroxy-3-methylphenyl) -acetamide (380 mg) N, N-dimethylformamide (4 mL) And potassium carbonate (315 mg) and sodium iodide (catalytic amount) were added at room temperature. After stirring at 80 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid and water, subsequently washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (284.3 mg) as a red brown solid.

Step 6
Preparation of 8-methyl-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (150 mg) was suspended in tetrahydrofuran (25 mL), and 8-methyl-4H-benzo [ 1,4] Oxazin-3-one (280 mg) was added in small portions. After heating to reflux for 7 hours, water (0.15 mL), 15% aqueous sodium hydroxide (0.15 mL), and water (0.45 mL) were sequentially added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (145.2 mg) as a red-brown oil.

Step 7
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 8-methyl-3,4-dihydro-2H -Benzo [1,4] oxazine (116.3 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (176 mg) obtained in Step 1 of Example 3 were dissolved in ethyl acetate (2 mL) and treated at 95 ° C. At rt overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (121.3 mg) as pale brown crystals.

Example 16
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone

Process 1
Preparation of 2-chloro-N- (2-hydroxynaphthalen-1-yl) -acetamide 1-aminonaphthalen-2-ol hydrochloride (1.1739 g) was suspended in tetrahydrofuran (20 mL) and triethylamine was cooled with ice. (2 mL) and chloroacetyl chloride (0.5 mL) were added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate, and the resulting ethyl acetate layer was washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.227 g) as a dark brown solid.

Process 2
Preparation of 1H-naphtho [2,1-b] [1,4] oxazin-2-one 2-Chloro-N- (2-hydroxynaphthalen-1-yl) -acetamide (1.22 g) was converted to N, N- Dissolved in dimethylformamide (10 mL), potassium carbonate (860 mg) and sodium iodide (catalytic amount) were added at room temperature. After stirring at 80 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid and water, subsequently washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.0553 g) as a dark brown solid.

Process 3
Preparation of 2,3-dihydro-1H-naphtho [2,1-b] [1,4] oxazine Lithium aluminum hydride (400 mg) was suspended in tetrahydrofuran (40 mL), and 1H-naphtho [2] under ice cooling. , 1-b] [1,4] oxazin-2-one (1.055 g) was added in small portions. After heating to reflux for 7 hours, water (0.4 mL), 15% aqueous sodium hydroxide (0.4 mL), and water (1.2 mL) were sequentially added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (361.4 mg) as a dark brown oil.

Process 4
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone 2,3-dihydro-1H- Naphtho [2,1-b] [1,4] oxazine (185 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (225 mg) obtained in Step 1 of Example 3 were dissolved in ethyl acetate (3 mL). And stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (334.5 mg) as gray crystals.

Example 17
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-amino-4-methoxyphenol 4-Methoxy-2-nitrophenol (3.38 g) was dissolved in tetrahydrofuran (100 mL). 7.5% Palladium-carbon (0.34 g) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washings were combined and concentrated under reduced pressure to give the title compound (2.8528 g) as a beige solid.

Process 2
Preparation of 6-methoxy-4H-benzo [1,4] oxazin-3-one 2-Amino-4-methoxyphenol (2.85 g) and benzyltriethylammonium chloride (4.56 g) were suspended in chloroform (50 mL). Then, sodium hydrogen carbonate (6.72 g) and chloroacetyl chloride (1.9 mL) were added under ice cooling, and stirring was continued for 1 hour under ice cooling. Thereafter, the mixture was heated and stirred at 55 ° C. overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (1.3884 g) as a pale orange solid. The mother liquor was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to obtain the title compound (151 mg) as a white solid.

Process 3
Preparation of 6-methoxy-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (700 mg) was suspended in tetrahydrofuran (50 mL), and 6-methoxy-4H-benzo [ 1,4] Oxazin-3-one (1.53 g) was added in small portions. After heating under reflux for 6 hours, water (0.7 mL), 15% aqueous sodium hydroxide (0.7 mL), and water (2.1 mL) were successively added under ice cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to obtain the title compound (1.3294 g) as a pale yellow solid.

Process 4
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-methoxy-3,4-dihydro-2H -Benzo [1,4] oxazine (600 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (818 mg) obtained in Step 1 of Example 3 were dissolved in ethyl acetate (14 mL) at 95 ° C. Stir overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (1.059 g) as white crystals.

Example 18
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-amino-5-methoxyphenol 5-Methoxy-2-nitrophenol (1.059 g) was dissolved in tetrahydrofuran (30 mL). 7.5% Palladium-carbon (0.1 g) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washings were combined and concentrated under reduced pressure to give the title compound (0.9615 g) as a pale orange solid.

Process 2
Preparation of 2-chloro-N- (2-hydroxy-4-methoxyphenyl) -acetamide 2-Amino-5-methoxyphenol (0.96 g) was dissolved in tetrahydrofuran (35 mL), and triethylamine (1. 15 mL) and chloroacetyl chloride (0.58 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound. (1.5106 g) was obtained as a bright yellow solid.

Process 3
Preparation of 7-methoxy-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2-hydroxy-4-methoxyphenyl) -acetamide (1.51 g) was converted to N, N-dimethylformamide ( 7 mL), and potassium carbonate (1.04 g) and sodium iodide (catalytic amount) were added at room temperature. After stirring at 80 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid and water, subsequently washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained solid was crystallized from ethyl acetate to give the title compound (682.6 mg) as a bright yellow solid.

Process 4
Preparation of 7-methoxy-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (300 mg) was suspended in tetrahydrofuran (20 mL), and 7-methoxy-4H-benzo [ 1,4] Oxazin-3-one (680 mg) was added in small portions. After heating to reflux for 6 hours, water (0.3 mL), 15% aqueous sodium hydroxide (0.3 mL), and water (0.9 mL) were sequentially added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 2: 1) to give the title compound (588.1 mg) as a red-brown oil.

Process 5
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 7-methoxy-3,4-dihydro-2H -Benzo [1,4] oxazine (367.6 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (496 mg) obtained in Step 1 of Example 3 were dissolved in ethyl acetate (4 mL) and treated at 95 ° C. At rt overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (518.2 mg) as mauve crystals.

Example 19
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone obtained in Step 4 of Example 17 ( 3,5-Dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (500 mg) was dissolved in methylene chloride (10 mL). After cooling to −78 ° C., boron tribromide (1.0 M methylene chloride solution, 2.1 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 10: 1) to obtain the title compound (157.6 mg) as a pale water crystal.

Example 20
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone obtained in Step 5 of Example 18 ( 3,5-Dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (504 mg) was dissolved in methylene chloride (10 mL). After cooling to −78 ° C., boron tribromide (1.0 M methylene chloride solution, 4.2 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, and the precipitated solid was collected by filtration. The solid collected by filtration was purified by silica gel chromatography (chloroform-methanol = 30: 1) to obtain the title compound (355.7 mg) as white crystals.

Example 21
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide

Process 1
Preparation of 3-amino-N, N-diethyl-4-hydroxybenzenesulfonamide 3-Amino-N, N-diethyl-4-methoxybenzenesulfonamide (5 g) was dissolved in methylene chloride (150 mL). Under ice-cooling, boron tribromide (1.0 M methylene chloride solution, 38.7 mL) was added dropwise, and the mixture was stirred at room temperature overnight. Water (150 mL) was added dropwise to the reaction solution under ice cooling, and the aqueous layer was washed with chloroform. To the obtained aqueous layer, 4N aqueous sodium hydroxide was added under ice cooling to make it weakly acidic. The precipitated solid was collected by filtration to give the title compound (4.0344 g) as a light beige solid.

Process 2
Preparation of 3-amino-4- (tert-butyldimethylsilyloxy) -N, N-diethylbenzenesulfonamide 3-amino-N, N-diethyl-4-hydroxybenzenesulfonamide (1.5 g) was converted to N, N- Dissolved in dimethylformamide (8 mL), imidazole (0.61 g) and tert-butylchlorodimethylsilane (1.18 g) were added under ice cooling. The mixture was stirred at room temperature for 1.5 hours, poured into water and extracted with ethyl ether. The obtained ethyl ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 7: 1) to give the title compound (2.0654 g) as a white solid.

Process 3
Preparation of 4-benzyloxy-3,5-dichloro-N- (5-diethylsulfamoyl-2-hydroxyphenyl) -benzamide 3-amino-4- (tert-butyldimethylsilyloxy) -N, N-diethylbenzene Sulfonamide (1.5 g) was dissolved in methylene chloride (40 mL), and benzyl (0.41 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride obtained in Step 3 of Example 8 under ice-cooling. (1.32 g) was added and stirred at room temperature overnight. After the solvent was distilled off, the residue was dissolved in N, N-dimethylformamide (5 mL), and potassium carbonate (2.89 g) was added at room temperature. After stirring with heating at 60 ° C. for 1.5 hours, the mixture was acidified by adding water and a 10% aqueous citric acid solution under ice cooling. The precipitated solid was collected by filtration to give the title compound (2.1455 g) as a cream solid.

Process 4
Preparation of 4- (4-benzyloxy-3,5-dichlorobenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide 4-Benzyloxy-3,5-dichloro- N- (5-diethylsulfamoyl-2-hydroxyphenyl) -benzamide (2.136 g) is dissolved in N, N-dimethylformamide (40 mL) and potassium carbonate (1.41 g) and 1,2- Dibromoethane (0.42 mL) was added. After stirring at 70 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 2) to obtain the title compound (1.6181 g) as a white amorphous.

Process 5
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide 4- (4-benzyloxy-3,5- Dichlorobenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide (1.6151 g) was dissolved in tetrahydrofuran (70 mL). 7.5% Palladium-carbon (0.16 g) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl ether to give the title compound (1.2863 g) as white crystals.

Example 22
Preparation of 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-sulfonyl) phenol 3,4-Dihydro-2H-benzo [1 obtained in Step 2 of Example 1 , 4] oxazine (246 mg) and 3,5-dichloro-4-hydroxybenzenesulfonyl chloride (475 mg) were dissolved in chloroform (8 mL) and stirred at room temperature overnight. The reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 2: 1) to give the title compound (146.8 mg) as beige crystals.

Example 23
Preparation of (6-tert-butyl-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone In the same manner as in Example 14, The title compound (539.6 mg) was obtained as white crystals by using 2-amino-4-tert-butylphenol instead of 2-amino-3-methylphenol.

Example 24
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -4H-benzo [1,4] oxazin-3-one

Process 1
Preparation of 4- (4-benzyloxy-3,5-dichlorobenzoyl) -4H-benzo [1,4] oxazin-3-one 4H-benzo [1,4] oxazin-3-one (224 mg) was added to tetrahydrofuran (224 mg). 10 mL), and 60% sodium hydride (78 mg) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (473 mg) obtained in Step 3 of Example 8 were sequentially added under ice-cooling and stirring at room temperature. Stir overnight. Water was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to give the title compound (294.3 mg) as a yellow solid.

Process 2
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -4H-benzo [1,4] oxazin-3-one 4- (4-Benzyloxy-3,5-dichlorobenzoyl) -4H-benzo [ 1,4] oxazin-3-one (290 mg) was dissolved in tetrahydrofuran (12 mL). 7.5% Palladium-carbon (29 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to give the title compound (176.8 mg) as yellow crystals.

Example 25
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid amide A method similar to steps 2-5 of Example 21 Used 3-amino-4-hydroxybenzenesulfonamide instead of 3-amino-N, N-diethyl-4-hydroxybenzenesulfonamide to give the title compound (160.6 mg) as white crystals.

Example 26
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone 1,2,3,4-tetrahydroquinoline (147 mg) in chloroform (6 mL) Then, triethylamine (0.18 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (347 mg) obtained in Step 3 of Example 8 were added under ice cooling. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to obtain the title compound (407.9 mg) as a white amorphous.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)-(3,4 Dihydro-2H-quinolin-1-yl) -methanone (398.7 mg) was dissolved in tetrahydrofuran (12 mL). 7.5% Palladium-carbon (40 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to give the title compound (267.4 mg) as white crystals.

Example 27
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone

Process 1
Preparation of 2,3,4,5-tetrahydro-1H-benzo [b] azepine Lithium aluminum hydride (100 mg) was suspended in tetrahydrofuran (10 mL), and 1,3,4,5-tetrahydrobenzoic acid was cooled with ice. [B] Azepin-2-one (245 mg) was added in small portions. After heating under reflux for 5.5 hours, water (0.1 mL), 15% aqueous sodium hydroxide (0.1 mL) and water (0.3 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added, dried and concentrated to give the title compound (301.6 mg) as a yellow oil.

Process 2
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone 2,3,4,5-tetrahydro-1H-benzo [B] Azepine (301 mg) was dissolved in methylene chloride (10 mL), and tribenzylamine (0.25 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride obtained in Step 3 of Example 8 under ice-cooling. (480 mg) was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to give the title compound (531.9 mg) as a yellow-green oil.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)- (2,3,4,5-Tetrahydrobenzo [b] azepin-1-yl) -methanone (530 mg) was dissolved in tetrahydrofuran (15 mL). 7.5% Palladium-carbon (53 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to give the title compound (259.6 mg) as white crystals.

Example 28
Preparation of (4-amino-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro-obtained in Step 2 of Example 1 2H-benzo [1,4] oxazine (270 mg), 4-amino-3,5-dichlorobenzoic acid (412 mg) and N, N-dimethylaminopyridine (269 mg) were dissolved in chloroform (8 mL), and ice-cooled. WSC · HCl (422 mg) was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to obtain the title compound (412.5 mg) as bright yellow crystals.

Example 29
Preparation of (5-chloro-6-hydroxypyridin-3-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4 obtained in step 2 of example 1 -Dihydro-2H-benzo [1,4] oxazine (270 mg), 5-chloro-6-hydroxynicotinic acid (347 mg) and 4-dimethylaminopyridine (269 mg) were dissolved in chloroform (12 mL), and ice-cooled. WSC · HCl (422 mg) was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (chloroform-methanol = 20: 1) to obtain the title compound (295.7 mg) as cream crystals.

Example 30
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dinitrophenyl) -methanone

Process 1
Production of 4-hydroxy-3,5-dinitrobenzoyl chloride 1,4-Dimethoxyethane (5 mL) was added to 4-hydroxy-3,5-dinitrobenzoic acid (1 g), and the mixture was heated to 70 ° C. and dissolved. Thionyl chloride (0.415 mL) was added, and the mixture was stirred at 70 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound as a yellow solid.

Process 2
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dinitrophenyl) -methanone 3,4-dihydro obtained in step 2 of example 1 -2H-benzo [1,4] oxazine (135 mg) and 4-hydroxy-3,5-dinitrobenzoyl chloride (271 mg) were dissolved in ethyl acetate (4 mL) and heated to reflux for 3 hours. The solvent was distilled off, and the obtained solid was crystallized from methanol to give the title compound (211 mg) as pale yellow crystals.

