JP2013177318A - Dihydropyrimidinone derivative and pharmaceutical use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a curative or preventive agent for various inflammation/diseases or the like related to elastase.SOLUTION: A dihydropyrimidinone derivative expressed by general formula (I) or a physiologically acceptable salt thereof is provided. (In the formula: Rrepresents -C(=O)NR-, -S(=O)NR-, -C(=O)O- or the like; Rrepresents a hydrogen atom, alkyl, an alicyclic group, an aromatic ring group or the like; Rrepresents alkyl; Rand Reach independently represents a hydrogen atom or alkyl; L represents a 5- to 6-membered aromatic ring group or -S(=O)-; and Arand Areach represents a 5- to 6-membered aromatic ring group).

Description

  The present invention relates to a novel dihydropyrimidinone derivative useful as a medicament having elastase inhibitory activity. More specifically, the present invention relates to a novel dihydropyrimidinone derivative useful as a prophylactic and / or therapeutic agent for diseases involving elastase such as inflammatory diseases.

  Human neutrophil elastase (hereinafter sometimes simply referred to as elastase) is a kind of serine protease having a molecular weight of about 30 KDa and is stored in azurophilic granules of neutrophils. In the physiological state, elastase plays a role in rapidly digesting and degrading phagocytosed bacteria and foreign substances in neutrophils, and in vivo, connective tissues such as lung, cartilage, blood vessel wall, and skin outside neutrophils. It degrades elastin, collagen (type III, type IV), proteoglycan, fibronectin, etc. that make up the stroma, and helps maintain tissue homeostasis.

  In vivo, endogenous elastase inhibitor protein exists. Among them, α1-antitrypsin (α1-AT) is the most well-known, and it is known that patients with genetic α1-AT deficiency present symptoms like chronic obstructive pulmonary disease (COPD). (Non-Patent Document 1). Thus, when there is an imbalance between endogenous elastase-inhibiting protein and elastase, or when excessive elastase is released due to a pathological condition caused by inflammation, etc., elastase actively promotes normal tissues. It is thought to induce various pathological conditions by destroying it.

  Diseases that have been suggested to be involved in the pathogenesis of elastase include, for example, chronic obstructive pulmonary disease (COPD), cystic pulmonary fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic Pulmonary fibrosis (IIP), chronic interstitial pneumonia, chronic bronchitis, chronic respiratory tract infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, rheumatoid arthritis, arthrosclerosis, Osteoarthritis, psoriasis, periodontitis, atherosclerosis, organ transplant rejection, early water rupture, blistering, shock, sepsis, systemic lupus erythematosus (SLE), Crohn's disease, disseminated intravascular coagulation ( DIC), tissue damage during ischemia-reperfusion, formation of corneal scar tissue, myelitis, lung squamous cell carcinoma, lung adenocarcinoma, lung cancer such as non-small cell lung cancer, breast cancer, liver cancer, bladder cancer, colon Rectal cancer, skin cancer Pancreatic cancer, glioma and the like are known. Therefore, a drug exhibiting an inhibitory activity against elastase is useful for the treatment or prevention of diseases involving these elastases.

  Under such expectation, various elastase inhibitors have been reported. For example, Patent Documents 1, 2, and 3 disclose 2-dihydropyrimidinone derivatives as neutrophil elastase inhibitors. For example, the first term in the claims of Patent Document 1 describes a compound represented by the following general formula (A-1) (formula I in the same publication).

[Wherein A represents an aryl or heteroaryl ring ...].

  However, since it has an aryl or heteroaryl ring at the 4-position of the 2-dihydropyrimidinone derivative, it is clearly structurally different from the compound of the present invention described later. Similarly, the 2-dihydropyrimidinone derivatives described in Patent Documents 2 and 3 are also clearly structurally different from the compounds of the present invention described later.

  In addition, as a compound having a p38 MAP kinase inhibitory action, the first term in claims of Patent Document 4 and Patent Document 5 is represented by the following general formula (A-2) (formula I in the same publication): Compounds are described.

[式中、環Ａはさらに置換基を有していてもよい、異原子として酸素原子、窒素原子または硫黄原子から選択される１ないし３個の原子を含む５員の単環式複素環を表し、環Ｂは置換基を有していてもよい少なくとも１個の窒素原子を含む複素環を表し、環Ｄは置換基を有していてもよい環状基を表し、環Ｅは置換基を有していてもよい環状基を表し、Ｒ¹は塩基性を有する窒素原子を含有する置換基を表す]（特許文献４）
[式中、環Ａは、さらに置換基を有していてもよい、酸素原子、窒素原子および硫黄原子から選択される１ないし３個の原子を含む５員の単環複素環を表し、環Ｂは、置換基を有していてもよい、表記の窒素原子以外に酸素原子、窒素原子および硫黄原子から選択される１ないし３個の原子を含んでいてもよい複素環を表し、環Ｄは、置換基を有していてもよい環状基を表し、環Ｅは、置換基を有していてもよい環状基を表し、Ｒ¹は、酸素原子および／または硫黄原子を含有する中性基または酸性基を表す酸素原子および／または硫黄原子を含有する中性基または酸性基を表す]（特許文献５）
しかしながら、特許文献４および５に記載の化合物は環Ａに置換基Ｒ¹を有する化合物であるのに対して、本発明化合物は環Ａ（本願明細書中式（Ｉ）におけるＬ）が無置換である化合物である点において構造が異なる。

[In the formula, ring A represents an optionally substituted 5-membered monocyclic heterocyclic ring containing 1 to 3 atoms selected from an oxygen atom, a nitrogen atom or a sulfur atom as a hetero atom. Ring B represents a heterocyclic ring containing at least one nitrogen atom which may have a substituent, ring D represents a cyclic group which may have a substituent, and ring E represents a substituent. Represents a cyclic group that may be present, and R ¹ represents a substituent containing a basic nitrogen atom] (Patent Document 4)
[Wherein, ring A represents a 5-membered monocyclic heterocycle containing 1 to 3 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, which may further have a substituent, B represents a heterocyclic ring which may have a substituent and may contain 1 to 3 atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in addition to the above-described nitrogen atom, and ring D Represents a cyclic group which may have a substituent, ring E represents a cyclic group which may have a substituent, and R ¹ is a neutral group containing an oxygen atom and / or a sulfur atom. Represents a neutral group or acidic group containing an oxygen atom and / or a sulfur atom representing a group or acidic group] (Patent Document 5)
However, while the compounds described in Patent Documents 4 and 5 are compounds having a substituent R ¹ on ring A, the compounds of the present invention are those in which ring A (L in formula (I) in the present specification) is unsubstituted. The structure is different in that it is a certain compound.

International Publication No. 2004/024700 Pamphlet International Publication No. 2005/082863 Pamphlet International Publication No. 2005/082864 Pamphlet International Publication No. 2006/051826 Pamphlet International Publication No. 2007/040208 Pamphlet

Eur. Respir. J. 2009, 33, 1345-1353

  The problem to be solved by the present invention is to provide therapeutic agents for various inflammatory diseases involving elastase.

As a result of intensive studies, the inventors have found that a novel compound represented by the following formula (I) exhibits an elastase inhibitory action and completed the present invention. According to the present invention, there is provided a dihydropyrimidinone derivative represented by the following formula (I) (hereinafter also referred to as “the compound of the present invention”).
[Item 1] Formula (I):

[Where
R ⁰ is —C (═O) NR ^a1 —, —S (═O) ₂ NR ^a2 —, —C (═O) O—, —C (═O) —, —S (═O) ₂ —. Or a single bond,
R ¹ may contain 1 to 2 heteroatoms selected from the group consisting of a hydrogen atom, C _1-10 alkyl, C _2-6 alkene, N, O and S 3-6 membered saturation Or an unsaturated aliphatic ring group, or a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S;
Wherein the alkyl and the alkene are in substitutable positions,
(1) hydroxyl group,
(2) a halogen atom,
(3) Cyano,
(4) C _1-6 alkoxy (wherein the alkoxy is substitutable,
Hydroxyl group,
Halogen atoms,
Cyano,
-C (= O) OR ^b1 ,
-C (= O) NR ^c1 R ^d1 ,
A 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a hydroxyl group at a substitutable position) Alternatively, C _1-3 alkyl which may be substituted with a halogen atom, hydroxyl group or C _1-3 alkoxy which may be substituted with a halogen atom, hydroxyl group, halogen atom, cyano, —NR ^a3 C (═O) R ^b2 , —NR ^a4 C (═O) NR ^c2 R ^d2 , —NR ^a5 S (═O) _m R ^b3 , —C (═O) OR ^b4 , —C (═O) NR ^c3 R ^d3 , —S (= O) _m NR ^c4 R ^d4 , optionally substituted with —S (═O) _m R ^b5 or —NR ^c5 R ^d5 ) or 1-2 hetero selected from the group consisting of N, O and S A 3- to 6-membered saturated or unsaturated aliphatic ring group which may contain an atom (the aliphatic ring group at a substitutable position) Hydroxyl or a halogen atom an optionally substituted C _1-3 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, ^{cyano, -NR a6 C (= O)} R ^{b6, -NR a7 C (= O} ) NR c6 R d6, -NR a8 S (= O) m R b7, -C (= O) OR b8, -C (= O) NR c7 R d7, -NR c8 ^Optionally substituted with R ^d8 or oxo)
May be substituted)
(5) C _1-6 alkylthio (the alkylthio is a hydroxyl group at a substitutable position,
Halogen atoms,
Cyano,
-C (= O) OR ^b9 ,
-C (= O) NR ^c9 R ^d9 ,
A 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a hydroxyl group at a substitutable position) Alternatively, C _1-3 alkyl which may be substituted with a halogen atom, hydroxyl group or C _1-3 alkoxy which may be substituted with a halogen atom, hydroxyl group, halogen atom, cyano, —NR ^a9 C (═O) R ^b10 , —NR ^a10 C (═O) NR ^c10 R ^d10 , —NR ^a11 S (═O) _m R ^b11 , —C (═O) OR ^b12 , —C (═O) NR ^c11 R ^d11 , —S (= O) _m NR ^c12 R ^d12 , ^optionally substituted with —S (═O) _m R ^b13 or —NR ^c13 R ^d13 ) or 1 to 2 hetero atoms selected from the group consisting of N, O and S 3 to 6-membered saturated or unsaturated aliphatic ring group which may contain an atom (the aliphatic ring group may be substituted) Position in a hydroxyl group or a halogen atom an optionally substituted C _1-3 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, cyano, -NR ^a12 C ( ═O) R ^b14 , —NR ^a13 C (═O) NR ^c14 R ^d14 , —NR ^a14 S (═O) _m R ^b15 , —C (═O) OR ^b16 , —C (═O) NR ^c15 R ^d15 , -NR ^c16 R ^d16 or oxo may be substituted)
May be substituted)
(6) a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is at a substitutable position) And
C _1-3 alkyl _optionally substituted with a hydroxyl group or a halogen atom,
C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom,
Hydroxyl group,
Halogen atoms,
Cyano,
-NR ^a15 C (= O) R ^b17 ,
-NR ^a16 C (= O) NR ^c17 R ^d17 ,
-NR ^a17 S (= O) _m R ^b18 ,
-C (= O) OR ^b19 ,
-C (= O) NR ^c18 R ^d18 ,
-S (= O) _m NR ^c19 R ^d19 ,
—S (═O) _m R ^b20 or —NR ^c20 R ^d20
May be substituted)
(7) a 3- to 6-membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S (the aliphatic ring group is At the replaceable position,
C _1-3 alkyl (the alkyl is a hydroxyl group, a halogen atom, cyano, —NR ^a18 C (═O) R ^b21 , —NR ^a19 C (═O) NR ^c21 R ^d21 , —NR ^a20 S (═O) _m ) R ^b22 , —C (═O) OR ^b23 , ^{optionally substituted} with —C (═O) NR ^c22 R ^d22 or —NR ^c23 R ^d23 ),
C _1-3 alkoxy (the alkoxy may be substituted with a hydroxyl group or a halogen atom),
Hydroxyl group,
Halogen atoms,
Cyano,
-NR ^a21 C (= O) R ^b24 ,
-NR ^a22 C (= O) NR ^c24 R ^d24 ,
-NR ^a23 S (= O) _m R ^b25 ,
-C (= O) OR ^b26 ,
^{-C (= O) NR c25 R} d25,
-S (= O) _m NR ^c26 R ^d26 ,
-S (= O) _m R ^b27 ,
In -NR ^c27 R ^d27 or oxo may be substituted),
(8) -NR ^a24 R ^e,
(9) -OR ^{e '} ,
(10) -C (= O) ^Rf ,
(11) -S (= O) _m R ^g ,
(12) may be substituted with one or more substituents selected from the group consisting of thiol and (13) nitro,
Here, the saturated or unsaturated aliphatic ring group is in a substitutable position,
A hydroxyl group, a halogen atom, cyano, nitro, C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), C _1-6 alkoxy (the alkoxy is , ^Optionally substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), —NR ^a25 C (═O) R ^b28 , —NR ^a26 C (═O) NR ^c28 R ^d28 , —NR ^{a27 _{S (= O) m R b29}} , -C (= O) oR b30, -C (= O) R b31, -C (= O) may be substituted with NR ^c29 R ^d29 or -NR ^c30 R ^d30 ,
Here, the aromatic ring group is a substitutable position,
A hydroxyl group, a halogen atom, cyano, nitro, C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), C _1-6 alkoxy (the alkoxy is And may be substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), —NR ^a28 C (═O) R ^b32 , —NR ^a29 C (═O) NR ^c31 R ^d31 , —NR ^{a30 _{S (= O) m R b33}} , -C (= O) OR b34, -C (= O) R b35, -C (= O) NR c32 R d32, -S (= O) m NR c33 R d33, -S (= O) _m R ^b36 or -NR ^{c 34} R ^d34 may be substituted with,
R ² represents C _1-3 alkyl (the alkyl may be substituted with a hydroxyl group or a halogen atom);
R ³ and R ⁴ each independently represent a hydrogen atom or C _1-3 alkyl (the alkyl may be substituted with a hydroxyl group or a halogen atom);
Ar ¹ is a 5- to 6-membered aromatic ring group which may contain 1 to 3 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a substitutable position). In C _1-6 alkyl optionally substituted with a hydroxyl group or a halogen atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro or —NR ^c35 R ^d35 or more are replaced)
L is a 5- to 6-membered unsubstituted aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S, or —S (═O) _q —. Show
Ar ² is a 5- to 6-membered aromatic ring group which may contain 1 to 3 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a substitutable position). In C _1-6 alkyl optionally substituted with a hydroxyl group, cyano, or a halogen atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro,- S (═O) _n R ^h or —NR ^c36 R ^d36 or more).
^Re is
Hydrogen atom,
C _1-6 alkyl (which may be substituted with a hydroxyl group, cyano, halogen atom, C _1-3 alkoxy or —NR ^c37 R ^d37 ),
-A,
-C (= O) -A ',
C _1-6 alkylcarbonyl (the alkyl part of the alkylcarbonyl may be substituted with a hydroxyl group or a halogen atom),
C _1-6 alkoxycarbonyl (the alkyl part of the alkoxycarbonyl may be substituted with a hydroxyl group or a halogen atom),
-C (= O) shows the NR ^C38 R ^d38 or ^{_{-S (= O) m R b37}} ,
R ^{e ′} represents —A ″ or —C (═O) NR ^c39 R ^d39 ,
R ^f is
Hydrogen atom,
Hydroxyl group,
C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano or halogen atom),
C _1-3 alkoxy (the alkoxy may be substituted with phenyl, hydroxyl, cyano or halogen atom optionally substituted with methoxy or nitro),
-B or -NR ^a30 R ⁱ ,
R ^g is
Hydroxyl group,
C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano or halogen atom),
-D or -NR ^a31 R ^{i '}
R ^h represents C _1-6 alkyl which may be substituted with a hydroxyl group or a halogen atom;
R ⁱ is
Hydrogen atom,
C _1-6 alkyl (said alkyl, hydroxyl, cyano, halogen atom, C _1-3 alkoxy, optionally substituted with C _3-6 cycloalkyl or -NR ^c40 R ^d40),
-B 'or -C (= O) R ^b38
Indicate
R ^{i ′} is
Hydrogen atom,
C _1-6 alkyl (which may be substituted with a hydroxyl group, cyano, halogen atom, C _1-3 alkoxy, C _3-6 cycloalkyl or —NR ^c41 R ^d41 ) or —D ′
Indicate
A, A ′, A ″, B, B′D, and D ′ are each independently
A 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a hydroxyl group at a substitutable position) Alternatively, C _1-3 alkyl optionally substituted with a halogen atom, hydroxyl group, or C _1-3 alkoxy optionally substituted with a halogen atom, hydroxyl group, halogen atom, cyano, —C (═O) OH, or —NR ^c42 R ^d42 ) or a 3-6 membered saturated or unsaturated aliphatic ring optionally containing 1-2 heteroatoms selected from the group consisting of N, O and S Group (the aliphatic cyclic group is a C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom at a substitutable position, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, Hydroxyl group, halogen atom, cyano, -C (= O) OH, ^optionally substituted with -NR ^c43 R ^d43 or oxo)
R ^{a1 to} R ^a31 each independently represent a hydrogen atom or a C _1-3 alkyl which may be substituted with a hydroxyl group or a halogen atom;
^{R b1, R b4, R b8} , R b9, R b12, R b16, R b19, R b23, R b26, R b30 and R ^b34 each independently represent a hydrogen atom, substituted by a hydroxyl group or halogen atom C _1-6 alkyl, which may be substituted, or benzyl optionally substituted with methoxy or nitro,
^{R b2, R b3, R b5} , R b6, R b7, R b10, R b11, R b13, R b14, R b15, R b17, R b18, R b20, R b21, R b22, R b24, R b25 , R ^b27 , R ^b28 , R ^b29 , R ^b31 , R ^b32 , R ^b33 , R ^b35 , R ^b36 , R ^b37 and R ^b38 are each independently C ₁ which may be substituted with a hydroxyl group or a halogen atom. _-6 alkyl, or C _3-6 cycloalkyl optionally substituted with a hydroxyl group or a halogen atom,
^{R c1, R c2, R c3} , R c4, R c6, R c7, R c8, R c9, R c10, R c11, R c12, R c14, R c15, R c17, R c18, R c19, R c21 ^{, R c22, R c24, R} c25, R c26, R c28, R c29, R c31, R c32, R c33, R c38, R c39, R d1, R d2, R d3, R d4, R d6, R ^{d7, R d8, R d9,} R d10, R d11, R d12, R d14, R d15, R d17, R d18, R d19, R d21, R d22, R d24, R d25, R d26, R d28, R ^d29 , R ^d31 , R ^d32 , R ^d33 , R ^d38, and R ^d39 each independently represent a hydrogen atom, or C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, or the same A 4-6 membered saturated or unsaturated aliphatic ring group containing 1-2 heteroatoms selected from the group consisting of N and O taken together by substituents attached to the nitrogen atom (the saturated Other unsaturated aliphatic cyclic group may be formed may be substituted with a hydroxyl group or a halogen atom) at substitutable positions,
^{R c5, R c13, R c16} , R c20, R c23, R c27, R c30, R c34, R c37, R c40, R c41, R c42, R c43, R d5, R d13, R d16, R d20 ^{, R d23, R d27, R} d30, R d34, R d37, R d40, R d41, R d42 and R ^d43 are each independently hydrogen atom or a hydroxyl group or a halogen atom which may be substituted in C, and 4-6 membered saturated or substituted with 1 to 2 heteroatoms selected from the group consisting of N and O, together with _1-3 substituents attached to the same nitrogen atom An unsaturated aliphatic cyclic group (the saturated or unsaturated aliphatic cyclic group may be substituted with a hydroxyl group, a halogen atom or oxo at a substitutable position);
R ^c35 , R ^c36 , R ^d35 and R ^d36 each independently represent a hydrogen atom, C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, or a substituent bonded to the same nitrogen atom 4-6 membered saturated aliphatic ring group containing 1 or 2 N together (the saturated aliphatic ring group is substituted with a hydroxyl group or a halogen atom at a substitutable position). May be formed)
m represents an integer of 1 or 2,
n represents an integer of 0 to 2,
q represents an integer of 0 to 2]
Or a physiologically acceptable salt thereof.

[Term 2] R ⁰ is —C (═O) NR ^a1 —, —S (═O) ₂ NR ^a2 —, —C (═O) O—, —C (═O) — or —S (= Item _2. The compound according to Item 1 or a physiologically acceptable salt thereof, which represents O) _2- .

[Claim 3] Ar ¹ is the following Ar ¹ -1 or Ar ¹ -2:

（各基中、Ｅ^１、Ｅ^２、Ｅ^３およびＥ^４は、それぞれ独立して、炭素原子または窒素原子を示し（但し、Ｅ^１、Ｅ^２、Ｅ^３およびＥ^４が全て同時に窒素原子を示す場合を除く）、Ｇ^１、Ｇ^２およびＧ^３は、それぞれ独立して、炭素原子またはＮ、ＯおよびＳからなる群から選択されるヘテロ原子を示し、Ｘは、水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-6アルキル、水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノ、ニトロまたは−ＮＲ^c35Ｒ^d35を示し、Ｅ^１、Ｅ^２、Ｅ^３、Ｅ^４、Ｇ^１、Ｇ^２またはＧ^３の置換可能な位置に、さらに水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-6アルキル、水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノ、ニトロおよび−ＮＲ^c35Ｒ^d35からなる群から選択される置換基を有していてもよく、Ｒ^c35およびＲ^d35は項１に記載の定義と同じものを示す）
を示す、項１または２に記載の化合物またはその生理的に許容される塩。

(In each group, E ¹ , E ² , E ³ and E ⁴ each independently represent a carbon atom or a nitrogen atom (provided that E ¹ , E ² , E ³ and E ⁴ all represent a nitrogen atom at the same time). G ¹ , G ² and G ³ each independently represent a carbon atom or a heteroatom selected from the group consisting of N, O and S, and X is substituted with a hydroxyl group or a halogen atom C _1-6 alkyl which may be substituted, C _1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro or —NR ^c35 R ^d35 , and E ¹ , E ² , E ³ , E ⁴ , G ¹ , G ² or G ³ may be further substituted with a C _1-6 alkyl, hydroxyl group or halogen atom which may be further substituted with a hydroxyl group or a halogen atom. Yo ^Or a substituent selected from the group consisting of C _1-3 alkoxy, hydroxyl group, halogen atom, cyano, nitro and —NR ^c35 R ^d35 , wherein R ^c35 and R ^d35 are defined as described in Item 1. Indicates the same)
Item 3. The compound according to Item 1 or 2, or a physiologically acceptable salt thereof.

[Claim 4] Ar ² is the following Ar ² -1 or Ar ² -2:

（各基中、Ｋ^１、Ｋ^２、Ｋ^３およびＫ^４は、それぞれ独立して炭素原子または窒素原子を示し（但し、Ｋ^１、Ｋ^２、Ｋ^３およびＫ^４が全て同時に窒素原子を示す場合を除く）、Ｌ^１、Ｌ^２およびＬ^３は、それぞれ独立して、炭素原子またはＮ、ＯおよびＳからなる群から選択されるヘテロ原子を示し、Ｙは、水酸基、シアノ若しくはハロゲン原子で置換されていてもよいＣ_1-6アルキル、水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノ、ニトロ、−Ｓ（＝Ｏ）_nＲ^ｈまたは−ＮＲ^c36Ｒ^d36を示し、Ｋ^１、Ｋ^２、Ｋ^３、Ｋ^４、Ｌ^１、Ｌ^２またはＬ^３の置換可能な位置に、さらに水酸基、シアノ若しくはハロゲン原子で置換されていてもよいＣ_1-6アルキル、水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノ、ニトロ、−Ｓ（＝Ｏ）_nＲ^ｈおよび−ＮＲ^c36Ｒ^d36からなる群より選択される置換基を有していてもよく、ｎ、Ｒ^ｈ、Ｒ^c36およびＲ^d36は項１に記載の定義と同じものを示す）
を示す、項１〜３のいずれかに記載の化合物またはその生理的に許容される塩。

(In each group, K ¹ , K ² , K ³ and K ⁴ each independently represent a carbon atom or a nitrogen atom (provided that K ¹ , K ² , K ³ and K ⁴ all simultaneously represent a nitrogen atom) L ¹ , L ² and L ³ each independently represents a carbon atom or a heteroatom selected from the group consisting of N, O and S, and Y represents a hydroxyl group, a cyano or a halogen atom. optionally substituted C _1-6 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, cyano, _{nitro, -S (= O) n R} h or -NR ^c36 R ^d36 represents C _1- which may be further substituted with a hydroxyl group, cyano or halogen atom at a substitutable position of K ¹ , K ² , K ³ , K ⁴ , L ¹ , L ² or L ^3. ₆ alkyl, hydroxyl Wakashi Which may be C _1-3 alkoxy substituted by halogen atom, a hydroxyl group, a halogen atom, cyano, nitro, -S (= O) _n R ^h and -NR ^c36 substituent selected from the group consisting of R ^d36 And n, R ^h , R ^c36 and R ^d36 are the same as defined in item 1)
Item 4. The compound according to any one of Items 1 to 3, or a physiologically acceptable salt thereof.

[Item 5] L is a 5- to 6-membered unsubstituted aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S. '):

で示される、項１〜４のいずれかに記載の化合物またはその生理的に許容される塩。

Item 5. The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 4, which is represented by:

CLAIM | ITEM 6 The compound or its physiologically acceptable salt in any one of claim | item 1-4 whose L is -S (= O) _q- and q is 1 or 2.

CLAIM | ITEM 7 The compound or its physiologically acceptable salt in any one of claim | item 1 -6 whose R < ³ > and R < ⁴ > is respectively independently a hydrogen atom or unsubstituted _C1-3 alkyl. .

[Item 8] The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 7, wherein R ⁰ is —C (═O) NH— or —S (═O) ₂ NH—.

[Item 9] R ¹ is a hydrogen atom, C _1-10 alkyl (wherein the alkyl may be substituted with the same substituent as defined in Item 1 at a substitutable position) or N, O, and S 3 to 6-membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of the above-mentioned (1), wherein the aliphatic ring group is a substitutable position; The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 8, which may be substituted with the same substituent as defined above.

[Claim 10] R ¹ is hydrogen atom or C _1-10 alkyl (in said alkyl substitutable position may be substituted by the same substituents as defined according to claim 1),
A and A ″ are each independently substituted, from the group consisting of phenyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl Selected from the group consisting of selected aromatic ring groups or optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrrolinyl, dihydropyridinyl and tetrahydropyridinyl A saturated aliphatic cyclic group,
A ′ is an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and isothiazolyl, or optionally substituted cyclopropyl, cyclobutyl, A saturated aliphatic ring group selected from the group consisting of cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl;
B and D are each independently selected from the group consisting of optionally substituted phenyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl Aromatic cyclic groups or optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl and isothiazolidinyl A saturated aliphatic cyclic group selected from the group consisting of:
B ′ and D ′ are each independently an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl and tetrazolyl, or A saturated aliphatic cyclic group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl, which may be substituted;
The substituent of the substituted aromatic ring group in this section is a C _1-3 alkyl which may be substituted with a hydroxyl group or a halogen atom, a C _1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group , A halogen atom, cyano, —C (═O) OH, or —NR ^c42 R ^d42 (wherein R ^c42 and R ^d42 are the same as defined in item 1),
The substituent of the substituted saturated aliphatic cyclic group is C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen Item ^{10. The} item according to any one of Items 1 to 9, which is an atom, cyano, —C (═O) OH, —NR ^c43 R ^d43 (wherein R ^c43 and R ^d43 are the same as defined in Item 1) or oxo. Or a physiologically acceptable salt thereof.

[Item 11] R ¹ is a hydrogen atom or C _1-10 alkyl (wherein the alkyl is a substitutable position,
(1) hydroxyl group,
(2) a halogen atom,
(3) Cyano,
(6) a 5-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is at a substitutable position;
C _1-3 alkyl _optionally substituted with a hydroxyl group or a fluorine atom,
C _1-3 alkoxy optionally substituted with a hydroxyl group or a fluorine atom,
Hydroxyl group,
Halogen atoms,
Cyano,
-NR ^a15 C (= O) R ^b17 ,
-NR ^a16 C (= O) NR ^c17 R ^d17 ,
-NR ^a17 S (= O) _m R ^b18 ,
-C (= O) OR ^b19 ,
-C (= O) NR ^c18 R ^d18 ,
-S (= O) _m NR ^c19 R ^d19 ,
—S (═O) _m R ^b20 or —NR ^c20 R ^d20
May be substituted)
(7) a 3- to 6-membered saturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S (the saturated aliphatic ring group is substitutable) In position,
C _1-3 alkyl (the alkyl is a hydroxyl group, a fluorine atom, cyano, —NR ^a18 C (═O) R ^b21 , —NR ^a19 C (═O) NR ^c21 R ^d21 , —NR ^a20 S (═O) _m ) R ^b22 , —C (═O) OR ^b23 , —C (═O) NR ^c22 R ^d22 or —NR ^c23 R ^d23 may be substituted),
C _1-3 alkoxy (the alkoxy may be substituted with a hydroxyl group or a fluorine atom),
Hydroxyl group,
Fluorine atom,
Cyano,
-NR ^a21 C (= O) R ^b24 ,
-NR ^a22 C (= O) NR ^c24 R ^d24 ,
-NR ^a23 S (= O) _m R ^b25 ,
-C (= O) OR ^b26 ,
^{-C (= O) NR c25 R} d25,
In -NR ^c27 R ^d27 or oxo may be substituted),
(8) -NR ^a24 R ^e,
(9) -OR ^{e '} ,
(10) -C (= O) R f and (11) -S (= O) m R g
And optionally substituted with one or more substituents selected from the group consisting of:
R ^{a1 to} R ^a17 and R ^{a25 to} R ^a29 each independently represent a hydrogen atom or methyl,
R ^{a18 to} R ^a24 and R ^{a30 to} R ^a31 each independently represent a hydrogen atom, or C _1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom,
^{R b1, R b4, R b8} , R b9, R b12, R b16, R b19, R b23, R b26, R b30 and R ^b34 each independently represent a hydrogen atom or an unsubstituted C _1-6 alkyl Indicate
^{R b2, R b3, R b5} , R b6, R b7, R b10, R b11, R b13, R b14, R b15, R b17, R b18, R b20, R b21, R b22, R b24, R b25 , R ^b27 , R ^b28 , R ^b29 , R ^b31 , R ^b32 , R ^b33 , R ^b35 , R ^b36 , R ^b37 and R ^b38 are each independently C ₁ which may be substituted with a hydroxyl group or a fluorine atom. _-6 alkyl, or C _3-6 cycloalkyl optionally substituted with a hydroxyl group or a fluorine atom,
^{R c17, R c18, R c19} , R c21, R c22, R c24, R c25, R c38, R d17, R d18, R d19, R d21, R d22, R d24, R d25 and R ^d38 are each Independently, a hydrogen atom, or C _1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom, or together, 1-2 hetero selected from the group consisting of N and O A 4- to 6-membered saturated aliphatic cyclic group containing atoms (the saturated aliphatic cyclic group may be substituted with a hydroxyl group or a fluorine atom at a substitutable position),
^{R c20, R c23, R c27} , R c37, R c40, R c41, R c42, R c43, R d20, R d23, R d27, R d37, R d40, R d41, R d42 and R ^d43 are each Independently represents 1 to 2 hetero atoms, selected from the group consisting of N and O, each independently representing a hydrogen atom, or a C _1-6 alkyl optionally substituted with a hydroxyl group or a fluorine atom A 4- to 6-membered saturated aliphatic cyclic group containing an atom (the saturated aliphatic cyclic group may be substituted with a hydroxyl group, a fluorine atom or oxo at a substitutable position);
R ^c35 , R ^c36 , R ^d35 and R ^d36 each independently represent a hydrogen atom, or C _1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom,
^Re is
C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, fluorine atom, C _1-3 alkoxy or —NR ^c37 R ^d37 ),
-A,
-C (= O) -A ',
C _1-6 alkylcarbonyl (the alkyl part of the alkylcarbonyl may be substituted with a hydroxyl group or a fluorine atom),
-C (= O) shows the NR ^C38 R ^d38 or ^{_{-S (= O) m R b37}} ,
R ^{e ′} is
-A ''
R ^f is
Hydroxyl group,
-B or -NR ^a30 R ⁱ ,
R ^g is
Hydroxyl group,
C _1-6 alkyl (which may be substituted with a hydroxyl group, cyano or fluorine atom),
-D or -NR ^a31 R ^{i '}
R ^h represents methyl,
R ⁱ is
Hydrogen atom,
C _1-6 alkyl (said alkyl, hydroxyl, cyano, fluorine atom, C _1-3 alkoxy, optionally substituted with _{C 3-6} cycloalkyl or -NR ^c40 R ^d40) indicates or -B ',
R ^{i ′} is
Hydrogen atom,
C _1-6 alkyl (wherein the alkyl may be substituted with a hydroxyl group, cyano, fluorine atom, C _1-3 alkoxy, C _3-6 cycloalkyl or —NR ^c41 R ^d41 ) or —D ′;
A and A ″ are each independently
An aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl (the aromatic ring group may be substituted with a hydroxyl group or a fluorine atom) C _1-3 optionally substituted with _1-3 alkyl, hydroxyl group or fluorine atom, optionally substituted with _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c42 R ^d42 ) Alternatively, a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the saturated aliphatic ring group may be substituted with a hydroxyl group or a fluorine atom) _1-3 alkyl, hydroxyl Wakashi Ku Fluorine atom in an optionally substituted C _1-3 alkoxy, indicates a hydroxyl group, a fluorine atom, cyano, -C a (= O) OH, may be substituted with -NR ^c43 R ^d43 or oxo),
A ′ is an aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and isothiazolyl (the aromatic group is a hydroxyl group or a C _1-3 alkyl which may be substituted with a fluorine atom, a hydroxyl group Or C _1-3 alkoxy optionally substituted with a fluorine atom, hydroxyl group, fluorine atom, cyano, optionally substituted with —C (═O) OH or —NR ^c42 R ^d42 ) or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, saturated aliphatic Hajime Tamaki selected from the group consisting of piperazinyl and morpholinyl (saturated aliphatic cyclic group may be substituted by hydroxyl or fluorine atom C _{1- 3} alkyl, optionally substituted with a hydroxyl group or a fluorine atom C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH, —NR ^c43 R ^d43 or oxo may be substituted),
B is an aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl (the aromatic group may be substituted with a hydroxyl group or a fluorine atom) C _1-3 alkyl, hydroxyl group or fluorine atom optionally substituted with C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c42 R ^d42 Or a saturated aliphatic ring group selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the saturated aliphatic ring group is a C _1-3 alkyl which may be substituted with a hydroxyl group or a fluorine atom, C _1-3A optionally substituted with a hydroxyl group or a fluorine atom Alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH, —NR ^c43 R ^d43 or oxo ^optionally substituted)
D is an aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl (the aromatic group may be substituted with a hydroxyl group or a fluorine atom) C _1-3 alkyl, hydroxyl group or fluorine atom optionally substituted with C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c42 R ^d42 Or a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the saturated aliphatic ring group is substituted with a hydroxyl group or a fluorine atom) Have been Good C _1-3 alkyl, hydroxyl or fluorine atom in an optionally substituted C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C (= O) OH, optionally substituted with -NR ^c43 R ^d43 or oxo You may)
B ′ is an aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and isothiazolyl (the aromatic group is a hydroxyl group or a C _1-3 alkyl which may be substituted with a fluorine atom, a hydroxyl group Or C _1-3 alkoxy optionally substituted with a fluorine atom, hydroxyl group, fluorine atom, cyano, optionally substituted with —C (═O) OH or —NR ^c42 R ^d42 ) or cyclopropyl, cyclobutyl, A saturated aliphatic ring group selected from the group consisting of cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the saturated aliphatic ring group is a hydroxyl group or a C _1-3 alkyl which may be substituted with a fluorine atom, a hydroxyl group; or fluorine atoms which may be substituted with C _1-3 alkoxy, hydroxyl, Tsu atom represents cyano, -C a (= O) OH, may be substituted with -NR ^c43 R ^d43 or oxo),
D ′ is an aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and isothiazolyl (the aromatic group is a hydroxyl group or a C _1-3 alkyl which may be substituted with a fluorine atom, a hydroxyl group Or C _1-3 alkoxy optionally substituted with a fluorine atom, hydroxyl group, fluorine atom, cyano, optionally substituted with —C (═O) OH or —NR ^c42 R ^d42 ) or cyclopropyl, cyclobutyl, A saturated aliphatic ring group selected from the group consisting of cyclopentyl, cyclohexyl and pyranyl (the saturated aliphatic ring group is substituted with a hydroxyl group or a C _1-3 alkyl which may be substituted with a fluorine atom, a hydroxyl group or a fluorine atom; which may be C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C (= O) OH, -N ^c43 R ^d43 or compound or a physiologically acceptable salt thereof according to any one of Items 1 to 10 indicating the may) be substituted by oxo.