Example 31
Preparation of (3-chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of methyl 3-chloro-4-methoxy-5-nitrobenzoate Concentrated sulfuric acid (200 mL) was added to methyl 3-chloro-4-methoxybenzoate (24.6 g) under ice-cooling, followed by fuming. A mixture of nitric acid (10.3 mL) and concentrated sulfuric acid (20 mL) was added dropwise under ice cooling. After stirring under ice cooling, the reaction solution was poured into ice water (1 L). The precipitated solid was collected by filtration to give the title compound (28.8 g) as a cream solid.

Process 2
Preparation of 3-chloro-4-hydroxy-5-nitrobenzoic acid Methyl 3-chloro-4-methoxy-5-nitrobenzoate (28.8 g) was suspended in dimethyl sulfoxide (130 mL) and under ice cooling, 50% aqueous potassium hydroxide (130 mL) was added. After stirring with heating at 80 ° C. for 1.5 hours, the mixture was ice-cooled, and 6N hydrochloric acid (200 mL) and water were added. The mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained solid was crystallized from n-hexane to obtain the title compound (21.3 g) as a lemon-colored solid.

Process 3
Preparation of 3-chloro-4-hydroxy-5-nitrobenzoyl chloride 1,2-Dimethoxyethane (5 mL) was added to 3-chloro-4-hydroxy-5-nitrobenzoic acid (1 g) and heated to 70 ° C. Dissolved. Thionyl chloride (0.436 mL) was added, and the mixture was stirred at 70 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound (1.10 g) as a yellow solid.

Process 4
Preparation of (3-chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4 obtained in step 2 of example 1 -Dihydro-2H-benzo [1,4] oxazine (270 mg) and 3-chloro-4-hydroxy-5-nitrobenzoyl chloride (519 mg) were dissolved in ethyl acetate (6 mL) and stirred at 95 ° C overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (537 mg) as yellow crystals.

Example 32
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 4-bromo-2-isopropylphenol 2-Isopropylphenol (25 g) was dissolved in acetic acid (250 mL) and 48% aqueous hydrogen bromide (125 mL), and dimethyl sulfoxide (125 mL) was added dropwise at room temperature. After stirring at room temperature for 2 hours, sodium carbonate (257 g) was added to the reaction solution to neutralize it. Water was added and extracted with ethyl ether. The obtained ethyl ether layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (40.2 g) as a pale yellow solid.

Process 2
Preparation of 4-bromo-2-isopropyl-6-nitrophenol To a mixture of 4-bromo-2-isopropylphenol (40.2 g) and sodium nitrite (41.5 g) prepared in Step 1, n-hexane (300 mL) ), Isopropyl ether (130 mL) and water (200 mL) were added, and 4.5N sulfuric acid (430 mL) was added dropwise at room temperature. After stirring for 1 hour at room temperature, the reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 20: 1) to obtain the title compound (41.1 g) as a yellow oil.

Process 3
Preparation of 2-amino-6-isopropylphenol hydrobromide 4-Bromo-2-isopropyl-6-nitrophenol (41.1 g) was dissolved in methanol (300 mL). 7.5% Palladium-carbon (8 g) was added to this solution to form a hydrogen atmosphere (2 kgf / cm ² ), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting solid was crystallized from ethyl acetate to give the title compound (27.4 g) as a beige solid.

Process 4
Preparation of 2-bromo-3-methylbutyryl chloride Chloroform (200 mL) was added to 2-bromo-3-methylbutyric acid (25 g), and oxalyl chloride (14.5 mL) and N, N-dimethylformamide ( 3 drops) was added. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound as a yellow oil.

Process 5
Preparation of 2-bromo-N- (2-hydroxy-3-isopropylphenyl) -3-methylbutyramide 2-amino-6-isopropylphenol hydrobromide obtained in Step 3 (6.14 g) was mixed with acetic acid. Ethyl (70 mL) and water (80 mL) were added and dissolved, and then sodium bicarbonate (6.68 g) and 2-bromo-3-methylbutyryl chloride (5.80 g) obtained in Step 4 were added at room temperature. Stir at room temperature for 2 hours. The reaction mixture was separated, and the obtained ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (9.0 g ) Was obtained as a pale pink solid.

Step 6
Preparation of 2,8-diisopropyl-4H-benzo [1,4] oxazin-3-one 2-Bromo-N- (2-hydroxy-3-isopropylphenyl) -3-methylbutyramide (9.0 g) , N-dimethylformamide (45 mL), potassium carbonate (4.94 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N hydrochloric acid, water was added, and the precipitated solid was collected by filtration. The obtained solid was crystallized from n-hexane-isopropyl ether to give the title compound (4.5 g) as a white solid.

Step 7
Preparation of 2,8-diisopropyl-3,4-dihydro-2H-benzo [1,4] oxazine 2,8-diisopropyl-4H-benzo [1,4] oxazin-3-one (1.0 g) was added to tetrahydrofuran (1.0 g). 10 mL), added borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 5.14 mL), and heated to reflux for 14.5 hours. 6N hydrochloric acid (5 mL) was added, and the mixture was heated and stirred again. The mixture was allowed to cool to room temperature, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to obtain the title compound (768 mg) as a colorless oil.

Process 8
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 2,8-diisopropyl-3,4 -Dihydro-2H-benzo [1,4] oxazine (150 mg) was dissolved in chloroform (5 mL), and 4-benzyloxy- obtained in Step 3 of Example 8 with pyridine (0.066 mL) under ice-cooling. 3,5-Dichlorobenzoyl chloride (227 mg) was added. After stirring overnight at room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to obtain the title compound (375 mg) as an oil.

Step 9
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (4-benzyloxy-3,5 -Dichlorophenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (370 mg) was dissolved in tetrahydrofuran (5 mL). 7.5% Palladium-carbon (70 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from n-hexane to give the title compound (212 mg) as white crystals.

Example 33
Preparation of (3,5-dichloro-4-hydroxyphenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone

Process 1
Production of 4-methoxy-3-nitrobenzenesulfonyl chloride 1-Methoxy-2-nitrobenzene (11 mL) was added dropwise to chlorosulfonic acid (25 mL) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice water and extracted with ethyl ether. The resulting ethyl ether layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (15.527 g) as a reddish brown oil. Obtained as a thing.

Process 2
Preparation of 1- (4-methoxy-3-nitrobenzenesulfonyl) pyrrolidine 4-Methoxy-3-nitrobenzenesulfonyl chloride (5.1353 g) was dissolved in pyridine (17 mL), and pyrrolidine (2.05 g) was added under ice cooling. And stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was poured into water, extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 1) to obtain the title compound (4.158 g) as a yellow solid.

Process 3
Preparation of 2-nitro-4- (pyrrolidine-1-sulfonyl) phenol 1- (4-Methoxy-3-nitrobenzenesulfonyl) pyrrolidine (2.054 g) was dissolved in dimethyl sulfoxide (40 mL), and the mixture was ice-cooled. 50% aqueous potassium hydroxide (40 mL) was added. After stirring with heating at 80 ° C. for 6 hours, the mixture was cooled with ice and 6N hydrochloric acid (80 mL) was added. The mixture was extracted with chloroform, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (2.198 g) as a yellow solid.

Process 4
Preparation of 2-amino-4- (pyrrolidine-1-sulfonyl) phenol 2-Nitro-4- (pyrrolidine-1-sulfonyl) phenol (2.19 g) was dissolved in tetrahydrofuran (50 mL). 7.5% Palladium-carbon (0.2 g) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 1) to obtain the title compound (1.5494 g) as a cream solid.

Process 5
Preparation of 2- (tert-butyldimethylsilyloxy) -5- (pyrrolidine-1-sulfonyl) phenylamine 2-amino-4- (pyrrolidine-1-sulfonyl) phenol (1.54 g) was converted to N, N-dimethylformamide. (9 mL) was dissolved, and imidazole (0.649 g) and tert-butylchlorodimethylsilane (1.254 g) were added under ice cooling. The mixture was stirred at room temperature for 1.5 hours, poured into water and extracted with ethyl ether. The obtained ethyl ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 7: 1) to give the title compound (2.1549 g) as a white solid.

Step 6
Preparation of 4-benzyloxy-3,5-dichloro-N- [2-hydroxy-5- (pyrrolidine-1-sulfonyl) phenyl] benzamide 2- (tert-butyldimethylsilyloxy) -5- (pyrrolidine-1- (Sulfonyl) phenylamine (727.8 mg) was dissolved in methylene chloride (17 mL), and 4-benzyloxy-3,5-dichloro obtained in Step 3 of Example 8 with pyridine (0.2 mL) under ice-cooling. Benzoyl chloride (644 mg) was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in N, N-dimethylformamide (4 mL), and potassium carbonate (1.41 g) was added at room temperature. After stirring with heating at 60 ° C. for 1.5 hours, the mixture was acidified by adding water and a 10% aqueous citric acid solution under ice cooling. The precipitated solid was collected by filtration to give the title compound (1.0619 g) as a cream solid.

Step 7
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone 4-Benzyloxy- 3,5-Dichloro-N- [2-hydroxy-5- (pyrrolidine-1-sulfonyl) phenyl] benzamide (500 mg) was dissolved in N, N-dimethylformamide (5 mL) and potassium carbonate (332 mg) was dissolved at room temperature. 1,2-Dibromoethane (0.099 mL) was added. After stirring at 70 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 2: 1) to obtain the title compound (459.5 mg) as a white amorphous.

Process 8
Preparation of (3,5-dichloro-4-hydroxyphenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone (4-benzyloxy -3,5-dichlorophenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone (442.5 mg) dissolved in tetrahydrofuran (20 mL) did. 7.5% Palladium-carbon (45 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 1) to obtain the title compound (384.5 mg) as an amorphous white solid.

Example 34
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid ethylamide Method similar to steps 2-8 of Example 33 Gave the title compound (341.8 mg) as an amorphous white solid using ethylamine instead of pyrrolidine.

Example 35
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid dimethylamide Similar to steps 2 to 8 of Example 33 The method gave the title compound (379.2 mg) as an amorphous white solid using dimethylamine instead of pyrrolidine.

Example 36
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone

Process 1
Production of 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine Lithium aluminum hydride (2 g) was suspended in tetrahydrofuran (80 mL), and 4H-pyrido [3 , 2-b] [1,4] oxazin-3-one (3.956 g) was added in small portions. After heating under reflux for 2 hours, water (2 mL), 15% aqueous sodium hydroxide (2 mL) and water (6 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added and dried. The solvent was distilled off, and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 9) to obtain the title compound (3.407 g) as a white solid.

Process 2
Preparation of (4-Benzyloxy-3,5-dichlorophenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone 3,4-Dihydro-2H-pyrido [3,2-b] [1,4] oxazine (272 mg) was dissolved in chloroform (15 mL), and tribenzylamine (0.335 mL) and 4-benzyloxy obtained in Step 3 of Example 8 under ice-cooling. −3,5-Dichlorobenzoyl chloride (662 mg) was added. After stirring at room temperature for 12 hours, the reaction solution was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (646 mg) as a white solid.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone (4-Benzyloxy-3,5 -Dichlorophenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone (415 mg) was dissolved in tetrahydrofuran (10 mL). 7.5% Palladium-carbon (40 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate-tetrahydrofuran to give the title compound (266 mg) as white crystals.

Example 37
Preparation of 5- (3,5-dichloro-4-hydroxybenzoyl) -1,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-2-one

Process 1
Preparation of 1,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-2-one Polyphosphoric acid (1.5 g) with acrylic acid (8.6 g) and benzene-1,2-diamine (5 .4g) was added and heated to reflux for 3 hours. Water (100 mL), chloroform (200 mL) and N, N-dimethylformamide (50 mL) were added to the reaction solution, and the mixture was extracted with chloroform. The obtained chloroform layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 4) to obtain the title compound (490 mg).

Process 2
Preparation of 5- (3,5-dichloro-4-hydroxybenzoyl) -1,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-2-one 1,3,4,5-tetrahydrobenzo [B] [1,4] diazepin-2-one (194.4 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (177.99 mg) obtained in Step 1 of Example 3 were mixed with ethyl acetate (3 mL). And heated and stirred at 95 ° C. for 12 hours. The reaction mixture was purified by silica gel chromatography to give the title compound (118 mg) as white crystals.

Example 38
Preparation of (3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 3,5-dichloro-2-hydroxybenzoyl chloride 3,5-Dichloro-2-hydroxybenzoic acid (600 mg) was suspended in toluene (6 mL), thionyl chloride (0.275 mL) and N, N-dimethyl. Formamide (1 drop) was added. After stirring with heating at 70 ° C. for 2 hr, the mixture was concentrated and azeotroped with toluene to give the title compound as a pale yellow solid.

Process 2
Preparation of (3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Example 1 -2H-benzo [1,4] oxazine (391.7 mg) and 3,5-dichloro-2-hydroxybenzoyl chloride obtained in the previous step were dissolved in ethyl acetate (6 mL) and heated at 90 ° C. for 1 hour. Stir. Ethyl acetate (6 mL) was added to the reaction mixture, and the mixture was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 85: 15) to obtain the title compound (457 mg) as pale yellow crystals.

Example 39
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone

Process 1
Preparation of 4-hydroxy-3-trifluoromethylbenzoyl chloride 4-hydroxy-3-trifluoromethylbenzoic acid (610 mg) was suspended in toluene (6 mL), thionyl chloride (0.28 mL) and N, N-dimethyl. Formamide (1 drop) was added. After stirring with heating at 70 ° C. for 2 hours, the mixture was concentrated and azeotroped with toluene to give the title compound.

Process 2
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone 3,4-dihydro obtained in step 2 of example 1 -2H-benzo [1,4] oxazine (400 mg) and 4-hydroxy-3-trifluoromethylbenzoyl chloride obtained in the previous step were dissolved in ethyl acetate (6 mL), and the mixture was heated and stirred at 90 ° C for 1 hour. . Ethyl acetate was added to the reaction mixture, which was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained solid was crystallized from ethyl acetate to give the title compound (359 mg) as crystals.

Example 40
Preparation of (3-chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 3-chloro-4-hydroxy-5-methoxybenzoyl chloride 3-Chloro-4-hydroxy-5-methoxybenzoic acid (598 mg) was suspended in toluene (6 mL), thionyl chloride (0.28 mL) and N , N-dimethylformamide (1 drop) was added. After stirring with heating at 70 ° C. for 2 hours, the mixture was concentrated and azeotroped with toluene to give the title compound.

Process 2
Preparation of (3-chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4 obtained in Step 2 of Example 1 -Dihydro-2H-benzo [1,4] oxazine (400 mg) and 3-chloro-4-hydroxy-5-methoxybenzoyl chloride obtained in the previous step were dissolved in ethyl acetate (6 mL), and 1 at 90 ° C. Stir for hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained solid was crystallized from ethyl acetate to give the title compound (428 mg) as crystals.