[Item 12] R ¹ represents C _1-10 alkyl (wherein the alkyl is a substitutable position,
(1) hydroxyl group,
(2) fluorine atom,
(3) Cyano,
(6) a 5-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is at a substitutable position,
C _1-3 alkyl _optionally substituted with a hydroxyl group or a fluorine atom,
C _1-3 alkoxy optionally substituted with a hydroxyl group or a fluorine atom,
Hydroxyl group,
Halogen atoms,
Cyano,
-C (= O) OH,
^{-C (= O) NR c18 R} d18 or -NR ^{c 20} R ^d20
May be substituted)
(7) a 3- to 6-membered saturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S (the saturated aliphatic ring group is substitutable) In position,
C _1-3 alkyl (which may be substituted with a hydroxyl group, a fluorine atom, cyano, —C (═O) OH or —C (═O) NR ^c22 R ^d22 ),
C _1-3 alkoxy (the alkoxy may be substituted with a hydroxyl group or a fluorine atom),
Hydroxyl group,
Fluorine atom,
Cyano,
-NR ^a21 C (= O) R ^b24 ,
-NR ^a22 C (= O) NR ^c24 R ^d24 ,
-NR ^a23 S (= O) _m R ^b25 ,
-C (= O) OH,
^{-C (= O) NR c25 R} d25,
In -NR ^c27 R ^d27 or oxo may be substituted),
(8) -NR ^a24 R ^e,
(10) -C (= O) R f and (11) -S (= O) m R g
And optionally substituted with one or more substituents selected from the group consisting of:
R ^{a21 to} R ^a23 and R ^{a30 to} R ^a31 each independently represent a hydrogen atom or methyl,
R ^a24 represents a hydrogen atom, or C _1-3 alkyl which may be substituted with a hydroxyl group or a fluorine atom;
R ^b24 ~R ^b25, R ^b37 are each independently a hydroxyl group or a fluorine atom in an optionally substituted C _1-6 alkyl or a hydroxyl group or fluorine optionally C _3-6 cycloalkyl optionally substituted with atoms, Indicate
^{R c18, R c22, R c24} , R c25, R c38, R d18, R d22, R d24, R d25 and R ^d38 are each independently optionally substituted with hydrogen atom or a hydroxyl group or a fluorine atom, or it represents an C _1-3 alkyl, or taken together, azetidine, pyrrolidine, piperidine, saturated heterocyclic aliphatic ring (saturated heteroaliphatic ring group selected from the group consisting of piperazine and morpholine, can be substituted And may be substituted with a hydroxyl group or a fluorine atom at any position)
^{R c20, R c27, R c37} , R c40, R c41, R c43, R d20, R d27, R d37, R d40, R d41 and R ^d43 are each independently hydrogen atom or a hydroxyl group or a fluorine atom, A saturated heteroalicyclic ring group selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine and oxazolidine (C _1-6 alkyl optionally substituted with The saturated heteroaliphatic ring group may be substituted with a hydroxyl group, a fluorine atom or oxo at a substitutable position),
R ^c35 , R ^c36 , R ^d35 and R ^d36 each independently represent a hydrogen atom, methyl or ethyl,
^Re is
C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, fluorine atom, C _1-3 alkoxy or —NR ^c37 R ^d37 ),
-A,
-C (= O) -A ',
C _1-6 alkylcarbonyl (the alkyl part of the alkylcarbonyl may be substituted with a hydroxyl group or a fluorine atom),
-C (= O) shows the NR ^C38 R ^d38 or ^{_{-S (= O) m R b37}} ,
R ^f is
Hydroxyl group,
-B or -NR ^a30 R ⁱ ,
R ^g is
C _1-6 alkyl (which may be substituted with a hydroxyl group, cyano or fluorine atom),
-D or -NR ^a31 R ^{i '}
R ⁱ is
Hydrogen atom,
C _1-6 alkyl (said alkyl, hydroxyl, cyano, fluorine atom, C _1-3 alkoxy, optionally substituted with _{C 3-6} cycloalkyl or -NR ^c40 R ^d40) indicates or -B ',
R ^{i ′} is
Hydrogen atom,
C _1-6 alkyl (wherein the alkyl may be substituted with a hydroxyl group, cyano, fluorine atom, C _1-3 alkoxy, C _3-6 cycloalkyl or —NR ^c41 R ^d41 ) or —D ′;
A is a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the saturated aliphatic ring group may be substituted with a hydroxyl group or a fluorine atom) good C _1-3 alkyl, hydroxyl or fluorine may be substituted with atoms C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C (= O) optionally substituted with OH or -NR ^c43 R ^d43 Good)
A ′ is a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the saturated aliphatic ring group is a hydroxyl group or a fluorine atom) C _1-3 alkyl which may be substituted, C _1-3 alkoxy which may be substituted with hydroxyl group or fluorine atom, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c43 R ^d43 Which may be substituted)
B is a saturated aliphatic ring group selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the saturated aliphatic ring group is a C _1-3 alkyl which may be substituted with a hydroxyl group or a fluorine atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a fluorine atom, a hydroxyl group, a fluorine atom, cyano, —C (═O) OH or —NR ^c43 R ^{d43 optionally} substituted)
D is a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the saturated aliphatic ring group is substituted with a hydroxyl group or a fluorine atom) Substituted with optionally substituted C _1-3 alkyl, hydroxyl group or fluorine atom, C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c43 R ^d43 May be)
B ′ is a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the saturated aliphatic ring group is substituted with a hydroxyl group or a fluorine atom) which may C _1-3 alkyl, hydroxyl or fluorine may be substituted with atoms C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C (= O) substituted with OH or -NR ^c43 R ^d43 Is good)
D 'is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and saturated aliphatic Hajime Tamaki (said saturated aliphatic ring group selected from the group consisting of pyranyl, the hydroxyl or fluorine may be substituted with atoms C _1-3 C _1-3 alkoxy optionally substituted with alkyl, hydroxyl group or fluorine atom, hydroxyl group, fluorine atom, cyano, optionally substituted with —C (═O) OH or —NR ^c43 R ^d43 ),
R ⁰ represents —C (═O) NH— or —S (═O) ₂ NH—,
R ² represents methyl,
R ³ and R ⁴ each independently represent a hydrogen atom or methyl;
L is a benzene ring group, thiophene ring group, furan ring group, pyrrole ring group, imidazole ring group, pyridine ring group, pyrazine ring group, isoxazole ring group, pyrazole ring group, isothiazole ring group, pyrimidine ring group, pyridazine ring. A group, an oxazole ring group, a thiazole ring group, a triazole ring group, a tetrazole ring group or -S (= O) _q-
q is 1 or 2,
Ar ¹ is the following Ar ¹ -1 ′:

（各基中、Ｅ^１、Ｅ^２およびＥ^３は、それぞれ独立して、炭素原子または窒素原子を示し、Ｘは、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-3アルキル、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-3アルコキシ、ハロゲン原子、シアノまたはニトロを示し、Ｅ^１、Ｅ^２またはＥ^３の置換可能な位置に、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-6アルキル、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノおよび−ＮＲ^c35Ｒ^d35から選択される置換基を有していてもよい）を示し、
Ａｒ²が、下記Ａｒ²−１'：

(In each group, E ¹ , E ² and E ³ each independently represents a carbon atom or a nitrogen atom, and X represents a C _1-3 alkyl, hydroxyl group or hydroxyl group which may be substituted with a hydroxyl group or a fluorine atom. C _1-3 alkoxy optionally substituted with a fluorine atom, halogen atom, cyano or nitro is shown, and may be substituted with a hydroxyl group or a fluorine atom at a substitutable position of E ¹ , E ² or E ³ A C _1-6 alkyl, a hydroxyl group or a substituent selected from C _1-3 alkoxy optionally substituted with a fluorine atom, a hydroxyl group, a halogen atom, cyano and —NR ^c35 R ^d35 ). Show
Ar ² is the following Ar ² -1 ′:

（各基中、Ｋ^１、Ｋ^２、Ｋ^３およびＫ^４は、それぞれ独立して、炭素原子または窒素原子を示し（但し、Ｋ^１、Ｋ^２、Ｋ^３およびＫ^４が全て同時に窒素原子を示す場合を除く）、Ｙは、ハロゲン原子、シアノまたはニトロを示し、Ｋ^１、Ｋ^２、Ｋ^３またはＫ^４の置換可能な位置に、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-3アルキル、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノおよび−ＮＲ^c36Ｒ^d36から選択される置換基を有していてもよい）を示す、項１〜１１のいずれかに記載の化合物またはその生理的に許容される塩。

(In each group, K ¹ , K ² , K ³ and K ⁴ each independently represent a carbon atom or a nitrogen atom (provided that K ¹ , K ² , K ³ and K ⁴ are all simultaneously nitrogen atoms) except where indicated), Y represents a halogen atom, a cyano or nitro, a substitutable position of K ^{1, K 2,} K ³ or K ^4, which may be substituted by a hydroxyl group or a fluorine atom C _{1- 3} which may have a substituent selected from C _1-3 alkoxy optionally substituted with alkyl, hydroxyl or fluorine atom, hydroxyl group, halogen atom, cyano and —NR ^c36 R ^d36 ) The compound in any one of 1-11, or its physiologically acceptable salt.

[Item 13] L ′ represents a benzene ring group, a thiophene ring group, a furan ring group, a pyrrole ring group, an imidazole ring group, a pyridine ring group, a pyrazine ring group, an isoxazole ring group, a pyrazole ring group, an isothiazole ring group, or a pyrimidine. The following formula (I ″), which is a cyclic group, a pyridazine ring group, an oxazole ring group, a thiazole ring group, a triazole ring group, or a tetrazole ring group:

で示される、項１〜５、７〜１２のいずれかに記載の化合物またはその生理的に許容される塩。

Item 13. The compound according to any one of Items 1 to 5 and 7 to 12, or a physiologically acceptable salt thereof.

[Item 14] The following formula (I ′ ″) in which q ′ is 1 or 2:

で示される項１〜４、６〜１２のいずれかに記載の化合物またはその生理的に許容される塩。

Item 14. The compound according to any one of Items 1 to 4 and 6 to 12, or a physiologically acceptable salt thereof.

[Item 15] L ′ is a benzene ring group, imidazole ring group, pyridine ring group, pyrazine ring group, isoxazole ring group, pyrazole ring group, pyrimidine ring group, oxazole ring group, triazole ring group or tetrazole ring group Formula (I '' ''):

で示される、項１〜５、７〜１２のいずれかに記載の化合物またはその生理的に許容される塩。

Item 13. The compound according to any one of Items 1 to 5 and 7 to 12, or a physiologically acceptable salt thereof.

[Item 16] A pharmaceutical composition comprising the compound according to any one of Items 1 to 15 or a physiologically acceptable salt thereof as an active ingredient.

CLAIM | ITEM 17 The elastase inhibitor which contains the compound in any one of claim | item 1 -15, or its physiologically acceptable salt as an active ingredient.

[Item 18] A therapeutic or prophylactic agent for inflammatory diseases comprising the compound according to any one of Items 1 to 15 or a physiologically acceptable salt thereof.

[Item 19] A therapeutic or prophylactic agent for a disease requiring an inhibitory activity of elastase, comprising the compound according to any one of Items 1 to 15 or a physiologically acceptable salt thereof.

  According to the present invention, since a compound having elastase inhibitory activity can be provided, a therapeutic or prophylactic agent for a disease involving elastase such as an inflammatory disease can be provided. Diseases that have been suggested to be involved in the pathogenesis of elastase include, for example, chronic obstructive pulmonary disease (COPD), cystic pulmonary fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic Pulmonary fibrosis (IIP), chronic interstitial pneumonia, chronic bronchitis, chronic respiratory tract infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, rheumatoid arthritis, arthrosclerosis, Osteoarthritis, psoriasis, periodontitis, atherosclerosis, organ transplant rejection, early water rupture, blistering, shock, sepsis, systemic lupus erythematosus (SLE), Crohn's disease, disseminated intravascular coagulation ( DIC), tissue damage during ischemia-reperfusion, formation of corneal scar tissue, myelitis, lung squamous cell carcinoma, lung adenocarcinoma, lung cancer such as non-small cell lung cancer, breast cancer, liver cancer, bladder cancer, colon Rectal cancer, skin cancer Pancreatic cancer, such as glioma, and the like.

  Hereinafter, the compound represented by the formula (I) of the present invention will be further described.

  The physiologically acceptable salt of the compound represented by the formula (I) is a physiologically acceptable acid addition salt of the compound of the formula (I) having a group capable of forming an acid addition salt in the structure, Or the salt with the physiologically acceptable base of the compound of the formula (I) which has a group which can form a salt with a base in a structure is meant. Specific examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate, and other inorganic acid salts, oxalate, malonate, Maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfone Organic acid salts such as acid salts, and amino acid salts such as glutamate and aspartate. Specific examples of salts with bases include alkali metal or alkaline earth metal salts such as sodium salt, potassium salt or calcium salt, salts with organic bases such as pyridine salt and triethylamine salt, and lysine, arginine and the like. Examples include salts with amino acids.

  Since the compounds of formula (I) and their salts may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also included in the compounds of the present invention. Is done. That is, the “compound of the present invention” includes these hydrates and / or solvates in addition to the compound represented by the above formula (I) and physiologically acceptable salts thereof.

  In addition, the compound of formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality, and therefore may exist as several stereoisomers. . In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.

  Terms used in this specification will be described below.

“Alkyl” means a linear or branched saturated hydrocarbon group. For example, “C _1-3 alkyl”, “C _1-6 alkyl” or “C _1-10 alkyl” It means a group having 1 to 3, 1 to 6 or 1 to 10 carbon atoms. Specific examples thereof include methyl, ethyl, propyl, isopropyl and the like as “C _1-3 alkyl”, and examples of “C _1-6 alkyl” include butyl, isobutyl, sec-butyl, tert. -Butyl, pentyl, isopentyl, neopentyl, hexyl and the like include "C _1-10 alkyl", in addition to the above, octyl, nonyl, decyl and the like. The alkyl may be linear. Further, it may be branched. The “alkyl” part of “alkylthio” and “alkylcarbonyl” has the same meaning as the above “alkyl”.

“Cycloalkyl” means a cyclic saturated hydrocarbon group. For example, “C _3-6 cycloalkyl” includes cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

“Alkene” means a linear or branched unsaturated hydrocarbon group. For example, “C _2-6 alkene” has 2 to 6 carbon atoms and has one unsaturated bond. Means one group. Specific examples thereof include ethene, 1-propylene, 2-propylene, 1-butene, 2-butene, 3-butene, 1-pentene, 2-pentene, 3-pentene, 4-pentene, 1-hexene, 2- Examples include hexene, 3-hexene, 4-hexene, 5-hexene, 2-methyl-3-butene, 2-methyl-4-pentene, and 3-methyl-4-pentene.

  Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The “alkyl” part of “alkoxy” has the same meaning as the above “alkyl”. For example, specific examples of “C _1-3 alkoxy” include methoxy, ethoxy, n-propoxy, isopropoxy and the like, and “C _1-6 alkoxy” includes n-butoxy, isobutoxy, sec- Examples include butoxy, tert-butoxy, pentyloxy, hexyloxy groups and the like. The “alkoxy” part of “alkoxycarbonyl” has the same meaning as the above “alkoxy”.

  As the “5- to 6-membered aromatic ring group optionally containing 1 to 3 heteroatoms selected from the group consisting of N, O and S”, phenyl, nitrogen atom, oxygen atom and sulfur It means a monocyclic 5-6 membered aromatic heterocyclic group consisting of 1 to 3 heteroatoms selected from the group consisting of atoms and carbon atoms. Specific examples include phenyl, thienyl, furyl, pyrrolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, pyridazinyl, triazolyl and the like.

  As the “5- to 6-membered aromatic ring group optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S”, phenyl, nitrogen atom, oxygen atom and sulfur It means a monocyclic 5 to 6-membered aromatic heterocyclic group consisting of 1 to 4 heteroatoms selected from the group consisting of atoms and carbon atoms, and includes tetrazolyl and the like in addition to the above examples.

  The “5-membered aromatic ring group optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S” is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom A monocyclic 5-membered aromatic heterocyclic group consisting of 1 to 4 heteroatoms and carbon atoms, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, Examples include thiadiazolyl, triazolyl, tetrazolyl and the like.

  The “3- to 6-membered saturated aliphatic cyclic group optionally containing 1 to 2 heteroatoms selected from the group consisting of N, O and S” is a monocyclic ring having 3 to 6 carbon atoms. Or a saturated 6-membered monocyclic saturated heterocyclic group having 1 to 2 atoms of the same or different types selected from a nitrogen atom, an oxygen atom and a sulfur atom. The nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring. Specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, isothiazolidinyl, isothiazolidinyl, Nil and the like.

  Examples of the “4- to 6-membered saturated aliphatic cyclic group containing 1 to 2 heteroatoms selected from the group consisting of N and O” include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolidinyl, oxazolidinyl and the like. It is done.

  The “4- to 6-membered unsaturated aliphatic cyclic group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S” is a monovalent group having 4 to 6 carbon atoms. An unsaturated hydrocarbon aliphatic cyclic group of a ring, or a 4-6 membered unsaturated heteroaliphatic cyclic group having 1 to 2 atoms of the same or different kinds selected from a nitrogen atom, an oxygen atom and a sulfur atom, etc. Can be mentioned. The nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring. Specific examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, dihydropyranyl, dihydrofuranyl, pyrrolinyl, imidazolinyl, pyrazolinyl, oxazolinyl, thiazolinyl, dihydropyridinyl, tetrahydropyridinyl and the like.

  The “4- to 6-membered unsaturated aliphatic cyclic group containing 1 to 2 heteroatoms selected from the group consisting of N and O” is the same or different 1 to 2 selected from a nitrogen atom and an oxygen atom Examples thereof include a 4- to 6-membered monocyclic unsaturated heteroaliphatic cyclic group having 2 atoms. Both the nitrogen atom and the oxygen atom are atoms constituting a ring. Specific examples include dihydropyranyl, dihydrofuranyl, pyrrolinyl, imidazolinyl, pyrazolinyl, oxazolinyl, dihydropyridinyl, tetrahydropyridinyl and the like.

  Examples of the “4- to 6-membered saturated aliphatic cyclic group containing 1 and 2 N” include 4- to 6-membered saturated heteroaliphatic cyclic groups having 1 to 2 nitrogen atoms. It is an atom constituting the nitrogen atom ring. Specific examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl and the like.

  “Alkyl substituted with a halogen atom” refers to one in which one or more (for example, 1 to 5, preferably 1 to 3) hydrogen atoms of the alkyl are substituted with a halogen atom. Specifically, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1-methyl-2,2,2-trifluoroethyl, 3,3, Examples include 3-trifluoropropyl, 4,4,4-trifluorobutyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, and the like. The same applies to each of the following substituents substituted with a halogen atom: alkoxy, alkiothio, alkylcarbonyl, alkoxycarbonyl, aromatic ring group, saturated aliphatic ring group, unsaturated aliphatic ring group and the like.

  “Alkyl substituted with a hydroxyl group” means one in which one or more (for example, 1 to 5, preferably 1 to 2) hydrogen atoms of the alkyl are substituted with a hydroxyl group. Specifically, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxy Butyl, 3,4-dihydroxybutyl, 2,4-dihydroxybutyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 2,5-hydroxypentyl, 3,5-hydroxypentyl, 2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 6-hydroxyhexyl, 2,6-dihydroxyhexyl, 3,6-dihydroxyhexyl, 4,6-dihydroxyhexyl, 2-hydroxyisopropyl 2-hydroxy sec-butyl, 3-hydroxy sec-butyl, 2-hydroxy tert-butyl, 3-methyl-5-hydroxypentyl, 3-methyl-3-hydroxypentyl, 4-methyl-5-hydroxypentyl, 4 -Methyl-4-hydroxypentyl, 4-methyl-3-hydroxypentyl and the like. The same applies to the following substituents substituted with a hydroxyl group: alkoxy, alkiothio, alkylcarbonyl, alkoxycarbonyl, aromatic ring group, saturated aliphatic ring group, unsaturated aliphatic ring group and the like.

  The “aromatic ring group substituted with cyano” refers to one in which one or more (for example, 1 to 2) hydrogen atoms of the aromatic ring group are substituted with cyano. Specific examples include p-cyanophenyl, m-cyanophenyl, 2-cyanopyridyl, 3-cyanopyridyl, 4-cyanopyridyl and the like. The same applies to the following substituents substituted with cyano: alkyl, alkoxy, alkiothio, alkylcarbonyl, saturated aliphatic cyclic group, unsaturated aliphatic cyclic group and the like.

  “Alkyl substituted with alkoxy” refers to one in which one or more (for example, 1 to 3) hydrogen atoms of the above alkyl are substituted with alkoxy. Specifically, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, isopropoxypropyl, methoxyisopropyl, ethoxyisopropyl, propoxyisopropyl, isopropoxyisopropyl, methoxybutyl, ethoxybutyl, Examples include propoxybutyl, isopropoxybutyl, methoxyisobutyl, ethoxyisobutyl, propoxyisobutyl, and isopropoxyisobutyl. The same applies to the following substituents substituted with alkoxy: aromatic group, alkylcarbonyl, saturated aliphatic cyclic group, unsaturated aliphatic cyclic group and the like.

  “Alkyl substituted with an optionally substituted aromatic ring group” means that one or more hydrogen atoms of the above alkyl are substituted with an “optionally substituted aromatic ring group”. Say. Specifically, an aromatic ring group such as phenyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl and the like which may be substituted may be substituted at any hydrogen atom of alkyl having 1 to 6 carbon atoms. Specific examples of the substituent of the aromatic ring group that may be used include methoxy, methanesulfonyl, dimethylamino, cyano and the like. Specifically, (4-methoxyphenyl) methyl, (4-methanesulfonylphenyl) propyl, (4-dimethylaminophenyl) propyl, (2-cyanopyridyl) butyl, 3- (4-cyanophenyl) -3- And methylpropyl. The same applies to the following substituents substituted with an optionally substituted aromatic ring group: alkoxy, alkiothio and the like.

  Examples of the saturated aliphatic cyclic group substituted with oxo include those in which the hydrogen atom of the saturated aliphatic cyclic group is substituted with 1 to 2 oxo groups, such as 2-oxocyclopentyl, 3-oxocyclopentyl, 2-oxocyclohexyl, 3-oxocyclohexyl, 4-oxocyclohexyl, 2-oxopyrrolidinyl, 3-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, 2-oxopiperidinyl, 3-oxopi Peridinyl, 4-oxopiperidinyl, 2,6-dioxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, 2-oxomorpholinyl, 2-oxothiomorpholinyl, oxoimidazo Illustrative examples include lydinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, etc. .

  The unsaturated aliphatic ring group substituted with oxo refers to one in which the hydrogen atom of the unsaturated aliphatic ring group is substituted with 1 to 2 oxo groups, for example, oxocyclopentenyl, oxocyclohexenyl, Examples include oxopyrrolinyl, oxoimidazolinyl, oxooxazolinyl, oxothiazolinyl, oxodihydropyridinyl, oxotetrahydropyridinyl and the like.

  Other groups are similarly defined and exemplified from the above examples. Moreover, an aliphatic cyclic group means an alicyclic group.

  Each group in the present invention will be described.

R ^{a1 to} R ^a31 each independently represents a hydrogen atom, or C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom;
Preferably, R ^{a1 to} R ^a17 and R ^{a25 to} R ^a29 each independently represent a hydrogen atom or methyl, and R ^{a18 to} R ^a24 and R ^{a30 to} R ^a31 each independently represent a hydrogen atom, a hydroxyl group, Represents C _1-3 alkyl _optionally substituted with a fluorine atom,
More preferably, R ^{a21 to} R ^a23 and R ^{a30 to} R ^a31 each independently represent a hydrogen atom or methyl.

^{R b1, R b4, R b8} , R b9, R b12, R b16, R b19, R b23, R b26, R b30 and R ^b34 each independently represent a hydrogen atom, substituted by a hydroxyl group or halogen atom _Represents optionally substituted C _1-6 alkyl, or benzyl optionally substituted with methoxy or nitro,
^{Preferably, R b1, R b4, R} b8, R b9, R b12, R b16, R b19, R b23, R b26, R b30 and R ^b34 are each independently, C ₁ hydrogen atom or an unsubstituted Represents _-6 alkyl.

^{R b2, R b3, R b5} , R b6, R b7, R b10, R b11, R b13, R b14, R b15, R b17, R b18, R b20, R b21, R b22, R b24, R b25 , R ^b27 , R ^b28 , R ^b29 , R ^b31 , R ^b32 , R ^b33 , R ^b35 , R ^b36 , R ^b37 and R ^b38 are each independently C ₁ which may be substituted with a hydroxyl group or a halogen atom. _-6 alkyl, a hydroxyl group or a C _3-6 cycloalkyl optionally substituted with a halogen atom,
^{Preferably, R b2, R b3, R} b5, R b6, R b7, R b10, R b11, R b13, R b14, R b15, R b17, R b18, R b20, R b21, R b22, R b24 ^{, R b25, R b27, R} b28, R b29, R b31, R b32, R b33, R b35, R b36, R b37 and R ^b38 are each independently be substituted with a hydroxyl group or a fluorine atom Good C _1-6 alkyl, or C _3-6 cycloalkyl optionally substituted with a hydroxyl group or a fluorine atom,

^{R c1, R c2, R c3} , R c4, R c6, R c7, R c8, R c9, R c10, R c11, R c12, R c14, R c15, R c17, R c18, R c19, R c21 ^{, R c22, R c24, R} c25, R c26, R c28, R c29, R c31, R c32, R c33, R c38, R c39, R d1, R d2, R d3, R d4, R d6, R ^{d7, R d8, R d9,} R d10, R d11, R d12, R d14, R d15, R d17, R d18, R d19, R d21, R d22, R d24, R d25, R d26, R d28, R ^d29 , R ^d31 , R ^d32 , R ^d33 , R ^d38, and R ^d39 each independently represent a hydrogen atom, C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, or the same A 4- to 6-membered saturated or unsaturated heteroaliphatic ring group containing 1 to 2 heteroatoms selected from the group consisting of N and O taken together by a substituent bonded to the nitrogen atom A saturated aliphatic cyclic group may be substituted with a hydroxyl group or a halogen atom at a substitutable position),
^{Preferably, R c17, R c18, R} c19, R c21, R c22, R c24, R c25, R c38, R d17, R d18, R d19, R d21, R d22, R d24, R d25 and R ^d38 Each independently represents a hydrogen atom or a C _1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom, or together, is selected from the group consisting of N and O 1-2 A 4- to 6-membered saturated heteroalicyclic group containing 1 heteroatom (the saturated aliphatic ring group may be substituted with a hydroxyl group or a fluorine atom at a substitutable position),
More ^{preferably, R c18, R c22, R} c24, R c25, R c38, R d18, R d22, R d24, R d25, and R ^d38 are each independently hydrogen atom or a hydroxyl group or a fluorine atom, A saturated heteroalicyclic group selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, and morpholine (which is optionally substituted _C1-3 alkyl) The cyclic group may be substituted with a hydroxyl group or a fluorine atom at a substitutable position.

^{R c5, R c13, R c16} , R c20, R c23, R c27, R c30, R c34, R c37, R c40, R c41, R c42, R c43, R d5, R d13, R d16, R d20 ^{, R d23, R d27, R} d30, R d34, R d37, R d40, R d41, R d42 and R ^d43 are each independently hydrogen atom or a hydroxyl group or a halogen atom which may be substituted in C, and _1-3 represents an alkyl, or substituted groups attached to the same nitrogen atom are taken together, containing 1-2 heteroatoms selected from the group consisting of N and O, 4 to 6 membered saturated or Represents an unsaturated heteroaliphatic cyclic group (which may be substituted with a hydroxyl group, a halogen atom or oxo at a substitutable position);
^{Preferably, R c20, R c23, R} c27, R c37, R c40, R c41, R c42, R c43, R d20, R d23, R d27, R d37, R d40, R d41, R d42 and R ^d43 Each independently represents a hydrogen atom, or a C _1-6 alkyl optionally substituted with a hydroxyl group or a fluorine atom, or together, is selected from the group consisting of N and O 1-2 A 4- to 6-membered saturated heteroalicyclic group containing 1 heteroatom (the saturated aliphatic ring group may be substituted with a hydroxyl group, a fluorine atom or oxo at a substitutable position) ,
More ^{preferably, R c20, R c27, R} c37, R c40, R c41, R c43, R d20, R d27, R d37, R d40, R d41 and R ^d43 are each independently hydrogen atom or, C _1-6 alkyl optionally substituted with a hydroxyl group or a fluorine atom, or together, a saturated hetero selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, and oxazolidine An aliphatic cyclic group (the saturated heteroaliphatic cyclic group may be substituted with a hydroxyl group, a fluorine atom or oxo at a substitutable position).

R ^c35 , R ^c36 , R ^d35 and R ^d36 each independently represent a hydrogen atom, C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, or a substituent bonded to the same nitrogen atom 4 to 6-membered saturated heteroaliphatic cyclic group containing 1 or 2 nitrogen atoms together (the saturated aliphatic cyclic group is substituted with a hydroxyl group or a halogen atom at a substitutable position) May be)
Preferably, R ^c35 , R ^c36 , R ^d35 and R ^d36 each independently represent a hydrogen atom or a C _1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom,
More preferably, R ^c35 , R ^c36 , R ^d35 and R ^d36 each independently represent a hydrogen atom, methyl or ethyl.

R ^e is a hydrogen atom, C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, a halogen atom, C _1-3 alkoxy, or —NR ^c37 R ^d37 ), —A, —C (═O) —A ′, C _1-6 alkylcarbonyl (the alkyl part of the alkylcarbonyl may be substituted with a hydroxyl group or a halogen atom), C _1-6 alkoxycarbonyl (the alkyl part of the alkoxycarbonyl is a hydroxyl group) Or optionally substituted with a halogen atom), -C (= O) NR ^c38 R ^d38 or -S (= O) _m R ^b37 ,
Preferably, C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, fluorine atom, C _1-3 alkoxy, or —NR ^c37 R ^d37 ), —A, —C (═O) -A ', C _1-6 alkylcarbonyl (the alkyl moiety of the alkylcarbonyl may be substituted with a hydroxyl group or a fluorine atom), -C (= O) NR ^c38 R ^d38 or -S (= O) _m R ^b37 is represented.

R ^{e ′} represents —A ″ or —C (═O) NR ^c39 R ^d39 , and preferably represents —A ″.