Example 41
Preparation of (4-chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 4-chloro-3-hydroxybenzoyl chloride 4-Chloro-3-hydroxybenzoic acid (510 mg) was suspended in toluene (6 mL), thionyl chloride (0.28 mL) and N, N-dimethylformamide (1 drop). ) Was added. After stirring with heating at 70 ° C. for 2 hours, the mixture was concentrated and azeotroped with toluene to give the title compound.

Process 2
Preparation of (4-chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro-2H obtained in step 2 of Example 1 -Benzo [1,4] oxazine (400 mg) and 4-chloro-3-hydroxybenzoyl chloride obtained in the previous step were dissolved in ethyl acetate (6 mL), and the mixture was heated and stirred at 90 ° C for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained solid was crystallized from ethyl acetate to give the title compound (583 mg) as crystals.

Example 42
Preparation of (2,6-dichloropyridin-4-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Example 1 -2H-benzo [1,4] oxazine (270 mg), 2,6-dichloroisonicotinic acid (384 mg) and 4-dimethylaminopyridine (269 mg) were dissolved in chloroform (12 mL), and WSC · HCl was cooled under ice cooling. (422 mg) was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (419.8 mg) as pale yellow crystals.

Example 43
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-nitrophenyl) -methanone 3,4-dihydro-2H-benzo [1 obtained in Step 2 of Example 1 , 4] oxazine (135 mg) and 4-nitrobenzoyl chloride (185 mg) were dissolved in ethyl acetate (3 mL), and the mixture was heated and stirred at 95 ° C. overnight. The reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to give the title compound (288.1 mg) as a yellow solid.

Example 44
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 6-fluoro-3,4-dihydro-2H-benzo [1,4] oxazine 6-fluoro-4H-benzo [1,4] oxazin-3-one (1.5 g) was dissolved in tetrahydrofuran (20 mL). Borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 11 mL) was added under ice cooling, and the mixture was stirred at room temperature overnight. 6N hydrochloric acid (5 mL) was added, and the mixture was heated with stirring at 70 ° C. The mixture was allowed to cool to room temperature, made weak alkaline by adding 4N aqueous sodium hydroxide and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (954 mg) as an oil.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-fluoro-3,4-dihydro-2H -Benzo [1,4] oxazine (230 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (338 mg) obtained in Step 1 of Example 3 were dissolved in ethyl acetate (3.5 mL) and treated at 95 ° C. At rt overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (374.9 mg) as pale beige crystals.

Example 45
Preparation of 2- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid 3,4-dihydro-2H-benzo [1,4] oxazine obtained in Step 2 of Example 1 ( 300 mg) and phthalic anhydride (329 mg) were dissolved in toluene (3 mL) and heated to reflux for 4 hours. The reaction mixture was allowed to cool, and the precipitated solid was collected by filtration to give the title compound (519 mg) as crystals.

Example 46
Preparation of methyl 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate 3,4-dihydro-2H-benzo [1,4] oxazine obtained in Step 2 of Example 1 (154 mg) was dissolved in chloroform (6 mL), and triethylamine (0.18 mL) and methyl 4-chlorocarbonylbenzoate (226 mg) were added under ice cooling. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 7: 2) to give the title compound (287.4 mg) as a pale orange solid.

Example 47
Preparation of 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl obtained in Example 46 ) Methyl benzoate (283 mg) was dissolved in methanol (10 mL) and tetrahydrofuran (5 mL), and 4N aqueous lithium hydroxide (1.5 mL) was added. After stirring overnight at room temperature, the reaction solution was concentrated under reduced pressure, and the residue was acidified with 1N hydrochloric acid under ice cooling. The precipitated solid was collected by filtration to give the title compound (207.6 mg) as a white solid.

Example 48
Preparation of methyl 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate

Process 1
Production of methyl 3-chlorocarbonylbenzoate Chloroform (5 mL) was added to isophthalic acid monomethyl ester (198 mg), and oxalyl chloride (0.12 mL) and N, N-dimethylformamide (1 drop) were added under ice cooling. After stirring at room temperature for 7 hours, it was concentrated and azeotroped with toluene to give the title compound.

Process 2
Preparation of methyl 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate 3,4-dihydro-2H-benzo [1,4] oxazine obtained in Step 2 of Example 1 (154 mg) was dissolved in chloroform (6 mL), and triethylamine (0.18 mL) and methyl 3-chlorocarbonylbenzoate obtained in the previous step were added under ice cooling. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to obtain the title compound (323.7 mg) as a white solid.

Example 49
Preparation of 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid 3- (2,3-dihydrobenzo [1,4] oxazine-obtained in Step 2 of Example 48 Methyl 4-carbonyl) benzoate (293 mg) was dissolved in methanol (10 mL) and tetrahydrofuran (5 mL), and 4N aqueous lithium hydroxide (1.5 mL) was added. After stirring overnight at room temperature, the reaction solution was concentrated under reduced pressure, and the residue was acidified with 1N hydrochloric acid under ice cooling. The precipitated solid was collected by filtration, and the obtained solid was purified by silica gel chromatography (chloroform-methanol = 10: 1) to obtain the title compound (71.8 mg) as an amorphous white solid.

Example 50
Preparation of (3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Production of 3,5-dichloro-2,4-dihydroxybenzoic acid 2,4-Dihydroxybenzoic acid (25.0 g) was dissolved in ethyl acetate (400 mL), and hypochlorous acid tert-butyl ester ( 61.9 g) was added dropwise and stirred for 2 hours. The reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was crystallized from ethyl ether-n-hexane to give the title compound (11.88 g) as a solid.

Process 2
Preparation of 3,5-dichloro-2,4-dihydroxybenzoyl chloride 3,5-Dichloro-2,4-dihydroxybenzoic acid (605 mg) was suspended in toluene (6 mL), thionyl chloride (0.25 mL) and N , N-dimethylformamide (1 drop) was added. After heating at reflux for 1 hour, the mixture was concentrated and azeotroped with toluene to give the title compound.

Process 3
Preparation of (3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4 obtained in Step 2 of Example 1 -Dihydro-2H-benzo [1,4] oxazine (366 mg) and 3,5-dichloro-2,4-dihydroxybenzoyl chloride obtained in the previous step were dissolved in ethyl acetate (6 mL) and heated to reflux for 1 hour. . The reaction solution was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was crystallized from ethyl acetate to give the title compound (171 mg) as crystals.

Example 51
Preparation of (6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone

Process 1
Preparation of 2-chloro-N- (5-chloro-2-hydroxyphenyl) -acetamide 2-Amino-4-chlorophenol (1.0061 g) was dissolved in ethyl acetate (10 mL) and water (10 mL) was cooled with ice. ) And sodium hydrogen carbonate (1.185 g) were added, followed by dropwise addition of chloroacetyl chloride (0.67 mL). After stirring at room temperature for 2.5 hours, water (20 mL) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (1.5455 g) as a yellow solid.

Process 2
Preparation of 6-chloro-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (5-chloro-2-hydroxyphenyl) -acetamide (1.54 g) was converted to N, N-dimethylformamide ( 15 mL) and potassium carbonate (1.26 g) was added at room temperature. After stirring at room temperature overnight, 1N hydrochloric acid (12 mL) was added under ice cooling, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (1.281 g) as a pale yellow solid.

Process 3
Preparation of 6-chloro-3,4-dihydro-2H-benzo [1,4] oxazine 6-Chloro-4H-benzo [1,4] oxazin-3-one (764 mg) was dissolved in tetrahydrofuran (8 mL), Borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 6.2 mL) was added under ice cooling, and the mixture was stirred at room temperature overnight. After stirring with heating at 70 ° C. for 1 hour, methanol (3 mL) was added dropwise at the same temperature, followed by further stirring with heating for 1 hour. Next, 1N hydrochloric acid (6.2 mL) was added dropwise with heating to 70 ° C., and the mixture was further stirred with heating for 0.5 hours, and then allowed to cool to room temperature. The mixture was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 99: 1) to obtain the title compound (640.1 mg) as a solid.

Process 4
Preparation of (6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone 6-chloro-3,4-dihydro-2H -Dissolve benzo [1,4] oxazine (168.4 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (242.7 mg) obtained in Step 1 of Example 3 in ethyl acetate (3 mL); Heated to reflux overnight. The solvent was distilled off, and the obtained solid was crystallized from methanol to give the title compound (318.4 mg) as white crystals.

Example 52
Preparation of (7-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone Similar to steps 1 to 4 of Example 51 By the method, 2-amino-5-chlorophenol was used instead of 2-amino-4-chlorophenol to obtain the title compound (749.3 mg) as white crystals.

Example 53
Preparation of [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl]-(3,5-dichloro-4-hydroxyphenyl) -methanone , 3,4-tetrahydroquinoxaline (68.1 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (250.5 mg) obtained in Step 1 of Example 3 were dissolved in ethyl acetate (5 mL) overnight. Heated to reflux. The solvent was distilled off, and the resulting solid was crystallized from methanol to give the title compound (122.0 mg) as light gray crystals.

Example 54
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone 1,2,3,4-Tetrahydroquinoxaline (805.3 mg) was dissolved in ethyl acetate (30 mL), triethylamine (1.0 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (1.8988 g) obtained in Step 3 of Example 8 were added under ice-cooling. And stirred overnight. Methanol was added to the reaction solution and then concentrated. The obtained solid was crystallized from ethyl acetate-water to give the title compound (2.042 g) as a pale-yellow solid.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)-(3,4 Dihydro-2H-quinoxalin-1-yl) -methanone (287.7 mg) was dissolved in tetrahydrofuran (6 mL). 7.5% Palladium-carbon (26 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from methanol to give the title compound (194.1 mg) as pale-yellow crystals.

Example 55
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester

Process 1
Preparation of methyl 4-hydroxy-3-nitrobenzoate Methanol (50 mL) and concentrated sulfuric acid (0.5 mL) were added to 4-hydroxy-3-nitrobenzoic acid (5.20022 g), and the mixture was stirred at 80 ° C. overnight. The solvent was distilled off, and the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. 1N Hydrochloric acid was added to the aqueous layer to make it acidic, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (5.3436 g) as a yellow solid.

Process 2
Preparation of methyl 3-amino-4-hydroxybenzoate Methyl 4-hydroxy-3-nitrobenzoate (5.3436 g) was dissolved in tetrahydrofuran (27 mL) and methanol (27 mL). 7.5% Palladium-carbon (276.6 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washings were combined and concentrated under reduced pressure to give the title compound (4.6803 g) as a solid.

Process 3
Preparation of 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester Methyl 3-amino-4-hydroxybenzoate (4.6803 g) and benzyltriethylammonium chloride (6 1787 g) was suspended in chloroform (50 mL), sodium bicarbonate (9.10 g) and chloroacetyl chloride (2.6 mL) were added under ice cooling, and stirring was continued for 1 hour under ice cooling. Then, it heated and stirred at 70 degreeC. The reaction mixture was concentrated, water and ethyl acetate were added, and the precipitated solid was collected by filtration. The mother liquor was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue and the previously collected solid were combined and crystallized from methanol to give the title compound (4.80805 g) as a solid.

Process 4
Preparation of 3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester 3-Oxo-3,4-dihydro in borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 11 mL) under ice-cooling -2H-Benzo [1,4] oxazine-6-carboxylic acid methyl ester (1.009 g) was added, and the mixture was heated and stirred at 70 ° C. for 3.5 hours. Methanol (3 mL) was added dropwise, and the mixture was further stirred with heating for 3 hours. The reaction solution was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 98: 2) to give the title compound (281.3 mg) as a pink solid and (3,4-dihydro- 2H-benzo [1,4] oxazin-6-yl) methanol (413.8 mg) was obtained.

Process 5
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester 3,4-Dihydro-2H-benzo [1 , 4] Oxazine-6-carboxylic acid methyl ester (81.2 mg) was dissolved in ethyl acetate (3 mL), and 3,5-dichloro-4-hydroxy obtained in Step 1 of Example 3 under ice-cooling. Benzoyl chloride (108.3 mg) was added, and the mixture was stirred at 80 ° C. overnight. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (167.8 mg) as an amorphous white solid.

Example 56
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 6- (tert-butyldimethylsilyloxymethyl) -3,4-dihydro-2H-benzo [1,4] oxazine (3,4-dihydro-2H-benzo [3] obtained in Step 4 of Example 55 1,4] oxazin-6-yl) methanol (406.1 mg) was dissolved in N, N-dimethylformamide (4 mL), and under ice cooling, imidazole (203.8 mg) and tert-butylchlorodimethylsilane (443. 4 mg) was added. The mixture was stirred at room temperature for 1 hour, poured into water, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to give the title compound (659.0 mg) as a pale yellow oil.

Process 2
Preparation of [6- (tert-butyldimethylsilyloxymethyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl]-(3,5-dichloro-4-hydroxyphenyl) -methanone 6- ( tert-Butyldimethylsilyloxymethyl) -3,4-dihydro-2H-benzo [1,4] oxazine (279.1 mg) was dissolved in ethyl acetate (3 mL), and triethylamine (0.167 mL) was cooled with ice. And 3,5-dichloro-4-hydroxybenzoyl chloride (249.4 mg) obtained in Step 1 of Example 3 was added, and the mixture was stirred at 80 ° C. overnight. The solvent was distilled off, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (131.7 mg) as a pale yellow solid.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone [6- (tert-butyldimethylsilyloxy Methyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl]-(3,5-dichloro-4-hydroxyphenyl) -methanone (131.7 mg) was dissolved in tetrahydrofuran (1.5 mL). Under ice-cooling, 1M tetrabutylammonium fluoride / tetrahydrofuran solution (0.34 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 97: 3) to obtain the title compound (50.0 mg) as crystals.

Example 57
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid 4- (4) obtained in Step 55 of Example 55 3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (140.8 mg), methanol (1.5 mL) and tetrahydrofuran ( 1.5N) and 2N aqueous sodium hydroxide (0.55 mL) was added. After stirring overnight at room temperature, the solvent was distilled off, and the mixture was acidified with 10% aqueous citric acid solution under ice cooling. The precipitated solid was collected by filtration, and the obtained solid was crystallized from methanol to give the title compound (81.3 mg) as crystals.

Example 58
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-5-carboxylic acid methyl ester Similar to steps 1-5 of Example 55 The method used 3-hydroxy-2-nitrobenzoic acid in place of 4-hydroxy-3-nitrobenzoic acid to give the title compound (246.0 mg) as an amorphous white solid.

Example 59
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid methyl ester Similar to steps 1 to 5 of Example 55 By the method, 3-hydroxy-4-nitrobenzoic acid was used instead of 4-hydroxy-3-nitrobenzoic acid to obtain the title compound (317.9 mg) as white crystals.

Example 60
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid 4- (3,5 obtained in Example 59 -Dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid methyl ester (257.4 mg), methanol (2.5 mL) and tetrahydrofuran (2.5 mL) 2N aqueous sodium hydroxide (1.0 mL) was added. After stirring with heating at 60 ° C. for 2.5 hours, the solvent was distilled off, and the mixture was acidified with 10% aqueous citric acid solution under ice cooling. The precipitated solid was collected by filtration, and the obtained solid was crystallized from methanol to give the title compound (76.6 mg) as crystals.

Example 61
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid methyl ester Similar to steps 1-5 in Example 55 By the method, 2-hydroxy-3-nitrobenzoic acid was used instead of 4-hydroxy-3-nitrobenzoic acid to obtain the title compound (313.8 mg) as white crystals.

Example 62
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid 4- (3,5 obtained in Example 61 -Dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid methyl ester (244.2 mg), methanol (2.5 mL) and tetrahydrofuran (2.5 mL) And 2N aqueous sodium hydroxide (0.96 mL) was added. After stirring overnight at room temperature, the solvent was distilled off, and the mixture was acidified with 10% aqueous citric acid solution under ice cooling. The precipitated solid was collected by filtration, and the obtained solid was crystallized from ethyl acetate to give the title compound (186.6 mg) as crystals.

Example 63
Preparation of (3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-Dihydro-2H-benzo [obtained in Step 2 of Example 1 1,4] oxazine (250.1 mg) and 3,5-dichlorobenzoyl chloride (426.9 mg) were dissolved in ethyl acetate (5 mL), and the mixture was heated and stirred at 80 ° C. overnight. The solvent was distilled off, and the obtained residue was crystallized from methanol to give the title compound (469.6 mg) as pale beige crystals.

Example 64
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(phenoxazin-10-yl) -methanone Phenoxazine (276.1 mg) and 3,5-dichloro-4 obtained in Step 1 of Example 3 -Hydroxybenzoyl chloride (370.8 mg) was dissolved in ethyl acetate (3 mL), and the mixture was heated and stirred at 80 ° C. overnight. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (397.6 mg) as a yellow green solid.

Example 65
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-phenyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone Similar to steps 2-5 in Example 21 By the method, 2-amino-4-phenylphenol was used instead of 3-amino-N, N-diethyl-4-hydroxybenzenesulfonamide to obtain the title compound (160.0 mg) as white crystals.

Example 66
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6,8-dimethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone Steps 1 to 4 of Example 51 and In the same manner, the title compound (152.7 mg) was obtained as crystals using 2-amino-4,6-dimethylphenol instead of 2-amino-4-chlorophenol.

Example 67
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 6-nitro-4H-benzo [1,4] oxazin-3-one 2-Amino-4-nitrophenol (4.6283 g) and benzyltriethylammonium chloride (6.8877 g) were suspended in chloroform (46 mL). Sodium bicarbonate (10.10 g) and chloroacetyl chloride (4.0707 g) were added under ice-cooling, and stirring was continued for 1 hour under ice-cooling. Then, it heated and stirred at 70 degreeC. The reaction mixture was concentrated, water and ethyl acetate were added, and the precipitated solid was collected by filtration. The mother liquor was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue and the previously collected solid were combined and crystallized from ethanol to give the title compound (5.4344 g) as a solid.

Process 2
Preparation of 6-nitro-3,4-dihydro-2H-benzo [1,4] oxazine Boron-tetrahydrofuran complex (1M tetrahydrofuran solution, 33.5 mL) was cooled to 6-nitro-4H-benzo [1, 4] Oxazin-3-one (3.00084 g) was added, and the mixture was heated with stirring at 70 ° C for 5 hours. Methanol (5 mL) was added dropwise, and the mixture was further stirred with heating for 2.5 hours. Concentrated hydrochloric acid (5 mL) was added dropwise, and the mixture was further stirred with heating for 1.5 hr. The reaction solution was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was crystallized from n-hexane-ethyl acetate to obtain the title compound (2.2092 g) as a solid.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-nitro-3,4-dihydro-2H -Benzo [1,4] oxazine (376.1 mg) was dissolved in ethyl acetate (3 mL), and 3,5-dichloro-4-hydroxybenzoyl chloride obtained in Step 1 of Example 3 under ice-cooling ( 270.7 mg) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (538.0 mg) as pale yellow crystals.

Example 68
Preparation of (6-amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone obtained in Step 3 of Example 67 ( 3,5-Dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (200.0 mg) was dissolved in tetrahydrofuran (12 mL). 7.5% Palladium-carbon (19.4 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to give the title compound (6.4 mg) as crystals.

Example 69
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6 obtained in Step 2 of Example 67 -Nitro-3,4-dihydro-2H-benzo [1,4] oxazine (179.8 mg) was dissolved in ethyl acetate (5 mL) and 3,3 obtained in Step 1 of Example 4 under ice cooling. 5-Dibromo-4-hydroxybenzoyl chloride (346.6 mg) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (437.0 mg) as yellow crystals.

Example 70
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone Similar to steps 1 to 3 of Example 67 By the method, 2-amino-5-nitrophenol was used instead of 2-amino-4-nitrophenol to give the title compound (485.2 mg) as yellow crystals.

Example 71
Preparation of (7-amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone obtained in Example 70 (3,5 -Dichloro-4-hydroxyphenyl)-(7-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (303.1 mg) dissolved in tetrahydrofuran (6 mL) and methanol (3 mL) did. 7.5% Palladium-carbon (30 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was crystallized from ethanol to give the title compound (257.9 mg) as yellow crystals.

Example 72
Preparation of N- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazin-7-yl] -methanesulfonamide obtained in Example 71 (7-amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (251.7 mg) in methylene chloride (5 mL) Suspension was performed, and pyridine (0.0776 mL) and methanesulfonyl chloride (0.0689 mL) were added under ice cooling, and the mixture was stirred at room temperature overnight. Methanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (173.6 mg) as an amorphous light orange solid.

Example 73
Preparation of 1- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone

Process 1
Preparation of 1- [4- (4-benzyloxy-3,5-dichlorobenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone Obtained in Step 54 of Example 54 (4- Benzyloxy-3,5-dichlorophenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone (400 mg) was suspended in methylene chloride (8 mL) and triethylamine (0. 162 mL) and acetyl chloride (0.082 mL) were added and stirred at room temperature overnight. Methanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 99: 1) to obtain the title compound (295.9 mg) as a pale yellow amorphous.

Process 2
Preparation of 1- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone 1- [4- (4-Benzyloxy-3,5 -Dichlorobenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone (288.6 mg) was dissolved in tetrahydrofuran (6 mL). 7.5% Palladium-carbon (27.7 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 97: 3) and crystallized from n-hexane-ethyl acetate to give the title compound (108.1 mg) as white crystals.

Example 74
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone

Process 1
Preparation of (4-Benzyloxy-3,5-dichlorophenyl)-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone (4-Benzyl) obtained in Step 1 of Example 54 Oxy-3,5-dichlorophenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone (401.6 mg) was dissolved in N, N-dimethylformamide (8 mL) and potassium carbonate (335. 7 mg) and iodomethane (0.076 mL) were added, and the mixture was heated and stirred at 50 ° C. Poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 99: 1) to give the title compound (114.7 mg) as amorphous.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)-( 4-Methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone (114.7 mg) was dissolved in tetrahydrofuran (5 mL). 7.5% Palladium-carbon (10.0 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (56.3 mg) as pale-yellow crystals.

Example 75
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-nitrophenyl) -methanone

Process 1
Production of 4-hydroxy-3-nitrobenzoyl chloride 1,4-Dimethoxyethane (20 mL) was added to 4-hydroxy-3-nitrobenzoic acid (1.83 g), and the mixture was heated to 80 ° C. to dissolve. Thionyl chloride (1.1 mL) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound (2.0551 g) as a yellow oil.

Process 2
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-nitrophenyl) -methanone 3,4-dihydro-2H obtained in Step 2 of Example 1 -Benzo [1,4] oxazine (203 mg) and 4-hydroxy-3-nitrobenzoyl chloride (302 mg) were dissolved in ethyl acetate (2 mL) and heated to reflux overnight. The reaction solution was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (460.7 mg) as an amorphous yellow solid.

Example 76
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone 2-methyl-2,3-dihydro-1H-indole (139.3 mg ) In methylene chloride (2.5 mL), pyridine (0.1 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (396.6 mg) obtained in Step 3 of Example 8 were added, Stir at room temperature overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to obtain the title compound (449.4 mg) as a yellow oil.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)-(2-methyl -2,3-Dihydroindol-1-yl) -methanone (437.1 mg) was dissolved in toluene (4 mL), and trifluoroacetic acid (2.5 mL) was added at room temperature. The mixture was heated and stirred at 80 ° C. and concentrated. The obtained solid was crystallized from n-hexane-ethyl acetate to give the title compound (300.3 mg) as white crystals.

Example 77
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl) -methanone By a method similar to steps 1 and 2 of Example 76, 2-methyl-2,3 Substituting 2,3-dihydro-1H-indole for dihydro-1H-indole, the title compound (230.6 mg) was obtained as white crystals.

Example 78
Preparation of (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(5-nitro-2,3-dihydroindol-1-yl) -methanone 5-nitro-2,3-dihydro-1H-indole (329.5 mg ) Was dissolved in methylene chloride (5 mL), pyridine (0.194 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (762.1 mg) obtained in Step 3 of Example 6 were added, and the mixture was added at room temperature. Stir overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (539.7 mg) as a yellow solid.

Process 2
Preparation of (5-amino-2,3-dihydroindol-1-yl)-(4-benzyloxy-3,5-dichlorophenyl) -methanone (4-benzyloxy-3,5-dichlorophenyl)-(5-nitro -2,3-Dihydroindol-1-yl) -methanone (539.7 mg) was dissolved in tetrahydrofuran (10 mL). Platinum (IV) oxide (14 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. Water was added and the mixture was extracted with chloroform. The resulting chloroform layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the mixture of the title compound and (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (489.5 mg) was yellow. Obtained as amorphous.

Process 3
Preparation of (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (5-amino-2,3-dihydroindol-1-yl)- A mixture of (4-benzyloxy-3,5-dichlorophenyl) -methanone and (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (489) 0.5 mg) was dissolved in toluene (5 mL), and trifluoroacetic acid (2.75 mL) was added at room temperature. The mixture was heated and stirred at 80 ° C. for 2.5 hours and then concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (282.4 mg) as pale gray crystals.

Example 79
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6 obtained in Step 44 of Example 44 -Fluoro-3,4-dihydro-2H-benzo [1,4] oxazine (230 mg) and 3,5-dibromo-4-hydroxybenzoyl chloride (472 mg) obtained in Step 1 of Example 4 were combined with ethyl acetate ( 3.5 mL) and stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (533.7 mg) as white crystals.

Example 80
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone Obtained in Step 16 of Example 16. Of 2,3-dihydro-1H-naphtho [2,1-b] [1,4] oxazine (140.9 mg) and 3,5-dibromo-4-hydroxybenzoyl obtained in Step 1 of Example 4 Chloride (239 mg) was dissolved in ethyl acetate (2.3 mL) and stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (298.8 mg) as dark blue crystals.

Example 81
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6 obtained in Step 1 of Example 12 -Methyl-3,4-dihydro-2H-benzo [1,4] oxazine (149 mg) and 3,5-dibromo-4-hydroxybenzoyl chloride (314 mg) obtained in Step 1 of Example 4 were combined with ethyl acetate ( 3.5 mL) and stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (368.2 mg) as beige crystals.

Example 82
Preparation of (6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dibromo-4-hydroxyphenyl) -methanone 6 obtained in step 3 of example 51 -Chloro-3,4-dihydro-2H-benzo [1,4] oxazine (170.6 mg) and 3,5-dibromo-4-hydroxybenzoyl chloride (349.3 mg) obtained in Step 1 of Example 4 Was dissolved in ethyl acetate (5 mL) and heated to reflux overnight. The solvent was distilled off, and the obtained solid was crystallized from methanol to give the title compound (441.0 mg) as crystals.

Example 83
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone obtained in Step 1 of Example 54 (4- Benzyloxy-3,5-dichlorophenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone (399.7 mg) was dissolved in methylene chloride (8 mL), and triethylamine (0 .162 mL) and methanesulfonyl chloride (0.094 mL) were added and stirred at room temperature overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 98: 2) to obtain the title compound (451.5 mg) as a pale yellow amorphous.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)- (4-Methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone (451.5 mg) was dissolved in tetrahydrofuran (10 mL). 7.5% Palladium-carbon (43.1 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (335.9 mg) as an amorphous light yellow solid.

Example 84
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-ethanesulfonyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-chloro-N- (5-ethanesulfonyl-2-hydroxyphenyl) acetamide 2-Amino-4-ethanesulfonylphenol (1.5063 g) was dissolved in ethyl acetate (15 mL), and water ( 15 mL) and sodium hydrogen carbonate (1.2588 g) were added, and chloroacetyl chloride (0.715 mL) was added dropwise. After stirring at room temperature for 5 hours, water (20 mL) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.9375 g) as a brown solid.

Process 2
Preparation of 6-ethanesulfonyl-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (5-ethanesulfonyl-2-hydroxyphenyl) acetamide (1.9375 g) was converted to N, N-dimethylformamide. (20 mL) and potassium carbonate (1.2520 g) was added at room temperature. After stirring at room temperature overnight, water (20 mL) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting solid was crystallized from methanol to give the title compound (1.3358 g) as a solid.

Process 3
Preparation of 6-ethanesulfonyl-3,4-dihydro-2H-benzo [1,4] oxazine 6-ethanesulfonyl-4H-benzo [1,4] oxazin-3-one (802.3 mg) in tetrahydrofuran (4 mL) Borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 7 mL) was added under ice cooling. After stirring with heating at 70 ° C. for 9 hours, methanol (5 mL) was added dropwise at the same temperature, and the mixture was further stirred with heating for 1 hour. Next, 1N hydrochloric acid (5 mL) was added dropwise with heating to 70 ° C., and the mixture was further stirred with heating for 1 hour, and then allowed to cool to room temperature. The mixture was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (748.7 mg) as an orange oil.

Process 4
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-ethanesulfonyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-ethanesulfonyl-3,4-dihydro -H-benzo [1,4] oxazine (233.5 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (255.4 mg) obtained in Step 1 of Example 3 were dissolved in ethyl acetate (5 mL). And heated to reflux overnight. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (446.9 mg) as an amorphous white solid.

Example 85
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-amino-4-trifluoromethylphenol 2-Nitro-4-trifluoromethylphenol (3.0951 g) was dissolved in tetrahydrofuran (15 mL). 7.5% Palladium-carbon (299.8 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washings were combined and concentrated under reduced pressure to give the title compound (2.6346 g) as a gray solid.