R ^f is a hydrogen atom, a hydroxyl group, C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano or a halogen atom), C _1-3 alkoxy (the alkoxy is substituted with methoxy or nitro) An optionally substituted phenyl, hydroxyl group, cyano or halogen atom), -B or -NR ^a30 R ⁱ ,
Preferably, it represents a hydroxyl group, —B or —NR ^a30 R ⁱ .

R ^g represents a hydroxyl group, C _1-6 alkyl (which may be substituted with a hydroxyl group, cyano or a halogen atom), —D or —NR ^a31 R ^{i ′} ;
Preferably, it represents a hydroxyl group, C _1-6 alkyl (which may be substituted with a hydroxyl group, cyano or a fluorine atom), —D or —NR ^a31 R ^{i ′} ;
More preferably, it represents C _1-6 alkyl (which may be substituted with a hydroxyl group, cyano or a fluorine atom), —D or —NR ^a31 R ^{i ′} .

R ^h represents C _1-6 alkyl which may be substituted with a hydroxyl group or a halogen atom, and preferably represents methyl.

R ⁱ is a hydrogen atom, C _1-6 alkyl (said alkyl, hydroxyl, cyano, halogen atom, C _1-3 alkoxy, optionally substituted with C _3-6 cycloalkyl or -NR ^c40 R ^d40) , -B 'or -C (= O) R ^b38 ,
Preferably, hydrogen atom, C _1-6 alkyl (said alkyl, hydroxyl, cyano, fluorine atom, C _1-3 alkoxy, optionally substituted C _3-6 cycloalkyl, or with -NR ^c40 R ^d40) Or -B 'is represented.

R ^{i ′} is a hydrogen atom, C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, a halogen atom, C _1-3 alkoxy, C _3-6 cycloalkyl, or —NR ^c41 R ^d41. ) Or -D '
Preferably, a hydrogen atom, C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, a fluorine atom, C _1-3 alkoxy, C _3-6 cycloalkyl, or —NR ^c41 R ^d41 ) Or -D 'is represented.

A is a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is at a substitutable position). C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C (═O) OH Or optionally substituted with —NR ^c42 R ^d42 ) or may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S 3-6 membered saturated or unsaturated aliphatic Hajime Tamaki (the aliphatic ring group may be at substitutable position, a hydroxyl group or a halogen atom which may be substituted C _1-3 alkyl, optionally substituted by a hydroxyl group or halogen atom C _{1- 3} alkoxy, hydroxyl, halogen atom, shea Ano, —C (═O) OH, —NR ^c43 R ^d43 or optionally substituted with oxo)
Preferably, an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl, or Represents an optionally substituted saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrrolinyl, dihydropyridinyl and tetrahydropyridinyl ( here, the substituent of the aromatic ring group, a hydroxyl group or optionally C _1-3 alkyl optionally substituted by a halogen atom, a hydroxyl group or an optionally C _1-3 Al may be substituted by a halogen atom Alkoxy, hydroxyl, halogen atom, cyano, -C (= O) OH or -NR ^{c 42} R ^d42, substituent a saturated aliphatic ring group may C _1-3 optionally substituted by a hydroxyl group or halogen atom C _1-3 alkoxy optionally substituted with alkyl, hydroxyl group or halogen atom, hydroxyl group, halogen atom, cyano, —C (═O) OH, —NR ^c43 R ^d43 or oxo),
More preferably, an aromatic heterocyclic group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl (the aromatic heterocyclic group is a hydroxyl group or a fluorine atom C _1-3 alkyl optionally substituted by C _1-3 alkyl, hydroxyl group or fluorine atom, C _1-3 alkoxy optionally substituted by fluorine atom, cyano, —C (═O) OH, or —NR ^c42 R ^d42 ), or a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the aliphatic ring group is a hydroxyl group or a fluorine atom) May be replaced by an atom C _1-3 alkyl, hydroxyl or fluorine atom in an optionally substituted C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C (= O) OH, -NR c43 R d43 or substituted by oxo, May represent)
Even more preferably, a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the aliphatic ring group is substituted with a hydroxyl group or a fluorine atom) which may C _1-3 alkyl, hydroxyl or fluorine atom in an optionally substituted C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C (= O) OH or substituted by -NR ^c43 R ^d43, May be).

A ′ is a 5- to 6-membered aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O, and S (the aromatic ring group is a substitutable position). A C _1-3 alkyl which may be substituted with a hydroxyl group or a halogen atom, a C _1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C (═O) OH or -NR ^c42 R ^d42 ) or 3-6 membered saturated or unsaturated optionally containing 1-2 heteroatoms selected from the group consisting of N, O and S aliphatic Hajime Tamaki (the aliphatic cyclic group, at substitutable position, a hydroxyl group or a halogen atom which may be substituted C _1-3 alkyl, optionally substituted by a hydroxyl group or halogen atom C _{1 -3} alkoxy, hydroxyl, halogen atom, Represents Ano, -C a (= O) OH, may be substituted with -NR ^c43 R ^d43 or oxo),
Preferably, an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and isothiazolyl, or optionally substituted cyclopropyl, cyclobutyl, Represents a saturated aliphatic cyclic group selected from the group consisting of cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (wherein the substituent of the aromatic ring group is substituted with a hydroxyl group or a halogen atom) which may be C _1-3 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, cyano, -C (= O) OH or -NR ^{c 42} R ^d42, saturated The substituent of the aliphatic ring group is a hydroxyl group Ku is a halogen atom in the optionally substituted C _1-3 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, cyano, -C (= O) OH, - NR ^c43 R ^d43 or oxo),
More preferably, an aromatic heterocyclic group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, and isothiazolyl (the aromatic heterocyclic group may be substituted with a hydroxyl group or a fluorine atom) C _1-3 alkyl, hydroxyl group, or optionally substituted with a fluorine atom, C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH, or —NR ^c42 R ^d42 Or a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the aliphatic ring group is substituted with a hydroxyl group or a fluorine atom) an optionally C _1-3 alkyl, hydroxyl or off Represents optionally C _1-3 alkoxy optionally substituted by atom, a hydroxyl group, a fluorine atom, cyano, -C a (= O) OH, may be substituted with -NR ^c43 R ^d43 or oxo),
Even more preferably, a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the aliphatic ring group is a hydroxyl group or a fluorine atom) C _1-3 alkyl which may be substituted, C _1-3 alkoxy which may be substituted with hydroxyl group or fluorine atom, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c43 R ^d43 Which may be substituted).

  A ″ is the same as the definition of A, preferably the same as the preferable definition of A, and more preferably the same as the more preferable definition of A.

B is a 5- to 6-membered aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O, and S (the aromatic ring group is at a substitutable position). C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C (═O) OH Or optionally substituted with —NR ^c42 R ^d42 ) or may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S 3-6 membered saturated or unsaturated aliphatic Hajime Tamaki (the aliphatic ring group may be at substitutable position, a hydroxyl group or a halogen atom which may be substituted C _1-3 alkyl, optionally substituted by a hydroxyl group or halogen atom C _{1- 3} alkoxy, hydroxyl, halogen atom, shea Ano, —C (═O) OH, —NR ^c43 R ^d43 or optionally substituted with oxo)
Preferably, an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl, or Selected from the group consisting of optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl and isothiazolidinyl (Wherein the substituent of the aromatic ring group is a C _1-3 alkyl optionally substituted by a hydroxyl group or a halogen atom) C _1-3 alkoxy optionally substituted with a kill, a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C (═O) OH or —NR ^c42 R ^d42 , and a substituent of a saturated aliphatic ring group Is C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C (═O) OH , -NR ^c43 R ^d43 or oxo),
More preferably, an aromatic heterocyclic group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl (the aromatic heterocyclic group is a hydroxyl group or a fluorine atom C _1-3 alkyl optionally substituted by C _1-3 alkyl, hydroxyl group or fluorine atom, C _1-3 alkoxy optionally substituted by fluorine atom, cyano, —C (═O) OH, or —NR ^c42 R ^d42 ), or a saturated heteroalicyclic group selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl (the saturated heteroaliphatic ring group is a hydroxyl group or a fluorine atom) in an optionally substituted C _1-3 alkyl, hydroxyl Wakashi Represents a fluorine atom in the optionally substituted C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C a (= O) OH, may be substituted with -NR ^c43 R ^d43 or oxo),
Even more preferably, a saturated heteroaliphatic ring group selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl (the saturated heteroaliphatic ring group may be substituted with a hydroxyl group or a fluorine atom) C _1-3 alkyl, hydroxyl group, or optionally substituted with a fluorine atom, C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH, or —NR ^c43 R ^d43 Good).

D is the same as the definition of B, preferably the same as the preferred definition of B;
More preferably, an aromatic heterocyclic group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl (the aromatic heterocyclic group is a hydroxyl group or a fluorine atom C _1-3 alkyl optionally substituted by C _1-3 alkyl, hydroxyl group or fluorine atom, C _1-3 alkoxy optionally substituted by fluorine atom, cyano, —C (═O) OH, or —NR ^c42 R ^d42 ), or a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl (the saturated aliphatic ring) The group is a hydroxyl group Fluorine atom in an optionally substituted C _1-3 alkyl, hydroxyl or fluorine atom in an optionally substituted C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C (= O) OH, -NR ^c43 R ^d43 , or optionally substituted with oxo)
Even more preferably, a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl (the saturated aliphatic ring group is a hydroxyl group or a fluorine C _1-3 alkyl optionally substituted with an atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a fluorine atom, hydroxyl group, fluorine atom, cyano, —C (═O) OH, or —NR ^c43 R ^d43 may be substituted).

B ′ is a 5- to 6-membered aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O, and S (the aromatic ring group is a substitutable position). A C _1-3 alkyl which may be substituted with a hydroxyl group or a halogen atom, a C _1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, —C (═O) OH or -NR ^c42 R ^d42 ) or 3-6 membered saturated or unsaturated optionally containing 1-2 heteroatoms selected from the group consisting of N, O and S aliphatic Hajime Tamaki (the aliphatic cyclic group, at substitutable position, a hydroxyl group or a halogen atom which may be substituted C _1-3 alkyl, optionally substituted by a hydroxyl group or halogen atom C _{1 -3} alkoxy, hydroxyl, halogen atom, Represents Ano, -C a (= O) OH, may be substituted with -NR ^c43 R ^d43 or oxo),
Preferably, an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl and tetrazolyl or optionally substituted cyclopropyl Represents a saturated aliphatic ring group selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (wherein the substituent of the aromatic ring group is substituted with a hydroxyl group or a halogen atom) which may C _1-3 alkyl, hydroxyl or optionally substituted with a halogen atom C _1-3 alkoxy, hydroxyl, halogen atom, cyano, -C (= O) OH or -NR ^{c 42} R ^d42, saturated fat The substituent of the aromatic ring group is a hydroxyl group. Halogen atom an optionally substituted C _1-3 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, cyano, -C (= O) OH, -NR ^c43 R ^d43 or oxo),
More preferably, an aromatic heterocyclic group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and isothiazolyl (the aromatic heterocyclic group is optionally substituted with a hydroxyl group or a fluorine atom) C _1-3 optionally substituted with _1-3 alkyl, hydroxyl group or fluorine atom, optionally substituted with _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c42 R ^d42 ) Alternatively, a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the saturated aliphatic ring group may be substituted with a hydroxyl group or a fluorine atom) _1-3 alkyl, optionally substituted by hydroxyl or fluorine atom _1-3 -alkoxy, hydroxyl, fluorine atom, cyano, -C a (= O) OH, may be substituted with -NR ^c43 R ^d43 or oxo),
Even more preferably, a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the saturated aliphatic ring group is substituted with a hydroxyl group or a fluorine atom) ^Optionally substituted with C _1-3 alkyl, hydroxyl group or fluorine atom, optionally substituted with C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c43 R ^d43. May be).

D ′ is the same as the definition of B ′, preferably the same as the preferable definition of B ′;
More preferably, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, aromatic Hajime Tamaki selected from the group consisting of thiazolyl and isothiazolyl (hetero groups to the aromatic is hydroxyl or fluorine may be substituted with atoms C _{1 -3} alkyl, hydroxyl group, or C _1-3 alkoxy optionally substituted with a fluorine atom or a hydroxyl group, fluorine atom, cyano, -C (= O) OH or -NR ^c42 R ^d42 ) or A saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and pyranyl (the saturated aliphatic ring group is a hydroxyl group or a C _1-3 alkyl which may be substituted with a fluorine atom, a hydroxyl group or C _1-3 alkoxy optionally substituted with a fluorine atom, hydroxyl group, fluorine atom, cyano, -C (= O) OH, ^optionally substituted with -NR ^c43 R ^d43 or oxo)
Even more preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and are the saturated aliphatic Hajime Tamaki selected from the group consisting of pyranyl (the aliphatic cyclic group is optionally substituted by hydroxyl or fluorine atom C _{1- 3} optionally substituted with alkyl, hydroxyl group or fluorine atom, optionally substituted with C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH, or —NR ^c43 R ^d43 ) Represent.

R ⁰ is —C (═O) NR ^a1 —, —S (═O) NR ^a2 —, —S (═O) ₂ NR ^a2 —, —C (═O) O—, —C (═O). -, -S (= O)-, -S (= O) _2- or a single bond,
Preferably, R ⁰ is —C (═O) NR ^a1 —, —S (═O) ₂ NR ^a2 —, —C (═O) O—, —C (═O) —, —S (═O ) Represents _2- or a single bond,
More preferably, —C (═O) NR ^a1 —, —S (═O) ₂ NR ^a2 —, —C (═O) O—, —C (═O) — or —S (═O) ₂ — Represents
Even more preferably, it represents —C (═O) NH— or —S (═O) ₂ NH—
Even more preferably, it represents —C (═O) NH—.

R ¹ may contain 1 to 2 heteroatoms selected from the group consisting of a hydrogen atom, C _1-10 alkyl, C _2-6 alkene, N, O and S 3-6 membered saturation Or an unsaturated aliphatic ring group or a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S;
Wherein the alkyl and the alkene are in substitutable positions,
(1) hydroxyl group,
(2) a halogen atom,
(3) Cyano,
(4) C _1-6 alkoxy (wherein the alkoxy is substitutable,
Hydroxyl group,
Halogen atoms,
Cyano,
-C (= O) OR ^b1 ,
-C (= O) NR ^c1 R ^d1 ,
A 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a hydroxyl group at a substitutable position) Alternatively, C _1-3 alkyl which may be substituted with a halogen atom, hydroxyl group or C _1-3 alkoxy which may be substituted with a halogen atom, hydroxyl group, halogen atom, cyano, —NR ^a3 C (═O) R ^b2 , —NR ^a4 C (═O) NR ^c2 R ^d2 , —NR ^a5 S (═O) _m R ^b3 , —C (═O) OR ^b4 , —C (═O) NR ^c3 R ^d3 , —S (= O) _m NR ^c4 R ^d4 , optionally substituted with —S (═O) _m R ^b5 or —NR ^c5 R ^d5 ) or 1-2 hetero selected from the group consisting of N, O and S A 3- to 6-membered saturated or unsaturated aliphatic ring group which may contain an atom (the aliphatic ring group is located at a substitutable position) , Hydroxyl or halogen atom an optionally substituted C _1-3 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, cyano, -NR ^a6 C (= O) R ^b6 , —NR ^a7 C (═O) NR ^c6 R ^d6 , —NR ^a8 S (═O) _m R ^b7 , —C (═O) OR ^b8 , —C (═O) NR ^c7 R ^d7 , —NR ^c8 R ^d8 or optionally substituted with oxo)
May be substituted)
(5) C _1-6 alkylthio (the alkylthio is a hydroxyl group at a substitutable position,
Halogen atoms,
Cyano,
-C (= O) OR ^b9 ,
-C (= O) NR ^c9 R ^d9 ,
A 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a hydroxyl group at a substitutable position) Alternatively, C _1-3 alkyl which may be substituted with a halogen atom, hydroxyl group or C _1-3 alkoxy which may be substituted with a halogen atom, hydroxyl group, halogen atom, cyano, —NR ^a9 C (═O) R ^b10 , —NR ^a10 C (═O) NR ^c10 R ^d10 , —NR ^a11 S (═O) _m R ^b11 , —C (═O) OR ^b12 , —C (═O) NR ^c11 R ^d11 , —S (= O) _m NR ^c12 R ^d12 , ^optionally substituted with —S (═O) _m R ^b13 or —NR ^c13 R ^d13 ) or 1 to 2 hetero atoms selected from the group consisting of N, O and S 3 to 6-membered saturated or unsaturated aliphatic ring group which may contain an atom (the aliphatic ring group may be substituted) Position in a hydroxyl group or a halogen atom an optionally substituted C _1-3 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, cyano, -NR ^a12 C ( ═O) R ^b14 , —NR ^a13 C (═O) NR ^c14 R ^d14 , —NR ^a14 S (═O) _m R ^b15 , —C (═O) OR ^b16 , —C (═O) NR ^c15 R ^d15 , -NR ^c16 R ^d16 or oxo may be substituted)
May be substituted)
(6) a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is at a substitutable position) And
C _1-3 alkyl _optionally substituted with a hydroxyl group or a halogen atom,
C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom,
Hydroxyl group,
Halogen atoms,
Cyano,
-NR ^a15 C (= O) R ^b17 ,
-NR ^a16 C (= O) NR ^c17 R ^d17 ,
-NR ^a17 S (= O) _m R ^b18 ,
-C (= O) OR ^b19 ,
-C (= O) NR ^c18 R ^d18 ,
-S (= O) _m NR ^c19 R ^d19 ,
—S (═O) _m R ^b20 or —NR ^c20 R ^d20
May be substituted)
(7) a 3- to 6-membered saturated or unsaturated aliphatic ring group that may contain 1 to 2 heteroatoms selected from the group consisting of N, O, and S (the aliphatic ring group is At the replaceable position,
C _1-3 alkyl (the alkyl is a hydroxyl group, a halogen atom, cyano, —NR ^a18 C (═O) R ^b21 , —NR ^a19 C (═O) NR ^c21 R ^d21 , —NR ^a20 S (═O) _m ) R ^b22 , —C (═O) OR ^b23 , ^{optionally substituted} with —C (═O) NR ^c22 R ^d22 or —NR ^c23 R ^d23 ),
C _1-3 alkoxy (the alkoxy may be substituted with a hydroxyl group or a halogen atom),
Hydroxyl group,
Halogen atoms,
Cyano,
-NR ^a21 C (= O) R ^b24 ,
-NR ^a22 C (= O) NR ^c24 R ^d24 ,
-NR ^a23 S (= O) _m R ^b25 ,
-C (= O) OR ^b26 ,
^{-C (= O) NR c25 R} d25,
-S (= O) _m NR ^c26 R ^d26 ,
-S (= O) _m R ^b27 ,
In -NR ^c27 R ^d27 or oxo may be substituted),
(8) -NR ^a24 R ^e,
(9) -OR ^{e '} ,
(10) -C (= O) ^Rf ,
(11) -S (= O) _m R ^g ,
(12) It may be substituted with 1 or 3 or more substituents selected from the group consisting of thiol and (13) nitro,
Here, the saturated or unsaturated aliphatic ring group is in a substitutable position,
A hydroxyl group, a halogen atom, cyano, nitro, C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), C _1-6 alkoxy (the alkoxy is , ^Optionally substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), —NR ^a25 C (═O) R ^b28 , —NR ^a26 C (═O) NR ^c28 R ^d28 , —NR ^{a27 _{S (= O) m R b29}} , -C (= O) oR b30, -C (= O) R b31, -C (= O) may be substituted with NR ^c29 R ^d29 or -NR ^c30 R ^d30 ,
Here, the aromatic ring group is a substitutable position,
A hydroxyl group, a halogen atom, cyano, nitro, C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), C _1-6 alkoxy (the alkoxy is And may be substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), —NR ^a28 C (═O) R ^b32 , —NR ^a29 C (═O) NR ^c31 R ^d31 , —NR ^{a30 _{S (= O) m R b33}} , -C (= O) OR b34, -C (= O) R b35, -C (= O) NR c32 R d32, -S (= O) m NR c33 R d33, -S (= O) _m R ^b36 or -NR ^{c 34} R ^d34 may be substituted with,

R ¹ is preferably a hydrogen atom, C _1-10 alkyl or 3-6 membered saturated or unsaturated optionally containing 1-2 heteroatoms selected from the group consisting of N, O and S An aliphatic cyclic group of
Here, the alkyl may be substituted with 1 or 3 or more substituents selected from the group consisting of the above (1) to (13),
Here, the saturated or unsaturated aliphatic ring group is a hydroxyl group, a halogen atom, cyano, nitro, C _1-6 alkyl at a substitutable position (the alkyl is a hydroxyl group, a halogen atom at a substitutable position). May be substituted with an atom or cyano), C _1-6 alkoxy (the alkoxy may be substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), —NR ^a25 C (= O) R ^b28 , —NR ^a26 C (═O) NR ^c28 R ^d28 , —NR ^a27 S (═O) _m R ^b29 , —C (═O) OR ^b30 , —C (═O) R ^b31 , —C (= O) NR ^c29 R ^d29 or -NR ^c30 R ^d30 may be substituted with 1 or 3 or less more substituents selected from,
R ¹ is more preferably a hydrogen atom or C _1-10 alkyl, and the alkyl is 1 or 3 or less selected from the group consisting of the above (1) to (3) and (6) to (11) May be substituted with a plurality of substituents of
R ¹ is even more preferably C _1-10 alkyl (wherein the alkyl is in a substitutable position,
(1) hydroxyl group,
(2) fluorine atom,
(3) Cyano,
(6) a 5-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is at a substitutable position;
C _1-3 alkyl _optionally substituted with a hydroxyl group or a fluorine atom,
C _1-3 alkoxy optionally substituted with a hydroxyl group or a fluorine atom,
Hydroxyl group,
Halogen atoms,
Cyano,
-C (= O) OH,
^{-C (= O) NR c18 R} d18 or -NR ^{c 20} R ^d20
May be substituted)
(7) a 3- to 6-membered saturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S (the saturated aliphatic ring group is substitutable) In position,
C _1-3 alkyl (which may be substituted with a hydroxyl group, a fluorine atom, cyano, —C (═O) OH or —C (═O) NR ^c22 R ^d22 ),
C _1-3 alkoxy (the alkoxy may be substituted with a hydroxyl group or a fluorine atom),
Hydroxyl group,
Fluorine atom,
Cyano,
-NR ^a21 C (= O) R ^b24 ,
-NR ^a22 C (= O) NR ^c24 R ^d24 ,
-NR ^a23 S (= O) _m R ^b25 ,
-C (= O) OH,
^{-C (= O) NR c25 R} d25,
In -NR ^c27 R ^d27 or oxo may be substituted),
(8) -NR ^a24 R ^e,
(10) -C (= O) R f and (11) -S (= O) m R g
And may be substituted with 1 or 3 or more substituents selected from the group consisting of:

R ² represents C _1-3 alkyl (the alkyl may be substituted with a hydroxyl group or a halogen atom), and preferably represents methyl.

R ³ and R ⁴ each independently represents a hydrogen atom or C _1-3 alkyl (the alkyl may be substituted with a hydroxyl group or a halogen atom);
Preferably, each independently represents a hydrogen atom or unsubstituted C _1-3 alkyl,
More preferably, each independently represents a hydrogen atom or methyl.

  m represents an integer of 1 or 2, and preferably represents 2.

  n represents an integer of 0 to 2, preferably 2.

L is a 5- to 6-membered unsubstituted aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S, or —S (═O) _q — ( q represents an integer of 0 to 2),
When L represents a 5- to 6-membered unsubstituted aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S,
A preferable bonding position of the aromatic ring is the following formula (I ′):

で表されるように、ジヒドロピリミジノン骨格とＡｒ²が芳香族環の隣接した炭素原子に結合した形であり、
Ｌは、好ましくは、ベンゼン環基、チオフェン環基、フラン環基、ピロール環基、イミダゾール環基、ピリジン環基、ピラジン環基、イソキサゾール環基、ピラゾール環基、イソチアゾール環基、ピリミジン環基、ピリダジン環基、オキサゾール環基、チアゾール環基、トリアゾール環基またはテトラゾール環基を表し、より好ましくは、ベンゼン環基、イミダゾール環基、ピリジン環基、ピラジン環基、イソキサゾール環基、ピラゾール環基、ピリミジン環基、オキサゾール環基、トリアゾール環基またはテトラゾール環基を表し（ジヒドロピリミジノン骨格とＡｒ²の結合位置は前述と同じ）、Ｌが、−Ｓ（＝Ｏ）_q−を表す場合、好ましくは、ｑが１または２を表す。

As shown by the formula, the dihydropyrimidinone skeleton and Ar ² are bonded to adjacent carbon atoms of the aromatic ring,
L is preferably a benzene ring group, a thiophene ring group, a furan ring group, a pyrrole ring group, an imidazole ring group, a pyridine ring group, a pyrazine ring group, an isoxazole ring group, a pyrazole ring group, an isothiazole ring group, or a pyrimidine ring group. Represents a pyridazine ring group, an oxazole ring group, a thiazole ring group, a triazole ring group or a tetrazole ring group, and more preferably a benzene ring group, an imidazole ring group, a pyridine ring group, a pyrazine ring group, an isoxazole ring group, or a pyrazole ring group. Represents a pyrimidine ring group, an oxazole ring group, a triazole ring group or a tetrazole ring group (the bonding position of the dihydropyrimidinone skeleton and Ar ² is the same as described above), and L represents —S (═O) _q — Preferably, q represents 1 or 2.

Ar ¹ is a 5- to 6-membered aromatic ring group which may contain 1 to 3 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a substitutable position). In C _1-6 alkyl optionally substituted with a hydroxyl group or a halogen atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro or —NR ^c35 R ^d35 or more are substituted)
Preferably, Ar ¹ -1 or Ar ¹ -2 below:

（各基中、Ｅ^１、Ｅ^２、Ｅ^３およびＥ^４は、それぞれ独立して、炭素原子または窒素原子を示し（但し、Ｅ^１、Ｅ^２、Ｅ^３およびＥ^４が全て同時に窒素原子を示す場合を除く）、Ｇ^１、Ｇ^２およびＧ^３は、それぞれ独立して、炭素原子またはＮ、ＯおよびＳからなる群から選択されるヘテロ原子を示し、Ｘは、水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-6アルキル、水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノ、ニトロまたは−ＮＲ^c35Ｒ^d35を表し、Ｅ^１、Ｅ^２、Ｅ^３、Ｅ^４、Ｇ^１、Ｇ^２またはＧ^３の置換可能な位置に、さらに水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-6アルキル、水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノ、ニトロおよび−ＮＲ^c35Ｒ^d35からなる群から選択される置換基を有していてもよい）を表し、
より好ましくは、下記Ａｒ¹−１'：

(In each group, E ¹ , E ² , E ³ and E ⁴ each independently represent a carbon atom or a nitrogen atom (provided that E ¹ , E ² , E ³ and E ⁴ all represent a nitrogen atom at the same time). G ¹ , G ² and G ³ each independently represent a carbon atom or a heteroatom selected from the group consisting of N, O and S, and X is substituted with a hydroxyl group or a halogen atom C _1-6 alkyl which may be substituted, C _1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro or —NR ^c35 R ^d35 , E ¹ , E ² , E ³ , E ⁴ , G ¹ , G ² or G ³ may be further substituted with a C _1-6 alkyl, hydroxyl group or halogen atom which may be further substituted with a hydroxyl group or a halogen atom. Yo And optionally having a substituent selected from the group consisting of C _1-3 alkoxy, hydroxyl group, halogen atom, cyano, nitro and —NR ^c35 R ^d35 ),
More preferably, Ar ¹ -1 ′ below:

（Ｅ^１、Ｅ^２およびＥ^３は、それぞれ独立して、炭素原子または窒素原子を示し、Ｘは、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-3アルキル、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-3アルコキシ、ハロゲン原子、シアノまたはニトロを表し、Ｅ^１、Ｅ^２またはＥ^３の置換可能な位置に、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-6アルキル、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノおよび−ＮＲ^c35Ｒ^d35から選択される置換基を有していてもよい）を表し、
さらにより好ましくは、下記Ａｒ¹−１''：

(E ¹ , E ² and E ³ each independently represents a carbon atom or a nitrogen atom, and X represents a C _1-3 alkyl which may be substituted with a hydroxyl group or a fluorine atom, a hydroxyl group or a fluorine atom. C _1-3 alkoxy which may be substituted, halogen atom, cyano or nitro is represented, and C _1-6 which may be substituted with a hydroxyl group or a fluorine atom at a substitutable position of E ¹ , E ² or E ³ An alkyl, a hydroxyl group, or a C _1-3 alkoxy optionally substituted with a fluorine atom, a hydroxyl group, a halogen atom, a cyano and a substituent selected from —NR ^c35 R ^d35 ).
Even more preferably, the following Ar ¹ -1 ″:

（Ｘは、１から３個のフッ素原子で置換されていてもよいＣ_1-3アルキル、塩素原子、シアノまたはニトロを表す。）を表す。

(X represents C _1-3 alkyl optionally substituted with 1 to 3 fluorine atoms, chlorine atom, cyano or nitro).

Ar ² is a 5- to 6-membered aromatic ring group which may contain 1 to 3 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a substitutable position). In C _1-6 alkyl optionally substituted with a hydroxyl group, cyano, or a halogen atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro,- S (═O) _n R ^h or —NR ^c36 R ^d36 or more).
Preferably, Ar ² -1 or Ar ² -2 shown below:

（各基中、Ｋ^１、Ｋ^２、Ｋ^３およびＫ^４は、それぞれ独立して炭素原子または窒素原子を示し（但し、Ｋ^１、Ｋ^２、Ｋ^３およびＫ^４が全て同時に窒素原子を示す場合を除く）、Ｌ^１、Ｌ^２およびＬ^３は、それぞれ独立して、炭素原子またはＮ、ＯおよびＳからなる群から選択されるヘテロ原子を示し、Ｙは、水酸基、シアノ若しくはハロゲン原子で置換されていてもよいＣ_1-6アルキル、水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノ、ニトロ、−Ｓ（＝Ｏ）_nＲ^hまたは−ＮＲ^c36Ｒ^d36を表し、Ｋ^１、Ｋ^２、Ｋ^３、Ｋ^４、Ｌ^１、Ｌ^２またはＬ^３の置換可能な位置に、さらに水酸基、シアノ若しくはハロゲン原子で置換されていてもよいＣ_1-6アルキル、水酸基若しくはハロゲン原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノ、ニトロ、−Ｓ（＝Ｏ）_nＲ^hおよび−ＮＲ^c36Ｒ^d36からなる群より選択される置換基を有していてもよい）を表し、
より好ましくは、下記Ａｒ²−１'：

(In each group, K ¹ , K ² , K ³ and K ⁴ each independently represent a carbon atom or a nitrogen atom (provided that K ¹ , K ² , K ³ and K ⁴ all simultaneously represent a nitrogen atom) L ¹ , L ² and L ³ each independently represents a carbon atom or a heteroatom selected from the group consisting of N, O and S, and Y represents a hydroxyl group, a cyano or a halogen atom. optionally substituted C _1-6 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, cyano, _{nitro, -S (= O) n R} h or -NR It represents ^{c36 R d36, K 1, K} 2, K 3, K 4, the substitutable position of L 1, ^{L 2} or ^{L 3,} further hydroxyl, optionally substituted by cyano or halogen atom C _{1- 6} alkyl, hydroxyl Wakashi Ku Yes halogen atom which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, cyano, nitro, -S (= O) _n R ^h and -NR ^c36 substituent selected from the group consisting of R ^d36 May be)
More preferably, the following Ar ² -1 ′:

（Ｋ^１、Ｋ^２、Ｋ^３およびＫ^４は、それぞれ独立して、炭素原子または窒素原子を示し（但し、Ｋ^１、Ｋ^２、Ｋ^３およびＫ^４が全て同時に窒素原子を示す場合を除く）、Ｙは、ハロゲン原子、シアノまたはニトロを示し、Ｋ^１、Ｋ^２、Ｋ^３またはＫ^４の置換可能な位置に、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-3アルキル、水酸基若しくはフッ素原子で置換されていてもよいＣ_1-3アルコキシ、水酸基、ハロゲン原子、シアノおよび−ＮＲ^c36Ｒ^d36から選択される置換基を有していてもよい）を表し、
さらにより好ましくは、下記Ａｒ²−１''：

(K ¹ , K ² , K ³ and K ⁴ each independently represent a carbon atom or a nitrogen atom (except when K ¹ , K ² , K ³ and K ⁴ all represent a nitrogen atom at the same time). ), Y represents a halogen atom, cyano or nitro, and C _1-3 alkyl, hydroxyl group which may be substituted with a hydroxyl group or a fluorine atom at a substitutable position of K ¹ , K ² , K ³ or K ⁴ Or a substituent selected from C _1-3 alkoxy optionally substituted with a fluorine atom, a hydroxyl group, a halogen atom, cyano and —NR ^c36 R ^d36 ),
Even more preferably, the following Ar ² -1 ″:

（Ｙは、塩素原子、シアノまたはニトロを表す）を表す。

(Y represents a chlorine atom, cyano or nitro).

Production method of the compound of the present invention The compound of the present invention represented by the formula (I) can be produced by the following production methods AP. The compound represented by the formula (I) or a physiologically acceptable salt thereof is a novel compound and can be produced, for example, by a production method described below, a method according to Examples described later or a known method. it can.

  The compound used in the following production method may form a salt as long as the reaction is not hindered.

[Production method A]
The compound of Formula (I) is manufactured by the following manufacturing method.

[Production method A]
In the formula (I), a compound in which R ³ and R ⁴ each represent a hydrogen atom [compound of the following formula 4] is produced by the following production method.