Process 2
Preparation of 2-chloro-N- (2-hydroxy-5-trifluoromethylphenyl) acetamide 2-Amino-4-trifluoromethylphenol (1.00075 g) was dissolved in ethyl acetate (10 mL), and the mixture was cooled with ice. Water (10 mL) and sodium bicarbonate (0.9531 g) were added, and chloroacetyl chloride (0.55 mL) was added dropwise. After stirring overnight at room temperature, the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.4341 g) as a light brown solid.

Process 3
Preparation of 6-trifluoromethyl-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2-hydroxy-5-trifluoromethylphenyl) acetamide (1.4244 g) was converted to N, N- Dissolved in dimethylformamide (14 mL) and potassium carbonate (1.00072 g) was added at room temperature. After stirring at room temperature for 2 hours, water (20 mL) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.2084 g) as a light gray solid.

Process 4
Preparation of 6-trifluoromethyl-3,4-dihydro-2H-benzo [1,4] oxazine 6-trifluoromethyl-4H-benzo [1,4] oxazin-3-one (810.8 mg) was added to tetrahydrofuran (810.8 mg). 4 mL), and borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 7.4 mL) was added under ice cooling. After stirring with heating at 70 ° C. for 6 hours, methanol (5 mL) was added dropwise at the same temperature, and the mixture was further stirred with heating for 1 hour. Next, 1N hydrochloric acid (5 mL) was added dropwise while heating to 70 ° C., and the mixture was further stirred with heating for 30 minutes, and then allowed to cool to room temperature. The mixture was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 99: 1) to obtain the title compound (718.3 mg) as a white solid.

Process 5
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-trifluoromethyl-3,4 -Dihydro-2H-benzo [1,4] oxazine (205.3 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (252.5 mg) obtained in Step 1 of Example 3 were mixed with ethyl acetate (5 mL). And heated to reflux overnight. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (286.5 mg) as white crystals.

Example 86
Preparation of (3,5-dichloro-4-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone obtained in step 2 of Example 3 (3,5- Dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (100 mg) was dissolved in acetone (5 mL), and potassium carbonate (47 mg) and iodomethane (0. 096 mL) was added, and the mixture was heated and stirred at 45 ° C. overnight. The reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to give the title compound (109.2 mg) as a white solid.

Example 87
Preparation of acetic acid 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl ester (3,5-dichloro-4-l) obtained in Step 2 of Example 3 Hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (100 mg) was dissolved in chloroform (5 mL), and triethylamine (0.064 mL) and acetyl chloride were cooled with ice. (0.026 mL) was added and stirred at room temperature overnight. The reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to give the title compound (123.1 mg) as white crystals.

Example 88
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxyphenyl) -methanone

Process 1
Preparation of (4-benzyloxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro-2H-benzo [obtained in Step 2 of Example 1 1,4] oxazine (270 mg), 4-benzyloxybenzoic acid (457 mg) and 4-dimethylaminopyridine (269 mg) were dissolved in chloroform (7 mL), and WSC · HCl (422 mg) was added under ice cooling. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (636.2 mg) as an orange oil.

Process 2
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxyphenyl) -methanone (4-benzyloxyphenyl)-(2,3-dihydrobenzo [1,4] oxazine -4-yl) -methanone (630 mg) was dissolved in tetrahydrofuran (20 mL). 7.5% Palladium-carbon (70 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (149.1 mg) as white crystals.

Example 89
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(5-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-chloro-N- (2,6-dihydroxyphenyl) -acetamide 2-Aminobenzene-1,3-diol hydrochloride (2.00 g) was dissolved in ethyl acetate (20 mL) and water (20 mL) was added. After adding sodium hydrogen carbonate (2.50 g), chloroacetyl chloride (1.02 mL) was added dropwise under ice cooling. After stirring at room temperature for 12 hours, the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 65: 35) to obtain the title compound (1.508 g) as a pale orange solid.

Process 2
Preparation of 5-hydroxy-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2,6-dihydroxyphenyl) -acetamide (1.274 g) was converted to N, N-dimethylformamide (10 mL). And potassium carbonate (873 mg) was added at room temperature. After stirring at room temperature for 2.5 hours, water (30 mL) was added. After stirring for 0.5 hour under ice-cooling, the precipitated solid was collected by filtration to obtain the title compound (915 mg) as a pale orange solid.

Process 3
Preparation of 5-benzyloxy-4H-benzo [1,4] oxazin-3-one 5-hydroxy-4H-benzo [1,4] oxazin-3-one (200 mg) was added to N, N-dimethylformamide (2 mL). And potassium carbonate (167 mg) and benzyl bromide (158 mL) were added at room temperature. The mixture was stirred at room temperature for 3 hours and further heated and stirred at 60 ° C. for 1 hour, and then water was added. The precipitated solid was collected by filtration to give the title compound (283 mg) as a pale yellow solid.

Process 4
Preparation of 5-benzyloxy-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (50 mg) was suspended in tetrahydrofuran (2 mL), and 5-benzyloxy-4H— was cooled with ice. Benzo [1,4] oxazin-3-one (276 mg) was added in small portions. Stir at room temperature for 1 hour, then heat and stir at 60 ° C. for 1 hour, and then add water (0.05 mL), 15% aqueous sodium hydroxide (0.05 mL), and water (0.15 mL) sequentially under ice cooling. And stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to give the title compound (54 mg) as an oil.

Process 5
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(5-benzyloxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 5-benzyloxy-3,4-dihydro -H-benzo [1,4] oxazine (47 mg) was dissolved in chloroform (2 mL), and tribenzylamine (0.0716 mL) and 4-benzyloxy-3,5-dichlorobenzoyl obtained in Step 3 of Example 8 were used. Chloride (689.3 mg) was added. After stirring at room temperature for 25 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 85: 15) to give the title compound (54.7 mg) as a white solid.

Step 6
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(5-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl )-(5-Benzyloxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (52 mg) was dissolved in tetrahydrofuran (2 mL). 7.5% Palladium-carbon (10 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The solvent was distilled off, and the resulting solid was crystallized from ethyl ether to give the title compound (14.8 mg) as a pale yellow solid.

Example 90
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(8-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-methoxy-6-nitrophenol 1,2-Dimethoxyethane (100 mL) was added to 2-methoxyphenol (6.21 g) and cooled to -50 ° C. Nitronium tetrafluoroborate (6.77 g) was added and stirred at −50 ° C. After completion of the reaction, the reaction solution was poured into ice water, and ethyl acetate and ethyl ether were added. The insoluble material was removed by filtration, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1-3: 1) to give the title compound (2.46 g) as a yellow solid.

Process 2
Preparation of 2-amino-6-methoxyphenol hydrochloride 2-Methoxy-6-nitrophenol (2.46 g) was dissolved in tetrahydrofuran (20 mL). 7.5% Palladium-carbon (400 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was filtered through celite, and the residue was washed with ethyl acetate. Under ice cooling, 4N hydrogen chloride-ethyl acetate (10 mL) was added dropwise and stirred for 30 minutes. The precipitated solid was collected by filtration to give the title compound (2.41 g) as a white solid.

Process 3
Preparation of 2-chloro-N- (2-hydroxy-3-methoxyphenyl) -acetamide 2-Amino-6-methoxyphenol hydrochloride (2.40 g) was dissolved in ethyl acetate (25 mL) and water was added under ice cooling. (30 mL) and sodium bicarbonate (2.76 g) were added, and chloroacetyl chloride (1.2 mL) was added dropwise. After stirring at room temperature for 0.5 hour, the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (2.95 g) as a pale orange solid.

Process 4
Preparation of 8-methoxy-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2-hydroxy-3-methoxyphenyl) -acetamide (2.95 g) was prepared from N, N-dimethylformamide (2.95 g). 20 mL) and potassium carbonate (2.46 g) was added under ice cooling. After stirring at room temperature for 4 hours, water was added. After stirring at room temperature for 0.5 hour, the precipitated solid was collected by filtration to give the title compound (2.06 g) as a pink solid.

Process 5
Preparation of 8-hydroxy-4H-benzo [1,4] oxazin-3-one 8-Methoxy-4H-benzo [1,4] oxazin-3-one (950 mg) was dissolved in methylene chloride (90 mL). After cooling to −78 ° C. and boron tribromide (1.0 M methylene chloride solution, 13.3 mL) was added dropwise, the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (864 mg) as an ocher solid.

Step 6
Preparation of 8- (tert-butyldimethylsilyloxy) -4H-benzo [1,4] oxazin-3-one 8-hydroxy-4H-benzo [1,4] oxazin-3-one (900 mg) was converted to N, N -Dissolved in dimethylformamide (10 mL), imidazole (482 mg) and tert-butylchlorodimethylsilane (986 mg) were added. After stirring at room temperature for 1 hour, water and a 10% aqueous citric acid solution were added. The mixture was extracted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 7: 3) to give the title compound (1.41 g) as a white solid.

Step 7
Preparation of 8- (tert-butyldimethylsilyloxy) -3,4-dihydro-2H-benzo [1,4] oxazine 8- (tert-butyldimethylsilyloxy) -4H-benzo [1,4] oxazine-3 -On (700 mg) was dissolved in tetrahydrofuran (5 mL), borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 3.76 mL) was added, and the mixture was heated to reflux for 2.5 hours. The mixture was allowed to cool to room temperature, made weak alkaline by adding water and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (675 mg) as an oil.

Process 8
Preparation of (4-Benzyloxy-3,5-dichlorophenyl)-[8- (tert-butyldimethylsilyloxy) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone 8- (tert -Butyldimethylsilyloxy) -3,4-dihydro-2H-benzo [1,4] oxazine (792 mg) dissolved in chloroform (10 mL) and obtained in Step 3 of Example 8 with pyridine (0.242 mL). 4-Benzyloxy-3,5-dichlorobenzoyl chloride (792 mg) was added. After stirring at room temperature for 1 hour, a 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 8: 1) to give the title compound (1.28 g) as a white solid.

Step 9
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(8-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl )-[8- (tert-Butyldimethylsilyloxy) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone (545 mg) was dissolved in toluene (2 mL) and trifluoroacetic acid at room temperature. (4 mL) was added. The mixture was heated and stirred at 85 ° C. for 7.5 hours, and then concentrated. The obtained residue was dissolved in tetrahydrofuran and treated with activated carbon. The solvent was evaporated, the residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 1), and crystallized from ethyl ether to obtain the title compound (220 mg) as a yellow solid.

Example 91
Preparation of [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid ethyl ester (3,5-dichloro-4-l) obtained in Example 3 Hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (1.0067 g) was dissolved in N, N-dimethylformamide (10 mL) and potassium carbonate (0. 6553 g) and ethyl bromoacetate (0.52 mL) were added. After heating and stirring overnight at 70 ° C., ethyl acetate (20 mL) and 10% aqueous citric acid solution (20 mL) were added under ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (1.2891 g) as a pale yellow oil.

Example 92
Preparation of [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid [2,6-dichloro-4- (2) obtained in Example 91 , 3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid ethyl ester (1.2753 g) in methanol (6.5 mL), 2N aqueous sodium hydroxide (3.1 mL) was added, Stir at room temperature for 0.5 hour. Water was added to the reaction solution, washed with ethyl ether, and acidified with 10% aqueous citric acid solution. After extraction with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was crystallized from methanol to give the title compound (156.4 mg) as white crystals.

Example 93
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 1- (2-nitrophenoxy) -propan-2-one 2-Nitrophenol (2.78 g) was dissolved in N, N-dimethylformamide (20 mL) and potassium carbonate (3.34 g) and bromo at room temperature. Acetone (1.85 mL) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to obtain the title compound (3.2101 g) as a bright yellow solid.

Process 2
Preparation of 3-methyl-3,4-dihydro-2H-benzo [1,4] oxazine 1- (2-Nitrophenoxy) propan-2-one (501.1 mg) was dissolved in tetrahydrofuran (10 mL). 7.5% Palladium-carbon (49.1 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to obtain the title compound (248.1 mg) as a yellow oil.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3-methyl-3,4-dihydro-2H -Benzo [1,4] oxazine (244.9 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (370.1 mg) obtained in Step 1 of Example 3 were dissolved in ethyl acetate (7 mL). And stirred at 80 ° C. for 3 hours. Ethyl acetate (15 mL) and water (20 mL) were added to the reaction mixture and the layers were separated, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained solid was crystallized from methanol to give the title compound (320.2 mg) as white crystals.

Example 94
Preparation of N- [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide

Process 1
Preparation of N-methanesulfonyl-N- [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide obtained in Example 28 (4 -Amino-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (323 mg) dissolved in N, N-dimethylformamide (5 mL) and 60% hydrogen Sodium chloride (52 mg) was added, and the mixture was stirred at room temperature for 0.5 hr, methanesulfonyl chloride (0.0851 mL) was added, and the mixture was stirred at room temperature. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) and crystallized from isopropyl ether to give the title compound (78 mg) as a white solid.

Process 2
Preparation of N- [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide N-methanesulfonyl-N- [2,6-dichloro- 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide (73 mg) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 0.168 mL) was dissolved. ) And stirred overnight at room temperature. A 10% aqueous citric acid solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was crystallized from ethyl acetate to give the title compound (48 mg) as a white solid.

Example 95
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone

Process 1
Preparation of tert-butyldimethyl [3- (2-nitrophenoxy) propoxy] silane 2-Nitrophenol (3 g) was dissolved in N, N-dimethylformamide (20 mL) and sodium hydride (1.04 g) was cooled under ice cooling. The mixture was stirred at room temperature for 0.5 hour, and then (3-bromopropoxy) -tert-butyldimethylsilane (5.49 mL) was added under ice cooling, followed by heating and stirring at 90 ° C. overnight. Furthermore, potassium carbonate (1 g) and (3-bromopropoxy) -tert-butyldimethylsilane (2.5 mL) were added, and the mixture was heated and stirred at 90 ° C. for 1.5 hours. A 10% aqueous citric acid solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to give the title compound (6.71 g) as a yellow oil.

Process 2
Preparation of 2- [3- (tert-butyldimethylsilyloxy) propoxy] phenylamine Tert-butyldimethyl [3- (2-nitrophenoxy) propoxy] silane (6.71 g) was dissolved in tetrahydrofuran (50 mL). 7.5% Palladium-carbon (1 g) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to obtain the title compound (5.88 g) as a pale orange oil.

Process 3
Preparation of 4-benzyloxy-N- {2- [3- (tert-butyldimethylsilyloxy) propoxy] phenyl} -3,5-dichlorobenzamide 2- [3- (tert-butyldimethylsilyloxy) propoxy] phenyl Amine (844 mg) was dissolved in chloroform (10 mL), and pyridine (0.314 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (947 mg) obtained in Step 3 of Example 8 were added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated, and the resulting residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to give the title compound (1.63 g) as a pale yellow oil. Obtained as a thing.

Process 4
Preparation of 4-benzyloxy-3,5-dichloro-N- [2- (3-hydroxypropoxy) phenyl] benzamide 4-benzyloxy-N- {2- [3- (tert-butyldimethylsilyloxy) propoxy] Phenyl} -3,5-dichlorobenzamide (1.62 g) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 4.33 mL) was added, and the mixture was stirred at room temperature for 1 hr. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was crystallized from isopropyl ether to give the title compound (1.19 g) as a white solid.

Process 5
Preparation of 4-benzyloxy-3,5-dichloro-N- [2- (3-chloropropoxy) phenyl] benzamide 4-benzyloxy-3,5-dichloro-N- [2- (3-hydroxypropoxy) phenyl Benzamide (1.00 g) was dissolved in pyridine (10 mL), methanesulfonyl chloride (0.225 mL) was added, and the mixture was stirred with heating at 70 ° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (713 mg) as a beige solid.

Step 6
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone 4-benzyloxy-3,5 -Dichloro-N- [2- (3-chloropropoxy) phenyl] benzamide (200 mg) was dissolved in N, N-dimethylformamide (3 mL) and 60% sodium hydride (21 mg) and sodium iodide (64 mg) were dissolved. In addition, the mixture was heated and stirred at 60 ° C. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to give the title compound (121 mg) as an oil.

Step 7
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone (4-benzyloxy-3, 5-Dichlorophenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone (115 mg) was dissolved in tetrahydrofuran (5 mL). 7.5% Palladium-carbon (15 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The solvent was distilled off, and the resulting residue was crystallized from isopropyl ether to give the title compound (69 mg) as a white solid.

¹ H-NMR spectral data of the compounds of Examples ^{1 to} 95 are shown in Tables 1 to 18.
¹ H-NMR spectrum was measured in CDCl ₃ or DMSO-d ₆ using tetramethylsilane as an internal standard, and all δ values were shown in ppm.
The symbols in the table have the following meanings.
s: singlet
d: doublet
t: triplet
dd: double doublet (double doublet)
ddd: double double doublet
brs: broad singlet
m: multiplet
J: Coupling constant

The powder X-ray diffraction patterns of the crystals of the present invention are shown in FIGS. The horizontal axis represents the diffraction angle (2θ), and the vertical axis represents the peak intensity (cps).
Tables 19 to 22 show diffraction angles (2θ) of diffraction peaks characteristic of each crystal from the powder X-ray diffraction pattern.
An aluminum cell is filled with the crystal sample of the present invention, and using a powder X-ray diffractometer (RINT2100 Ultimate +, manufactured by Rigaku Corporation), X-ray source: Cu-Kα1 line, applied voltage: 40 kV, applied current: 40 mA, scanning speed : The powder X-ray diffraction pattern of each crystal of the present invention was measured at 5 ° per minute, scanning width: 0.02 °, and scanning range: 5 ° to 40 °. Since there is a diffraction peak due to the aluminum cell in the vicinity of 38.20 ° to 38.40 °, the diffraction peak in the vicinity is not listed as a diffraction peak characteristic of each crystal.

  In general, the diffraction angle (2θ) and peak intensity (cps) of the powder X-ray diffraction pattern may vary depending on the measuring instrument, measurement conditions, and the like. The crystal in the present specification may be a crystal having a value different from the diffraction angle (2θ) and the peak intensity of the diffraction pattern of the powder X-ray described in the present specification as long as it is within a normal error range.

  If the compound of the present invention is in the form of crystals, it has excellent physical and chemical stability, and therefore has the advantage that the quality can be maintained over a long period of time and storage becomes easy. In addition, there is an advantage that various pharmaceutical compositions and drug substances can be handled easily during production, and the production cost can be reduced. Therefore, the crystal of the present invention is extremely useful as a medicine.

  Next, the present invention will be specifically described by the following formulation examples. However, the present invention is not limited by these formulation examples.

Formulation Example 1 (Manufacture of capsules)
1) 30 mg of the compound of Example 1
2) Fine powder cellulose 10mg
3) Lactose 19mg
4) Magnesium stearate 1mg
1), 2), 3) and 4) are mixed and filled into gelatin capsules.

Formulation Example 2 (Manufacture of tablets)
1) 30 g of the compound of Example 1
2) Lactose 50g
3) Corn starch 15g
4) Carboxymethylcellulose calcium 44g
5) Magnesium stearate 1g
The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, dried in vacuum, and then sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
For the compounds of Examples 2 to 95, capsules or tablets can be produced in the same manner as in Preparation Example 1 or Production Example 2.

Test Example 1 Urate transport inhibition test using human URAT1-expressing cells Human URAT1 full-length cDNA was subcloned into the expression vector pcDNA3.1, and the human URAT1 gene was transferred to human fetal kidney-derived cells (HEK293 cells) by the liposomal method using Lipofectamine 2000. ). At the same time, HEK293 cells (hereinafter referred to as mock cells) transfected with only the expression vector pcDNA3.1 were also prepared. HEK293 cells or mock cells expressing the human URAT1 gene were selected using geneticin resistance as an index. It was also confirmed that the human URAT1 gene was functionally expressed in the same manner as described below, using as an index the transport of uric acid labeled with ¹⁴ C into cells.

Human URAT1-expressing HEK293 cells or mock cells in Dulbecco's modified Eagle MEM medium (high glucose) containing 10% fetal bovine serum, 0.5 mg / mL geneticin sulfate, 100 units / mL penicillin and 100 μg / mL streptomycin The cells were cultured in an incubator under conditions of 37 ° C. and 5% carbon dioxide gas. Cells were seeded in 96 well plate (poly-D-Lysine coated) at 1 × 10 ⁵ cells / well, and the following uric acid transport inhibition test was performed 24 hours later. In addition, the said test was implemented under room temperature conditions.

After removing the medium from each well by suction, the cells were washed once with Hank's Balanced Salt Solution (HBSS) and preincubated for 5 minutes in 100 μL / well of HBSS. After aspirating and removing HBSS, an assay buffer (NaCl in the above HBSS was replaced with Na-gluconate) containing various concentrations of the example compound and radioligand ( ¹⁴ C-labeled uric acid; final concentration 50 μM) was used. The addition reaction was performed at 50 μL / well, and the uptake reaction was performed for 5 minutes. Immediately after completion of the reaction, the mixture was washed twice with 150 μL / well of ice-cooled HBSS, and Microcinti ™ 20 (PerkinElmer) was added at 50 μL / well. After the cells were lysed by stirring, the radioactivity of each well was measured with a liquid scintillation counter (TOP COUNT, Packard).

Radioactivity indicating URAT1-specific uric acid transport (difference in radioactivity between human URAT1-expressing HEK293 cells and mock cells in the case where no example compound was added (DMSO added)) and 100%, and the degree of uric acid transport at each concentration of the example compound (%) Was calculated, and the concentration of the Example compound (IC ₅₀ ) at which the uric acid transport rate was inhibited by 50% was determined. The results are shown in Tables 23-24. In Table 23 to Table 24, "+++" indicates that _{an IC 50} value of less than 100nM, "++" the _{IC 50} value of 100nM or less than 1000nM, "+" the _{IC 50} value less than 1000nM to 3000 nM.

Test Example 2 CYP Inhibition Test Using Human Liver Microsomes Human liver microsomes (purchased from Xenotech LLC, Lenexa KS) 20 mg protein / mL 5 μL was suspended in 100 μM potassium phosphate buffer (pH 7.4) 70 μL, and further DMSO 0.5 μL of the dissolved example compound solution was mixed and preincubated at 37 ° C. for 5 minutes. NADPH generating coenzyme solution (β-nicotinamide adenine phosphate: 5.2 mM, D-glucose-6-phosphate: 13.2 mM, magnesium chloride: 13.2 mM, glucose-6-phosphate dehydrogenase: 1.8 U / mL) Model substrate dissolved in 25 μL and DMSO (CYP3A4: midazolam 1 mM, CYP2D6: bufuralol 1 mM,
The reaction was started by adding 0.5 μL of CYP2C9: diclofenac 2 mM), and after incubation at 37 ° C. for 10 minutes, 200 μL of acetonitrile containing an internal standard substance (propranol 1 μM) was added and centrifuged (room temperature 3000 rpm, 20 minutes). The amount of metabolite produced from each model substrate in the supernatant was measured using high performance liquid chromatography / mass spectrometry (LC / MS / MS) to determine each CYP enzyme activity. The concentration (IC50) showing 50% inhibition rate was calculated with the enzyme activity at the time when no Example compound was added (0.5 μL of DMSO added) being 100%. The results are shown in Tables 25 to 27.

  As is apparent from Test Example 1 (Uric acid transport inhibition test using human URAT1-expressing cells), the compound of the present invention and a pharmaceutically acceptable salt thereof have an excellent URAT1 activity inhibitory action. Further, as is clear from Test Example 2 (CYP inhibition test), the compound of the present invention and its pharmaceutically acceptable salt have no or very low CYP inhibitory action.

  Therefore, the compound of the present invention and a pharmaceutically acceptable salt thereof have an effect of strongly suppressing reabsorption of uric acid, and further, do not substantially inhibit CYP. It shows that the risk of side effects is very low.

  Therefore, the compound of the present invention inhibits reabsorption of uric acid by inhibiting URAT1 activity, thereby causing hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis It is a therapeutic or prophylactic agent for pathological conditions involving uric acid such as renal dysfunction, coronary artery disease, ischemic heart disease and the like.

  Furthermore, as the causative disease, complication or likely comorbidity of the above-mentioned pathological condition involving uric acid, for example, gout arthritis, urinary calculus, hypertension or hypertension complications, hyperlipidemia or hyperlipidemia Complications, diabetes or diabetic complications, obesity or obesity complications, reduced uric acid excretion type secondary hyperuricemia. Use of a therapeutic or preventive agent for these diseases including hyperuricemia in combination with a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof is effective for the treatment or prevention of these diseases. In addition, using a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof together with a drug that increases blood uric acid level is effective for suppressing an increase in blood uric acid level.

  The present invention relates to treatment of pathological conditions involving uric acid such as hyperuricemia, gouty nodules, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease, ischemic heart disease or the like. Useful for prevention.

X-ray powder diffraction pattern of (3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 1). X-ray powder diffraction pattern of (3-bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 2). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 3). X-ray powder diffraction pattern of (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 4). X-ray powder diffraction pattern of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone (Example 5). X-ray powder diffraction pattern of (3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 6). X-ray powder diffraction pattern of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone (Example 7). (3,5-Dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone (Example 10) X-ray diffraction pattern. X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 12). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 14). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 15). X-ray powder of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone (Example 16) Diffraction pattern. X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 17). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 18). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 19). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(7-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 20). X-ray powder diffraction pattern of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide (Example 21). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone (Example 26). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone (Example 27). X-ray powder diffraction pattern of (3-chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 31). Powder X-ray diffraction of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone (Example 36) pattern. X-ray powder diffraction pattern of (3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 38). X-ray powder diffraction pattern of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone (Example 39). X-ray powder diffraction pattern of (3-chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 40). X-ray powder diffraction pattern of (4-chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 41). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 44). X-ray powder diffraction pattern of (3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 50). X-ray powder diffraction pattern of (6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (Example 51). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 56) . Powder X-ray diffraction of (3,5-dichloro-4-hydroxyphenyl)-(6,8-dimethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 66) pattern. X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 67). X-ray powder diffraction pattern of (3,5-dibromo-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 69). X-ray powder diffraction pattern of 1- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone (Example 73). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone (Example 76). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl) -methanone (Example 77). X-ray powder diffraction pattern of (3,5-dibromo-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 79). X-ray powder of (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone (Example 80) Diffraction pattern. X-ray powder diffraction pattern of (3,5-dibromo-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 81). X-ray powder diffraction pattern of (6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dibromo-4-hydroxyphenyl) -methanone (Example 82). X-ray powder diffraction of (3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Example 85) pattern. X-ray powder diffraction pattern of acetic acid 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl ester (Example 87).

Claims (80)

  A URAT1 activity inhibitor comprising a substance that inhibits URAT1 activity and does not substantially inhibit CYP.   The URAT1 activity inhibitor according to claim 1, wherein CYP is CYP2C9.   The URAT1 activity inhibitor according to claim 1 or 2, wherein a 50% inhibitory concentration against CYP2C9 of a substance that inhibits URAT1 activity and does not substantially inhibit CYP is 1 µM or more. A URAT1 activity inhibitor comprising a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof.

[Where:
R ¹ , R ² and R ³ are the same or different,
1) a hydrogen atom, or 2) a group selected from the following group A, or 3) saturated or unsaturated having 3 to 14 carbon atoms together with the carbon atom to which R ¹ and R ² are bonded Or the carbocycle may be substituted with one or more substituents selected from group A below, or 4) R ² and R ³ are bonded to each other A saturated or unsaturated carbocycle having 3 to 14 carbon atoms together with the carbon atom to be substituted (the carbocycle may be substituted with one or more substituents selected from the following group A). May form;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is,
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom, or (b) a group selected from group A below, or (c) R ³ and R ⁴ are saturated with 3 to 14 carbon atoms together with the carbon atom to which they are bonded. Alternatively, an unsaturated carbocycle (the carbocycle may be substituted with one or more substituents selected from the same or different groups selected from group A below) may be formed. )
Is;
X ² is,
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below. ),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the following group A;
(E) a cycloalkylalkoxy group optionally substituted by one or more substituents selected from the following group A,
(F) an aralkyl group optionally substituted with one or more substituents selected from the following group A, or (g) substituted with one or more substituents selected from the following group A. A good aralkoxy group. ),
4) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above),
5) -N (CONR ⁷ R ⁸ )-(wherein R ⁷ and R ⁸ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the following group A, or the same or different. ) May be formed. ),
6) sulfur atom,
7) -S (= O)-,
8) —S (═O) ₂ —, or 9) —CR ⁹ R ¹⁰ — (wherein R ⁹ and R ¹⁰ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁹ and R ¹⁰ Together may form an oxo group. )
Is;
-X ³ -X ⁴ -is
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different groups selected from the following group B, or (c) the same carbon atom R ¹¹ and R ^{12 to} be bonded together form an oxo group, or (d) two of n R ¹¹ and R ¹² bonded to the same or adjacent two carbon atoms are the carbon atoms And a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle may be substituted with one or more substituents selected from the following group A). May be. )
And ring A is
1) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following group A), or 2) A saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is substituted with one or more substituents selected from the following group A; May be.)
It is.
[Group A]
1) a halogen atom,
2) —OR ¹³ (wherein R ¹³ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group which may be substituted with one or different substituents selected from the following group B, or (c) —COR ¹⁴ (wherein R ¹⁴ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
7) —COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
8) —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ¹⁵ and R ¹⁶ A nitrogen-containing saturated heterocycle comprising a single ring together with the nitrogen atom to which they are bonded (the heterocycle is substituted with one or more substituents selected from the following (i) and (ii)): May be.
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ) May be formed. ),
9) -CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
10) —NR ¹⁷ COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above, and R ¹⁷ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below. ),
11) —NR ¹⁷ S (═O) ₂ R ¹⁴ (wherein R ¹⁴ and R ¹⁷ are as defined above),
12) —NR ¹⁷ CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above),
13) —SR ¹³ (wherein R ¹³ has the same meaning as described above),
14) —S (═O) R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
18) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
19) Aryloxy group (the aryloxy group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
20) Cyano group, and 21) Nitro group [Group B]
1) a halogen atom,
2) a hydroxyl group,
3) a C _1-6 alkoxy group,
4) -NR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁸ and R ¹⁹ together with a nitrogen atom to which they are bonded to form a monocycle. A ring may be formed. ),
5) -CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are as defined above),
6) -COR ²⁰ (wherein R ²⁰ represents
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7) —NR ²¹ COR ²⁰ (wherein R ²⁰ has the same meaning as described above, and R ²¹ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8) —NR ²¹ CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ , R ¹⁹ and R ²¹ are as defined above),
9) —NR ²¹ S (═O) ₂ R ²² (wherein R ²¹ has the same meaning as described above, and R ²² represents a C _1-6 alkyl group), and 10) —S (═O ₂ R ²² (wherein R ²² has the same meaning as described above.)
Here, the C _1-6 alkyl group and the C _1-6 alkoxy group in the above 3) to 10) may be further substituted with one or more substituents selected from Group B, Moreover, the nitrogen-containing saturated heterocyclic ring consisting of a single ring in the above 4), 5) and 8) may be further substituted with one or more substituents selected from group B and C _1-6 alkyl group. ]] A nitrogen-containing fused ring compound represented by the following general formula [2] or a pharmaceutically acceptable salt thereof.