(In the formula, Ar ¹ , Ar ² , L, R ⁰ , R ¹ , R ² are the same as defined in item 1, and R ^3a , R ^4a both represent a hydrogen atom or are Represents a carbon atom that becomes methylene.)

[Step 1]: When R ^3a and R ^4a of Compound 1 both represent a hydrogen atom, Compound 3 can be produced by subjecting Compound 1 and Compound 2 to an addition reaction according to a conventional method. For example, in this reaction, compound 1 and compound 2 are converted into aldehyde reagents such as formaldehyde and paraformaldehyde, Lewis acids such as titanium tetrachloride and boron trifluoride / diethyl ether complex, copper chloride in a suitable solvent or without solvent. It is achieved by reacting in the presence of a copper reagent such as In some cases, this reaction is carried out in an acid reagent solvent such as hydrochloric acid or acetic acid, or under a condition where an appropriate amount of an acid reagent such as hydrochloric acid or acetic acid is added.

When R ^3a and R ^4a of Compound 1 together represent a carbon atom that forms an exomethylene, Compound 3 can be produced by subjecting Compound 1 and Compound 2 to an addition reaction according to a conventional method. . For example, this reaction can be achieved by reacting compound 1 and compound 2 in the presence of a Lewis acid such as boron trifluoride / diethyl ether complex, or a copper reagent such as copper chloride in an appropriate solvent or without solvent. Is done. In some cases, this reaction is performed in an acid reagent such as hydrochloric acid or acetic acid, or in the presence of the above reagent and an acid reagent such as hydrochloric acid or acetic acid.

[Step 2]: Compound 4 can be produced by subjecting compound 3 to a cyclization reaction according to a conventional method. For example, this reaction can be achieved by reacting compound 3 in the presence of an acid reagent such as acetic acid or paratoluenesulfonic acid in a suitable solvent or without solvent. (See Example 22)

[Step 3]: When R ^3a and R ^4a of Compound 1 both represent a hydrogen atom, Compound 4 can be produced by subjecting Compound 1 and Compound 2 to a cyclization reaction according to a conventional method. For example, in this reaction, compound 1 and compound 2 are converted into aldehyde reagents such as formaldehyde and paraformaldehyde, Lewis acids such as titanium tetrachloride and boron trifluoride / diethyl ether complex, copper chloride in a suitable solvent or without solvent. It is achieved by reacting in the presence of a copper reagent such as In some cases, this reaction is performed in an acid reagent such as hydrochloric acid or acetic acid, or in the presence of the above reagent and an acid reagent such as hydrochloric acid or acetic acid.

In the case where R ^3a and R ^4a of Compound 1 together represent a carbon atom that becomes exomethylene, Compound 4 can be produced by subjecting Compound 1 and Compound 2 to a cyclization reaction according to a conventional method. it can. For example, this reaction can be achieved by reacting compound 1 and compound 2 in the presence of a Lewis acid such as boron trifluoride / diethyl ether complex, or a copper reagent such as copper chloride in an appropriate solvent or without solvent. Is done. In some cases, this reaction is performed in an acid reagent such as hydrochloric acid or acetic acid, or in the presence of the above reagent and an acid reagent such as hydrochloric acid or acetic acid. (See Examples 1, 2, and 3)

  Specific examples of the solvent in each reaction of Production Method A should be selected according to the type of raw material compound, etc., but for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, acetonitrile, toluene, Examples include ethyl acetate, acetic acid or alcohols such as methanol, ethanol, and isopropanol, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production method B]
In the formula (I), a 5- to 6-membered unsubstituted aromatic ring group (L ^a ) optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S A compound in which R ³ and R ⁴ each represent a hydrogen atom [compound of the following formula 7] is also produced by the following production method.

^{(Wherein, Ar 1, Ar 2, R} 0, R 1, R 2 are the same as defined in claim 1, to 4 heteroatoms ^{which L a} is selected from the group consisting of N, O and S Represents an optionally substituted 5- to 6-membered unsubstituted aromatic ring group, R ^3a and R ^4a are the same as defined above, and W ¹ represents a hydrogen atom, an amino group or a halogen atom, Z ¹ is a substituent on Ar ² , and represents a metal substituent such as boronic acid, boronic acid ester, organotin, zinc halide, magnesium halide, organosilicon, organolithium, etc., and Z ² is a ring in Ar ² And represents a halogen atom.)

[Step 1]: Compound 6 can be produced by subjecting Compound 5 and Compound 2 to a cyclization reaction according to the same method as Production Method A. (See Reference Example 17)

[Step 2]:
Production method B-1:
When W ¹ in Compound 7 represents a halogen atom, Compound 7 is produced by performing a coupling reaction between Compound 6 and Z ¹ -Ar ² (Z ¹ is as defined above) according to a conventional method. Can do. For example, in this reaction, compound 6 and Z ¹ -Ar ² are converted into a palladium catalyst typified by tetrakistriphenylphosphine palladium, a copper catalyst typified by copper iodide, nickel chloride in a suitable solvent or in the absence of a solvent. In the presence of a nickel catalyst represented by a 1,2-bis (diphenylphosphino) ethane complex, a zinc reagent, an iron chelating reagent, etc., in some cases, 2,2′-bis (diphenylphosphino) -1,1 -It is achieved by adding a phosphorus ligand typified by binaphthalene, 2- (di-t-butyl) phosphinobiphenyl, etc., and carrying out a cross-coupling reaction. In these coupling reactions, in addition to the above reagents, alkali metal carbonates (for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal phosphates (potassium phosphate, etc.), organic bases (triethylamine, diisopropylethylamine, etc.), In some cases, the reaction may be performed in the presence of an alkali metal halide (lithium chloride, cesium fluoride, etc.), an alkali metal hydroxide (sodium hydroxide, etc.), a metal alkoxide (t-butoxypotassium, etc.). (See Example 8)

Production method B-2:
Further, W ¹ in the compound 6, if a hydrogen atom, compound 7, the L ^a group of the compound 6 After halogenation can be produced by performing a coupling reaction with Z ¹ -Ar ² . For example, this halogenation reaction is achieved by reacting compound 6 with a halogenating agent such as N-iodosuccinimide, N-bromosuccinimide, iodine, bromine or the like in a suitable solvent or in the absence of a solvent. Is achieved according to the same method as Production Method B-1.

Production method B-3:
When W ¹ in Compound 6 represents a halogen atom, Compound 7 converts W ^{1 of} Compound 6 into a coupling reagent such as a boride, zinc halide, magnesium halide, and the like. ^2- Ar ² (Z ² is as defined above) can be produced by performing a coupling reaction according to a conventional method. For example, this reaction is prepared by reacting compound 6 with a boron reagent typified by bis (pinacolato) diboron reagent and a palladium catalyst typified by tetrakistriphenylphosphine palladium in a suitable solvent or without solvent. A coupling reagent such as a boron halide, a zinc halide prepared by reacting compound 3 with zinc powder, or a magnesium halide prepared by reacting compound 6 with magnesium powder, and Z ² -Ar ² , a palladium catalyst typified by tetrakistriphenylphosphine palladium, a copper catalyst typified by copper iodide, a nickel catalyst typified by nickel chloride-1,2-bis (diphenylphosphino) ethane complex, a zinc reagent, In the presence of an iron chelating reagent or the like, in some cases, 2,2′-bis (diphenyl) Ruphosphino) -1,1-binaphthalene, 2- (di-t-butyl) phosphinobiphenyl, and other phosphorus ligands, or organic arsenic and other ligand compounds are added to perform a cross-coupling reaction. Achieved by doing. In these coupling reactions, in addition to the above reagents, alkali metal carbonates (for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal phosphates (potassium phosphate, etc.), organic bases (triethylamine, diisopropylethylamine, etc.), In some cases, the reaction may be performed in the presence of an alkali metal halide (lithium chloride, cesium fluoride, etc.), an alkali metal hydroxide (sodium hydroxide, etc.), a metal alkoxide (t-butoxypotassium, etc.).

Production method B-4:
When W ^{1 of} Compound 6 represents an amino group, Compound 7 converts W ¹ to a halogen atom such as bromine or iodine by a Sandmeyer reaction according to a conventional method, and then converts this to Z ¹ -Ar ² . According to the method similar to the manufacturing method B-1, it can manufacture also by carrying out a coupling reaction. For example, in the Sandmeyer reaction, compound 6 is reacted with nitrite typified by sodium nitrite and copper halide typified by copper bromide or copper iodide in an appropriate solvent or without solvent. To be achieved.

Production method B-5:
Also, if ^{the L a} Compound 6 has an NH group in the ring, i.e., if they contain NH groups in group constituting ^{L a,} compound 7, compound 6 and ^{Z 2 -Ar} 2 ^(Z 2 is the The same as the definition) or Z ³ -Ar ² (Z ³ is a substituent on a carbon atom in the ring of Ar ² and represents a boronic acid or a boronic acid ester) or a substitution reaction or coupling according to a conventional method It can manufacture by performing reaction. For example, a suitable or without a solvent in a solvent, and a ring L ^a and Z ² -Ar ² with an NH group in the ring, an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc. cesium carbonate), phosphoric acid React in the presence of alkali metal (potassium phosphate, etc.), organic base (triethylamine, diisopropylethylamine, etc.), halogenated alkali metal (lithium chloride, cesium fluoride, etc.) or alkali hydroxide metal (sodium hydroxide, etc.). Is achieved. Further, the ring L ^a and Z ³ -Ar ² having an NH group in the ring, a palladium catalyst represented by tetrakistriphenylphosphine palladium or palladium acetate, copper catalysts typified by copper iodide or zinc reagents, iron In the presence of a chelating reagent or the like, in some cases, a phosphorus catalyst typified by 2,2′-bis (diphenylphosphino) -1,1-binaphthalene, 2- (di-t-butyl) phosphinobiphenyl, It can also be achieved by adding a diamine reagent typified by 2,2-diaminocyclohexane or the like and carrying out a cross-coupling reaction. In these coupling reactions, in addition to the above reagents, alkali metal carbonates (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal phosphates (eg, potassium phosphate), organic bases (triethylamine, diisopropylethylamine, etc.) ), Alkali metal halides (such as lithium chloride and cesium fluoride), alkali metal hydroxides (such as sodium hydroxide), metal alkoxides (such as potassium t-butoxy), and the like. For example, J.Am.Chem.Soc. 1998, 120, 827-828., J.Am.Chem.Soc. 2001, 123, 7727-7729., J.Org.Chem. 2002,67,1699- It can be produced according to the method described in 1702. etc. or a method analogous thereto.

Production method B-6:
Z ¹ -Ar ² represents, according to a conventional method, Z ⁴ -Ar ² (Z ⁴ is a substituent on a carbon atom in the ring of Ar ² and represents a halogen atom or a hydrogen atom) as various metal atoms. It can be manufactured by substitution. For example, a suitable solvent or without a solvent The solvent, Z ⁴ -Ar ² and bis (pinacolato) to diboron reagent and tetrakistriphenylphosphine palladium diboron reagents reacting a palladium catalyst represented, or Z ⁴ - After reacting Ar ² with an alkyl lithium reagent such as butyl lithium, a boron reagent can be produced by reacting a trialkoxy borane reagent such as a trimethyl borate reagent. An organotin reagent can be produced by reacting Z ⁴ -Ar ² with an alkyllithium reagent such as butyllithium in an appropriate solvent or without a solvent, and then reacting an alkyltin reagent such as tributyltin chloride. . A zinc halide reagent can be produced by reacting Z ⁴ —Ar ² with zinc powder in a suitable solvent or without a solvent. A magnesium halide reagent can be produced by reacting Z ⁴ —Ar ² with magnesium powder in a suitable solvent or without a solvent. An organosilicon reagent is produced by reacting Z ⁴ -Ar ² with an alkyllithium reagent such as butyllithium in an appropriate solvent or without solvent, and then reacting an alkylsilicon reagent such as trialkylsilicon chloride. Can do. An organolithium reagent can be produced by reacting Z ⁴ —Ar ² with an alkyllithium reagent such as butyllithium in a suitable solvent or without a solvent.

  Specific examples of the solvent in each reaction of production method B should be selected according to the type of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N- Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method C]
In formula (I), L is a 5- to 6-membered unsubstituted aromatic ring group (L ^a ) which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S; The compound wherein R ⁰ represents a single bond [compound of the following formula 11] is also produced by the following production method.

（式中、Ａｒ^１、Ａｒ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４は、項１の定義に同じであり、Ｌ^ａ、Ｚ^１、Ｚ^２は上記定義に同じであり、Ｘ^１はハロゲン原子を表す。）

^{(Wherein, Ar 1, Ar 2, R} 1, R 2, R 3, R 4 are the same as defined in claim ^{1, L a, Z 1,} Z 2 are defined the same as above, ^{X 1} Represents a halogen atom.)

[Step 1]: Compound 9 can be produced by subjecting compound 8 to a cyclization reaction according to a conventional method. For example, this reaction can be achieved by reacting compound 8 in the presence of an acid reagent such as acetic acid or paratoluenesulfonic acid in a suitable solvent or in the absence of a solvent. (See Reference Example 28)

[Step 2]: Compound 10 can be produced by halogenating compound 9 according to a conventional method. For example, this reaction is carried out by reacting compound 9 with a halogenating agent such as N-iodosuccinimide, N-bromosuccinimide, potassium iodide and cerium ammonium nitrate, iodine, bromine or the like in a suitable solvent or without solvent. Achieved. In some cases, the alkyl group of R ² may be halogenated, but by reacting a reducing agent such as sodium borohydride, the halogen atom substituted by R ² is selectively converted to a hydrogen atom. can do. (See Reference Examples 29, 30, and 33)

[Step 3]: Compound 11 is produced by subjecting compound 10 and Z ¹ -L ^a -Ar ² (Z ¹ is the same as defined above) to a coupling reaction according to the method of production method B-1. Can do. (See Example 7)

In addition, Compound 11 is obtained by converting X ¹ in Compound 10 into a coupling reagent such as a boride, zinc halide, magnesium halide, etc. according to the method of Production Method B-3, and then converting the compound and Z ² -L ^a -Ar ^{2 (Z} 2 are as defined above) can be prepared by carrying out the coupling reaction with.

Z ¹ -L ^a -Ar ² is obtained by substituting various metal atoms for Z ⁴ -L ^a -Ar ² (Z ⁴ is the same as defined above) according to the production method B-6 according to a conventional method. Can be manufactured. For example, it can be produced by following a method described in WO2007 / 129996 or the like, or a method based thereon.

Z ⁴ -L ^a -Ar ² is a known compound, or a production method using Z ⁴ -L ^a -Z ¹ and Ar ² -Z ² or Z ⁴ -L ^a -Z ² and Ar ² -Z ¹ also carrying out the coupling reaction of an aromatic ring L ^a and Ar ² in B-1 and the same methods can be produced.

In Z ⁴ -L ^a -Ar ^2, coupling of an aromatic ring ^{L a} and Ar ² are the case of N-C bond, it can be produced by performing a substitution reaction. For example, this reaction is carried out in a suitable solvent or without a solvent, an aromatic ring ^Z 4 -L ^a and ^Z 2 -Ar ² or ^{Z 3 -Ar} 2 ^(Z 3 having an NH group in the ring in the above definition The same can be achieved by carrying out the reaction according to the method of production method B-5.

In Z ⁴ -L ^a -Ar ^2, where the binding of the aromatic ring ^{L a} and Ar ² is a C-N bond can be produced by performing a substitution reaction. For example, in this reaction, Ar ² having an NH group in the ring and Z ² -L ^a -Z ⁴ or Z ³ -L ^a -Z ⁴ may be produced in a suitable solvent or without solvent in the production method B- This can be achieved by carrying out the reaction according to the method of 5.

  Specific examples of the solvent in each reaction of Production Method C should be selected according to the type of raw material compound, etc., and for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N— Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method D]
In the formula (I), R ⁰ is a single bond, L is a 5- to 6-membered unsubstituted aromatic ring which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S The compound representing the group (L ^a ) [compound of the following formula 11] is also produced by the following production method.

（式中、Ａｒ^１、Ａｒ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４は、項１の定義に同じであり、Ｌ^ａ、Ｚ^１、Ｚ^２、Ｗ^１、Ｘ^１は上記定義に同じである。）

(In the formula, Ar ¹ , Ar ² , R ¹ , R ² , R ³ , R ⁴ are the same as defined in item 1, and ^La , Z ¹ , Z ² , W ¹ , X ¹ are defined as above. Same.)

[Step 1]: Compound 12 is produced by subjecting compound 10 and Z ¹ -L ^a -W ¹ (Z ¹ is the same as defined above) to a coupling reaction according to the method of production method B-1. be able to.

Moreover, compound 12 is obtained according to the process of Preparation B-3, the X ¹ in compound 10, boron embodying, zinc halide body, after converting the coupling reagent magnesium halide and the like, the compound and Z ² -L ^a- W ¹ (Z ² is the same as defined above) can be produced by performing a coupling reaction.

[Step 2]: When W ¹ in Compound 12 represents a halogen atom, Compound 11 is a cup of Compound 12 and Z ¹ -Ar ² (Z ¹ is as defined above) according to the method of Production Method B-1. It can manufacture by performing a ring reaction.

Further, when W ¹ in Compound 12 represents a halogen atom, Compound 11 is prepared by using W ^{1 of} Compound 12 as a coupling reagent such as a boride, zinc halide, or magnesium halide according to the method of Production Method B-3. After the conversion, it can be produced by performing a coupling reaction between the compound and Z ² —Ar ² (Z ² is the same as defined above).

Further, ^{when W 1} in compound 12 is a hydrogen atom, compound 11 is obtained according to the process of Preparation B-2, after the ^{L a} group of the Compound 12 was halogenating ^performs Z 1 -Ar ² and coupling reactions Can be manufactured.

Further, W ¹ of compound 12 is, if an amino group, compound 11, after which according to the method of Preparation B-4, was converted to W ¹ to halogen atoms of bromine or iodine by Sandmeyer reaction, this and Z ^1- Ar ² can also be produced by a coupling reaction according to the same method as production method B-1.

Also, if ^{the L a} compound 12 having a NH group in the ring, i.e., if they contain NH groups in group constituting ^{L a,} compound 11 is obtained according to the process of Preparation B-5, compound 12 and Z ^2- Ar ² (Z ² is the same as defined above) or Z ³ -Ar ² (Z ³ is defined as defined above) can be produced by performing a substitution reaction or a coupling reaction.

  Specific examples of the solvent in each reaction of Production Method D should be selected according to the type of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N— Examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, and alcohols such as methanol, ethanol, and isopropanol, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method E]
In the formula (I), a compound in which R ⁰ is a single bond and R ¹ is a hydrogen atom [compound of the following formula 14] is also produced by the following production method.

(In the formula, Ar ¹ , Ar ² , L, R ² , R ³ , R ⁴ are the same as defined in item 1, and W ⁰ is a protecting group such as a benzyl group which may be substituted with methoxy or nitro. Represents.)

  Compound 14 can be produced by subjecting compound 13 to a reduction reaction according to a conventional method. For example, this reaction may be carried out by reacting compound 13 with a catalytic reducing reagent such as palladium carbon or palladium hydroxide in a hydrogenated state or in the presence of ammonium formate, or in a suitable solvent or without solvent, or trifluoroacetic acid or the like. The reaction is carried out in the presence of an acid, or in the presence of an oxidizing agent such as 2,3-dichloro-5,6-dicyano-para-benzoquinone.

  Specific examples of the solvent in each reaction of the production method E should be selected according to the type of the raw material compound, etc., and for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N- Examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method F]
In formula (I), R ⁰ is a single bond, R ¹ is optionally substituted, C _1-10 alkyl, C _2-6 alkene, or 1-2 selected from the group consisting of N, O and S A compound [compound of the following formula 15] representing a 3- to 6-membered saturated or unsaturated aliphatic ring group (R ^1a ) which may contain a heteroatom of the above is also produced by the following production method.

(In the formula, Ar ¹ , Ar ² , L, R ² , R ³ , R ⁴ are the same as defined in item 1, and R ^1a is defined as above (optionally substituted, C _1-10 alkyl, C _2-6 alkene, represents a 3-6 membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S) X ² represents a leaving group represented by a halogen atom, triflate, etc.)

Compound 15 can be produced by subjecting compound 14 to an alkylation reaction according to a conventional method. For example, in this reaction, compound 14 is converted into a metal hydride reagent such as sodium hydride, an alkali metal carbonate reagent such as potassium carbonate, an alkali metal phosphate reagent such as potassium phosphate, in a suitable solvent or without solvent. React with X ² -R ^{1a in} the presence of an organic base reagent such as triethylamine, an alkali metal halide reagent such as lithium chloride, an alkali metal hydroxide (such as sodium hydroxide), a metal alkoxide (such as potassium t-butoxy) Is achieved. (See Example 23)

  Specific examples of the solvent in each reaction of production method F should be selected according to the type of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N- Examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate and the like, and they can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production method G]
Wherein (I), ^{R 0} is -C (= O) O -, - C (= O) -, - S (= O) 2 - group ^{(R 0a)} compound represents the compound of formula 16] Is also produced by the following production method.

(In the formula, Ar ¹ , Ar ² , L, R ¹ , R ² , R ³ , R ⁴ are the same as defined in item 1, and R ^0a represents the above definition (—C (═O) O—, — And C (═O) — and —S (═O) ₂ —.

Compound 16 can be produced by subjecting compound 14 to carbamation, acetylation or sulfonation according to a conventional method. For example, this reaction may be carried out in an appropriate solvent or in the absence of a solvent, such as a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, an alkali metal phosphate reagent such as potassium phosphate, or an organic compound such as triethylamine. In the presence of a base reagent, an alkali metal halide such as lithium chloride, an alkali metal hydroxide (such as sodium hydroxide), a metal alkoxide (such as t-butoxypotassium), compound 14 is converted to the carboxylic acid derivative of R ¹ and sulfone. active esters derived from acid derivatives, acid anhydrides of R ^1, is accomplished by reacting an acid halide of R ¹ and the like. Specific examples of the active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxypiperidine ester , 2-pyridylthiol ester, N-methylimidazole ester and the like. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isovaleric acid and the like. (See Examples 31, 32, and 33)

  Specific examples of the solvent in each reaction of the production method G should be selected according to the type of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N- Examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate and the like, and they can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method H]
In the formula (I), a compound in which R ⁰ represents —C (═O) NH— [compound of the following formula 17] is also produced by the following production method.

(In the formula, Ar ¹ , Ar ² , L, R ¹ , R ² , R ³ , and R ⁴ are the same as defined in item 1).

Compound 17 can be produced by urea compound 14 according to a conventional method. For example, this reaction may be carried out in an appropriate solvent or in the absence of a solvent, such as a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, an alkali metal phosphate reagent such as potassium phosphate, or an organic such as triethylamine. base reagent, an alkali metal halide reagent such as lithium chloride, an alkali metal hydroxide (sodium hydroxide, etc.), a metal alkoxide (t-butoxy potassium or the like) in the presence of compound 14 with an isocyanate compound of R ^1, such as (R ¹ - N = C = O) can be produced. (See Example 39)

  Specific examples of the solvent in each reaction of the production method H should be selected according to the kind of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N- Examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate and the like, and they can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method I]
In the formula (I), a compound in which R ⁰ represents —S (═O) ₂ NR ^a2 — [compound of the following formula 20] is produced by the following production method.

(In the formula, Ar ¹ , Ar ² , L, R ¹ , R ² , R ³ , R ⁴ , and R ^a2 are the same as defined in Item 1.)

[Step 1]: Compound 18 or 19 is prepared by subjecting a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, phosphorus such as potassium phosphate, etc. In the presence of an alkali metal reagent, an organic base reagent such as triethylamine, an alkali metal halide reagent such as lithium chloride, an alkali metal hydroxide (such as sodium hydroxide), a metal alkoxide (such as t-butoxypotassium), etc. It can be produced by reacting sulfonyldiimidazole or 2-oxo-1,3-oxazolidine-3-sulfonyl chloride. (See Example 105)

[Step 2]: Compound 20 is prepared by a conventional method, using a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, an alkali metal phosphate reagent such as potassium phosphate, an organic base reagent such as triethylamine, By reacting compound 18 or 19 with R ¹ R ^a2 NH in the presence of an alkali metal halide reagent such as lithium chloride, an alkali metal hydroxide (such as sodium hydroxide), or a metal alkoxide (such as t-butoxypotassium). Can be manufactured. In some cases, for example, according to the method described in J. Org. Chem. 2003, 68, 115-119. Or the like, a compound 18 is reacted with a trifluoroacetate such as methyl trifluoroacetate. Then, it can also be produced by reacting R ¹ R ^a2 NH.

  Specific examples of the solvent in each reaction of Production Method I should be selected according to the type of raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N- Examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, and alcohols such as methanol, ethanol, and isopropanol, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

R ¹ R ^a2 NH is a known compound, or in some cases, for example, can be produced according to the method described in J. Med. Chem. 2010, 53, 3517-3531, etc., or a method analogous thereto. it can.

[Production Method J]
In the formula (I), a compound in which R ⁰ represents —C (═O) NR ^a1 — [compound of the following formula 22] is produced by the following production method.

(In the formula, Ar ¹ , Ar ² , L, R ¹ , R ² , R ³ , R ⁴ , R ^a1 are the same as defined in item 1, and W ² represents phenyl, p-nitrophenyl, and the like. )

Compound 22 is prepared according to a conventional method, such as a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, an alkali metal phosphate reagent such as potassium phosphate, an organic base reagent such as triethylamine, or a halogen such as lithium chloride. It can be produced by reacting compound 21 with R ¹ R ^a1 NH in the presence of an alkali metal halide reagent, an alkali metal hydroxide such as sodium hydroxide, or a metal alkoxide such as t-butoxy potassium).

  Specific examples of the solvent in each reaction of Production Method J should be selected according to the type of raw material compound, etc., for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N— Examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene and ethyl acetate, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production method K]
In formula (I), R ¹ is C _1-10 alkyl or C _2-6 alkene substituted with —C (═O) OH or —S (═O) ₂ OH, —C (═O) OH A 3- to 6-membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of substituted N, O and S, or -C (= O ) A compound representing a 5- to 6-membered aromatic ring group (R ^1c ) optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S substituted with OH [the following formula 24 compounds], and R ¹ is —C (═O) NR ^a30 R ⁱ , —S (═O) ₂ NR ^a31 R ^{i ′} or —C (═O) OR ^b2 (R ^b2 is . defined in the same) _{C 1-10} alkyl or _{C 2-6} alkene substituted ^{with, -C (= O) NR c29} R d29 or - A 3-6 membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S substituted with C (= O) OR ^b30 Or 1-4 heteroatoms selected from the group consisting of N, O and S substituted with —C (═O) NR ^c32 R ^d32 or —C (═O) OR ^b34 A compound representing a good 5- to 6-membered aromatic ring group (R ^1d ) [compound of the following formula 25] is produced by the following production method.

(In the formula, Ar ¹ , Ar ² , L, R ⁰ , R ² , R ³ , R ⁴ are the same as defined in item 1, and R ^1b is —C (═O) OR ^b39 (R ^b39 C _1-6 alkyl optionally substituted with a hydroxyl group or a halogen atom, or benzyl optionally substituted with methoxy or nitro) or C _1-10 alkyl substituted with —S (═O) ₂ OR ^b39 or _{C 2-6} ^{alkene, -C (= O) oR b39} N substituted with saturated O and 1-2 may 3-6 membered optionally containing a hetero atom selected from the group consisting of S Or an unsaturated aliphatic ring group or 1 to 4 heteroatoms selected from the group consisting of N, O and S substituted with —C (═O) OR ^b39 represents a 6-membered aromatic ring ^{group, R 1c} is, -C (= O) OH or Is -S (= _{O) C 1-10} alkyl or _{C 2-6} alkene substituted with 2 OH, -C (= O) N substituted with OH, is selected from the group consisting of O and S. 1 to 3 to 6-membered saturated or unsaturated aliphatic ring group which may contain 2 heteroatoms, or 1 to 4 heteroatoms selected from the group consisting of N, O and S Represents an ^{optionally substituted} 5- to 6-membered aromatic ring group, and R ^1d represents —C (═O) NR ^a30 R ⁱ , —S (═O) ₂ NR ^a31 R ^{i ′} or —C (═O) OR _{C 1-10} alkyl or _{C 2-6} alkene substituted with ^{b2, -C (= O) NR} c29 R d29 or -C (= ^O) N substituted with ^{oR b30,} selected from the group consisting of O and S 3-6 membered saturated or unsaturated aliphatic optionally containing 1 to 2 heteroatoms Group or ^{-C (= O) NR c32 R} d32 or -C (= ^O) N substituted with ^{OR b34,} contain 1 to 4 heteroatoms selected from the group consisting of O and S,, Represents a 5- to 6-membered aromatic ring group.

[Step 1]: Compound 24 can be produced by subjecting compound 23 to hydrolysis according to a conventional method. For example, this reaction can be achieved by performing a hydrolysis reaction in an appropriate solvent or in the absence of a solvent under alkaline conditions such as an aqueous sodium hydroxide solution or acidic conditions such as hydrochloric acid. (See Examples 80 and 98)

In addition, when R ^{b39 of} Compound 23 represents a benzyl group that may be substituted with methoxy or nitro, Compound 24 can be produced by performing a reduction reaction of Compound 23 according to a conventional method. For example, this reaction may be performed by reacting a catalytic reduction reagent such as palladium carbon or palladium hydroxide in a hydrogenated state or in the presence of ammonium formate, or in the presence of an acid such as trifluoroacetic acid, in a suitable solvent or in the absence of a solvent. Or by reacting in the presence of an oxidant such as 2,3-dichloro-5,6-dicyano-para-benzoquinone.

[Step 2]: Compound 25 can be produced by subjecting compound 24 to amidation or esterification according to a conventional method. For example, in this reaction, compound 24 is converted into a reactive derivative (for example, active ester, acid anhydride, acid halide, etc.) in an appropriate solvent or without solvent, and reacted with various amines or various alcohols. Achieved. Specific examples of the active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxypiperidine ester , 2-pyridylthiol ester, N-methylimidazole ester and the like. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isovaleric acid and the like.

  Compound 25 can also be produced by reacting compound 24 with various amines and various alcohols in the presence of a condensing agent according to a conventional method. Specific examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride, Examples include 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, benzotriazol-1-yl-oxytris (pyrrolidino) phosphonium-hexafluorophosphate, and the like. These condensing agents may be used alone or in combination with these condensing agents and peptide synthesis reagents such as N-hydroxysuccinimide and N-hydroxybenzotriazole. (See Example 85)

  Specific examples of the solvent in each reaction of production method K should be selected according to the type of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N- Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method L]
In formula (I), ¹ to 2 heteroatoms selected from the group consisting of C _1-10 alkyl substituted with sulfo, sulfonyl, sulfoxide, C _2-6 alkene, N, O and S in formula (I) 3-6 membered saturated or unsaturated aliphatic ring group which may contain or 5-6 member which may contain 1-4 heteroatoms selected from the group consisting of N, O and S The compound representing the aromatic ring group (R ^1f ) of [the compound of the following formula 27] is produced by the following production method.

^{(Wherein, Ar 1, Ar 2, L} , R 0, R 2, R 3, R 4 are the same as defined in claim 1, R ^1e is substituted with thiol, alkylthio or sulfoxide _{C 1- A} 3-6 membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of ₁₀ alkyl, C _2-6 alkene, N, O and S; Represents a 5- to 6-membered aromatic ring group optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, wherein R ^1f is substituted with sulfo, sulfoxide, sulfonyl A 3-6 membered saturated or unsaturated aliphatic ring optionally containing 1-2 heteroatoms selected from the group consisting of _C1-10 alkyl, _C2-6 alkene, N, O and S 1 to 4 groups selected from the group consisting of N or O and S Represents a 5- to 6-membered aromatic ring group which may contain a heteroatom).

  Compound 27 can be produced by oxidizing compound 26 according to a conventional method. For example, this reaction can be achieved by reacting compound 26 with a peroxidant such as metachloroperbenzoic acid, hydrogen peroxide, oxone, sodium perborate or the like in a suitable solvent.

  Specific examples of the solvent in each reaction of Production Method L should be selected according to the type of raw material compound, etc., for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, toluene, ethyl acetate And acetic acid and the like, and can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production method M]
In formula (I), ¹ to 2 heteroatoms selected from the group consisting of C _1-10 alkyl, C _2-6 alkene, N, O and S, wherein R ¹ is substituted with aldehyde, oxo, carboxy 3-6 membered saturated or unsaturated aliphatic ring group which may contain or 5-6 member which may contain 1-4 heteroatoms selected from the group consisting of N, O and S The compound [the compound of the following formula 28] representing the aromatic ring group (R ^1h ) is produced by the following production method.

(In the formula, Ar ¹ , Ar ² , L, R ⁰ , R ² , R ³ , R ⁴ are the same as defined in item 1, and R ^1g is a C _1-10 alkyl substituted with a hydroxyl group or an aldehyde. A 3-6 membered saturated or unsaturated aliphatic ring group or N, which may contain 1 to 2 heteroatoms selected from the group consisting of C _2-6 alkene, N, O and S; C ₁ represents a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of O and S, and R ^1h is substituted with aldehyde, oxo, carboxy _A 3-6 membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of _-10 alkyl, C _2-6 alkene, N, O and S; Contains 1 to 4 heteroatoms selected from the group consisting of N, O and S And it represents an aromatic ring group which may 5-6 membered.)

  Compound 29 can be produced by oxidizing compound 28 according to a conventional method. For example, this reaction can be achieved by reacting Compound 28 with an oxidizing agent such as Dess-Martin reagent, potassium dichromate, sodium hypochlorite, Jones reagent, pyridinium dichromate in an appropriate solvent or without solvent. Is done.