[Wherein, R ¹ , R ² , R ³ , Y, X ¹ , X ³ and X ⁴ are as defined in claim 4,
Ring A ′ is
1) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group is substituted with one or more substituents selected from the following group C), or 2) nitrogen A saturated or unsaturated heterocyclic group having at least one heteroatom selected from an atom, an oxygen atom and a sulfur atom (the heterocyclic group is substituted with one or more substituents selected from the following group C; ing.)
And the ring A ′ is substituted with at least one —OR ¹³ ′ (R ¹³ ′ is defined in group C below);
X ² '
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below. ),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the following group A;
(E) a cycloalkylalkoxy group optionally substituted by one or more substituents selected from the following group A,
(F) an aralkyl group optionally substituted with one or more substituents selected from the following group A, or (g) substituted with one or more substituents selected from the following group A. A good aralkoxy group. ),
4) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above),
5) -N (CONR ⁷ R ⁸ )-(wherein R ⁷ and R ⁸ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the following group A, or the same or different. ) May be formed. ),
6) sulfur atom,
7) -S (= O)-,
8) —S (═O) ₂ —, or 9) —CH ₂ —.
It is.
(However, when X ² ′ is —CH ₂ —,
-X ³ -X ⁴ -is
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or
(B) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n two R ¹¹ and R ¹² are bonded to the same or adjacent two carbon atoms. The two bonded together with the carbon atom are a saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (the carbocyclic ring is substituted with one or more substituents selected from the following group A; May be formed). )
Is;
R ¹³ ′ is a hydrogen atom; and ring A ′ is further substituted with at least one halogen atom;
However, when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms. )
[Group A]
1) a halogen atom,
2) —OR ¹³ (wherein R ¹³ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group which may be substituted with one or different substituents selected from the following group B, or (c) —COR ¹⁴ (wherein R ¹⁴ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
7) —COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
8) —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ¹⁵ and R ¹⁶ A nitrogen-containing saturated heterocycle comprising a single ring together with the nitrogen atom to which they are bonded (the heterocycle is substituted with one or more substituents selected from the following (i) and (ii)): May be.
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ) May be formed. ),
9) -CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
10) —NR ¹⁷ COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above, and R ¹⁷ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below. ),
11) —NR ¹⁷ S (═O) ₂ R ¹⁴ (wherein R ¹⁴ and R ¹⁷ are as defined above),
12) —NR ¹⁷ CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above),
13) —SR ¹³ (wherein R ¹³ has the same meaning as described above),
14) —S (═O) R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
18) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
19) Aryloxy group (the aryloxy group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
20) Cyano group, and 21) Nitro group [Group B]
1) a halogen atom,
2) a hydroxyl group,
3) a C _1-6 alkoxy group,
4) -NR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁸ and R ¹⁹ together with a nitrogen atom to which they are bonded to form a monocycle. A ring may be formed. ),
5) -CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are as defined above),
6) -COR ²⁰ (wherein R ²⁰ represents
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7) —NR ²¹ COR ²⁰ (wherein R ²⁰ has the same meaning as described above, and R ²¹ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8) —NR ²¹ CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ , R ¹⁹ and R ²¹ are as defined above),
9) —NR ²¹ S (═O) ₂ R ²² (wherein R ²¹ has the same meaning as described above, and R ²² represents a C _1-6 alkyl group), and 10) —S (═O ₂ R ²² (wherein R ²² has the same meaning as described above.)
Here, the C _1-6 alkyl group and the C _1-6 alkoxy group in the above 3) to 10) may be further substituted with one or more substituents selected from Group B, Moreover, the nitrogen-containing saturated heterocyclic ring consisting of a single ring in the above 4), 5) and 8) may be further substituted with one or more substituents selected from group B and C _1-6 alkyl group. )
[Group C]
1) a halogen atom,
2) —OR ¹³ ′ (wherein R ¹³ ′ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B, or (c) —COR ¹⁴ ′ (wherein R ¹⁴ ′ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
7) —COR ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
8) -NR ¹⁵ 'R ¹⁶ ' (wherein R ¹⁵ 'and R ¹⁶ ' are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B, or (c) R ¹⁵ ′ and R ¹⁶ 'is a nitrogen-containing saturated heterocycle consisting of a single ring together with the nitrogen atom to which they are bonded (wherein the heterocycle is one or more substituents selected from the following (i) and (ii): May be substituted.
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ) May be formed. ),
9) —NR ¹⁷ ′ COR ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above, and R ¹⁷ ′ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
_{^{10) -NR 17 'S (=}} O) 2 R 14' ( ^{wherein, R 14} 'and ^{R 17'} has the same meaning as defined above.)
11) —NR ¹⁷ ′ CONR ¹⁵ ′ R ¹⁶ ′ (wherein R ¹⁵ ′, R ¹⁶ ′ and R ¹⁷ ′ are as defined above),
12) —SR ¹³ ′ (wherein R ¹³ ′ has the same meaning as described above),
13) —S (═O) R ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
14) —S (═O) ₂ R ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
15) —S (═O) ₂ NR ¹⁵ ′ R ¹⁶ ′ (wherein R ¹⁵ ′ and R ¹⁶ ′ are as defined above),
16) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
17) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
18) Aryloxy group (The aryloxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
19) cyano group, and 20) nitro group] (A) X ² ′ is
1) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
2) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different groups selected from the group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the same or different groups selected from the group A;
(E) a cycloalkylalkoxy group that may be substituted with one or more substituents selected from the same or different groups selected from the group A;
(F) an aralkyl group optionally substituted with one or more substituents selected from the group A, or (g) substituted with one or more substituents selected from the group A. A good aralkoxy group. ),
3) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above), or 4) —N (CONR ⁷ R ⁸ ) — (wherein R ⁷ and R ⁸ is the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from Group B, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the group A or the same or different. ) May be formed. )
If it is,
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
(B) X ² ′
1) -S (= O)-, or 2) -S (= O) _2-
If it is,
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - is;
(C) X ² ′ is a sulfur atom, and Y is
1) -CO-, or 2) -CS-,
If it is,
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
(D) X ² ′ is an oxygen atom and Y is
1) -CO-, or 2) -CS-,
If it is,
R ¹ , R ² and R ³ are the same or different,
1) a hydrogen atom, or 2) a group selected from the following group D, or 3) R ¹ and R ² together with the carbon atom to which they are bonded, saturated or unsaturated having 3 to 14 carbon atoms Or the carbocycle may be substituted with one or more substituents selected from group D below or the same or different from each other, or 4) R ² and R ³ are bonded to each other And a saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (the carbocyclic ring may be substituted with one or more substituents selected from the following group D). And —X ³ —X ⁴ — is —CH ₂ —CH ₂ —;
(E) X ² '
When 1) an oxygen atom, or 2) a sulfur atom and Y is —S (═O) ₂ —,
When —X ³ —X ⁴ — is —CH ₂ —CH ₂ —; and R ¹³ ′ is a hydrogen atom; or (F) X ² ′ is —CH ₂ —,
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or (b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n R ¹¹ and R ¹² Two of them bonded to the same or adjacent two carbon atoms together with the carbon atom are saturated or unsaturated carbocycles having 3 to 14 carbon atoms (the carbocycle is the same or selected from the group A or May be substituted with one or more different substituents. )
Is;
R ¹³ ′ is a hydrogen atom; and ring A ′ is further substituted with at least one halogen atom;
However, in the case of (F), R ¹¹ and R ¹² are both hydrogen atoms, and when n is 2, R ¹ , R ² and R ³ are all hydrogen atoms;
6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof.
[Group D]
1) a halogen atom,
2) —OR ¹³ ″ (wherein R ¹³ ″ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B, or (c) —COR ¹⁴ ″ (wherein R ¹⁴ ″ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
7) —COR ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
8) —NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B, or (c) R ¹⁵ ″ and R ¹⁶ ″ is a nitrogen-containing saturated heterocyclic ring composed of a single ring together with a nitrogen atom to which they are bonded (the heterocyclic ring is one or more selected from the same or different selected from the following (i) and (ii)) It may be substituted with a substituent.
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ) May be formed. ),
9) -CONR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are as defined above),
10) —NR ¹⁷ ″ COR ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above, and R ¹⁷ ″ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
11) —NR ¹⁷ ″ S (═O) ₂ R ¹⁴ ″ (wherein R ¹⁴ ″ and R ¹⁷ ″ are as defined above),
12) —NR ¹⁷ ″ CONR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″, R ¹⁶ ″ and R ¹⁷ ″ are as defined above),
13) -SR ¹³ ″ (wherein R ¹³ ″ has the same meaning as described above),
14) —S (═O) R ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
18) Aryloxy group (The aryloxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
19) Cyano group, and 20) Nitro group X ² '
1) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
2) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different groups selected from the group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the same or different groups selected from the group A;
(E) a cycloalkylalkoxy group that may be substituted with one or more substituents selected from the same or different groups selected from the group A;
(F) an aralkyl group optionally substituted with one or more substituents selected from the group A, or (g) substituted with one or more substituents selected from the group A. A good aralkoxy group. ),
3) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above), or 4) —N (CONR ⁷ R ⁸ ) — (wherein R ⁷ and R ⁸ is the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from Group B, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the group A or the same or different. ) May be formed. );
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof. Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
The compound according to claim 7 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
2) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group, or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (wherein the carbocyclic group is the same or different one or more selected from a halogen atom and a hydroxyl group) . it may be substituted with group)), or _{3) -N (S (= O} ) 2 -C 1-6 alkyl) -,
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
The compound according to claim 7 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
2) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group, or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (wherein the carbocyclic group is the same or different one or more selected from a halogen atom and a hydroxyl group) . it may be substituted with group)), or _{3) -N (S (= O} ) 2 -C 1-6 alkyl) -,
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
The compound according to claim 7 or a pharmaceutically acceptable salt thereof. X ² '
1) -S (= O)-, or 2) -S (= O) _2-
In it; and ^-X 3 -X ⁴ - it _is, -CH ₂ -CH 2 - is;
6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof. Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is —OR ¹³ ′ (R ¹³ ′ is as defined in claim 5). is there. );
The compound according to claim 11 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) -S (= O)-, or 2) -S (= O) _2-
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group that may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups;
5) -O-CO-C _1-6 alkyl group,
6) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
7) -COOH,
8) —CO—C _1-6 alkoxy group,
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group, or 11) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group, a C _1-6 alkoxy group (the C _{1 -6} alkoxy groups may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups) and —O—CO—C _1-6 alkyl groups. The group to be selected. );
The compound according to claim 11 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) -S (= O)-, or 2) -S (= O) _2-
Is;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
The compound according to claim 11 or a pharmaceutically acceptable salt thereof. Y is
1) -CO-, or 2) -CS-,
Is;
X ² 'is a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof. Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
The compound according to claim 15 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-, or 2) -CS-,
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
The compound according to claim 15 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
The compound according to claim 15 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) a hydrogen atom, or 2) a group selected from the following group D, or 3) R ¹ and R ² together with the carbon atom to which they are bonded, saturated or unsaturated having 3 to 14 carbon atoms Or the carbocycle may be substituted with one or more substituents selected from group D below or the same or different from each other, or 4) R ² and R ³ are bonded to each other And a saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (the carbocyclic ring may be substituted with one or more substituents selected from the following group D). May form;
Y is
1) -CO-, or 2) -CS-,
Is;
X ² ′ is an oxygen atom; and —X ³ —X ⁴ — is —CH ₂ —CH ₂ —;
6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof.
[Group D]
1) a halogen atom,
2) —OR ¹³ ″ (wherein R ¹³ ″ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B, or (c) —COR ¹⁴ ″ (wherein R ¹⁴ ″ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
7) —COR ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
8) —NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B, or (c) R ¹⁵ ″ and R ¹⁶ ″ is a nitrogen-containing saturated heterocyclic ring composed of a single ring together with a nitrogen atom to which they are bonded (the heterocyclic ring is one or more selected from the same or different selected from the following (i) and (ii)) It may be substituted with a substituent.
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ) May be formed. ),
9) -CONR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are as defined above),
10) —NR ¹⁷ ″ COR ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above, and R ¹⁷ ″ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
11) —NR ¹⁷ ″ S (═O) ₂ R ¹⁴ ″ (wherein R ¹⁴ ″ and R ¹⁷ ″ are as defined above),
12) —NR ¹⁷ ″ CONR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″, R ¹⁶ ″ and R ¹⁷ ″ are as defined above),
13) -SR ¹³ ″ (wherein R ¹³ ″ has the same meaning as described above),
14) —S (═O) R ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ ″ (wherein R ¹⁴ ″ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
18) Aryloxy group (The aryloxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
19) Cyano group, and 20) Nitro group Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is —OR ¹³ ′ (R ¹³ ′ is as defined in claim 5). is there. );
20. A compound according to claim 19 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) R ¹⁵ ″ and R ¹⁶ ″ together with the nitrogen atom to which they are attached comprise a single ring A nitrogen-containing saturated heterocyclic ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is an oxygen atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group that may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups;
5) -O-CO-C _1-6 alkyl group,
6) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
7) -COOH,
8) —CO—C _1-6 alkoxy group,
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group, or 11) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group, a C _1-6 alkoxy group (the C _{1 -6} alkoxy groups may be substituted with one or more substituents selected from the same or different groups selected from —COOH and —CO—C _1-6 alkoxy groups) and —O—CO—C _1-6 alkyl groups. The group to be selected. );
20. A compound according to claim 19 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ ″ R ¹⁶ ″ (wherein R ¹⁵ ″ and R ¹⁶ ″ are the same or different;
(A) a C _1-6 alkyl group, or (b) R ¹⁵ ″ and R ¹⁶ ″ together with the nitrogen atom to which they are attached form a nitrogen-containing saturated heterocycle consisting of a single ring. May be. Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² 'is an oxygen atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
20. A compound according to claim 19 or a pharmaceutically acceptable salt thereof. Y is —S (═O) ₂ —;
X ² '
1) an oxygen atom, or 2) a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and ^{R 13} 'are hydrogen atoms;
6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof. Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
24. A compound according to claim 23 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is —S (═O) ₂ —;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) an oxygen atom, or 2) a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
24. A compound according to claim 23 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is —S (═O) ₂ —;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² '
1) an oxygen atom, or 2) a sulfur atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
24. A compound according to claim 23 or a pharmaceutically acceptable salt thereof. X ² ′ is —CH ₂ —;
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or (b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n R ¹¹ and R ¹² Two of them bonded to the same or adjacent two carbon atoms together with the carbon atom are saturated or unsaturated carbocycles having 3 to 14 carbon atoms (the carbocycle is the same or selected from the group A or May be substituted with one or more different substituents. )
Is;
R ¹³ ′ is a hydrogen atom; and ring A ′ is further substituted with at least one halogen atom;
Provided that when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms;
6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof. Ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, at least one of R ^{23 to} R ²⁷ is a hydroxyl group, and at least one of R ^{23 to} R ²⁷ is a halogen atom. . );
28. A compound according to claim 27 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) -COOH,
7) —CO—C _1-6 alkoxy group,
8) an amino group,
_{9) -NHS (= O) 2} -C 1-6 alkyl group,
_{10) -S (= O) 2} -C 1-6 alkyl group,
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁵ and R ¹⁶ together with a nitrogen atom to which they are bonded to form a single ring. A ring may be formed. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or 13) a nitro group;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² ′ is —CH ₂ —;
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3, and n R ¹¹ and R ¹² are the same or different, respectively, (a) are hydrogen atoms, or ( b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) Bonded to two identical or adjacent carbon atoms of n R ¹¹ and R ¹² And two of them, together with the carbon atom, a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle is substituted with one or more substituents selected from the same or different group A) Or may be formed.)
And ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different,
5) -COOH,
6) —CO—C _1-6 alkoxy group,
7) an amino group,
8) —NHS (═O) ₂ —C _1-6 alkyl group, or 9) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group, and at least any of R ^{23 to} R ²⁷ One of them is a halogen atom. );
Provided that when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms;
28. A compound according to claim 27 or a pharmaceutically acceptable salt thereof. R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkoxy group,
5) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different from a halogen atom and a hydroxyl group;
6) —CO—C _1-6 alkoxy group,
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group, or (b) R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached may form a nitrogen-containing saturated heterocyclic ring consisting of a single ring. . Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a —CO—C _1-6 alkoxy group, or (e) R ³ and R ⁴ are carbon atoms together with the carbon atom to which they are attached. A saturated or unsaturated carbocyclic ring of several 3 to 14 may be formed. )
Is;
X ² ′ is —CH ₂ —;
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3, and n R ¹¹ and R ¹² are the same or different, respectively, (a) are hydrogen atoms, or ( b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) Bonded to two identical or adjacent carbon atoms of n R ¹¹ and R ¹² And two of them, together with the carbon atom, a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle is substituted with one or more substituents selected from the same or different group A) Or may be formed.)
And ring A ′ is