  Specific examples of the solvent in each reaction of Production Method M should be selected according to the type of raw material compound, etc., but for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N— Examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production method N]
Wherein (I), _C wherein R ¹ is substituted with an aldehyde _1-10 alkyl (R ^1j), Compound [compound of formula 31], _{C 1-10} alkyl R ¹ is substituted with ^NR a24 ^{R e1} A compound [compound of the following formula 32] which is (R ^1k ) is also produced by the following production method.

(In the formula, Ar ¹ , Ar ² , L, R ⁰ , R ² , R ³ , R ⁴ are the same as defined in item 1, and R ¹ⁱ is an acetal group ((OR ^h ) ₂ , R ^h is , are as defined in claim 1.) represents _{C 1-10} alkyl substituted ^{by, R 1j} is, represents _{C 1-10} alkyl substituted with an aldehyde, R ^{1k is} substituted with ^NR a24 ^{R e1} has been _{C 1-10} ^{alkyl, R a24} are the same as defined in claim 1, R ^e1 is _{a C 1-6} alkyl (said alkyl, hydroxyl, cyano, halogen atom, C _1-3 alkoxy, or - NR ^c37 R ^d37 may be substituted, and R ^c37 and R ^d37 are each the same as defined in item 1.)

  [Step 1]: Compound 31 can be produced by deprotecting the acetal group of compound 30 according to a conventional method. For example, this reaction can be achieved by reacting compound 30 with an acid reagent such as p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid, or the like in a suitable solvent or without a solvent.

[Step 2]: Compound 32 can be produced by subjecting compound 31 to a reductive amination reaction according to a conventional method. For example, in this reaction, compound 31 and NR ^a24 R ^e1 are mixed with a hydride reagent such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or the like in an appropriate solvent or in the absence of a solvent. This is achieved by reacting in the presence of an acid such as acetic acid or hydrochloric acid.

  Specific examples of the solvent in each reaction of Production Method N should be selected according to the type of raw material compound, etc., but for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, toluene, ethyl acetate , Acetic acid or alcohols such as methanol, ethanol, isopropanol and the like, and can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production method O]
In formula (I), R ¹ is 1-2 selected from the group consisting of C _1-10 alkyl or C _2-6 alkene substituted with NHR ^a24 , N, O and S substituted with NHR ^a25 1 to 4 hetero atoms selected from the group consisting of 3 to 6-membered saturated or unsaturated aliphatic ring group, or N, O and S substituted with NHR ^a28 A compound [compound of the following formula 34] which is a 5- to 6-membered aromatic ring group (R ^1m ) which may contain an atom, and R ¹ is NR ^a24 C (═O) —A ′, NR ^a24 C ( = O) R ^h (R ^h is the same as defined in item 1), NR ^a24 C (= O) OR ^h , NR ^a24 C (= O) NR ^c38 R ^d38 or NR ^a24 S (= O) _m R ^b37 C _1-10 alkyl or C _2-6 alkene substituted with Selected from the group consisting of N, O and S substituted with NR ^a25 C (═O) R ^b28 , —NR ^a25 C (═O) NR ^c28 R ^d28 or —NR ^a25 S (═O) _m R ^b29 A 3-6 membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms, or —NR ^a28 C (═O) R ^b32 , —NR ^a28 C (═O) NR 5- to 6-membered fragrance optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S substituted with ^c31 R ^d31 or —NR ^a28 S (═O) _m R ^b33 The compound [compound of the following formula 35] which is a group ring group (R ¹ⁿ ) is also produced by the following production method.

(In the formula, Ar ¹ , Ar ² , L, R ⁰ , R ² , R ³ , R ⁴ are the same as defined in item 1, and R ^1l is NR ^a24 C (═O) OR ^b39 (R ^b39 is C _1-6 alkyl optionally substituted with a hydroxyl group or a halogen atom, or C _1-10 alkyl substituted with methoxy or nitro optionally substituted with nitro), C _2-6 alkene, NR ^a25 C (═O) 3-6 membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S substituted with OR ^b39 , or NR ^a28 C (═O) OR represents a 5- to 6-membered aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O, and S substituted with ^b39 ; _{C 1-1} where R ^{1 m} is substituted by ^{NHR a24} Alkyl or _{C 2-6} ^{alkene, NHR} N substituted with ^a25, O and 1-2 saturated or unsaturated fat may also be 3-6 membered contain a hetero atom selected from the group consisting of S ^Represents a 5- or 6-membered aromatic ring group optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S substituted with NHR ^a28 ; ¹ⁿ is NR ^a24 C (═O) -A ′, NR ^a24 C (═O) R ^h , NR ^a24 C (═O) OR ^h , NR ^a24 C (═O) NR ^c38 R ^d38 or NR ^a24 S ( ═O) C _1-10 alkyl or C _2-6 alkene substituted with _m R ^b37 , —NR ^a25 C (═O) R ^b28 , —NR ^a25 C (═O) NR ^c28 R ^d28 or —NR ^a25 S (= O) _m R ^b29 N substituted with O and 1-2 alicyclic group, saturated or unsaturated may also be 3-6 membered contain a hetero atom selected from the group consisting of S, or ^{-NR a28 C (= O) R} b32 , —NR ^a28 C (═O) NR ^c31 R ^d31 or —NR ^a28 S (═O) _m R ^b33 containing 1 to 4 heteroatoms selected from the group consisting of N, O and S Represents an optionally substituted 5- to 6-membered aromatic ring group, wherein m represents an integer of 1 or 2.)

  [Step 1]: Compound 34 can be produced by deprotecting the carbamate group by hydrolysis or reduction of compound 33 according to a conventional method. For example, this reaction is achieved according to the same method as [Step 1] of production method K. (See Example 100)

  [Step 2]: Compound 35 can be produced by subjecting compound 34 to an amidation reaction according to a conventional method. For example, this reaction can be achieved by reacting compound 34 with various active esters derived from carboxylic acid derivatives and sulfonic acid derivatives, various acid anhydrides or various acid halides in a suitable solvent or without solvent. The Specific examples of the active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxypiperidine ester , 2-pyridylthiol ester, N-methylimidazole ester and the like. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isovaleric acid and the like. (See Example 102)

  Compound 35 can also be produced by reacting compound 34 with various carboxylic acids and sulfonic acids in the presence of a condensing agent according to a conventional method. Specific examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride, Examples include 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, benzotriazol-1-yl-oxytris (pyrrolidino) phosphonium-hexafluorophosphate, and the like. These condensing agents may be used alone or in combination with these condensing agents and peptide synthesis reagents such as N-hydroxysuccinimide and N-hydroxybenzotriazole.

  In addition, compound 35 can be produced by urea formation of compound 34 according to a conventional method. For example, this reaction can be produced by reacting compound 34 with various substituted isocyanate compounds in a suitable solvent or without a solvent. Compound 35 can also be produced by converting compound 34 to a reactive derivative (eg, active carbamate) and reacting with various amines according to a conventional method. For example, this reaction can be achieved by reacting compound 34 with phenyl chloroformate, carbodiimidazole, or the like in an appropriate solvent or without a solvent, and then reacting various amines. In some cases, these urealation reactions may be performed by metal hydride reagents such as sodium hydride and potassium hydride, inorganic bases such as potassium carbonate and sodium hydrogen carbonate, or triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine, It may be carried out in the presence of an organic base such as 4-dimethylaminopyridine.

  Specific examples of the solvent in each reaction of Production Method O should be selected according to the type of raw material compound, etc., but for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N— Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production method P]
In the formula (I), a compound in which L is —S (═O) — or —S (═O) ₂ — [compound of the following formula 37] is also produced by the following production method.

(In the formula, Ar ¹ , Ar ² , R ⁰ , R ¹ , R ² , R ³ , R ⁴ are the same as defined in item 1, and q ¹ represents an integer of 1 or 2.)

  Compound 37 can be produced by oxidizing compound 36 according to a conventional method. For example, this reaction can be achieved by reacting compound 35 with a peroxidant such as metachloroperbenzoic acid, hydrogen peroxide, oxone, sodium perborate or the like in a suitable solvent. (See Example 106)

  Specific examples of the solvent in each reaction of Production Method P should be selected according to the type of raw material compound, etc., but for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, toluene, ethyl acetate And acetic acid and the like, and can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

  Next, the synthesis | combination of the various raw material compounds in the said manufacturing method AC is shown.

[Production method Q]
The raw material compound in which L represents pyrazole is produced by the following production method.

(In the formula, Ar ² and R ² are the same as defined in item 1, and R ⁶ represents C _1-6 alkyl.)

  Compound 38 is a known compound, or can be produced according to a known method for producing a compound. For example, it can be produced according to the method described in Journal of Fluorine Chemistry, 2007, 128, 1255-1259 or the like, or a method analogous thereto.

[Step 1]:
Compound 39 can be produced by performing an addition reaction of a propargyl dialkyl acetal compound to compound 38 according to a conventional method. For example, this reaction can be achieved by reacting a propargyl dialkyl acetal compound with an alkyl metal reagent such as butyl lithium in a suitable solvent or without solvent, and then reacting with compound 38. This addition reaction may be performed in the presence of hexamethylphosphoric triamide, iodine or the like. This reaction can also be achieved, for example, according to the method described in J. Am. Chem. Soc. 2003, 125, 14702-14703, or a method analogous thereto. (See Reference Example 1)

[Step 2]:
Compounds 41, 42 and 43 are produced by reacting compound 39 with a compound (Ar ² —NHNH ₂ ) in which a carbon atom in the ring of Ar ² is substituted with hydrazine in an appropriate solvent according to a conventional method. be able to. Ar ² —NHNH ₂ in this reaction may be a hydrochloride, and in some cases, it may be carried out in the presence of an acid such as hydrochloric acid, sulfuric acid or acetic acid. (See Reference Examples 2, 3, 4, and 5)

[Step 3]:
Compounds 42 and 43 are produced by subjecting compound 41 to a cyclization reaction in the presence of an acid such as hydrochloric acid or acetic acid or a Lewis acid such as gold trichloride in an appropriate solvent or without a solvent according to a conventional method. can do. (See Reference Example 6)

[Step 4]: Compounds 44 and 45 can be produced by subjecting compounds 42 and 43 to an oxidation reaction according to a conventional method. For example, this reaction is achieved by reacting compounds 42 and 43 with an oxidizing agent such as Dess Martin reagent, Jones reagent, pyridinium dichromate, or performing an oxidation reaction such as swan oxidation in an appropriate solvent or in the absence of a solvent. Is done. (See Reference Example 7)

  Specific examples of the solvent in each reaction of production method Q should be selected according to the type of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N— Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production method R]
The raw material compound in which L represents triazole is produced by the following production method.

(In the formula, Ar ² and R ² are the same as defined in item 1.)

Compound 46 is a known compound, or can be produced according to a method for producing a known compound. For example, it can be produced according to the method described in J. Org. Chem. 2009, 74, 6410-6413.

[Step 1]: Compound 48 can be produced by subjecting compound 46 and compound 47 to a cyclization reaction according to a conventional method. For example, this reaction can be achieved by reacting Compound 46 and Compound 47 with N, N-dimethylformamide dimethyl acetal in the presence of acetic acid in a suitable solvent or without solvent. For example, it can be produced according to the method described in Org. Lett. 2004, 17 (6), 2969-2971. (See Reference Example 8)

  Compound 47 is a known compound, or can be produced according to a method for producing a known compound. For example, it can be produced according to the method described in WO2008122767 or the like, or a method analogous thereto.

[Step 2]:
Compound 49 can be produced by subjecting compound 48 to an oxidation reaction according to a conventional method. For example, this reaction is achieved according to the same method as [Step 4] of production method Q. (See Reference Example 9)

  Specific examples of the solvent in each reaction of the production method R should be selected according to the type of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N- Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method S]
The raw material compound in which L represents imidazole is produced by the following production method.

(In the formula, Ar ² and R ² are the same as defined in item 1.)

Compound 50 is a known compound, or can be produced according to a known method for producing a compound. For example, by performing a reduction reaction of Ar ² —CO ₂ R ⁷ (R ⁷ represents C _1-6 alkyl or a hydrogen atom), an oxidation reaction of Ar ² —CH ₂ OH, a formylation reaction of Ar ² , and the like. Can be manufactured.

[Step 1]: Compound 51 can be produced by reacting compound 47 with compound 50 according to a conventional method. For example, this reaction can be achieved by reacting Compound 47 and Compound 50 in the presence of an acid catalyst such as paratoluenesulfonic acid in a suitable solvent or in the absence of a solvent. This reaction can also be produced according to the method described in J. Med. Chem. 2003, 46, 3463-3475, or a method analogous thereto.

[Step 2]: Compound 53 can be produced by subjecting compound 51 and compound 52 (tosylmethyl isocyanide) to a cyclization reaction in a suitable solvent or in the absence of a solvent according to a conventional method. This reaction can also be achieved, for example, according to the method described in J. Med. Chem. 2003, 46, 3463-3475, or a method analogous thereto.

[Step 3]: Compound 54 can be produced by subjecting compound 53 to an oxidation reaction according to a conventional method. For example, this reaction is achieved according to the same method as [Step 4] of production method Q.

  Specific examples of the solvent in each reaction of the production method S should be selected according to the kind of the raw material compound, and the like. Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method T]
The raw material compound representing ^a 5- to 6-membered unsubstituted aromatic ring group (L ^a ) that may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S is It is also manufactured by a manufacturing method.

^(Wherein, Ar 2, ^{R 2} is the same as defined in claim 1, ^{L a} is, N, may contain 1-4 heteroatoms selected from the group consisting of O and S 5 Represents a 6-membered unsubstituted aromatic ring group, and X ¹ represents a halogen atom.)

Compound 55 is a known compound, or can be produced according to a known compound production method. For example, it can be produced by performing an oxidation reaction of Ar ² —CHOHCH ₃ , an acetylation reaction of Ar ² or the like.

[Step 1]: Compound 56 can be produced by carrying out addition reaction of compound 55 to compound 38 according to a conventional method. For example, this reaction can be achieved by reacting Compound 55 with a metal reagent such as lithium bistriethylsilylamide or lithium diisopropylamide and then reacting with Compound 38 in a suitable solvent or without solvent. This reaction can also be achieved, for example, according to the method described in Tetrahedron Letters, 1991, 32, 7583-7586.

[Step 2]: Compound 58 can be produced by carrying out addition reaction of compound 57 to compound 38 according to a conventional method. For example, this reaction is achieved by reacting compound 57 with an alkyl metal reagent such as butyl lithium in a suitable solvent or without solvent, and then reacting with compound 38. This addition reaction may be performed in the presence of hexamethylphosphoric triamide, iodine or the like. This reaction can also be achieved, for example, according to the method described in J. Am. Chem. Soc. 2003, 125, 14702-14703, or a method analogous thereto.

Compound 57 is a known compound or can be produced by reacting Ar ² with an acetylene reagent according to the method described in J. Med. Chem. 2010, 53, 699-714.

[Step 3]: Compound 56 can be produced by subjecting compound 58 to water addition reaction according to a conventional method. For example, this reaction can be achieved by reacting Compound 58 with trimethylsilyl triflate or formic acid in a suitable solvent or without solvent. This reaction can also be achieved, for example, according to the method described in Eur. J. Org. Chem. 2008, 5461-5469.

[Step 4]: Compound 59 can be produced by halogenating compound 56 according to a conventional method. For example, this reaction may be carried out by reacting compound 56 with a halogenating agent such as N-iodosuccinimide, N-bromosuccinimide, potassium iodide and cerium ammonium nitrate, iodine or bromine in a suitable solvent or in the absence of a solvent. To be achieved.

[Step 5]: Compound 60 can be produced by subjecting compound 59 to a cyclization reaction according to a conventional method. For example, this reaction can be achieved by reacting compound 59 with methanethioamide, formamide, methanimidamide, or the like in a suitable solvent or without solvent. These cyclization reactions are carried out by alkali metal carbonates (for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal phosphates (potassium phosphate, etc.), organic bases (triethylamine, diisopropylethylamine, etc.), alkali metal halides (chloride chloride). Lithium, cesium fluoride, etc.), alkali metal hydroxide (sodium hydroxide, etc.), metal alkoxide (t-butoxypotassium, etc.), ammonium acetate, etc. may be used. This reaction can also be achieved, for example, according to the method described in WO2006137658, Bioorganic & Medicinal Chemistry Letters, 2007, 17, 5115-5120.

[Step 6]: Compound 61 can be produced by subjecting compound 60 to an oxidation reaction according to a conventional method. For example, this reaction is achieved according to the same method as [Step 4] of production method Q.

  Specific examples of the solvent in each reaction of the production method T should be selected according to the type of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N— Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production method U]
The raw material compound representing ^a 5- to 6-membered unsubstituted aromatic ring group (L ^a ) that may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S is It is also manufactured by a manufacturing method.

^(Wherein, Ar 2, ^{R 2} is the same as defined in claim ^{1, L a, W 1,} Z 1 is the same as defined above, ^{M 2} is lithium, magnesium halide, zinc halide, etc. Represents.)

W ¹ -L ^a -M ² is a known compound or can be produced according to a known production method. For example, it can be produced by reacting W ¹ -L ^a -Z ⁴ (Z ⁴ is the same as defined above) with an alkyl lithium reagent such as butyl lithium according to a conventional method. In addition, when Z ⁴ represents halogen, Z ⁴ can be substituted with magnesium halide by reacting Z ⁴ with an alkyl magnesium halide reagent such as methyl magnesium bromide according to a conventional method. by reacting the powder or alkyl zinc halide reagent and the like, it can be substituted for Z ⁴ zinc halide. However, when W ¹ represents an amino group, it is protected with t-butoxycarbonyl or the like. These reactions can also be achieved, for example, according to the method described in Org. Lett. 2001, 3, 835-838.

[Step 1]: Compound 62 can be produced by an addition reaction of W ¹ -L ^a -M ² to compound 38 in a suitable solvent or without solvent in accordance with a conventional method. This addition reaction may be performed in the presence of hexamethylphosphoric triamide, iodine or the like. These reactions can also be achieved, for example, according to the method described in Bioorganic & Medicinal Chemistry Letters, 2009, 19, 1559-1563.

[Step 2]: When W ¹ in Compound 62 represents a halogen atom, Compound 60 is a cup of Compound 62 and Z ¹ -Ar ² (Z ¹ is as defined above) according to the method of Production Method B-1. It can manufacture by performing a ring reaction.

In the case where W ¹ in compound 62 represents a halogen atom, compound 60 is prepared by using W ^{1 of} compound 62 as a coupling reagent such as a boride, zinc halide, or magnesium halide according to the method of production method B-3. After the conversion, it can be produced by performing a coupling reaction between the compound and Z ² —Ar ² (Z ² is the same as defined above).

Further, ^{when W 1} in the compound 62 is a hydrogen atom, compound 60 is obtained according to the process of Preparation B-2, after the ^{L a} group of the Compound 62 was halogenating ^performs Z 1 -Ar ² and coupling reactions Can be manufactured.

Further, when W ^{1 of} Compound 62 represents an amino group protected with t-butoxycarbonyl or the like, Compound 60 performs deprotection of the amino group, and halogen atoms such as bromine and iodine are subjected to Sandmeyer reaction according to a conventional method. Then, it can also be produced by subjecting it and Z ¹ -Ar ² to a coupling reaction according to the same method as in Production Method B-1.

Also, if ^{the L a} compound 62 having a NH group in the ring, i.e., if they contain NH groups in group constituting ^{L a,} compound 60 is obtained according to the process of Preparation B-5, compound 62 and Z ^2- Ar ² (Z ² is the same as defined above) or Z ³ -Ar ² (Z ³ is defined as defined above) can be produced by performing a substitution reaction or a coupling reaction.

[Step 3]: Compound 61 can be produced by subjecting compound 60 to an oxidation reaction according to a conventional method. For example, this reaction is achieved according to the same method as [Step 4] of production method Q.

  Specific examples of the solvent in each reaction of Production Method U should be selected according to the type of raw material compound, etc., but for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N— Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method V]
The raw material compound representing ^a 5- to 6-membered unsubstituted aromatic ring group (L ^a ) that may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S is It is also manufactured by a manufacturing method.

(In the formula, Ar ² and R ² are the same as defined in item 1, and L ^a and M ² are the same as defined above.)

Ar ² -L ^a -M ² is a known compound, or can be produced using Ar ² -L ^a -Z ⁴ according to the synthesis method of W ¹ -L ^a -M ² in Production Method U. it can.

[Step 1]: Compound 60 can be produced by performing an addition reaction of Ar ² -L ^a -M ² to compound 38 in a suitable solvent or without solvent according to a conventional method. This addition reaction may be performed in the presence of hexamethylphosphoric triamide, iodine or the like. This reaction can also be achieved, for example, according to the method described in Bioorganic & Medicinal Chemistry Letters, 2009, 19, 1559-1563.

[Step 2]: Compound 61 can be produced by subjecting compound 60 to an oxidation reaction according to a conventional method. For example, this reaction is achieved according to the same method as [Step 4] of production method Q.

  Specific examples of the solvent in each reaction of the production method V should be selected according to the kind of the raw material compound, etc. Examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method W]
The following raw material compounds are also produced by the following production method.

(In the formula, Ar ² , L and R ² are the same as defined in item 1).

  Compound 64 can be produced by subjecting compound 63 to exomethyleneation according to a conventional method. For example, this reaction is accomplished by reacting Compound 63 with an aqueous formaldehyde solution or paraformaldehyde in the presence of an acid such as acetic acid or hydrochloric acid and an amine reagent such as piperidine or dimethylamine in an appropriate solvent or without a solvent. Is done. (See Reference Examples 16 and 17)

  Compound 64 can also be produced by reacting compound 63 with N, N, N, N-tetramethyldiaminomethane in the presence of acetic anhydride in an appropriate solvent or without solvent according to a conventional method. it can. This reaction can also be achieved according to the method described in J. Med. Chem. 1987, 30, 1497-1502. (See Reference Example 13)

Compound 64 can also be produced by reacting compound 63 with an Eshenmoser salt (Me ₂ C ⁺ = CH ₂ I ⁻ ) in a suitable solvent or under no solvent according to a conventional method.

  Specific examples of the solvent in each reaction of production method W should be selected according to the type of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N- Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production Method X]
The following raw material compounds are also produced by the following production method.

(In the formula, Ar ² , L and R ² are the same as defined in item 1, and R ^c44 and R ^d44 each independently represent C _1-3 alkyl, or together, represent azetidine. Represents pyrrolidine, piperidine, piperazine.)

[Step 1]: Compound 65 can be produced by reacting compound 63 with an aqueous formaldehyde solution, paraformaldehyde, or the like, with an amine reagent such as piperidine or dimethylamine, in an appropriate solvent or without a solvent, according to a conventional method. it can. In some cases, this reaction is carried out in the presence of an acid such as acetic acid or hydrochloric acid.

[Step 2]: Compound 64 is prepared by reacting compound 65 with an alkyl halide such as methyl iodide in a suitable solvent or without solvent in the usual manner, and then a metal hydride reagent such as sodium hydride, potassium carbonate Reacting alkali metal carbonate reagents such as potassium phosphate, alkali metal phosphate reagents such as potassium phosphate, organic base reagents such as triethylamine, alkali metal hydroxides (such as sodium hydroxide), metal alkoxides (such as potassium t-butoxy), etc. Can be manufactured. This reaction can also be achieved according to the method described in Tetrahedron Asymmetry, 2000, 1217-1225.

  Specific examples of the solvent in each reaction of production method X should be selected according to the type of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N- Examples include dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, ethyl acetate, acetic acid or alcohols such as methanol, ethanol, isopropanol, and the like, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

[Production method Y]
The raw material compound in which L represents -S (= O) _2- is also produced by the following production method.

(In the formula, Ar ² is the same as defined in item 1.)

  Compound 66 is a known compound, or can be produced according to a known compound production method. For example, it can be produced according to the method described in Research on Chemical Intermediates, 2009, 35, 137-144.

[Steps 1 and 2]: Compounds 67 and 68 can be produced according to known methods for producing compounds. For example, it can be produced according to the method described in J. Org. Chem. 1993, 56, 4098-4112.

[Production method Z]
The starting compound of production method C can also be produced by the following production method.

(In the formula, Ar ¹ , R ¹ , R ² , R ³ and R ⁴ are the same as defined in item 1).

  Compound 69 is a known compound, or can be produced according to a known compound production method. For example, it can be produced according to the method described in Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (5), 1114-17; 1980 etc., or a method analogous thereto. it can.

[Step 1]: Compound 70 is a known compound, or can be produced using compound 69 and R ¹ —NH ₂ according to a known method for producing a compound. For example, it can be produced according to the method described in WO2008 / 8518 or the like, or a method analogous thereto.

[Step 2]: Compound 8 can be produced by urea-converting compound 70 according to a conventional method. For example, this reaction may be carried out in an appropriate solvent or in the absence of a solvent, such as a metal hydride reagent such as sodium hydride, an alkali metal reagent such as potassium carbonate, an alkali metal phosphate reagent such as potassium phosphate, or an organic compound such as triethylamine. base reagent, an alkali metal halide reagent such as lithium chloride, an alkali metal hydroxide (sodium hydroxide, etc.), a metal alkoxide (t-butoxy potassium or the like) in the presence, isocyanate compounds compound 70 and Ar ¹ such as (Ar ¹ - N = C = O) can be produced. Compound 8 can also be produced by converting compound 70 into a reactive derivative (eg, active carbamate) and reacting with Ar ¹ —NH ₂ according to a conventional method. (See Reference Example 27)

  Specific examples of the solvent in each reaction of the production method Z should be selected according to the kind of the raw material compound and the like. For example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N, N- Examples thereof include dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid or alcohols such as methanol, ethanol and isopropanol, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and reagent used, etc., it is generally −40 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. In some cases, the reaction may be carried out under pressurized conditions. .

  When the compound of the present invention represented by the formula (I), its intermediate or its raw material compound has a functional group, a substituent introduction reaction or a functional group conversion is carried out according to a conventional method of a person skilled in the art, if necessary Reactions can be performed. These were described in “Experimental Chemistry Course (Chemical Society of Japan, Maruzen)” or “Comprehensive Organic Transformation, RC Rallock, (VCH Publishers, Inc, 1989)”. A method or the like can be used. For example, functional group conversion reactions include carbon-carbon bond formation reactions such as Friedel-Crafts reaction and Wittig reaction, carbon-nitrogen such as reductive amination reaction or amine alkylation reaction. Examples include bond formation reactions, oxidation or reduction reactions.

  In addition, when the compound of the present invention represented by formula (I) or an intermediate thereof has a functional group such as an amino group, a carboxyl group, a hydroxyl group or an oxo group, protection or deprotection may be performed as necessary. Can be done. Suitable protecting groups, methods for protecting and deprotecting are described in detail in “Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc .; 1990)”. Further, when two or more halogen atoms are present in the structure of the compound of the present invention represented by formula (I), an intermediate thereof, or a reaction compound, the difference in the reaction activity of the halogen atom at the bonding position It is possible to specify the halogen atom to be reacted and control the reaction position by changing the type of halogen atom and the type of halogen atom bonded thereto.

  The compound of the formula (I) produced | generated by each said manufacturing method can be isolated and refine | purified by conventional methods, such as chromatography, recrystallization, and reprecipitation. In addition, the compound of the formula (I) or a pharmaceutically acceptable salt thereof may have axial asymmetry or may have a substituent having an asymmetric carbon. There is a body. The compounds of the present invention include mixtures of these isomers and isolated ones. Examples of a method for purely obtaining such optical isomers include an optical resolution method by chromatography using an optically active column, a preferential crystallization method, a diastereomer method and an optical resolution method.

  As the optical resolution method, when the compound of the present invention or an intermediate thereof has a basic functional group, it is used in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, 2-propanol, or an ether solvent such as diethyl ether). Solvents, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, acetonitrile and the like, and mixed solvents thereof), optically active acids (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, and lactic acid) Acids, tartaric acid, o-diisopropylidene tartaric acid, dicarboxylic acids such as malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid) can also be formed into salts.

In addition, when the compound of the present invention or an intermediate thereof has an acidic substituent such as a carboxyl group, an optically active amine (for example, organic amines such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine) and a salt Can also be formed. Examples of the temperature at which the salt is formed include a range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the collected salt is collected by filtration, it can be cooled as necessary to improve the yield. The amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate. Crystals in an inert solvent as necessary (for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, It can also be recrystallized with acetonitrile or a mixed solvent thereof to obtain a highly pure optically active salt. If necessary, the obtained salt can be treated with an acid or a base by a conventional method to obtain a free form.
The compound of formula (I) can be obtained in the form of a free base or a free acid, or an acid addition salt or a base addition salt, depending on the type of functional group present in the structural formula, the selection of the raw material compound, and the reaction treatment conditions. Can be converted to compounds of formula (I) according to conventional methods. On the other hand, the compound of formula (I) is converted into an acid addition salt by treating with various acids according to a conventional method depending on the type of functional group present in the structural formula, and into a base addition salt by treating with various bases Can lead.

  Since the dihydropyrimidinone derivative of the present invention has potent neutrophil elastase inhibitory activity as described later, it is a useful pharmaceutical agent for a disease for which neutrophil elastase inhibitory activity is desired and / or required. Can be expected. The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like. For example, in the case of oral administration, usually about 0.01 to 3000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses. In the case of parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 500 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses.

  Diseases for which neutrophil elastase inhibitory activity is desired and / or required include, for example, chronic obstructive pulmonary disease (COPD), cystic pulmonary fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute Lung disorder (ALI), idiopathic pulmonary fibrosis (IIP), chronic interstitial pneumonia, chronic bronchitis, chronic respiratory tract infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, chronic Rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection in organ transplantation, early water rupture, blistering, shock, sepsis, systemic lupus erythematosus (SLE), Crohn's disease, Disseminated intravascular coagulation (DIC), tissue damage during ischemia-reperfusion, formation of corneal scar tissue, myelitis, lung squamous cell carcinoma, lung adenocarcinoma, lung cancer such as non-small cell lung cancer, breast cancer, Liver cancer, bladder cancer Colorectal cancer, skin cancer, pancreatic cancer, and the like glioma.

  The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier when used for the above-mentioned pharmaceutical use. As the pharmaceutical carrier, a non-toxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, citric acid, glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose, methyl paraoxybenzoate, propyl paraoxybenzoate, and metasilicate aluminum Magnesium sulfate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose , Polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate Light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, bee gum, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil Wax, propylene glycol, ethanol, benzyl alcohol, sodium chloride, sodium hydroxide, hydrochloric acid, water and the like.

  Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like. These preparations can be prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In addition, these formulations may contain other therapeutically valuable ingredients.

  For the treatment of the diseases described in the specification in which elastase inhibitory activity is required, the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation containing the compound of the present invention comprises: It may be administered in combination with a therapeutic or prophylactic agent.

  Specific examples of therapeutic or prophylactic agents that may be used in combination are shown below. Examples of the short-term or long-term muscarinic receptor (subtype M1, M2 and M3) antagonist include ipratropium bromide, tiotropium bromide and the like, and short-term or long-term β receptor ( Examples of the subtype β1, β2, β3, and β4) agonist include fenoterol hydrobromide, salbutamol sulfate, salmeterol xinafoic acid, formoterol fumarate, etc., and inhaled or oral steroids include fluticasone Propionate, beclomethasone propionate, budesonide, etc. Examples of the combination of β receptor agonist and inhaled steroid include, for example, a combination of salmeterol xinafoate and fluticasone propionate, phosphodiesterase ( PDE Examples of the inhibitor include PDE4 inhibitors such as theophylline and aminoxylline containing methylxanthanine. Examples of the expectorants include carbocysteine. Examples of the antibiotics include erythromycin and clarithromycin. Mycin etc. are mentioned.

  Hereinafter, the present invention will be described more specifically with reference to reference examples, examples, and test examples, but these examples do not limit the present invention. The compound was identified by elemental analysis, mass spectrum, high performance liquid chromatography / mass spectrometer; LCMS, IR spectrum, NMR spectrum, high performance liquid chromatography (HPLC) and the like.

  In order to simplify the description of the specification, the following abbreviations may be used in the reference examples, examples, and tables in the examples.

As abbreviations used as substituents, Me represents a methyl group, Et represents an ethyl group, Ph represents a phenyl group, CN represents a cyano group, and NO ₂ represents a nitro group.
The symbols used in NMR are as follows: s is a single line, d is a double line, dd is a double double line, t is a triple line, td is a triple line double line, q is a quadruple line, quin is A quintet, m is a multiple line, br is broad, brs is a wide single line, brd is a wide double line, brt is a wide triple line, and J is a coupling constant.

The NMR measurement conditions are as follows.
Measurement condition 1: 300 MHz, CDCl ₃
Measurement condition 2: 300 MHz, DMSO-d ₆
Measurement condition 3: 300 MHz, CD ₃ OD
Measurement condition 4: 400 MHz, CDCl ₃
Measurement condition 5: 400 MHz, DMSO-d ₆
Measurement condition 6: 400 MHz, CD ₃ OD
High-performance liquid chromatograph mass spectrometer; LCMS measurement conditions are as follows (measurement conditions 7 and 8), the observed mass spectrometry value [MS (m / z)] is MH +, and the retention time is Rt ( In minutes).

Measurement condition 7:
Detector: LC / MS-2010EV (manufactured by SHIMAZU)
HPLC: LC / MS-2010C HT (manufactured by SHIMAZU)
Column: CAPCELL PAK, C18 MGII (manufactured by SHISEIDO) (S-3 μm, 4.6 × 35 mm)
Solvent: A solution; acetonitrile, B solution; 0.05% trifluoroacetic acid / water elution conditions:
0.0-5.0 (minutes); A: B = 10: 90 → 99: 1
5.0-7.0 (min); A: B = 99: 1
7.0-10.0 (min); A: B = 99: 1 → 10: 90
Flow rate: 0.35 ml / min UV: 220 nm
Column temperature: 40 ° C.

Measurement condition 8:
MS detection device: Waters micromass ZQ
HPLC: Waters2790 separations module
Column: Impact Cadenza CD-C18 2.0mm x 20mm
Flow rate: 1.0 ml / min
Measurement wavelength: 254 nm
Moving bed: A liquid; water B liquid; acetonitrile C liquid; 2% formic acid acetonitrile solution elution condition:
0.0-0.1 (min); Liquid A: Liquid B: Liquid C = 95: 2: 3
0.1-3.1 (min); Liquid A: Liquid B: Liquid C = 95: 2: 3 → 1: 96: 3
3.1-3.5 (min); Liquid A: Liquid B: Liquid C = 1: 96: 3.

Reference Example 1-3 :

[Process 1] Reference Example 1
N-Butyllithium (3.1 ml) was added dropwise to a solution of propargylaldehyde diethylacetal (1.0 g) and hexamethylphosphoric triamide (1.5 ml) in tetrahydrofuran (30.0 ml) at −78 ° C. Then, the temperature was raised to room temperature and stirred for 30 minutes, and again adjusted to −78 ° C. Then, after propylene oxide (1.4 g) was added dropwise, the temperature was raised to room temperature and stirred for 18 hours. A saturated aqueous ammonium chloride solution (30 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (2 × 50 ml). The organic layer was washed with water (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 6,6-diethoxy-4hexyne-2-ol (1.8 g). It was.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.22 (dd, 6H, J = 13.5, 6.9Hz), 2.32−2.46 (m, 2H), 2.62 (d, 3H, J = 9.3Hz), 3.53 (q, 1H, J = 6.9Hz), 3.56 (q , 1H, J = 6.9Hz), 3.69 (q, 1H, J = 6.9Hz), 3.72 (q, 1H, J = 6.9Hz), 3.91−4.01 (m, 1H), 5.25 (t, 1H, J = 1.6Hz).

[Step 2] Reference examples 2, 3
4-Cyanophenylhydrazine hydrochloride (4.0 g) was added to an ethanol (30 mL) solution of 6,6-diethoxy-4-hexyne-2-ol (4.00 g) obtained in step 1. And stirred for 8 hours under reflux. Water (100 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (twice with 300 ml). The organic layer was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 4- [5- (2-hydroxypropyl) -1H-pyrazol-1-yl] benzonitrile (1.35 g) and 4 -[3- (2-Hydroxypropyl) -1H-pyrazol-1-yl] benzonitrile (667.8 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
Reference example 2:
4- [5- (2-hydroxypropyl) -1H-pyrazol-1-yl] benzonitrile: 1.18 (d, 3H, J = 6.2Hz), 2.81 (d, 2H, J = 5.9Hz), 4.00-4.08 ( m, 1H), 6.32 (brs, 1H), 7.58 (brs, 1H), 7.60-7.62 (m, 2H), 7.70-7.73 (m, 2H).
Reference Example 3:
4- [3- (2-hydroxypropyl) -1H-pyrazol-1-yl] benzonitrile: 1.29 (d, 3H, J = 6.3Hz), 2.77 (dd, 1H, J = 15.0, 5.4Hz), 2.88 ( dd, 1H, J = 15.0, 3.6Hz), 4.15-4.21 (m, 1H), 6.36 (d, 1H, J = 2.4Hz), 7.71 (d, 2H, J = 9.0Hz), 7.78 (d, 2H , J = 8.7Hz), 7.91 (d, 1H, J = 2.7Hz).

Reference Example 4-6 :

[Step 1] Reference Examples 4 and 5
A solution of 6,6-diethoxy-4hexyne-2-ol (4.82 g) and 4-cyanophenylhydrazine hydrochloride (6.57 g) obtained in Reference Example 1 in N, N-dimethylformamide (100 ml) After dropwise addition of hydrochloric acid (1M aqueous solution, 28.5 mL) under ice cooling, the mixture was stirred at room temperature for 26 hours. Water (150 ml) was added to the reaction mixture, and the mixture was extracted with hexane / ethyl acetate = 1/1 (2 × 500 ml). The organic layer was washed with water (150 mL) and saturated brine (150 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to obtain (Z) -4- [2- (5-hydroxy-2-hexylidene) hydrazinyl] benzonitrile (1.15 g). , (E) -4- [2- (5-hydroxy-2-hexylidene) hydrazinyl] benzonitrile (2.76 g) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
Reference example 4:
(Z) -4- [2- (5-Hydroxy-2-hexylidene) hydrazinyl] benzonitrile:
1.17 (d, 3H, J = 6.2Hz), 2.62 (dd, 2H, J = 5.8, 1.6Hz), 3.86-3.94 (m, 1H), 5.13 (brs, 1H), 6.64 (brs, 1H), 7.25 (d, 2H, J = 8.8Hz), 7.64 (d, 2H, J = 8.6Hz), 10.19 (s, 1H).
Reference example 5:
(E) -4- [2- (5-Hydroxy-2-hexylidene) hydrazinyl] benzonitrile:
1.16 (d, 3H, J = 6.2Hz), 2.42-2.51 (m, 2H), 3.77-3.85 (m, 1H), 4.86 (d, 1H, J = 4.6Hz), 7.03 (d, 2H, J = 8.4Hz), 7.19 (s, 1H), 7.61 (d, 2H, J = 8.2Hz), 11.18 (s, 1H).

[Step 2] Reference Example 6a
To a solution of (Z) -4- [2- (5-hydroxy-2-hexylidene) hydrazinyl] benzonitrile (102.4 mg) obtained in Step 1 in N, N-dimethylformamide (2.5 ml), 1N Hydrochloric acid (0.9 ml) was added, and the mixture was stirred at 140 ° C. for 0.5 hr with a microwave synthesizer. Water (30 ml) was added to the reaction mixture, followed by extraction with hexane / ethyl acetate = 1/2 (twice with 40 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 4- [5- (2-hydroxypropyl) -1H-pyrazol-1-yl] benzonitrile (36.0 mg). Obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
Same as Reference Example 2.

[Step 2] Reference Example 6b
To a solution of (Z) -4- [2- (5-hydroxy-2-hexylidene) hydrazinyl] benzonitrile (200.0 mg) obtained in Step 1 in methylene chloride (5.0 ml) was added gold trichloride (54. 0 mg) was added and stirred at room temperature for 14 hours. A saturated aqueous sodium hydrogen carbonate solution (30 ml) was added to the reaction mixture, and the mixture was extracted with chloroform (twice with 20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 4- [5- (2-hydroxypropyl) -1H-pyrazol-1-yl] benzonitrile (176.1 mg). Obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
Same as Reference Example 2.

[Step 2] Reference Example 6c
To a solution of (E) -4- [2- (5-hydroxy-2-hexylidene) hydrazinyl] benzonitrile (220.0 mg) obtained in Step 1 in methylene chloride (6.0 ml) was added gold trichloride (59. 4 mg) was added and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution (30 ml) was added to the reaction mixture, and the mixture was extracted with chloroform (twice with 20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 4- [5- (2-hydroxypropyl) -1H-pyrazol-1-yl] benzonitrile (187.0 mg). Obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
Same as Reference Example 2.

Reference Example 7 :

To a solution of 4- [5- (2-hydroxypropyl) -1H-pyrazol-1-yl] benzonitrile (278.0 mg) obtained in Reference Examples 2 and 6 in dichloromethane (6.0 ml), desmartin reagent (570.7 mg) was added and stirred at 0 ° C. for 2 hours. To the reaction mixture was added aqueous sodium hydrogen carbonate solution (50 ml), and the mixture was extracted with chloroform (twice with 30 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 4- [5- (2-oxopropyl) -1H-pyrazol-1-yl] benzonitrile (177.6 mg). Obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
2.18 (s, 3H), 3.85 (s, 2H), 6.37 (d, 1H, J = 1.8Hz), 7.52−7.56 (m, 2H), 7.70 (d, 1H, J = 1.8Hz), 7.74−7.78 (m, 2H).

Reference Example 8-9 :

  Starting material of the above formula: 4-cyanobenzohydrazide was produced according to the production method described in J. Org. Chem. 2009, 74, 6410-6413.

[Step 1] Reference Example 8
A solution of 4-cyanobenzohydrazide (300.0 mg) and dimethylformamide dimethylacetate (330 μl) in acetonitrile (10 ml) was stirred at 50 ° C. for 30 minutes and then brought to room temperature, and 2-hydroxy-propylamine (240 μl) and Acetic acid (16 μl) was added, and the mixture was stirred for 4 hours with heating under reflux. Water (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (2 x 30 ml). The organic layer was washed with water (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was chloroform / methanol) to give 4- [4- (2-hydroxypropyl) -4H-1,2,4-triazol-3-yl] benzonitrile. (112.2 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.28 (d, 3H, J = 6.4Hz), 3.76−3.94 (m, 2H), 4.24−4.32 (m, 1H), 7.70−7.74 (m, 2H), 7.81−7.84 (m, 2H), 8.13 ( s, 1H).

[Step 2] Reference Example 9
To a solution of 4- [4- (2-hydroxypropyl) -4H-1,2,4-triazol-3-yl] benzonitrile (60.0 mg) in methylene chloride (10 ml) was added pyridinium dichromate (197.8 mg). ) And stirred at room temperature for 3.5 hours. The reaction mixture was filtered through Celite with chloroform and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was chloroform / methanol) to give 4- [4- (2-oxopropyl) -4H-1,2,4-triazol-3-yl] benzonitrile. (19.3 mg) was obtained.
LC / MS (measurement condition 8)
227 (M + H) /1.42 (min).

Reference examples 10 and 11 :

[Step 1] Reference Example 10
To a 1,4-dioxane (200 ml) solution of 3-trifluoromethylphenylurea (13.6 g) and copper (I) chloride (1.3 g), a solution of formaldehyde (13.4 g) in chloroform (20 ml), 2- Bromophenylacetone (9.5 g), acetic acid (1.0 ml) and boron trifluoride diethyl ether complex (8.5 ml) were added, and the mixture was stirred for 6 hours under heating to reflux. A saturated aqueous sodium hydrogen carbonate solution (100 ml) and aqueous ammonia (5 ml) were added to the reaction mixture, followed by extraction with ethyl acetate (2 × 50 ml). The organic layer was washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 1- [2- (2-bromophenyl) -3-oxobutyl] -3- [3- (trifluoromethyl) phenyl. ] Urea (2.0 g) was obtained.
¹ H-NMR (CD ₃ OD: 300 MHz) δ:
2.06 (s, 3H), 3.48−3.57 (m, 1H), 3.74−3.82 (m, 1H), 4.62 (t, 1H, J = 6.8Hz), 6.18 (brs, 1H), 7.18−7.24 (m, 3H), 7.33-7.46 (m, 3H), 7.68 (d, 1H, J = 8.1Hz), 7.77 (s, 1H).

[Step 2] Reference Example 11
1- [2- (2-Bromophenyl) -3-oxobutyl] -3- [3- (trifluoromethyl) phenyl] urea (1.6 g) obtained in Reference Example 10 in acetic acid (3.0 ml) solution Was stirred under reflux with heating for 6 hours. Water (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (2 x 30 ml). The organic layer was washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 5- (2-bromophenyl) -6-methyl-1- [3- (trifluoromethyl) phenyl] -3, 4-Dihydropyrimidin-2 (1H) -one (565.0 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.24 (t, 3H, J = 1.7Hz), 3.96 (brd, 1H, J = 14.1Hz), 4.19 (brd, 1H, J = 14.1Hz), 5.22 (s, 1H), 7.08−7.14 (m, 1H ), 7.17-7.20 (m, 2H), 7.24-7.29 (m, 1H), 7.45-7.58 (m, 5H).

Reference Example 12 :

1- [2- (2-Bromophenyl) -3-oxobutyl] -3- [3- (trifluoromethyl) phenyl] urea (194.0 mg) obtained in Reference Example 10, 4-cyanophenylboronic acid ( 332.0 mg), sodium carbonate (479.0 mg) in tetrahydrofuran (5.0 ml) / water (0.8 ml), tetrakistriphenylphosphine palladium (52.2 mg) was added, and the mixture was heated to reflux for 2.5. Stir for hours. Water (20 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (twice with 10 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 1- [2- (4′-cyanobiphenyl-2-yl) -3-oxobutyl] -3- [3- ( Trifluoromethyl) phenyl] urea (53.6 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.79 (s, 3H), 3.50−3.57 (m, 1H), 3.62−3.70 (m, 1H), 3.94 (dd, 1H, J = 9.2, 4.0Hz), 5.16 (brs, 1H), 6.34 (brs, 1H), 6.99−7.03 (m, 1H), 7.24−7.37 (m, 5H), 7.42−7.47 (m, 2H), 7.54 (d, 2H, J = 8.3Hz), 7.72 (d, 2H, J = (8.3Hz).

Reference Example 13 :

A solution of 4-fluorophenylthioacetone (2.0 g) in acetic anhydride (2.1 ml) was heated to 60 ° C., and N, N, N, N-hexamethylmethylenediamine (1.5 ml) was added dropwise. Stir for minutes. Saturated aqueous sodium hydrogen carbonate solution (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to obtain 3- (4-fluorophenylthio) -3-buten-2-one (493.9 mg).
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
2.40 (s, 3H), 5.21 (d, 1H, J = 1.5Hz), 6.10 (d, 1H, J = 1.5Hz), 7.06−7.11 (m, 2H), 7.41−7.46 (m, 2H).

Reference Example 14 :
The corresponding compounds were used and reacted in the same manner as in the method described in Reference Example 13 to obtain the compounds shown below.

¹ H-NMR (CDCl ₃ : 300 MHz) δ:
2.37 (s, 3H), 5.94 (s, 1H), 6.15 (s, 1H), 7.13-7.18 (m, 2H), 7.36-7.40 (m, 2H).

Reference Example 15-16 :

[Step 1] Reference Example 15
To a solution of 1- (4-bromophenylthio) propan-2-one (300.0 mg), zinc cyanide (718.4 mg), zinc powder (39.9 mg) in N, N-dimethylformamide (4.0 ml). , Tetrakistriphenylphosphine palladium (282.0 mg) was added, and the mixture was stirred at 100 ° C. for 4 hours. The reaction mixture was filtered through ethyl acetate, water (20 ml) was added to the filtrate, and the mixture was extracted with ethyl acetate (twice with 10 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 4- (2-oxopropylthio) benzonitrile (161.0 mg).
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
2.29 (s, 3H), 3.75 (s, 2H), 7.29-7.32 (m, 2H), 7.51-7.54 (m, 2H).

[Step 2] Reference Example 16
A solution of 4- (2-oxopropylthio) benzonitrile (130.0 mg), aqueous formaldehyde solution (178 μl), acetic acid (9 μl), piperidine (9 μl) in acetonitrile (6.0 ml) was stirred with heating under reflux for 1 hour. . The reaction mixture was concentrated under reduced pressure, water (10 ml) was added, and the mixture was extracted with ethyl acetate (twice with 20 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to obtain 4- (3-oxo-1-buten-2-ylthio) benzonitrile (57.6 mg).
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
2.38 (s, 3H), 5.79 (d, 1H, J = 0.9Hz), 6.40 (d, 1H, J = 0.9Hz), 7.39-7.42 (m, 2H), 7.57-7.60 (m, 2H).

Reference Example 17-21 :

[Step 1] Reference Example 17
A solution of 2-bromophenylacetone (298.0 mg), an aqueous formaldehyde solution (366 μl), acetic acid (18 μl) and piperidine (18 μl) in methanol (5.0 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, water (10 ml) was added, and the mixture was extracted with chloroform (twice with 20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 3- (2-bromophenyl) -3-buten-2-one (255.0 mg).
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
2.36 (s, 3H), 5.79 (s, 1H), 6.30 (s, 1H), 7.16-7.23 (m, 2H), 7.29-7.34 (m, 1H), 7.54-7.58 (m, 1H).

Reference Example 18-19 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Reference Example 17 to obtain the compounds shown in Table 1.

[Step 2] Reference Example 20
3- (2-bromophenyl) -3-buten-2-one (100.0 mg), 3-trifluoromethylphenylurea (100.0 mg), copper (I) chloride (13.2 mg), boron trifluoride diethyl ether -A solution of ter complex (113 µl) in tetrahydrofuran (5.0 ml) was stirred with heating under reflux for 10 hours. Water (20 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (twice with 20 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 5- (2-bromophenyl) -6-methyl-1- [3- (trifluoromethyl) phenyl] -3, 4-Dihydropyrimidin-2 (1H) -one (107.0 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
Same as Reference Example 11.

Reference Example 21 :
Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in the method described in Reference Example 20 to obtain the compounds shown below.

¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.47 (t, 3H, J = 1.7Hz), 4.20 (t, 2H, J = 1.7Hz), 4.97 (brs, 1H), 7.13-7.16 (m, 1H), 7.22-7.25 (m, 1H), 7.36 −7.41 (m, 2H), 7.46−7.61 (m, 4H).

Reference Example 22-24 :

3- (2-Bromophenyl) -3-buten-2-one (1.05 g), 1-methyl-3- [3- (trifluoromethyl) phenyl] urea (1.5 mg), copper (I) chloride (100.1 mg), a solution of boron trifluoride diethyl ether complex (0.98 ml) in tetrahydrofuran (5.0 ml) was stirred at 100 ° C. for 20 minutes using a microwave synthesizer. Water (30 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (2 × 80 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 5- (2-bromophenyl) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl]- 3,4-Dihydropyrimidin-2 (1H) -one (1.43 g) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.28 (s, 3H), 2.98 (s, 3H), 3.95 (dd, 1H, J = 14.1, 2.1Hz), 4.17 (dd, 1H, J = 14.1, 1.8Hz), 7.14-7.19 (m, 1H) , 7.26 (d, 1H, J = 1.8Hz), 7.29-7.34 (m, 1H), 7.45-7.63 (m, 5H).

Reference Example 23-24 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Reference Example 22 to give the compounds shown in Table 2.

Reference Example 25-26 :

[Step 1] Reference Example 25
4- [4- (2-oxopropyl) -4H-1,2,4-triazol-3-yl] benzonitrile (19.0 mg), aqueous formaldehyde solution (25 μl), acetic acid (1 μl), piperidine (1 μl) The solution (2.0 ml) was stirred under heating to reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, water (10 ml) was added, and the mixture was extracted with chloroform (twice with 20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4- [4- (1-methoxy-3-oxobutan-2-yl) -4H-1,2,4-triazol-3-yl] benzonitrile (14 0.9 mg).
LC / MS (measurement condition 8)
271 (M + H) /1.35 (min).

[Step 2] Reference Example 26
A solution of 4- [4- (1-methoxy-3-oxobutan-2-yl) -4H-1,2,4-triazol-3-yl] benzonitrile (48.0 mg) in acetic acid (1.0 ml) was added to 90 Stir at 0 ° C. for 3 hours. Water (30 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (twice with 20 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was chloroform / methanol) to give 4- [4- (3-oxo-1-buten-2-yl) -4H-1,2,4- Triazol-3-yl] benzonitrile (28.0 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
2.35 (s, 3H), 6.24 (d, 1H, J = 2.0Hz), 6.49 (d, 1H, J = 2.2Hz), 7.66 (s, 4H), 8.11 (s, 1H).

Reference Example 27-30 :

[Step 1] Reference Example 27
The compound of the above formula, 1- [2-methyl-4-oxopentan-2-yl] -3- [3- (trifluoromethyl) phenyl] urea, is produced according to the production method described in JP-A-8-311026. did.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.42 (s, 6H), 2.15 (s, 3H), 2.93 (s, 2H), 6.67 (brs, 1H), 7.22 (d, 1H, J = 8.4Hz), 7.33 (t, 1H, J = 7.9Hz ), 7.42 (d, 1H, J = 8.4Hz), 7.61 (s, 1H).

[Step 2] Reference Example 28
A solution of 1- [2-methyl-4-oxopentan-2-yl] -3- [3- (trifluoromethyl) phenyl] urea (1.3 g) in acetic acid (4.0 ml) was heated under reflux for 5 Stir for hours. Water (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (2 x 30 ml). The organic layer was washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate), whereby 4,4,6-trimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidine- 2- (1H) -one (650.0 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.33 (s, 6H), 1.49 (d, 3H, J = 1.1Hz), 4.69 (dd, 1H, J = 2.2, 1.1Hz), 4.89 (brs, 1H), 7.41 (d, 1H, J = 7.7Hz ), 7.46 (s, 1H), 7.51 (t, 1H, J = 7.7Hz), 7.57 (brd, 1H, J = 6.6Hz).

[Step 3] Reference Examples 29 and 30
To a solution of 4,4,6-trimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2- (1H) -one (620.0 mg) in tetrahydrofuran (20.0 ml), N-bromosuccinimide (392.4 mg) was added and stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution (30 ml) and a saturated aqueous sodium thiosulfate solution (30 ml) were added to the reaction mixture, followed by extraction with ethyl acetate (twice with 30 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 6- (bromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4 -Dihydropyrimidin-2- (1H) -one (604.9 mg) and 5-bromo-4,4,6-trimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidine- 2- (1H) -one (14.0 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
Reference Example 29:
6- (Bromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2- (1H) -one:
1.46 (s, 6H), 3.83 (d, 1H, J = 1.5Hz), 4.57 (d, 1H, J = 1.5Hz), 4.99 (s, 1H), 7.40−7.53 (m, 2H), 7.66−7.72 (m, 2H).
Reference Example 30:
5-Bromo-4,4,6-trimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2- (1H) -one:
1.48 (s, 6H), 1.72 (s, 3H), 4.98 (brs, 1H), 7.40 (d, 1H, J = 7.7Hz), 7.44 (s, 1H), 7.52 (t, 1H, J = 7.7Hz ), 7.60 (d, 1H, J = 7.7Hz).

Reference Example 31-32 :

6- (Bromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2- (1H) -one (604.0 mg) in chloroform (10.0 ml) ) Bromine (1N chloroform solution, 1.7 ml) was added to the solution under ice-cooling, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous sodium hydrogen carbonate solution (30 ml) and a saturated aqueous sodium thiosulfate solution (30 ml) were added to the reaction mixture, followed by extraction with chloroform (twice with 30 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 5-bromo-6- (bromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl]. -3,4-dihydropyrimidin-2- (1H) -one (162.0 mg) and 6- (dibromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl] -3, 4-Dihydropyrimidin-2- (1H) -one (541.4 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
Reference Example 31:
5-Bromo-6- (bromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2- (1H) -one:
1.44 (s, 6H), 3.80 (s, 2H), 5.14 (brs, 1H), 7.52−7.55 (m, 3H), 7.58−7.63 (m, 1H).
Reference Example 32:
6- (Dibromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2- (1H) -one:
1.41 (s, 6H), 5.00 (s, 1H), 5.14 (d, 1H, J = 1.8Hz), 5.41 (s, 1H), 7.39 (d, 1H, J = 7.5Hz), 7.44 (s, 1H ), 7.51-7.60 (m, 2H).

Reference Example 33 :

6- (Bromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2- (1H) -one (150.0 mg) in tetrahydrofuran (4.0 ml) ) Sodium hydroxyborate (55.7 mg) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 8 hours, and then stirred at 50 ° C. for 2 hours. A saturated aqueous ammonium chloride solution (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (twice with 20 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 5-bromo-4,4,6-trimethyl-1- [3- (trifluoromethyl) phenyl] -3,4. -Dihydropyrimidin-2- (1H) -one (96.2 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
Same as Reference Example 30.

Reference Example 34-35 :

[Step 1] Reference Example 34
6- (Dibromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2- (1H) -one (611.0 mg) in chloroform (10. 0 ml), bromine (1N chloroform solution, 1.4 ml) was added to the solution under ice-cooling, stirred at room temperature for 3 hours, bromine (1N chloroform solution, 0.4 ml) was added, and 1.5 ml was added. Stir for hours. A saturated aqueous sodium hydrogen carbonate solution (30 ml) and a saturated aqueous sodium thiosulfate solution (30 ml) were added to the reaction mixture, followed by extraction with chloroform (twice with 30 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 5-bromo-6- (dibromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl. ] -3,4-dihydropyrimidin-2- (1H) -one (425.0 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.51 (s, 6H), 5.26 (brs, 1H), 6.87 (s, 1H), 7.47−7.49 (m, 1H), 7.54−7.60 (m, 1H), 7.64−7.72 (m, 2H).

[Step 2] Reference Example 35
5-bromo-6- (dibromomethyl) -4,4-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2- (1H) -one (200.0 mg) Sodium borohydride (58.0 mg) was added to a dimethyl sulfoxide (3.0 ml) solution, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (twice with 20 ml). The organic layer was washed with water (20 ml) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 5-bromo-4,4,6-trimethyl-1- [3- (trifluoromethyl) phenyl] -3,4. -Dihydropyrimidin-2- (1H) -one (45.6 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
Same as Reference Example 30.

Reference Example 36 :

To a solution of 1- (4-cyanophenyl) -1H-pyrazol-5-ylboronic acid (100.0 mg) in tetrahydrofuran (2.0 ml), pinacol (145.0 mg) and powder molecular sieves (180.0 mg) were added, Stir at room temperature for 7 hours. Ethyl acetate (20 ml) was added to the reaction mixture, followed by filtration. Hexane (10 ml) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. -Dioxaborolan-2-yl) -1H-pyrazol-1-yl] benzonitrile (120.0 mg) was obtained.
¹ H-NMR (DMSO-d ₆ : 300 MHz) δ:
1.26 (s, 12H), 6.94 (d, 1H, J = 1.8Hz), 7.76-7.79 (m, 2H), 7.87 (d, 1H, J = 1.8Hz), 7.95-7.98 (m, 2H).

Example 1 : 4- [5- (6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -1H-pyrazole -1-yl] benzonitrile

3-trifluoromethylphenylurea (204.0 mg), 4- [5- (3-oxo-2-buten-2-yl) -1H-pyrazol-1-yl] benzox obtained in Reference Example 19 A solution of nitrile (95.0 mg), copper (I) chloride (19.8 mg), boron trifluoride diethyl ether complex (130 μl) in tetrahydrofuran (2.0 ml) was added at 165 ° C. using a microwave reaction synthesizer. Stir for hours. Water (10 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (twice with 10 ml). The organic layer was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: first: hexane / ethyl acetate, second chloroform / methanol) to give 4- [5- (6-methyl-2-oxo-1- (3 -(Trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -1H-pyrazol-1-yl] benzonitrile (19.4 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.28 (s, 3H), 3.95 (s, 2H), 5.18 (s, 1H), 6.34 (d, 1H, J = 1.8Hz), 7.49 (t, 1H, J = 7.7Hz), 7.56 (d, 1H , J = 7.5Hz), 7.67 (d, 1H, J = 1.8Hz), 7.72-7.77 (m, 4H).

Example 2 : 4- [4- (3,6-dimethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -4H -1,2,4-triazol-3-yl] benzonitrile

1-methyl-3- [3- (trifluoromethyl) phenyl] urea (16.7 mg), 4- [4- (3-oxo-1-buten-2-yl) -4H obtained in Reference Example 26 A solution of -1,2,4-triazol-3-yl] benzonitrile (14.0 mg), copper (I) chloride (0.6 mg), boron trifluoride diethyl ether complex (14 μl) in tetrahydrofuran (1.0 ml). The mixture was stirred at 120 ° C. for 30 minutes using a microwave reaction synthesizer. Saturated aqueous sodium hydrogen carbonate solution (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (twice with 10 ml). The organic layer was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was chloroform / methanol) to give 4- [4- (3,6-dimethyl-2-oxo-1- (3- (trifluoromethyl) phenyl)- 1,2,3,4-Tetrahydropyrimidin-5-yl) -4H-1,2,4-triazol-3-yl] benzonitrile (1.8 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.29 (t, 3H, J = 1.7Hz), 2.92 (s, 3H), 3.85-4.15 (m, 2H), 7.33 (d, 1H, J = 7.5Hz), 7.39 (s, 1H), 7.52 (t , 1H, J = 7.9Hz), 7.61 (d, 1H, J = 7.9Hz), 7.78-7.81 (m, 2H), 7.98-8.01 (m, 2H), 8.20 (s, 1H).

Example 3 5- (4-fluorophenylthio) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one

1-methyl-3- [3- (trifluoromethyl) phenyl] urea (133.4 mg), 3- (4-fluorophenylthio) -3-buten-2-one obtained in Reference Example 13 (100. 0 mg), copper chloride (I) (5.0 mg), and boron trifluoride diethyl ether complex (120 μl) in tetrahydrofuran (3.0 ml) were stirred at 100 ° C. for 30 minutes using a microwave reaction synthesizer. Saturated aqueous sodium hydrogen carbonate solution (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (twice with 10 ml). The organic layer was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 5- (4-fluorophenylthio) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl]. -3,4-Dihydropyrimidin-2 (1H) -one (25.5 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.83 (t, 3H, J = 1.6Hz), 2.89 (s, 3H), 3.92 (d, 2H, J = 1.7Hz), 7.00-7.06 (m, 2H), 7.22-7.27 (m, 2H), 7.42 (d, 1H, J = 7.9Hz), 7.49 (s, 1H), 7.53 (t, 1H, J = 7.8Hz), 7.60 (d, 1H, J = 7.9Hz).

Example 4-6 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Example 3 to obtain the compounds shown in Table 3.
Example 4:
5- (4-Fluorophenylthio) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one Example 5:
5- (4-Fluorophenylthio) -6-methyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one Example 6:
5- (4-Bromophenylthio) -6-methyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one

Example 7 : 4- [5- (4,4,6-trimethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -1H-pyrazol-1-yl] benzonitrile

5-Bromo-4,4,6-trimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2- (1H) -one obtained in Reference Example 30 (60.0 mg ), 4- [5- (4,4,5,5-tetramethyl-1,3,2, -dioxaborolan-2-yl) -1H-pyrazol-1-yl] benzonitrile obtained in Reference Example 36 1,14′-bis (diphenylphosphino) ferrocenepalladium (II) chloride in a solution of (145.0 mg), potassium phosphate (210.0 mg) and water (20 μl) in 1,4-dioxane (2.0 ml) -Dichloromethane complex (27.0 mg) was added, and it stirred at 110 degreeC for 6 hours. Water (20 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (twice with 20 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 4- [5- (4,4,6-trimethyl-2-oxo-1- (3- (trifluoromethyl) Phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -1H-pyrazol-1-yl] benzonitrile (24.9 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.24 (s, 3H), 1.28 (s, 3H), 1.46 (s, 3H), 6.53 (d, 1H, J = 1.8Hz), 7.49-7.55 (m, 2H), 7.62-7.73 (m, 2H) , 7.79-7.85 (m, 3H), 7.91-7.95 (m, 2H).

Example 8 2 ′-[6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile

5- (2-Bromophenyl) -6-methyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one (460.0 mg) obtained in Reference Example 20 ), 4-cyanophenylboronic acid (658.0 mg), sodium carbonate (950.0 mg), water (2 ml) in 1,4-dioxane (10 ml), tetrakistriphenylphosphine palladium (129 mg) was added, Stir at 100 ° C. for 3 hours. Water (20 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (twice with 20 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 2 ′-[6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2 , 3,4-Tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile (362 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.12 (s, 3H), 3.75 (brd, 1H, J = 14.1Hz), 4.04 (brd, 1H, J = 14.1Hz), 4.83 (s, 1H), 7.26-7.52 (m, 8H), 7.60 (brd , 1H, J = 8.1Hz), 7.69 (brd, 2H, J = 8.3Hz), 7.78 (brd, 1H, J = 8.1Hz).

Example 9-18 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Example 8 to obtain the compounds shown in Table 4.
Example 9:
5- (4′-Chlorophenyl-2-yl) -6-methyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one Example 10:
6-Methyl-5- (4′-nitrobiphenyl-2-yl) -1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one Example 11:
6-Methyl-5- [4 ′-(methylsulfonyl) biphenyl-2-yl] -1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one Example 12 :
6-Methyl-5- [4 ′-(trifluoromethyl) biphenyl-2-yl] -1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one 13:
2-Methyl-2 ′-[6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile Example 14:
5- [4′-Chloro-2 ′-(trifluoromethyl) biphenyl-2-yl] -6-methyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidine-2 (1H ) -On Example 15:
5- [2 ′, 4′-Dichlorobiphenyl-2-yl] -6-methyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one Example 16 :
5- [3 ′, 4′-Dichlorobiphenyl-2-yl] -6-methyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one Example 17 :
2- [2 ′-(6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) biphenyl-4-yl] acetonitrile Example 18:
3 ′-[6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile

Example 19 5- (4'-chlorobiphenyl-2-yl) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one

5- (2-Bromophenyl) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one (50) obtained in Reference Example 22 0.04), 4-chlorophenylboronic acid (55.2 mg), sodium carbonate (71.0 mg), water (0.2 ml) in 1,4-dioxane (2 ml) solution with tetrakistriphenylphosphine palladium (13.5 mg). ) And stirred at 100 ° C. for 5 hours. Water (20 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (twice with 20 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 5- (4′-chlorobiphenyl-2-yl) -3,6-dimethyl-1- [3- (trifluoro Methyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one (27.8 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.22 (t, 3H, J = 1.6Hz), 2.78 (s, 3H), 3.65 (d, 1H, J = 13.6Hz), 3.94 (d, 1H, J = 14.7Hz), 7.27-7.31 (m, 4H ), 7.33-7.42 (m, 6H), 7.46 (t, 1H, J = 7.7Hz), 7.52 (d, 1H, J = 7.9Hz).