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group which may be substituted with one or more halogen atoms which are the same or different, or 5) a nitro group,
And at least one of R ^{23 to} R ²⁷ is a hydroxyl group, and at least one of R ^{23 to} R ²⁷ is a halogen atom. );
Provided that when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms;
28. A compound according to claim 27 or a pharmaceutically acceptable salt thereof. The compound according to claim 5 or a pharmaceutically acceptable salt thereof selected from the following group.
(1) (3-Chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(2) (3-Bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(3) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(4) (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(5) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone,
(6) (3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(7) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone,
(8) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone,
(9) (3,5-dichloro-4-hydroxyphenyl)-(1-oxo-2,3-dihydro-1H-1λ ⁴ -benzo [1,4] thiazin-4-yl) -methanone,
(10) (3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone,
(11) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanethione,
(12) (3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(13) (3,5-dichloro-4-hydroxyphenyl)-(7-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(14) (3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(15) (3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(16) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone,
(17) (3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(18) (3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(19) (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(20) (3,5-dichloro-4-hydroxyphenyl)-(7-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(21) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide,
(22) 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-sulfonyl) phenol,
(23) (6-tert-butyl-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(24) 4- (3,5-dichloro-4-hydroxybenzoyl) -4H-benzo [1,4] oxazin-3-one,
(25) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid amide,
(26) (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone,
(27) (3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone,
(28) (4-amino-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(29) (5-chloro-6-hydroxypyridin-3-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(30) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dinitrophenyl) -methanone,
(31) (3-Chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(32) (3,5-dichloro-4-hydroxyphenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(33) (3,5-dichloro-4-hydroxyphenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone,
(34) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid ethylamide,
(35) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid dimethylamide;
(36) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone,
(37) 5- (3,5-dichloro-4-hydroxybenzoyl) -1,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-2-one,
(38) (3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(39) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone,
(40) (3-Chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(41) (4-Chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(42) (2,6-dichloropyridin-4-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(43) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-nitrophenyl) -methanone,
(44) (3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(45) 2- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(46) methyl 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate,
(47) 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(48) methyl 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate,
(49) 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(50) (3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(51) (6-Chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(52) (7-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(53) [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl]-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(54) (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(55) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester,
(56) (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(57) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid,
(58) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-5-carboxylic acid methyl ester,
(59) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid methyl ester,
(60) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid,
(61) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid methyl ester,
(62) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid,
(63) (3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(64) (3,5-dichloro-4-hydroxyphenyl)-(phenoxazin-10-yl) -methanone,
(65) (3,5-dichloro-4-hydroxyphenyl)-(6-phenyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(66) (3,5-dichloro-4-hydroxyphenyl)-(6,8-dimethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(67) (3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(68) (6-Amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(69) (3,5-dibromo-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(70) (3,5-dichloro-4-hydroxyphenyl)-(7-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(71) (7-amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(72) N- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazin-7-yl] -methanesulfonamide,
(73) 1- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone,
(74) (3,5-dichloro-4-hydroxyphenyl)-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(75) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-nitrophenyl) -methanone,
(76) (3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone,
(77) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl) -methanone,
(78) (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(79) (3,5-dibromo-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(80) (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone,
(81) (3,5-dibromo-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(82) (6-Chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dibromo-4-hydroxyphenyl) -methanone,
(83) (3,5-dichloro-4-hydroxyphenyl)-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(84) (3,5-dichloro-4-hydroxyphenyl)-(6-ethanesulfonyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(85) (3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(86) (3,5-dichloro-4-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(87) Acetic acid 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl ester,
(88) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxyphenyl) -methanone,
(89) (3,5-dichloro-4-hydroxyphenyl)-(5-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(90) (3,5-dichloro-4-hydroxyphenyl)-(8-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(91) [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid ethyl ester,
(92) [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid,
(93) (3,5-dichloro-4-hydroxyphenyl)-(3-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(94) N- [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide, and (95) (3,5-dichloro-4 -Hydroxyphenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone.   32. A pharmaceutical composition comprising the compound according to any one of claims 5 to 31 or a pharmaceutically acceptable salt thereof.   A URAT1 activity inhibitor comprising the compound according to any one of claims 5 to 31 or a pharmaceutically acceptable salt thereof.   A blood uric acid level-lowering agent comprising the substance that inhibits URAT1 activity and does not substantially inhibit CYP according to any one of claims 1 to 3.   A blood uric acid level-lowering agent comprising the compound of the general formula [1] according to claim 4 or a pharmaceutically acceptable salt thereof.   A blood uric acid level-lowering agent comprising the compound according to any one of claims 5 to 31 or a pharmaceutically acceptable salt thereof.   A therapeutic or prophylactic agent for a disease state involving uric acid, comprising the substance that inhibits URAT1 activity and does not substantially inhibit CYP according to any one of claims 1 to 3.   A therapeutic or prophylactic agent for a pathological condition involving uric acid, comprising the compound of the general formula [1] according to claim 4 or a pharmaceutically acceptable salt thereof.   A therapeutic or prophylactic agent for a pathological condition involving uric acid, comprising the compound according to any one of claims 5 to 31 or a pharmaceutically acceptable salt thereof.   The pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease 40. The therapeutic or prophylactic agent for a disease state involving uric acid according to any of 39.   A method for treating or preventing a pathological condition involving uric acid, comprising administering a pharmaceutically effective amount of a substance that inhibits the URAT1 activity according to any one of claims 1 to 3 and does not substantially inhibit CYP. .   A method for treating or preventing a pathological condition involving uric acid, which comprises administering a pharmaceutically effective amount of the compound of the general formula [1] according to claim 4 or a pharmaceutically acceptable salt thereof.   A method for treating or preventing a pathological condition involving uric acid, comprising administering a pharmaceutically effective amount of the compound according to any one of claims 5 to 31 or a pharmaceutically acceptable salt thereof.   The pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease 44. The method of treatment or prevention according to any one of 43.   A method for inhibiting URAT1 activity comprising administering a pharmaceutically effective amount of a substance that inhibits URAT1 activity according to any one of claims 1 to 3 and does not substantially inhibit CYP.   A method for inhibiting URAT1 activity comprising administering a pharmaceutically effective amount of a compound of the general formula [1] according to claim 4 or a pharmaceutically acceptable salt thereof.   A method for inhibiting URAT1 activity, comprising administering a pharmaceutically effective amount of the compound according to any one of claims 5 to 31 or a pharmaceutically acceptable salt thereof.   A method for lowering blood uric acid levels, comprising administering a pharmaceutically effective amount of a substance that inhibits URAT1 activity and does not substantially inhibit CYP according to any one of claims 1 to 3.   A method for lowering a blood uric acid level, comprising administering a pharmaceutically effective amount of the compound of the general formula [1] according to claim 4 or a pharmaceutically acceptable salt thereof.   32. A method for reducing blood uric acid levels, comprising administering a pharmaceutically effective amount of the compound according to any one of claims 5 to 31 or a pharmaceutically acceptable salt thereof.   Use of the substance that inhibits URAT1 activity and does not substantially inhibit CYP according to any one of claims 1 to 3, for producing a therapeutic or prophylactic agent for a pathological condition involving uric acid.   Use of the compound of the general formula [1] or a pharmaceutically acceptable salt thereof according to claim 4 for producing a therapeutic or prophylactic agent for a pathological condition involving uric acid.   Use of the compound according to any one of claims 5 to 31 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a pathological condition involving uric acid.   The pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease 53. Use according to any of 53.   Use of a substance that inhibits URAT1 activity and does not substantially inhibit CYP according to any one of claims 1 to 3, for producing a URAT1 activity inhibitor.   Use of the compound of the general formula [1] described in claim 4 or a pharmaceutically acceptable salt thereof for producing a URAT1 activity inhibitor.   Use of the compound according to any one of claims 5 to 31 or a pharmaceutically acceptable salt thereof for producing a URAT1 activity inhibitor.   Use of the substance that inhibits URAT1 activity and does not substantially inhibit CYP according to any one of claims 1 to 3, for producing a blood uric acid level-lowering agent.   Use of the compound of the general formula [1] described in claim 4 or a pharmaceutically acceptable salt thereof for producing a blood uric acid level-lowering agent.   Use of the compound according to any one of claims 5 to 31 or a pharmaceutically acceptable salt thereof for producing a blood uric acid level-lowering agent.   A pharmaceutical composition for treating or preventing a pathological condition involving uric acid, comprising the substance that inhibits URAT1 activity and does not substantially inhibit CYP according to any one of claims 1 to 3.   A pharmaceutical composition for the treatment or prevention of a pathological condition involving uric acid, comprising the compound of the general formula [1] according to claim 4 or a pharmaceutically acceptable salt thereof.   32. A pharmaceutical composition for treating or preventing a pathological condition involving uric acid, comprising the compound according to any one of claims 5 to 31 or a pharmaceutically acceptable salt thereof.   The pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease 64. The pharmaceutical composition according to any of 63.   A pharmaceutical composition according to any one of claims 61 to 64, and said pharmaceutical composition comprising hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal dysfunction, A commercial package containing a description relating to the pharmaceutical composition that can be used or should be used for the treatment or prevention of a disease selected from coronary artery disease and ischemic heart disease. The pharmaceutical composition according to claim 32, for use in combination with 1 to 3 agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist The URAT1 activity inhibitor according to any one of claims 1 to 4 and 33, which is used in combination with 1 to 3 agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist 37. The blood uric acid level-lowering agent according to any one of claims 34 to 36, for use in combination with 1 to 3 agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist The therapeutic or prophylactic agent for a disease state involving uric acid according to any one of claims 37 to 40, for use in combination with one to three agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist The method for treating or preventing a disease state involving uric acid according to any one of claims 41 to 44, further comprising administering 1 to 3 agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist 48. The method of inhibiting URAT1 activity according to any one of claims 45 to 47, further comprising administering 1 to 3 agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist 51. The method for reducing blood uric acid level according to any one of claims 48 to 50, further comprising administering 1 to 3 agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist The use according to any one of claims 51 to 54 for producing a therapeutic or prophylactic agent for a pathological condition involving uric acid for use in combination with one to three agents selected from the following groups (1) to (11): .
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist The use according to any one of claims 55 to 57, for producing a URAT1 activity inhibitor for use in combination with one to three agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist The use according to any one of claims 58 to 60, for producing a blood uric acid level-lowering agent for use in combination with one to three agents selected from the following groups (1) to (11).
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or (10) treatment and / or prevention agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid metabolism antagonist   The pharmaceutical composition according to claim 32, which is used in combination with a drug that increases blood uric acid level to suppress an increase in blood uric acid level.   34. The URAT1 activity inhibitor according to any one of claims 1 to 4 and 33 for suppressing an increase in blood uric acid level in combination with a drug that increases blood uric acid level.   48. The method of inhibiting URAT1 activity according to any one of claims 45 to 47, further comprising administering a drug that increases blood uric acid level.   58. The use according to any one of claims 55 to 57, for producing a URAT1 activity inhibitor for suppressing an increase in blood uric acid level in combination with a drug that increases blood uric acid level.   A method for suppressing an increase in blood uric acid level, comprising administering a drug that increases blood uric acid level in combination with the URAT1 activity inhibitor according to any one of claims 1 to 4 and 33.

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