Example 20-21 :
The corresponding starting materials were used and reacted and treated in the same manner as in Example 19 to give the compounds shown in Table 5.
Example 20:
5- (4′-Chlorophenyl-2-yl) -3,6-dimethyl-1- (3-chlorophenyl) -3,4-dihydropyrimidin-2 (1H) -one Example 21:
5- (4′-Chlorobiphenyl-2-yl) -3,6-dimethyl-1- (3-methoxyphenyl) -3,4-dihydropyrimidin-2 (1H) -one

Example 22 2 ′-[6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile

1- [2- (4′-Cyanobiphenyl-2-yl) -3-oxobutyl] -3- [3- (trifluoromethyl) phenyl] urea (53.0 mg) obtained in Reference Example 12, paratoluene A toluene (5.0 ml) solution of sulfonic acid (4.5 mg) was stirred at 105 ° C. for 3 hours, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 2 ′-[6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2 , 3,4-Tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile (12.8 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
Same as Example 8.

Example 23 : 2 ′-[3,6-dimethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4- Carbonitrile

2 ′-[6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4 obtained in Example 8 -Sodium hydride (0.7 mg) was added to a solution of carbonitrile (6.0 mg) in tetrahydrofuran (0.5 ml) under ice-cooling, stirred for 5 minutes, methyl iodide (2 μl) was added, and the mixture was stirred at room temperature. Stir for 1.5 hours. Saturated aqueous ammonium chloride solution (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (twice with 10 ml). The organic layer was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 2 ′-[3,6-dimethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1 , 2,3,4-Tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile (2.8 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.14 (s, 3H), 2.74 (s, 3H), 3.61 (brd, 1H, J = 14.6Hz), 3.94 (brd, 1H, J = 14.6Hz), 7.19-7.22 (m, 2H), 7.26-7.33 (m, 2H), 7.35-7.39 (m, 2H), 7.41-7.50 (m, 4H), 7.68 (d, 2H, J = 8.3Hz).

Examples 24-28 :
The corresponding starting materials were used and reacted and treated in the same manner as in Example 23 to give the compounds shown in Table 6.
Example 24:
2- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -2,3-dihydropyrimidine-1 (6H)- Yl] acetamide Example 25:
2 ′-[3-Butyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile Example 26:
2 ′-[6-Methyl-2-oxo-3- (4,4,4-trifluorobutyl) -1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidine- 5-yl] biphenyl-4-carbonitrile Example 27:
2 ′-[6-Methyl-2-oxo-3- (3-phenylpropyl) -1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl -4-carbonitrile Example 28:
4- [5- (4'-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -2,3-dihydropyrimidine-1 (6H)- Yl] butanoic acid ethyl ester

Examples 29-30 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Example 1 to obtain the compounds shown in Table 7.
Example 29:
4- [5- (3,6-Dimethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl) -1H-pyrazole-1 -Yl] benzonitrile Example 30:
4- [5- (3,4,4,6-tetramethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl)- 1H-pyrazol-1-yl] benzonitrile

Example 31 2 ′-[3-acetyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl- 4-carbonitrile

2 ′-[6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4 obtained in Example 8 -Sodium hydride (0.7 mg) was added to a solution of carbonitrile (6.0 mg) in tetrahydrofuran (0.5 ml) under ice-cooling, stirred for 5 minutes, acetyl chloride (2 μl) was added, and the mixture was stirred at room temperature for 3 minutes. Stir for hours. Saturated aqueous ammonium chloride solution (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (twice with 10 ml). The organic layer was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 2 ′-[3-acetyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl). -1,2,3,4-Tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile (3.5 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.22 (s, 3H), 2.40 (s, 3H), 4.06 (brd, 1H, J = 15.8Hz), 4.45 (brd, 1H, J = 15.8Hz), 7.24-7.31 (m, 4H), 7.35-7.40 (m, 4H), 7.49 (t, 1H, J = 8.2Hz), 7.56 (d, 1H, J = 8.1Hz), 7.66 (d, 2H, J = 8.3Hz).

Examples 32-36 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Example 31 to give the compounds shown in Table 8.
Example 32:
5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxylate phenyl Ester Example 33:
5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxylic acid 4 -Nitrophenyl ester Example 34:
5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Examples 35:
5- (4′-cyanobiphenyl-2-yl) -N, N, 4-trimethyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide Example 36:
2 ′-[3-Formyl-6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile

Examples 37-38 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Example 1 to obtain the compounds shown in Table 9.
Example 37:
5- [1- (4-Cyanophenyl) -1H-pyrazol-5-yl] -4,6,6-trimethyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3- Dihydropyrimidine-1 (6H) -carboxylic acid phenyl ester Example 38:
5- [1- (4-Cyanophenyl) -1H-pyrazol-5-yl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxylic acid phenyl ester

Example 39 4- [5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6- Tetrahydropyrimidine-1-carboxamide] butanoic acid ethyl ester

2 ′-[6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4 obtained in Example 8 -Sodium hydride (24.0 mg) was added to a solution of carbonitrile (200.0 mg) in N, N-dimethylformamide (5.0 ml) under ice-cooling, and the mixture was stirred for 5 minutes. Ethyl 4-isocyanatobutyrate (135 μl) was added and stirred for 2 hours. Saturated aqueous ammonium chloride solution (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (twice with 20 ml). The organic layer was washed with water (10 ml) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 4- [5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- ( 3- (Trifluoromethyl) phenyl) -1,2,3,6-tetrahydropyrimidine-1-carboxamide] butanoic acid ethyl ester (118.3 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.13 (s, 3H), 1.17 (t, 3H, J = 7.1Hz), 1.73-1.83 (m, 2H), 2.28 (t, 2H, J = 7.5Hz), 3.19-3.26 (m, 2H), 4.04 (q, 2H, J = 7.1Hz), 4.15 (brd, 1H, J = 16.1Hz), 4.60 (brd, 1H, J = 16.1Hz), 7.22-7.32 (m, 4H), 7.36-7.40 (m, 4H), 7.48 (t, 1H, J = 7.7Hz), 7.56 (d, 1H, J = 7.7Hz), 7.66 (d, 2H, J = 8.4Hz), 8.66 (brs, 1H).

Examples 40-44 :
The corresponding starting materials were used and reacted and treated in the same manner as in Example 39 to give the compounds shown in Table 10.
Example 40:
5- (4′-cyanobiphenyl-2-yl) -N-ethyl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide Example 41:
5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-N-propyl-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide Example 42:
N-butyl-5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide Example 43:
2- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6-tetrahydropyrimidine-1 -Carboxamide] acetic acid ethyl ester Example 44:
3- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6-tetrahydropyrimidine-1 -Carboxamide] propanoic acid ethyl ester

Examples 45-46 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Example 39 to give the compounds shown in Table 11.
Example 45:
5- [1- (4-Cyanophenyl) -1H-pyrazol-5-yl] -N-ethyl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2, 3- Dihydropyrimidine-1 (6H) -carboxamide Example 46:
2- [5- (1- (4-Cyanophenyl) -1H-pyrazol-5-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3 , 6-Tetrahydropyrimidine-1-carboxamide] acetic acid ethyl ester

Example 47 : 5- (4'-cyanobiphenyl-2-yl) -N- [4- (dimethylamino) propyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide

5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 obtained in Example 32 3-Dimethylaminopropylamine (5 μl) was added to a solution of (6H) -phenyl ester (6.0 mg) in acetonitrile (1.0 ml), and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 5- (4′-cyanobiphenyl-2-yl) -N- [4- (dimethylamino) propyl] -4- Methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide (4.1 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.17 (s, 3H), 1.62-1.72 (m, 2H), 2.18 (s, 6H), 2.29 (t, 2H, J = 7.2Hz), 3.24-3.31 (m, 2H), 4.20 (brd, 1H, J = 16.5Hz), 4.66 (brd, 1H, J = 16.5Hz), 7.26-7.36 (m, 4H), 7.40-7.44 (m, 4H), 7.53 (t, 1H, J = 7.6Hz), 7.60 ( d, 1H, J = 7.9Hz), 7.70 (d, 2H, J = 8.3Hz), 8.73 (brs, 1H).

Examples 48-77 :
The corresponding starting materials were used and reacted and treated in the same manner as in Example 47 to give the compounds shown in Table 12.
Example 48:
5- (4′-cyanobiphenyl-2-yl) -N, 4-dimethyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 49:
5- (4′-cyanobiphenyl-2-yl) -N-isopropyl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide Example 50:
5- (4′-cyanobiphenyl-2-yl) -N-cyclohexyl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide Example 51:
N-benzyl-5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide Example 52:
4- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -1,2,3,6-tetrahydropyrimidine-1 -Carboxamide] piperidine-1-ethyl ester Example 53:
5- (4′-cyanobiphenyl-2-yl) -N- (3-methoxypropyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine -1 (6H) -carboxamide Example 54:
5- (4′-cyanobiphenyl-2-yl) -N- (3-hydroxypropyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine -1 (6H) -carboxamide Example 55:
N- [3- (bis (2-hydroxyethyl) amino) propyl] -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) Phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 56:
5- (4'-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-N- [3- (pyrrolidin-1-yl) propyl) -3- [3- (trifluoromethyl) phenyl]- 2,3-Dihydropyrimidine-1 (6H) -carboxamide Example 57:
5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-N- [3- (pyrrolidin-1-yl) butyl) -3- [3- (trifluoromethyl) phenyl]- 2,3-Dihydropyrimidine-1 (6H) -carboxamide Example 58:
5- (4′-cyanobiphenyl-2-yl) -4-methyl-N- [3- (4-methylpiperazin-1-yl) propyl) -2-oxo-3- [3- (trifluoromethyl) Phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 59:
5- (4′-cyanobiphenyl-2-yl) -4-methyl-N- (3-morpholinopropyl) -2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine -1 (6H) -carboxamide Example 60:
Tertiary butyl 3- [5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6-tetrahydro Pyrimidine-1-carboxamide] propyl carbamate Example 61:
5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-N- [3- (2-oxopyrrolidin-1-yl) propyl) -3- [3- (trifluoromethyl) Phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 62:
5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-N- [3- (2-oxopyrrolidin-1-yl) ethyl) -3- [3- (trifluoromethyl) Phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 63:
5- (4′-Cyanobiphenyl-2-yl) -N-isobutyl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) Carboxamide Example 64:
5- (4′-cyanobiphenyl-2-yl) -N- (2-hydroxypropyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine -1 (6H) -carboxamide Example 65:
5- (4′-cyanobiphenyl-2-yl) -N- (cyclopropylmethyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine- 1 (6H) -carboxamide Example 66:
5- (4′-cyanobiphenyl-2-yl) -N- (cyclohexylmethyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -Carboxamide Example 67:
5- (4′-cyanobiphenyl-2-yl) -N- [2- (dimethylamino) ethyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3 -Dihydropyrimidine-1 (6H) -carboxamide Example 68:
5- (4′-cyanobiphenyl-2-yl) -N- [2- (dimethylamino) butyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3 -Dihydropyrimidine-1 (6H) -carboxamide Example 69:
5- [5- (4'-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6-tetrahydropyrimidine-1 -Carboxamide] pentanoic acid ethyl ester Example 70:
5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-N- [2- (2-oxoimidazolidin-1-yl) ethyl] -3- [3- (trifluoromethyl ) Phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 71:
N- (1-acetylpiperidin-4-yl) -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2, 3-Dihydropyrimidine-1 (6H) -carboxamide Example 72:
(R) -tertiarybutyl 3-[(5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -1,2, 3,6-tetrahydropyrimidine-1-carboxamido) methyl] pyrrolidine-1-carboxylate Example 73:
5- (4′-cyanobiphenyl-2-yl) -4-methyl-N- [2- (methanesulfonyl) ethyl] -2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3 -Dihydropyrimidine-1 (6H) -carboxamide Example 74:
5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-N- (sulfamoylethyl) -3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine -1 (6H) -carboxamide Example 75:
5- (4′-cyanobiphenyl-2-yl) -N- [3- (2- (hydroxymethyl) pyrrolidin-1-yl) propyl] -4-methyl-2-oxo-3- [3- (tri Fluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 76:
5- (4'-Cyanobiphenyl-2-yl) -N- (cyanomethyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 ( 6H) -Carboxamide Example 77:
5- (4′-Cyanobiphenyl-2-yl) -N-cyclopropyl-4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H ) -Carboxamide

Examples 78-79 :
The corresponding starting materials were used and reacted and treated in the same manner as in Example 47 to give the compounds shown in Table 13.
Example 78: 5- [1- (4-cyanophenyl) -1H-pyrazol-5-yl] -4-methyl-2-oxo-N- (3- (pyrrolidin-1-yl) propyl) -3- [3- (Trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 79: 5- [1- (4-Cyanophenyl) -1H-pyrazol-5-yl] -4 -Methyl-2-oxo-N- (3- (2-oxopyrrolidin-1-yl) propyl) -3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H)- Carboxamide

Example 80 4- [5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6- Tetrahydropyrimidine-1-carboxamide] butanoic acid

4- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3 obtained in Example 39 , 6-tetrahydropyrimidine-1-carboxamide] butanoic acid ethyl ester (17.0 mg) in ethanol (1.0 mL) was added with 1N aqueous sodium hydroxide solution (30 μL) under ice-cooling, and the mixture was heated to 50 ° C. And stirred for 1.5 hours. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with chloroform (2 × 10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was chloroform / methanol) to give 4- [5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3 -(Trifluoromethyl) phenyl) -1,2,3,6-tetrahydropyrimidine-1-carboxamide] butanoic acid (8.1 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.14 (s, 3H), 1.75-1.81 (m, 2H), 2.32 (t, 2H, J = 7.3Hz), 3.21-3.28 (m, 2H), 4.15 (brd, 1H, J = 16.3Hz), 4.59 (brd, 1H, J = 16.3Hz), 7.22-7.31 (m, 4H), 7.34-7.40 (m, 4H), 7.48 (t, 1H, J = 7.8Hz), 7.56 (d, 1H, J = 8.1 Hz), 7.66 (d, 2H, J = 8.3Hz), 8.71 (brs, 1H).

Examples 81-84 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Example 80 to give the compounds shown in Table 14.
Example 81:
2- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6-tetrahydropyrimidine-1 -Carboxamide] acetic acid Example 82:
3- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6-tetrahydropyrimidine-1 -Carboxamide] propanoic acid Example 83:
5- [5- (4'-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3,6-tetrahydropyrimidine-1 -Carboxamide] pentanoic acid Example 84:
2- [5- (1- (4-Cyanophenyl) -1H-pyrazol-5-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1,2,3 , 6-Tetrahydropyrimidine-1-carboxamide] acetic acid

Example 85 : 5- (4′-cyanobiphenyl-2-yl) -4-methyl-N- [4- (methylamino) -4-oxobutyl] -2-oxo-3- [3- (trifluoromethyl ) Phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide

4- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl] -1,2,3 obtained in Example 80 , 6-tetrahydropyrimidine-1-carboxamide] butanoic acid (7.0 mg) in N, N-dimethylformamide (0.5 ml), triethylamine (5 μL), 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide (13.8 mg), 1-hydroxy-7-azabenzotriazole (15.9 mg), methylamine (2M tetrahydrofuran solution, 62 μL) were added, and the mixture was stirred at room temperature for 2 hours. An aqueous solution (10 ml) was added, followed by extraction with ethyl acetate (twice with 10 ml), and the organic layer was washed with water (10 ml) and saturated brine (10 m). The residue was purified by silica gel column chromatography (elution solvent was chloroform / methanol) to give 5- (4′-cyanobiphenyl-2-yl). -4-Methyl-N- [4- (methylamino) -4-oxobutyl] -2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide (5.6 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.19 (s, 3H), 1.80-1.87 (m, 2H), 2.19 (t, 2H, J = 7.0Hz), 2.78 (d, 3H, J = 4.8Hz), 3.23-3.34 (m, 2H), 4.20 (brd, 1H, J = 16.3Hz), 4.58 (brd, 1H, J = 16.3Hz), 6.00 (s, 1H), 7.29-7.37 (m, 4H), 7.41-7.45 (m, 4H), 7.54 ( t, 1H, J = 7.8Hz), 7.62 (d, 1H, J = 8.4Hz), 7.71 (d, 2H, J = 8.3Hz), 8.73 (t, 1H, J = 4.8Hz).

Examples 86-96 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Example 85 to give the compounds shown in Table 15.
Example 86:
N- (2-amino-2-oxoethyl) -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2, 3 -Dihydropyrimidine-1 (6H) -carboxamide Example 87:
5- (4′-cyanobiphenyl-2-yl) -N- [2- (methylamino) -2-oxoethyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl]- 2,3-Dihydropyrimidine-1 (6H) -carboxamide Example 88:
5- (4′-cyanobiphenyl-2-yl) -N- [2- (dimethylamino) -2-oxoethyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl]- 2,3-Dihydropyrimidine-1 (6H) -carboxamide Example 89:
5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-N- [2-oxo-2- (pyrrolidin-1-yl) ethyl] -3- [3- (trifluoromethyl ) Phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 90:
5- (4′-cyanobiphenyl-2-yl) -N- [2- (2- (dimethylamino) ethylamino) -2-oxoethyl] -4-methyl-2-oxo-3- [3- (tri Fluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 91:
5- (4′-Cyanobiphenyl-2-yl) -4-methyl-N- [3- (methylamino) -3-oxopropyl] -2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3-Dihydropyrimidine-1 (6H) -carboxamide Example 92:
N- (4-amino-4-oxoethyl) -5- (4'-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2,3 -Dihydropyrimidine-1 (6H) -carboxamide Example 93:
5- (4′-cyanobiphenyl-2-yl) -N- [4- (dimethylamino) -4-oxobutyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl]- 2,3-Dihydropyrimidine-1 (6H) -carboxamide Example 94:
5- (4'-cyanobiphenyl-2-yl) -N- [4- (ethylamino) -4-oxobutyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl]- 2,3-Dihydropyrimidine-1 (6H) -carboxamide Example 95:
5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-N- [4-oxo-4- (pyrrolidin-1-yl) butyl] -3- [3- (trifluoromethyl ) Phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 96:
N- [4- (azetidin-1-yl) -4-oxobutyl] -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) Phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide Example 97:
5- (4'-cyanobiphenyl-2-yl) -N- [4- (isopropylamino) -4-oxobutyl] -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl]- 2,3-Dihydropyrimidine-1 (6H) -carboxamide

Example 98 :
4- [5- (4'-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -2,3-dihydropyrimidine-1 (6H)- Yl] butanoic acid

4- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -2,3-dihydro obtained in Example 28 A solution of pyrimidine-1 (6H) -yl] butanoic acid ethyl ester (20.7 mg) in tetrahydrofuran (1.0 mL) was ice-cooled, 5N aqueous sodium hydroxide solution (10 μL) was added, and then at room temperature for 2 hours. Stir. Thereafter, an aqueous sodium hydroxide solution (5 N, 25 μL) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Then, it stirred at 60 degreeC for 3 hours. After adding water (20 mL) to the reaction mixture and extracting with diethyl ether (20 mL), the aqueous layer was acidified with potassium hydrogen sulfate (pH is about 3), and the aqueous layer was extracted with chloroform (3 times with 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (elution solvent was chloroform / methanol), and 4- [5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- ( 3- (Trifluoromethyl) phenyl) -2,3-dihydropyrimidin-1 (6H) -yl] butanoic acid (8.9 mg) was obtained.
¹ H-NMR (CD ₃ OD: 300 MHz) δ:
0.90 (t, 2H, J = 5.4Hz), 1.11 (s, 3H), 1.76 (t, 2H, J = 6.6Hz), 2.25 (t, 2H, J = 6.3Hz), 3.91 (d, 1H, J = 14.1Hz), 4.19 (d, 1H, J = 13.5Hz), 7.31-7.42 (m, 2H), 7.42-7.47 (m, 5H), 7.54-7.62 (m, 3H), 7.55 (d, 2H, J = 8.7Hz).

Example 99 :
4- [5- (4'-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -2,3-dihydropyrimidine-1 (6H)- Yl] -N-methylbutanamide

4- [5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -2,3-dihydro obtained in Example 98 Pyrimidin-1 (6H) -yl] butanoic acid (8.9 mg) in N, N-dimethylformamide (0.5 mL) was added O- (7-azabenzotriazol-1-yl) -N, N, N ′. , N′-tetramethyluronium hexafluorophosphate (14.6 mg), 1-hydroxy-7-aza-benzotriazole (5.3 mg), triethylamine (50 μL), methylamine hydrochloride (6.2 mg) were added. Stir at room temperature for 62 hours. Ethyl acetate (30 mL) was added to the reaction mixture, washed with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (elution solvent was chloroform / methanol) to give 4- [5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3. -(3- (Trifluoromethyl) phenyl) -2,3-dihydropyrimidin-1 (6H) -yl] -N-methylbutanamide (1.7 mg) was obtained.
¹ H-NMR (CD ₃ OD: 300 MHz) δ:
1.13 (s, 3H), 1.61-1.75 (m, 2H), 2.07 (t, 2H, J = 6.6Hz), 2.69 (d, 3H, J = 4.5Hz), 2.98-3.07 (m, 1H), 3.27 -3.36 (m, 1H), 3.63 (d, 1H, J = 14.1Hz), 4.04 (d, 1H, J = 14.1Hz), 6.11 (brs, 1H), 7.22 (brs, 1H), 7.28-7.56 ( m, 9H), 7.68 (d, 2H, J = 8.1Hz).

Example 100 : N- (3-aminopropyl) -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2, 3-Dihydropyrimidine-1 (6H) -carboxamide hydrochloride

Tertiary butyl 3- [5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- (3- (trifluoromethyl) phenyl) -1, obtained in Example 60, To a solution of 2,3,6-tetrahydropyrimidine-1-carboxamido] propylcarbamate (20.0 mg) in ethanol (2.0 ml) was added 4N hydrochloric acid / ethanol (48 μl) solution, and the mixture was stirred at 90 ° C. for 2 hours. . The reaction mixture was concentrated under reduced pressure and azeotroped with chloroform / hexane to give N- (3-aminopropyl) -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo- as a solid. 3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide hydrochloride (16.4 mg) was obtained.
¹ H-NMR (CD ₃ OD: 300 MHz) δ:
1.29 (s, 3H), 1.82-1.91 (m, 2H), 2.95 (t, 2H, J = 7.2Hz), 3.29-3.36 (m, 2H), 4.24 (brd, 1H, J = 15.6Hz), 4.47 (brd, 1H, J = 15.6Hz), 7.40-7.50 (m, 5H), 7.55-7.72 (m, 5H), 7.81 (d, 2H, J = 8.4Hz), 8.83 (brs, 1H).

Example 101 :
Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in the method described in Example 100 to obtain the compounds shown below.
Example 101:
(S) -5- (4′-Cyanobiphenyl-2-yl) -4-methyl-2-oxo-N- (pyrrolidin-3-ylmethyl) -3- [3- (trifluoromethyl) phenyl] -2 3-dihydropyrimidine-1 (6H) -carboxamide hydrochloride

¹ H-NMR (CD ₃ OD: 300 MHz) δ:
1.33 (s, 3H), 1.68-1.79 (m, 1H), 2.10-2.20 (m, 1H), 2.53-2.63 (m, 1H), 2.92-3.00 (m, 1H), 3.31-3.41 (m, 5H ), 4.24 (d, 1H, J = 15.4Hz), 4.39 (d, 1H, J = 15.8Hz), 7.38-7.41 (m, 1H), 7.46-7.52 (m, 4H), 7.57-7.61 (m, 3H), 7.65 (t, 1H, J = 7.8Hz), 7.71 (d, 1H, J = 8.1Hz), 7.78-7.82 (m, 2H).

Example 102 : N- (3-acetamidopropyl) -5- (4'-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -2, 3-Dihydropyrimidine-1 (6H) -carboxamide

N- (3-aminopropyl) -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] obtained in Example 100 -2,3-Dihydropyrimidine-1 (6H) -carboxamide To a solution of hydrochloride (5.0 mg) and triethylamine (4 μl) in methylene chloride (0.5 ml) was added acetyl chloride (1 μl) under ice-cooling. Stir for minutes and stir at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution (10 ml) was added to the reaction mixture, and the mixture was extracted with chloroform (twice with 10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was chloroform / methanol) to give N- (3-acetamidopropyl) -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2- Oxo-3- [3- (trifluoromethyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide (2.1 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.20 (s, 3H), 1.62 (t, 2H, J = 6.5Hz), 1.91 (s, 3H), 3.18-3.26 (m, 4H), 4.17 (brd, 1H, J = 15.2Hz), 4.48 (brd , 1H, J = 15.2Hz), 6.06 (s, 1H), 7.27-7.33 (m, 4H), 7.37-7.41 (m, 4H), 7.49 (t, 1H, J = 7.8Hz), 7.57 (d, 1H, J = 7.9Hz), 7.67 (d, 2H, J = 8.1Hz), 8.69 (brs, 1H).

Examples 103-104 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Example 102 to give the compounds shown in Table 16.
Example 103:
5- (4′-cyanobiphenyl-2-yl) -4-methyl-N- [3- (methylsulfonamido) propyl] -2-oxo-3- [3- (trifluoromethyl) phenyl] -2, 3-Dihydropyrimidine-1 (6H) -carboxamide Example 104:
(R) -N-[(1-acetylpyrrolidin-3-yl) methyl] -5- (4′-cyanobiphenyl-2-yl) -4-methyl-2-oxo-3- [3- (trifluoro Methyl) phenyl] -2,3-dihydropyrimidine-1 (6H) -carboxamide

Example 105 2 ′-[3- (1H-imidazol-1-ylsulfonyl) -6-methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4 Tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile

2 ′-[6-Methyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4 obtained in Example 8 -Sodium hydride (6.1 mg) was added to a solution of carbonitrile (50.0 mg) in N, N-dimethylformamide (1.5 ml) under ice cooling, and the mixture was stirred for 5 minutes. Imidazole (34.3 mg) was added and stirred for 1 hour. Saturated aqueous ammonium chloride solution (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (twice with 10 ml). The organic layer was washed with water (10 ml) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was hexane / ethyl acetate) to give 2 ′-[3- (1H-imidazol-1-ylsulfonyl) -6-methyl-2-oxo-1- ( 3- (Trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-yl] biphenyl-4-carbonitrile (26.5 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.23 (s, 3H), 4.19 (d, 1H, J = 14.3Hz), 4.48 (d, 1H, J = 13.9Hz), 6.95-6.96 (m, 1H), 7.22-7.31 (m, 4H), 7.33 -7.50 (m, 6H), 7.55 (d, 1H, J = 7.7Hz), 7.71-7.73 (m, 2H), 7.93 (s, 1H).

Example 106 5- (4-fluorophenylsulfinyl) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one

5- (4-Fluorophenylthio) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one obtained in Example 3 ( To a solution of 24.0 mg) in methylene chloride (2.0 ml) was added metachloroperbenzoic acid (16.2 mg) under ice-cooling, and the mixture was stirred for 30 minutes. Water (10 ml) was added to the reaction mixture, followed by extraction with chloroform (twice with 10 ml), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent was chloroform / methanol) to give 5- (4-fluorophenylsulfinyl) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl]- 3,4-Dihydropyrimidin-2 (1H) -one (13.7 mg) was obtained.
¹ H-NMR (CDCl ₃ : 300 MHz) δ:
1.97 (t, 3H, J = 1.4Hz), 2.81 (s, 3H), 3.38 (dd, 1H, J = 13.8, 1.6Hz), 4.08 (dd, 1H, J = 13.8, 1.3Hz), 7.17-7.23 (m, 2H), 7.35 (d, 1H, J = 7.7Hz), 7.42 (s, 1H), 7.50-7.55 (m, 3H), 7.61 (d, 1H, J = 7.7Hz).

Examples 107-108 :
The corresponding starting materials were used and reacted and treated in the same manner as described in Example 106 to give the compounds shown in Table 17.
Example 107:
5- (4-Chlorophenylsulfinyl) -3,6-dimethyl-1- [3- (trifluoromethyl) phenyl] -3,4-dihydropyrimidin-2 (1H) -one Example 108:
4- [3,6-Dimethyl-2-oxo-1- (3- (trifluoromethyl) phenyl) -1,2,3,4-tetrahydropyrimidin-5-ylsulfonyl] benzonitrile

Test Example 1 Inhibitory Action on Human Neutrophil Elastase Hereinafter, pharmacological test results of representative compounds of the present invention will be shown, but the present invention is not limited to these test examples.

  Assay buffer (0.4 unit / ml HNE (human neutrophil elastase, elastin products), 200 mM HEPES [N- (2-hydroxyethyl) piperazine-N ′-(2-ethanesulfonic acid)], pH 7.5 , 2M NaCl, 0.002% Brij-35) 100 μl, water for injection 40 μl, 20 μl of DMSO (dimethyl sulfoxide) solution of the compound of the present invention were mixed in a 96-well plate, and the mixed solution was preincubated at 37 ° C. for 5 minutes. MeOSuc-AAPV-AMC (methoxysuccinyl-alanyl-alanyl-prolyl-valyl-aminomethylcoumalide (Sigma-Aldrich) solution, a fluorescent substrate dissolved in 10% DMSO solution to 0.5 mM after pre-incubation The reaction was started by adding 40 μl to the above mixed solution, incubated at 37 ° C. for 5 minutes, and the fluorescence intensity of AMC was measured at an excitation wavelength of 380 nM and a fluorescence wavelength of 460 nm to determine the inhibition rate.

Table 18 shows the IC ₅₀ value (μM), which is the concentration of the compound necessary for inhibiting human neutrophil elastase by 50%, or the inhibition rate (%) at 10 μM for the example compounds.

  The compound of the present invention is useful as a therapeutic or prophylactic agent for diseases involving elastase such as inflammatory diseases. Diseases that have been suggested to be involved in the pathogenesis of elastase include, for example, chronic obstructive pulmonary disease (COPD), cystic pulmonary fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic Pulmonary fibrosis (IIP), chronic interstitial pneumonia, chronic bronchitis, chronic respiratory tract infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, rheumatoid arthritis, arthrosclerosis, Osteoarthritis, psoriasis, periodontitis, atherosclerosis, organ transplant rejection, early water rupture, blistering, shock, sepsis, systemic lupus erythematosus (SLE), Crohn's disease, disseminated intravascular coagulation ( DIC), tissue damage during ischemia-reperfusion, formation of corneal scar tissue, myelitis, lung squamous cell carcinoma, lung adenocarcinoma, lung cancer such as non-small cell lung cancer, breast cancer, liver cancer, bladder cancer, colon Rectal cancer, skin cancer Pancreatic cancer, such as glioma, and the like.

SEQ ID NO: 1 enzyme substrate

Claims (16)

Formula (I):

[Where
R ⁰ is —C (═O) NR ^a1 —, —S (═O) ₂ NR ^a2 —, —C (═O) O—, —C (═O) —, —S (═O) ₂ —. Or a single bond,
R ¹ may contain 1 to 2 heteroatoms selected from the group consisting of a hydrogen atom, C _1-10 alkyl, C _2-6 alkene, N, O and S 3-6 membered saturation Or an unsaturated aliphatic ring group, or a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S;
Wherein the alkyl and the alkene are in substitutable positions,
(1) hydroxyl group,
(2) a halogen atom,
(3) Cyano,
(4) C _1-6 alkoxy (wherein the alkoxy is substitutable,
Hydroxyl group,
Halogen atoms,
Cyano,
-C (= O) OR ^b1 ,
-C (= O) NR ^c1 R ^d1 ,
A 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a hydroxyl group at a substitutable position) Alternatively, C _1-3 alkyl which may be substituted with a halogen atom, hydroxyl group or C _1-3 alkoxy which may be substituted with a halogen atom, hydroxyl group, halogen atom, cyano, —NR ^a3 C (═O) R ^b2 , —NR ^a4 C (═O) NR ^c2 R ^d2 , —NR ^a5 S (═O) _m R ^b3 , —C (═O) OR ^b4 , —C (═O) NR ^c3 R ^d3 , —S (= O) _m NR ^c4 R ^d4 , optionally substituted with —S (═O) _m R ^b5 or —NR ^c5 R ^d5 ) or 1-2 hetero selected from the group consisting of N, O and S A 3- to 6-membered saturated or unsaturated aliphatic ring group which may contain an atom (the aliphatic ring group at a substitutable position) Hydroxyl or a halogen atom an optionally substituted C _1-3 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, ^{cyano, -NR a6 C (= O)} R ^{b6, -NR a7 C (= O} ) NR c6 R d6, -NR a8 S (= O) m R b7, -C (= O) OR b8, -C (= O) NR c7 R d7, -NR c8 ^Optionally substituted with R ^d8 or oxo)
May be substituted)
(5) C _1-6 alkylthio (the alkylthio is a hydroxyl group at a substitutable position,
Halogen atoms,
Cyano,
-C (= O) OR ^b9 ,
-C (= O) NR ^c9 R ^d9 ,
A 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a hydroxyl group at a substitutable position) Alternatively, C _1-3 alkyl which may be substituted with a halogen atom, hydroxyl group or C _1-3 alkoxy which may be substituted with a halogen atom, hydroxyl group, halogen atom, cyano, —NR ^a9 C (═O) R ^b10 , —NR ^a10 C (═O) NR ^c10 R ^d10 , —NR ^a11 S (═O) _m R ^b11 , —C (═O) OR ^b12 , —C (═O) NR ^c11 R ^d11 , —S (= O) _m NR ^c12 R ^d12 , ^optionally substituted with —S (═O) _m R ^b13 or —NR ^c13 R ^d13 ) or 1 to 2 hetero atoms selected from the group consisting of N, O and S 3 to 6-membered saturated or unsaturated aliphatic ring group which may contain an atom (the aliphatic ring group may be substituted) Position in a hydroxyl group or a halogen atom an optionally substituted C _1-3 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, cyano, -NR ^a12 C ( ═O) R ^b14 , —NR ^a13 C (═O) NR ^c14 R ^d14 , —NR ^a14 S (═O) _m R ^b15 , —C (═O) OR ^b16 , —C (═O) NR ^c15 R ^d15 , -NR ^c16 R ^d16 or oxo may be substituted)
May be substituted)
(6) a 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is at a substitutable position) And
C _1-3 alkyl _optionally substituted with a hydroxyl group or a halogen atom,
C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom,
Hydroxyl group,
Halogen atoms,
Cyano,
-NR ^a15 C (= O) R ^b17 ,
-NR ^a16 C (= O) NR ^c17 R ^d17 ,
-NR ^a17 S (= O) _m R ^b18 ,
-C (= O) OR ^b19 ,
-C (= O) NR ^c18 R ^d18 ,
-S (= O) _m NR ^c19 R ^d19 ,
—S (═O) _m R ^b20 or —NR ^c20 R ^d20
May be substituted)
(7) a 3- to 6-membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S (the aliphatic ring group is At the replaceable position,
C _1-3 alkyl (the alkyl is a hydroxyl group, a halogen atom, cyano, —NR ^a18 C (═O) R ^b21 , —NR ^a19 C (═O) NR ^c21 R ^d21 , —NR ^a20 S (═O) _m ) R ^b22 , —C (═O) OR ^b23 , ^{optionally substituted} with —C (═O) NR ^c22 R ^d22 or —NR ^c23 R ^d23 ),
C _1-3 alkoxy (the alkoxy may be substituted with a hydroxyl group or a halogen atom),
Hydroxyl group,
Halogen atoms,
Cyano,
-NR ^a21 C (= O) R ^b24 ,
-NR ^a22 C (= O) NR ^c24 R ^d24 ,
-NR ^a23 S (= O) _m R ^b25 ,
-C (= O) OR ^b26 ,
^{-C (= O) NR c25 R} d25,
-S (= O) _m NR ^c26 R ^d26 ,
-S (= O) _m R ^b27 ,
In -NR ^c27 R ^d27 or oxo may be substituted),
(8) -NR ^a24 R ^e,
(9) -OR ^{e '} ,
(10) -C (= O) ^Rf ,
(11) -S (= O) _m R ^g ,
(12) may be substituted with one or more substituents selected from the group consisting of thiol and (13) nitro,
Here, the saturated or unsaturated aliphatic ring group is in a substitutable position,
A hydroxyl group, a halogen atom, cyano, nitro, C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), C _1-6 alkoxy (the alkoxy is , ^Optionally substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), —NR ^a25 C (═O) R ^b28 , —NR ^a26 C (═O) NR ^c28 R ^d28 , —NR ^{a27 _{S (= O) m R b29}} , -C (= O) oR b30, -C (= O) R b31, -C (= O) may be substituted with NR ^c29 R ^d29 or -NR ^c30 R ^d30 ,
Here, the aromatic ring group is a substitutable position,
A hydroxyl group, a halogen atom, cyano, nitro, C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), C _1-6 alkoxy (the alkoxy is And may be substituted with a hydroxyl group, a halogen atom or cyano at a substitutable position), —NR ^a28 C (═O) R ^b32 , —NR ^a29 C (═O) NR ^c31 R ^d31 , —NR ^{a30 _{S (= O) m R b33}} , -C (= O) OR b34, -C (= O) R b35, -C (= O) NR c32 R d32, -S (= O) m NR c33 R d33, -S (= O) _m R ^b36 or -NR ^{c 34} R ^d34 may be substituted with,
R ² represents C _1-3 alkyl (the alkyl may be substituted with a hydroxyl group or a halogen atom);
R ³ and R ⁴ each independently represent a hydrogen atom or C _1-3 alkyl (the alkyl may be substituted with a hydroxyl group or a halogen atom);
Ar ¹ is a 5- to 6-membered aromatic ring group which may contain 1 to 3 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a substitutable position). In C _1-6 alkyl optionally substituted with a hydroxyl group or a halogen atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro or —NR ^c35 R ^d35 or more are replaced)
L is a 5- to 6-membered unsubstituted aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S, or —S (═O) _q —. Show
Ar ² is a 5- to 6-membered aromatic ring group which may contain 1 to 3 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a substitutable position). In C _1-6 alkyl optionally substituted with a hydroxyl group, cyano, or a halogen atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro,- S (═O) _n R ^h or —NR ^c36 R ^d36 or more).
^Re is
Hydrogen atom,
C _1-6 alkyl (which may be substituted with a hydroxyl group, cyano, halogen atom, C _1-3 alkoxy or —NR ^c37 R ^d37 ),
-A,
-C (= O) -A ',
C _1-6 alkylcarbonyl (the alkyl part of the alkylcarbonyl may be substituted with a hydroxyl group or a halogen atom),
C _1-6 alkoxycarbonyl (the alkyl part of the alkoxycarbonyl may be substituted with a hydroxyl group or a halogen atom),
-C (= O) shows the NR ^C38 R ^d38 or ^{_{-S (= O) m R b37}} ,
R ^{e ′} represents —A ″ or —C (═O) NR ^c39 R ^d39 ,
R ^f is
Hydrogen atom,
Hydroxyl group,
C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano or halogen atom),
C _1-3 alkoxy (the alkoxy may be substituted with phenyl, hydroxyl, cyano or halogen atom optionally substituted with methoxy or nitro),
-B or -NR ^a30 R ⁱ ,
R ^g is
Hydroxyl group,
C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano or halogen atom),
-D or -NR ^a31 R ^{i '}
R ^h represents C _1-6 alkyl which may be substituted with a hydroxyl group or a halogen atom;
R ⁱ is
Hydrogen atom,
C _1-6 alkyl (said alkyl, hydroxyl, cyano, halogen atom, C _1-3 alkoxy, optionally substituted with C _3-6 cycloalkyl or -NR ^c40 R ^d40),
-B 'or -C (= O) R ^b38
Indicate
R ^{i ′} is
Hydrogen atom,
C _1-6 alkyl (which may be substituted with a hydroxyl group, cyano, halogen atom, C _1-3 alkoxy, C _3-6 cycloalkyl or —NR ^c41 R ^d41 ) or —D ′
Indicate
A, A ′, A ″, B, B′D, and D ′ are each independently
A 5- to 6-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is a hydroxyl group at a substitutable position) Alternatively, C _1-3 alkyl optionally substituted with a halogen atom, hydroxyl group, or C _1-3 alkoxy optionally substituted with a halogen atom, hydroxyl group, halogen atom, cyano, —C (═O) OH, or —NR ^c42 R ^d42 ) or a 3-6 membered saturated or unsaturated aliphatic ring optionally containing 1-2 heteroatoms selected from the group consisting of N, O and S Group (the aliphatic cyclic group is a C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom at a substitutable position, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, Hydroxyl group, halogen atom, cyano, -C (= O) OH, ^optionally substituted with -NR ^c43 R ^d43 or oxo)
R ^{a1 to} R ^a31 each independently represent a hydrogen atom or a C _1-3 alkyl which may be substituted with a hydroxyl group or a halogen atom;
^{R b1, R b4, R b8} , R b9, R b12, R b16, R b19, R b23, R b26, R b30 and R ^b34 each independently represent a hydrogen atom, substituted by a hydroxyl group or halogen atom C _1-6 alkyl, which may be substituted, or benzyl optionally substituted with methoxy or nitro,
^{R b2, R b3, R b5} , R b6, R b7, R b10, R b11, R b13, R b14, R b15, R b17, R b18, R b20, R b21, R b22, R b24, R b25 , R ^b27 , R ^b28 , R ^b29 , R ^b31 , R ^b32 , R ^b33 , R ^b35 , R ^b36 , R ^b37 and R ^b38 are each independently C ₁ which may be substituted with a hydroxyl group or a halogen atom. _-6 alkyl, or C _3-6 cycloalkyl optionally substituted with a hydroxyl group or a halogen atom,
^{R c1, R c2, R c3} , R c4, R c6, R c7, R c8, R c9, R c10, R c11, R c12, R c14, R c15, R c17, R c18, R c19, R c21 ^{, R c22, R c24, R} c25, R c26, R c28, R c29, R c31, R c32, R c33, R c38, R c39, R d1, R d2, R d3, R d4, R d6, R ^{d7, R d8, R d9,} R d10, R d11, R d12, R d14, R d15, R d17, R d18, R d19, R d21, R d22, R d24, R d25, R d26, R d28, R ^d29 , R ^d31 , R ^d32 , R ^d33 , R ^d38, and R ^d39 each independently represent a hydrogen atom, or C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, or the same A 4-6 membered saturated or unsaturated aliphatic ring group containing 1-2 heteroatoms selected from the group consisting of N and O taken together by substituents attached to the nitrogen atom (the saturated Other unsaturated aliphatic cyclic group may be formed may be substituted with a hydroxyl group or a halogen atom) at substitutable positions,
^{R c5, R c13, R c16} , R c20, R c23, R c27, R c30, R c34, R c37, R c40, R c41, R c42, R c43, R d5, R d13, R d16, R d20 ^{, R d23, R d27, R} d30, R d34, R d37, R d40, R d41, R d42 and R ^d43 are each independently hydrogen atom or a hydroxyl group or a halogen atom which may be substituted in C, and 4-6 membered saturated or substituted with 1 to 2 heteroatoms selected from the group consisting of N and O, together with _1-3 substituents attached to the same nitrogen atom An unsaturated aliphatic cyclic group (the saturated or unsaturated aliphatic cyclic group may be substituted with a hydroxyl group, a halogen atom or oxo at a substitutable position);
R ^c35 , R ^c36 , R ^d35 and R ^d36 each independently represent a hydrogen atom, C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, or a substituent bonded to the same nitrogen atom 4-6 membered saturated aliphatic ring group containing 1 or 2 N together (the saturated aliphatic ring group is substituted with a hydroxyl group or a halogen atom at a substitutable position). May be formed)
m represents an integer of 1 or 2,
n represents an integer of 0 to 2,
q represents an integer of 0 to 2]
Or a physiologically acceptable salt thereof. R ⁰ is —C (═O) NR ^a1 —, —S (═O) ₂ NR ^a2 —, —C (═O) O—, —C (═O) — or —S (═O) ₂ —. The compound according to claim 1 or a physiologically acceptable salt thereof, wherein Ar ¹ is Ar ¹ -1 or Ar ¹ -2 below:

(In each group, E ¹ , E ² , E ³ and E ⁴ each independently represent a carbon atom or a nitrogen atom (provided that E ¹ , E ² , E ³ and E ⁴ all represent a nitrogen atom at the same time). G ¹ , G ² and G ³ each independently represent a carbon atom or a heteroatom selected from the group consisting of N, O and S, and X is substituted with a hydroxyl group or a halogen atom C _1-6 alkyl which may be substituted, C _1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen atom, cyano, nitro or —NR ^c35 R ^d35 , and E ¹ , E ² , E ³ , E ⁴ , G ¹ , G ² or G ³ may be further substituted with a C _1-6 alkyl, hydroxyl group or halogen atom which may be further substituted with a hydroxyl group or a halogen atom. Yo ^Or a substituent selected from the group consisting of C _1-3 alkoxy, hydroxyl group, halogen atom, cyano, nitro and —NR ^c35 R ^d35 , wherein R ^c35 and R ^d35 are ^defined in claim 1. (Same as definition)
The compound according to claim 1 or 2, or a physiologically acceptable salt thereof, wherein Ar ² is the following Ar ² -1 or Ar ² -2:

(In each group, K ¹ , K ² , K ³ and K ⁴ each independently represent a carbon atom or a nitrogen atom (provided that K ¹ , K ² , K ³ and K ⁴ all simultaneously represent a nitrogen atom) L ¹ , L ² and L ³ each independently represents a carbon atom or a heteroatom selected from the group consisting of N, O and S, and Y represents a hydroxyl group, a cyano or a halogen atom. optionally substituted C _1-6 alkyl, hydroxyl or halogen atoms which may be substituted C _1-3 alkoxy, hydroxyl, halogen atom, cyano, _{nitro, -S (= O) n R} h or -NR ^c36 R ^d36 represents C _1- which may be further substituted with a hydroxyl group, cyano or halogen atom at a substitutable position of K ¹ , K ² , K ³ , K ⁴ , L ¹ , L ² or L ^3. ₆ alkyl, hydroxyl Wakashi Which may be C _1-3 alkoxy substituted by halogen atom, a hydroxyl group, a halogen atom, cyano, nitro, -S (= O) _n R ^h and -NR ^c36 substituent selected from the group consisting of R ^d36 And n, R ^h , R ^c36 and R ^d36 are the same as defined in claim 1)
The compound according to any one of claims 1 to 3 or a physiologically acceptable salt thereof. The following formula (I ′), wherein L is a 5- to 6-membered unsubstituted aromatic ring group that may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S:

The compound in any one of Claims 1-4 shown by these, or its physiologically acceptable salt. The compound or physiologically acceptable salt thereof according to any one of claims 1 to 4, wherein L is -S (= O) _q- , and q is 1 or 2. The compound or physiologically acceptable salt thereof according to any one of claims 1 to 6, wherein R ³ and R ⁴ are each independently a hydrogen atom or unsubstituted C _1-3 alkyl. R ⁰ is, -C (= O) a NH- or -S _{(= O)} 2 NH-, a compound or a physiologically acceptable salt thereof according to any one of claims 1 to 7. R ¹ is a hydrogen atom, C _1-10 alkyl (wherein the alkyl may be substituted by the same substituent as defined in claim 1 at a substitutable position) or a group consisting of N, O and S The 3- or 6-membered saturated or unsaturated aliphatic ring group which may contain 1 to 2 heteroatoms selected (wherein the aliphatic ring group is a substitutable position, the definition according to claim 1). Or a physiologically acceptable salt thereof. 9. The compound according to any one of claims 1 to 8, which may be substituted with the same substituent as R ¹ is a hydrogen atom or C _1-10 alkyl (wherein the alkyl may be substituted with the same substituent as defined in claim 1 at a substitutable position);
A and A ″ are each independently substituted, from the group consisting of phenyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl Selected from the group consisting of selected aromatic ring groups or optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrrolinyl, dihydropyridinyl and tetrahydropyridinyl A saturated aliphatic cyclic group,
A ′ is an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and isothiazolyl, or optionally substituted cyclopropyl, cyclobutyl, A saturated aliphatic ring group selected from the group consisting of cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl;
B and D are each independently selected from the group consisting of optionally substituted phenyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl Aromatic cyclic groups or optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl and isothiazolidinyl A saturated aliphatic cyclic group selected from the group consisting of:
B ′ and D ′ are each independently an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl and tetrazolyl, or A saturated aliphatic cyclic group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl, which may be substituted;
The substituent of the substituted aromatic ring group in this section is a C _1-3 alkyl which may be substituted with a hydroxyl group or a halogen atom, a C _1-3 alkoxy which may be substituted with a hydroxyl group or a halogen atom, a hydroxyl group , A halogen atom, cyano, —C (═O) OH or —NR ^c42 R ^d42 (wherein R ^c42 and R ^d42 represent the same as defined in claim 1),
The substituent of the substituted saturated aliphatic cyclic group is C _1-3 alkyl optionally substituted with a hydroxyl group or a halogen atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a halogen atom, a hydroxyl group, a halogen The atom, cyano, -C (= O) OH, -NR ^c43 R ^d43 (wherein R ^c43 and R ^d43 are the same as defined in claim 1) or oxo. Or a physiologically acceptable salt thereof. R ¹ is a hydrogen atom or C _1-10 alkyl (wherein the alkyl is a substitutable position,
(1) hydroxyl group,
(2) a halogen atom,
(3) Cyano,
(6) a 5-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is at a substitutable position;
C _1-3 alkyl _optionally substituted with a hydroxyl group or a fluorine atom,
C _1-3 alkoxy optionally substituted with a hydroxyl group or a fluorine atom,
Hydroxyl group,
Halogen atoms,
Cyano,
-NR ^a15 C (= O) R ^b17 ,
-NR ^a16 C (= O) NR ^c17 R ^d17 ,
-NR ^a17 S (= O) _m R ^b18 ,
-C (= O) OR ^b19 ,
-C (= O) NR ^c18 R ^d18 ,
-S (= O) _m NR ^c19 R ^d19 ,
—S (═O) _m R ^b20 or —NR ^c20 R ^d20
May be substituted)
(7) a 3- to 6-membered saturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S (the saturated aliphatic ring group is substitutable) In position,
C _1-3 alkyl (the alkyl is a hydroxyl group, a fluorine atom, cyano, —NR ^a18 C (═O) R ^b21 , —NR ^a19 C (═O) NR ^c21 R ^d21 , —NR ^a20 S (═O) _m ) R ^b22 , —C (═O) OR ^b23 , —C (═O) NR ^c22 R ^d22 or —NR ^c23 R ^d23 may be substituted),
C _1-3 alkoxy (the alkoxy may be substituted with a hydroxyl group or a fluorine atom),
Hydroxyl group,
Fluorine atom,
Cyano,
-NR ^a21 C (= O) R ^b24 ,
-NR ^a22 C (= O) NR ^c24 R ^d24 ,
-NR ^a23 S (= O) _m R ^b25 ,
-C (= O) OR ^b26 ,
^{-C (= O) NR c25 R} d25,
In -NR ^c27 R ^d27 or oxo may be substituted),
(8) -NR ^a24 R ^e,
(9) -OR ^{e '} ,
(10) -C (= O) R f and (11) -S (= O) m R g
And optionally substituted with one or more substituents selected from the group consisting of:
R ^{a1 to} R ^a17 and R ^{a25 to} R ^a29 each independently represent a hydrogen atom or methyl,
R ^{a18 to} R ^a24 and R ^{a30 to} R ^a31 each independently represent a hydrogen atom, or C _1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom,
^{R b1, R b4, R b8} , R b9, R b12, R b16, R b19, R b23, R b26, R b30 and R ^b34 each independently represent a hydrogen atom or an unsubstituted C _1-6 alkyl Indicate
^{R b2, R b3, R b5} , R b6, R b7, R b10, R b11, R b13, R b14, R b15, R b17, R b18, R b20, R b21, R b22, R b24, R b25 , R ^b27 , R ^b28 , R ^b29 , R ^b31 , R ^b32 , R ^b33 , R ^b35 , R ^b36 , R ^b37 and R ^b38 are each independently C ₁ which may be substituted with a hydroxyl group or a fluorine atom. _-6 alkyl, or C _3-6 cycloalkyl optionally substituted with a hydroxyl group or a fluorine atom,
^{R c17, R c18, R c19} , R c21, R c22, R c24, R c25, R c38, R d17, R d18, R d19, R d21, R d22, R d24, R d25 and R ^d38 are each Independently, a hydrogen atom, or C _1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom, or together, 1-2 hetero selected from the group consisting of N and O A 4- to 6-membered saturated aliphatic cyclic group containing atoms (the saturated aliphatic cyclic group may be substituted with a hydroxyl group or a fluorine atom at a substitutable position),
^{R c20, R c23, R c27} , R c37, R c40, R c41, R c42, R c43, R d20, R d23, R d27, R d37, R d40, R d41, R d42 and R ^d43 are each Independently represents 1 to 2 hetero atoms, selected from the group consisting of N and O, each independently representing a hydrogen atom, or a C _1-6 alkyl optionally substituted with a hydroxyl group or a fluorine atom A 4- to 6-membered saturated aliphatic cyclic group containing an atom (the saturated aliphatic cyclic group may be substituted with a hydroxyl group, a fluorine atom or oxo at a substitutable position);
R ^c35 , R ^c36 , R ^d35 and R ^d36 each independently represent a hydrogen atom, or C _1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom,
^Re is
C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, fluorine atom, C _1-3 alkoxy or —NR ^c37 R ^d37 ),
-A,
-C (= O) -A ',
C _1-6 alkylcarbonyl (the alkyl part of the alkylcarbonyl may be substituted with a hydroxyl group or a fluorine atom),
-C (= O) shows the NR ^C38 R ^d38 or ^{_{-S (= O) m R b37}} ,
R ^{e ′} is
-A ''
R ^f is
Hydroxyl group,
-B or -NR ^a30 R ⁱ ,
R ^g is
Hydroxyl group,
C _1-6 alkyl (which may be substituted with a hydroxyl group, cyano or fluorine atom),
-D or -NR ^a31 R ^{i '}
R ^h represents methyl,
R ⁱ is
Hydrogen atom,
C _1-6 alkyl (said alkyl, hydroxyl, cyano, fluorine atom, C _1-3 alkoxy, optionally substituted with _{C 3-6} cycloalkyl or -NR ^c40 R ^d40) indicates or -B ',
R ^{i ′} is
Hydrogen atom,
C _1-6 alkyl (wherein the alkyl may be substituted with a hydroxyl group, cyano, fluorine atom, C _1-3 alkoxy, C _3-6 cycloalkyl or —NR ^c41 R ^d41 ) or —D ′;
A and A ″ are each independently
An aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl (the aromatic ring group may be substituted with a hydroxyl group or a fluorine atom) C _1-3 optionally substituted with _1-3 alkyl, hydroxyl group or fluorine atom, optionally substituted with _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c42 R ^d42 ) Alternatively, a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the saturated aliphatic ring group may be substituted with a hydroxyl group or a fluorine atom) _1-3 alkyl, hydroxyl Wakashi Ku Fluorine atom in an optionally substituted C _1-3 alkoxy, indicates a hydroxyl group, a fluorine atom, cyano, -C a (= O) OH, may be substituted with -NR ^c43 R ^d43 or oxo),
A ′ is an aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and isothiazolyl (the aromatic group is a hydroxyl group or a C _1-3 alkyl which may be substituted with a fluorine atom, a hydroxyl group Or C _1-3 alkoxy optionally substituted with a fluorine atom, hydroxyl group, fluorine atom, cyano, optionally substituted with —C (═O) OH or —NR ^c42 R ^d42 ) or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, saturated aliphatic Hajime Tamaki selected from the group consisting of piperazinyl and morpholinyl (saturated aliphatic cyclic group may be substituted by hydroxyl or fluorine atom C _{1- 3} alkyl, optionally substituted with a hydroxyl group or a fluorine atom C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH, —NR ^c43 R ^d43 or oxo may be substituted),
B is an aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl (the aromatic group may be substituted with a hydroxyl group or a fluorine atom) C _1-3 alkyl, hydroxyl group or fluorine atom optionally substituted with C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c42 R ^d42 Or a saturated aliphatic ring group selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the saturated aliphatic ring group is a C _1-3 alkyl which may be substituted with a hydroxyl group or a fluorine atom, C _1-3A optionally substituted with a hydroxyl group or a fluorine atom Alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH, —NR ^c43 R ^d43 or oxo ^optionally substituted)
D is an aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl (the aromatic group may be substituted with a hydroxyl group or a fluorine atom) C _1-3 alkyl, hydroxyl group or fluorine atom optionally substituted with C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c42 R ^d42 Or a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the saturated aliphatic ring group is substituted with a hydroxyl group or a fluorine atom) Have been Good C _1-3 alkyl, hydroxyl or fluorine atom in an optionally substituted C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C (= O) OH, optionally substituted with -NR ^c43 R ^d43 or oxo You may)
B ′ is an aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and isothiazolyl (the aromatic group is a hydroxyl group or a C _1-3 alkyl which may be substituted with a fluorine atom, a hydroxyl group Or C _1-3 alkoxy optionally substituted with a fluorine atom, hydroxyl group, fluorine atom, cyano, optionally substituted with —C (═O) OH or —NR ^c42 R ^d42 ) or cyclopropyl, cyclobutyl, A saturated aliphatic ring group selected from the group consisting of cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the saturated aliphatic ring group is a hydroxyl group or a C _1-3 alkyl which may be substituted with a fluorine atom, a hydroxyl group; or fluorine atoms which may be substituted with C _1-3 alkoxy, hydroxyl, Tsu atom represents cyano, -C a (= O) OH, may be substituted with -NR ^c43 R ^d43 or oxo),
D ′ is an aromatic ring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and isothiazolyl (the aromatic group is a hydroxyl group or a C _1-3 alkyl which may be substituted with a fluorine atom, a hydroxyl group Or C _1-3 alkoxy optionally substituted with a fluorine atom, hydroxyl group, fluorine atom, cyano, optionally substituted with —C (═O) OH or —NR ^c42 R ^d42 ) or cyclopropyl, cyclobutyl, A saturated aliphatic ring group selected from the group consisting of cyclopentyl, cyclohexyl and pyranyl (the saturated aliphatic ring group is substituted with a hydroxyl group or a C _1-3 alkyl which may be substituted with a fluorine atom, a hydroxyl group or a fluorine atom; which may be C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C (= O) OH, -N ^c43 R ^d43 or compound or a physiologically acceptable salt thereof according to any one of claims 1 to 10 show a good) be substituted by oxo. R ¹ is C _1-10 alkyl (wherein the alkyl is a substitutable position,
(1) hydroxyl group,
(2) fluorine atom,
(3) Cyano,
(6) a 5-membered aromatic ring group which may contain 1 to 4 heteroatoms selected from the group consisting of N, O and S (the aromatic ring group is at a substitutable position,
C _1-3 alkyl _optionally substituted with a hydroxyl group or a fluorine atom,
C _1-3 alkoxy optionally substituted with a hydroxyl group or a fluorine atom,
Hydroxyl group,
Halogen atoms,
Cyano,
-C (= O) OH,
^{-C (= O) NR c18 R} d18 or -NR ^{c 20} R ^d20
May be substituted)
(7) a 3- to 6-membered saturated aliphatic ring group which may contain 1 to 2 heteroatoms selected from the group consisting of N, O and S (the saturated aliphatic ring group is substitutable) In position,
C _1-3 alkyl (which may be substituted with a hydroxyl group, a fluorine atom, cyano, —C (═O) OH or —C (═O) NR ^c22 R ^d22 ),
C _1-3 alkoxy (the alkoxy may be substituted with a hydroxyl group or a fluorine atom),
Hydroxyl group,
Fluorine atom,
Cyano,
-NR ^a21 C (= O) R ^b24 ,
-NR ^a22 C (= O) NR ^c24 R ^d24 ,
-NR ^a23 S (= O) _m R ^b25 ,
-C (= O) OH,
^{-C (= O) NR c25 R} d25,
In -NR ^c27 R ^d27 or oxo may be substituted),
(8) -NR ^a24 R ^e,
(10) -C (= O) R f and (11) -S (= O) m R g
And optionally substituted with one or more substituents selected from the group consisting of:
R ^{a21 to} R ^a23 and R ^{a30 to} R ^a31 each independently represent a hydrogen atom or methyl,
R ^a24 represents a hydrogen atom, or C _1-3 alkyl which may be substituted with a hydroxyl group or a fluorine atom;
R ^b24 ~R ^b25, R ^b37 are each independently a hydroxyl group or a fluorine atom in an optionally substituted C _1-6 alkyl or a hydroxyl group or fluorine optionally C _3-6 cycloalkyl optionally substituted with atoms, Indicate
^{R c18, R c22, R c24} , R c25, R c38, R d18, R d22, R d24, R d25 and R ^d38 are each independently optionally substituted with hydrogen atom or a hydroxyl group or a fluorine atom, or it represents an C _1-3 alkyl, or taken together, azetidine, pyrrolidine, piperidine, saturated heterocyclic aliphatic ring (saturated heteroaliphatic ring group selected from the group consisting of piperazine and morpholine, can be substituted And may be substituted with a hydroxyl group or a fluorine atom at any position)
^{R c20, R c27, R c37} , R c40, R c41, R c43, R d20, R d27, R d37, R d40, R d41 and R ^d43 are each independently hydrogen atom or a hydroxyl group or a fluorine atom, A saturated heteroalicyclic ring group selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine and oxazolidine (C _1-6 alkyl optionally substituted with The saturated heteroaliphatic ring group may be substituted with a hydroxyl group, a fluorine atom or oxo at a substitutable position),
R ^c35 , R ^c36 , R ^d35 and R ^d36 each independently represent a hydrogen atom, methyl or ethyl,
^Re is
C _1-6 alkyl (the alkyl may be substituted with a hydroxyl group, cyano, fluorine atom, C _1-3 alkoxy or —NR ^c37 R ^d37 ),
-A,
-C (= O) -A ',
C _1-6 alkylcarbonyl (the alkyl part of the alkylcarbonyl may be substituted with a hydroxyl group or a fluorine atom),
-C (= O) shows the NR ^C38 R ^d38 or ^{_{-S (= O) m R b37}} ,
R ^f is
Hydroxyl group,
-B or -NR ^a30 R ⁱ ,
R ^g is
C _1-6 alkyl (which may be substituted with a hydroxyl group, cyano or fluorine atom),
-D or -NR ^a31 R ^{i '}
R ⁱ is
Hydrogen atom,
C _1-6 alkyl (said alkyl, hydroxyl, cyano, fluorine atom, C _1-3 alkoxy, optionally substituted with _{C 3-6} cycloalkyl or -NR ^c40 R ^d40) indicates or -B ',
R ^{i ′} is
Hydrogen atom,
C _1-6 alkyl (wherein the alkyl may be substituted with a hydroxyl group, cyano, fluorine atom, C _1-3 alkoxy, C _3-6 cycloalkyl or —NR ^c41 R ^d41 ) or —D ′;
A is a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the saturated aliphatic ring group may be substituted with a hydroxyl group or a fluorine atom) good C _1-3 alkyl, hydroxyl or fluorine may be substituted with atoms C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C (= O) optionally substituted with OH or -NR ^c43 R ^d43 Good)
A ′ is a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the saturated aliphatic ring group is a hydroxyl group or a fluorine atom) C _1-3 alkyl which may be substituted, C _1-3 alkoxy which may be substituted with hydroxyl group or fluorine atom, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c43 R ^d43 Which may be substituted)
B is a saturated aliphatic ring group selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the saturated aliphatic ring group is a C _1-3 alkyl which may be substituted with a hydroxyl group or a fluorine atom, C _1-3 alkoxy optionally substituted with a hydroxyl group or a fluorine atom, a hydroxyl group, a fluorine atom, cyano, —C (═O) OH or —NR ^c43 R ^{d43 optionally} substituted)
D is a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (the saturated aliphatic ring group is substituted with a hydroxyl group or a fluorine atom) Substituted with optionally substituted C _1-3 alkyl, hydroxyl group or fluorine atom, C _1-3 alkoxy, hydroxyl group, fluorine atom, cyano, —C (═O) OH or —NR ^c43 R ^d43 May be)
B ′ is a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (the saturated aliphatic ring group is substituted with a hydroxyl group or a fluorine atom) which may C _1-3 alkyl, hydroxyl or fluorine may be substituted with atoms C _1-3 alkoxy, hydroxyl, fluorine atom, cyano, -C (= O) substituted with OH or -NR ^c43 R ^d43 Is good)
D 'is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and saturated aliphatic Hajime Tamaki (said saturated aliphatic ring group selected from the group consisting of pyranyl, the hydroxyl or fluorine may be substituted with atoms C _1-3 C _1-3 alkoxy optionally substituted with alkyl, hydroxyl group or fluorine atom, hydroxyl group, fluorine atom, cyano, optionally substituted with —C (═O) OH or —NR ^c43 R ^d43 ),
R ⁰ represents —C (═O) NH— or —S (═O) ₂ NH—,
R ² represents methyl,
R ³ and R ⁴ each independently represent a hydrogen atom or methyl;
L is a benzene ring group, thiophene ring group, furan ring group, pyrrole ring group, imidazole ring group, pyridine ring group, pyrazine ring group, isoxazole ring group, pyrazole ring group, isothiazole ring group, pyrimidine ring group, pyridazine ring. A group, an oxazole ring group, a thiazole ring group, a triazole ring group, a tetrazole ring group or -S (= O) _q-
q is 1 or 2,
Ar ¹ is the following Ar ¹ -1 ′:

(In each group, E ¹ , E ² and E ³ each independently represents a carbon atom or a nitrogen atom, and X represents a C _1-3 alkyl, hydroxyl group or hydroxyl group which may be substituted with a hydroxyl group or a fluorine atom. C _1-3 alkoxy optionally substituted with a fluorine atom, halogen atom, cyano or nitro is shown, and may be substituted with a hydroxyl group or a fluorine atom at a substitutable position of E ¹ , E ² or E ³ A C _1-6 alkyl, a hydroxyl group or a substituent selected from C _1-3 alkoxy optionally substituted with a fluorine atom, a hydroxyl group, a halogen atom, cyano and —NR ^c35 R ^d35 ). Show
Ar ² is the following Ar ² -1 ′:

(In each group, K ¹ , K ² , K ³ and K ⁴ each independently represent a carbon atom or a nitrogen atom (provided that K ¹ , K ² , K ³ and K ⁴ are all simultaneously nitrogen atoms) except where indicated), Y represents a halogen atom, a cyano or nitro, a substitutable position of K ^{1, K 2,} K ³ or K ^4, which may be substituted by a hydroxyl group or a fluorine atom C _{1- 3} may have a substituent selected from C _1-3 alkoxy optionally substituted with an alkyl, hydroxyl group or fluorine atom, a hydroxyl group, a halogen atom, cyano and —NR ^c36 R ^d36 ), Item 12. The compound according to any one of Items 1 to 11 or a physiologically acceptable salt thereof.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a physiologically acceptable salt thereof as an active ingredient.   The elastase inhibitor which contains the compound in any one of Claims 1-12, or its physiologically acceptable salt as an active ingredient.   The therapeutic or prophylactic agent of the inflammatory disease containing the compound in any one of Claims 1-12, or those physiologically acceptable salts.   A therapeutic or prophylactic agent for a disease requiring an elastase inhibitory activity comprising the compound according to any one of claims 1 to 12 or a physiologically acceptable salt thereof.